ART Side Effects - pocketguideSecondEd

Antiretroviral Therapy
in South Africa
A Pocket Guide on Prevention and
Management of Side Effects
and
Drug Interactions
Second Edition
Dr. Henry Fomundam

HIV/AIDS Pharmaceutical Care Program/
Howard University, South Africa
Prof. Christopher Mathews

I-Tech South Africa & HRSA Global AIDS Program
1
Antiretroviral Therapy in South Africa: A Pocket Guide on Prevention and Management
of Side Effects and Drug Interactions.
Second Edition, 2009

Published by the National Department of Health, South Africa.
REVIEWED BY:
Dr H. Sunpath
Head of Medicine
McCord Hospital Durban, Kwazulu-Natal
Dr N. Dlamini
Acting Comprehensive Care Management & Treatment Manager
National Department of Health, South Africa
Dr V. Tihon
Advisor
National HIV/AIDS-TB Program, National Department of Health, South Africa

Dr. M. Tlangula
Medical Advisor
HIV/AIDS Directorate, National Department of Health
Dr A. Grimwood
HIV/AIDS Clinician
South Africa
Dr. Henry Mbah

Director
Laboratory Services, The GHAIN Project, Nigeria
Mr. M Dheda
National Coordinator
Pharmacovigilance Program, Medicines Control Council, National Department of
Health, South Africa
Dr. B. Futshane
Chief Medical Officer
The Eastern Cape Regional Training Centre,LWalter Sisulu University
Dr. T. Marshal
Programme Head: Laboratory - Comprehensive Care Management and Treatment
Programme for HIV and AIDS
National Laboratory Health Services, South Africa
i
This pocket guide serves as a quick reference for clinicians and health-care workers,
providing guidelines on the management of patients on antiretroviral drugs. The guide
complements treatment guidelines outlined in the Comprehensive HIV and AIDS Care,
Management and Treatment Plan for South Africa, and other detailed guidelines.
Information in the pocket guide will be revised as necessary to reflect the dynamic nature
of HIV and AIDS treatment.
Disclaimers:
Development of this publication was supported by the HHS Centers for Disease Control
and Prevention (CDC), National Center for HIV, STD, and TB Prevention (NCHSTP),
Global AIDS Program (GAP). Its contents are solely the responsibility of the authors and
do not necessarily represent the official views of CDC.
The National Department of Health and the authors do not accept responsibility for
errors or omissions. This pocket guide must be used in conjunction with the National
Antiretroviral Treatment Guidelines and other references.
ii
CONTENTS
iii
Acronyms...................................................................................................... v
Preface........................................................................................................ vii
SECTION A
Management of Common Side Effects of ARV Drugs . ...........................................1
Section B
Drug Interactions . ..........................................................................................21
Section C
The Role of Laboratory Services and
the Prevention and Management of Side Effects..........................................81
Section D
Drug Information for current ARV Drugs Registered in South Africa .......................87
Tables
1. Routes of Elimination of HAART and the Effect on CYP450...........................24
2. Common Drug-Drug Interactions Among ARV Drugs Registered in South Africa
2.1 Protease Inhibitors...................................................................................32
2.2 Non-Nucleoside Reverse Transcriptase Inhibitors.........................................41
2.3 Nucleoside Reverse Transcriptase Inhibitors................................................50
3. Selected ARVs with Mechanisms of Drug Interactions and Management
Recommendations
3.1 Nucleoside Reverse Transcriptase Inhibitors................................................55
3.2 Non-Nucleoside Reverse Transcriptase Inhibitors.........................................61
3.3 Protease Inhibitors...................................................................................68
4. Clinically Relevant Laboratory Anomalies (Adverse Events)
Associated with ART................................................................................79
5. ARVs Registered in South Africa................................................................83
Appendix
Guidelines for manuscript preparation - IAEA format..................................109
iv
ACRONYMS AND
ABBREVIATIONS
v
3TC Lamivudine MTCT Mother-To-Child Transmission
ABC Abacavir NNRTI Non-Nucleoside Reverse
ADR Adverse Drug Reaction Transcriptase Inhibitor
AIDS Acquired Immune Deficiency NP Neuro-Psychiatric
Syndrome NRTI Nucleoside Reverse
ALP Alkaline Phosphatase Transcriptase Inhibitor
ALT Alanine Amino Transferase NSAID Non-Steroidal Anti-Inflammatory
ANC Absolute Neutrophil Count Drug
ART Antiretroviral Treatment NVP Nevirapine
ARV Antiretroviral OI Opportunistic Infection
AST Aspartate Aminotransferase PEP Post-Exposure Prophylaxis
AZT Zidovudine (Azidothymidine) PI Protease Inhibitor
BNST Brief Neuropathy Screening Tool PMTCT Prevention of Mother-to-Child
CHD Coronary Heart Disease Transmission
CMV Cytomegalovirus RTV Ritonavir
CNS Central Nervous System TB Tuberculosis
d4T Stavudine TLC Total Lymphocyte Count
DDC Zalcitabine TSH Thyroid Stimulating Hormone
ddI Didanosine VCT Voluntary Counselling and
DNA Deoxyribonucleic Acid Testing
DSP Distal Symmetric Polyneuropathy
EDL Essential Drugs List
EFV Efavirenz
GI Gastrointestinal
HAART Highly Active Antiretroviral
Therapy
HBC Home-Based Care
hCG Human Chorionic
Gonadotrophin
HDL High-Density Lipoprotein
HIV Human Immunodeficiency Virus
HSR Hyper-Sensitivity Reaction
INH Isoniazid
INR International Normalized Ratio
IRS Immune Reconstitution Syndrome
LDL Low-Density Lipoprotein
Lh Leutinizing Hormone
LPV Lopinavir
M&E Monitoring and Evaluation
MCH Maternal and Child Health
vi
PREFACE AND
ACKNOWLEDGEMENTS
vii
PREFACE
T he second edition of the Pocket Guide on Prevention and Management of Side Effects
and Drug Interactions comes at the time when South Africa has been implementing the
Comprehensive HIV and AIDS Care, Management and Treatment Plan for five years; this
is also the third year of implementing the National Strategic Plan, 2007-2011. South
Africa has the largest antiretroviral treatment (ART) programme in the world with more than
750,000 patients initiated on ART by March 2009. The country is, therefore, faced with
the major challenge of ensuring and sustaining the quality of services, including preventing
and managing side effects, and improving drug adherence, which are all critical for the
success of such a comprehensive treatment program.
Guides and handbooks contributing to the better understanding of therapeutics of the drug
armamentarium used for the treatment of HIV and AIDS are important tools that ensure
improved patient outcomes and quality of life. Successful treatment of HIV and AIDS usually
require the use of several medicines concomitantly and these can be further complicated by
the multiple medicines used to treat co-morbid conditions such as diabetes, and hypertension
in same patients. The use of these several medicines can result in drug-drug interactions,
drug-food interactions, drug-herbal/traditional medicines interactions, and drug-laboratory
test interactions.
These interactions, in turn, can result in therapeutic failure, drug resistance, side effects,
and toxicities. These chemical entities also come with inherent potential side effects and
increased potential for medication errors that must be prevented as much as possible and
properly managed when they do occur. This is a reality of pharmacotherapy (the use of
medicines), which is most likely to be compounded by human resources and health-care
infrastructure challenges. These therapeutic challenges can therefore result in decreased
adherence, patients lost to follow-up, patients’ lack of confidence in the health-care system,
and frustration on the part of the health worker.
This handbook is meant to be used as a quick reference source and a companion to
the National Antiretroviral Treatment Guidelines as well as other detailed reference
sources. It addresses the pertinent therapeutics information on HIV and AIDS treatment
and has been divided into four parts: prevention and management of common side effects
(with flow charts); mechanisms of drug interactions and common drug interactions with
contraindications; laboratory monitoring of drug therapy; and a drug information section
that highlights important information about antiretroviral (ARV) drugs that are registered in
South Africa.
This quick reference source is also meant to sensitise health-care workers to the need
for improved quality assurance and quality of life through individualised patient
pharmacotherapy. After five years of the implementation of the Comprehensive HIV and
AIDS Care, Management and Treatment Plan, the focus will continue to be placed on the
active reporting and sharing experiences for the better patient care and management in
all our facilities.
Mr. Thami Mseleku

Director General, National Department of Health, South Africa
viii
ACKNOWLEDGEMENTS
T he prevention and management of side effects in the HIV and AIDS treatment as part
of the Comprehensive HIV and AIDS Care, Management and Treatment Plan remains
a major challenge threatening the quality of care as well as the quality of life of patients
on ART. This pocket guide will go a long way in assisting health-care workers who are
involved in managing patients on ART. I sincerely thank Dr. Henry Fomundam and Prof.
Christopher Mathews for their professional expertise that led to the production of the
second edition of this guide. We are also equally grateful to all the reviewers for their
technical input and to the Centers for Disease Control and Prevention (CDC) South Africa
for funding this project. Finally, thanks go to Lucia Chanetsa from Howard University,
Celicia Serenata and Helen Savva from CDC South Africa for their contributions to the
publication of this booklet.
Dr. David Kalombo

Comprehensive Care Management & Treatment Manager
National Department of Health, South Africa
ix
x
SECTION A
Management of Common Side Effects
of ARV Drugs
1
1. Introduction
S everal studies in the last decade show that medicine-related morbidity and mortality is
one of the major health problems faced by several countries, including those with very
advanced health systems. Safety data for new medicines are limited to pre-registration
clinical trials that often have significant limitations. These include small sample sizes
(sometimes just a few hundred participants); multiple exclusion criteria (not reflective of the
real-life use of the products once registered); lack of population or race diversity (children,
women, ethnic groups, etc.); the time during which patients are studied (sometimes just
a few weeks); and the general conditions under which the clinical trials are performed
(controlled). Post-marketing (which implies post-registration) surveillance is essential in
determining the ongoing safety of medicines in real-life clinical use in large populations.
The use of multi-source generic drugs and fixed-dose combination products sometimes
has variable pharmacokinetic profile resulting in sub-therapeutic levels, side effects, or
toxicities. The nuisance of side effects has been reported, in several studies, to affect
adherence greatly (including mild and persistent side effects), which, in turn, may lead to
discontinuation of treatment in many cases.
Prevention and management of side effects of drugs used to manage HIV and AIDS remain
a challenge for clinicians, patients, drug regulators, researchers, government officials,
health-care workers, family members, and all those affected by the virus. Acute and long-
term side effects, mild to severe and sometimes fatal reactions continue to affect patient
decisions to start treatment, to continue treatment, and to adhere to prescribed regimens.
The health-care worker is also faced with the task of selecting the right regimen, educating
or counselling the patient on possible side effects, using prevention and management
strategies, and monitoring the patient to ensure that benefits always outweigh the risks.
Generally, these side effects can be divided into three time-related outcomes:
Early side effects usually occur within the first days to weeks of initiating
treatment;
Medium-term side effects occur within the first months to a year of therapy;
and
Late side effects typically occur from the second year of therapy onwards.
However, there is considerable overlap within these groups and many side effects can
occur at any time during therapy. Several factors may contribute to side effects in this class,
including, but not limited to health-care worker’s knowledge of class and individual drug
toxicities, the efficacy of the health-care system, co-morbidities, medication errors, patient
knowledge and adherence to prescribed regimens, and the quality of the product, including
recognition of counterfeit drugs. Other factors that may lead to side effects include missed
dose, wrong administration technique, illegible prescription, duplicate therapy, drug-drug
interaction as well as inadequate monitoring. Prevention and appropriate management of
side effects will invariably increase patient adherence, decrease drug resistance, improve
patient outcomes and quality of life, and overall increase the patient’s confidence in the
health-care worker and system.
2
There are four major categories of side effects that are commonly reported in patients on
ART and these include:
Mitochondrial toxicity with symptoms including lactic acidosis, hepatic toxicity,
pancreatitis and peripheral neuropathy;
Metabolic abnormalities are often manifested through lipodystrophy,
hyperlipidemia, hyperglycemia and insulin resistance, bone disorders;
Hematologic complications such as bone marrow suppression; and
Allergic reactions presented through hypersensitivity reactions and skin rashes.
Note that these complications are increasingly becoming significant because patients
on ART are living longer, and adverse effects to ART will affect adherence especially
if the patients are not adequately informed. A proper process for monitoring side
effects (pharmacovigilance) will therefore be required at each facility accredited for
initiation and continuation of antiretroviral therapy. When evaluating cases for adverse
drug reactions, clinicians must be careful because some drug toxicities may be difficult
to distinguish from HIV complications. For instance, drug interactions can compound
toxicities, limited experience in managing side effects in special groups like children, and
new or undocumented effects in a patient population may hinder accurate diagnosis.
A brief description and algorithms for the management of common or severe adverse
drug reactions (ADRs) with the regimens for the treatment of HIV on the national formulary
have been outlined for quick reference.
2. Flow Charts for Most Common or Severe Adverse Drug

Reactions
2.1. Efavirenz - Central Nervous System Side Effects
Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) that acts by
non-competitive inhibition of HIV-1. Central nervous system (CNS) side effects have been
reported in more than 53% of people taking efavirenz in some studies, with the most
common ones being dizziness, insomnia, impaired concentration, somnolence, abnormal
dreams, depression, and hallucinations. These side effects occur during the first two days
of treatment and last for several hours after each dose. Efavirenz neurologic symptoms
are self-limiting and generally resolve without treatment by the fourth week, but can
persist as mild symptoms for a longer time. These CNS effects can be aggravated by
psychoactive drugs or alcohol.
According to Barlett and Gallant (2004), when initiating treatment with efavirenz, the
health-care worker should:
Prepare the patient by screening and stabilizing pre-existing neuropsychiatric
(NP) symptoms.
Educate the patient regarding most common NP side effects.
Reassure the patient about efavirenz’ effectiveness and the severity of its side
effects, which are usually mild to moderate and of limited duration.
3
Management of Efavirenz-related Central Nervous System Side Effects
Before starting treatment, screen for
pre-existing substance abuse or psychiatric
symptoms including
suicidally and depression
Yes No
Pre-existing
symptoms
present?
Educate patient regarding

Evaluate and treat
risk and types of CNS
symptoms
side effects
If symptoms are moderate-

Dose initiation evening
severe, delay initiation of
or at bedtime on empty
ARVs or use alternative
stomach
agent instead of EFV
Side effects and

Management
Disturbing Impaired
Agitation Sleep Disturbances Dizziness Depression
Dreams Concentration
Evaluate potential causes (psych, Adjust efavirenz administration

Adjust efavirenz Adjust efavirenz Adjust efavirenz
medical, substance abuse). timing depending on when Evaluate severity and
administration timing administration timing administration timing
Minimize stimulants. Suggest impaired concentration occurs suicidality
stress-reducing activities (e.g., give during the day) (e.g., give during the day) (e.g., give during the day)
or is most severe
Provide psychotherapy
Consider anxiolytics or Consider short term (2-3 Assess home and work- Assess home and and psychosocial support
Institute a trial of short-
short term neuroleptic (for weeks) benzodiazepine or place safety for falls and workplace safety for for mild to moderate
acting benzodiazepine
severe cases) trazadone at bedtime accident potential accident potential symptoms
Ensure patient access to

crisis support services
Provide close patient

follow-up or monitoring
Psychiatric referral and antidepressant therapy

for severe depression or suicidality.
DISCONTINUE ARVs or substitute EFV
Notes:
1. If a switch from Efavirenz to Nevirapine is made the lead-in dose is not required and nevirapine should
be started at a dose of 200mg bd
References:
1. Gill et al. Canadian J of Infect Dis 2001; 12(Suppl C): 20C-30C
2. Winston et al. Dose escalation or immediate full dose when switching from efavirenz to nevirapine-
based highly active antiretroviral therapy in HIV-1-infected individuals? AIDS 2004;18: 572-574
3. South Africa National Department of Health. CLINICAL GUIDELINES FOR THE MANAGEMENT OF HIV
& AIDS IN HEALTH FACILITIES (2008) Section 3.6
4
2.2. AZT-Induced Haematological Side Effects
Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI) was the first
antiretroviral to be approved for the treatment of patients with HIV. Common adverse
reactions with AZT include headache, malaise, myalgia, anorexia, nausea, anaemia
and neutropenia. According to some studies, between 5 to10% of people taking
AZT develop anaemia. Predisposing factors include advanced stage of HIV infection,
concurrent myelosuppressive agents or chemotherapy. Anaemia can be detected as
early as four to six weeks after initiation of AZT. Haemoglobin levels are usually used to
evaluate the extent and progress of AZT-induced anaemia.
Neutropenia occurs less frequently than anaemia. Neutropenia usually occurs within
12 to 24 weeks of initiating AZT. Absolute Neutrophil Count can be used as a
marker to determine the extent of AZT-induced neutropenia. Predisposing factors also
include advanced stage of HIV infection and concomitant myelosuppressive drugs.
Granulocytopenia and very rarely, thrombocytopenia, has also been reported in patients
on AZT treatment.
AZT-related Hematologic Toxicity
AZT can cause
anemia and neutropenia,
but not thrombocytopenia
Anemia (usually macrocytic) Neutropenia
Correct other causes Calculate absolute neutrophil

(e.g. iron deficiency, folate count (ANC) =
deficiency) WBC x %(segs+bands)
• ANC < 0.75 • ANC < 0.75

Hgb 7.0 - 9.4 Hgb < 7.0 ANC 0.75 - 0.95
• No fever • Fever
• Replace AZT with Tenofovir • Obtain blood cultures

Reduce AZT dose to Reduce AZT dose to Replace AZT
• Blood transfusion may be • & Administer
200 mg 12 hourly 200 mg 12 hourly with Tenofovir
required Ciprofloxacin
750 mg +
Gentamicin at once
Repeat Hgb in Repeat Hgb Repeat ANC Repeat ANC • Replace AZT with
1 - 2 weeks in 1 week in 1 - 2 weeks in 1 week Tenofovir
Replace AZT Replace AZT Refer

with Tenofovir if no with Tenofovir if no immediately
improvement improvement to hospital
Notes:
1. Systematic evaluation of anaemia is based on MCV (microcytic, normocytic, macrocytic), whether
bone marrow response is appropriate (high reticulocyte count), whether all cell lines are involved (
pancytopenia) or not.
2. AZT causes a hypoproliferative macrocytic anemia. Another cause of severe hypoproliferative anaemia
in HIV patients is Parvovirus induced pure red cell aplasia.
3. If anaemia and thrombocytopenia are present, consider the possibility of thrombotic thrombocytopenic
purpura (TTP) and examine blood smear for schistocytes.
4. Reference: South Africa. National Department of Health. CLINICAL GUIDELINES FOR THE
MANAGEMENT OF HIV & AIDS IN HEALTH FACILITIES (2008). Section 3.8
5
2.3. Dyslipidemia (Lipid Abnormalities)
Lipid abnormalities in levels associated with increased risk of cardiovascular disease
have been linked to patients receiving ART. Dyslipidemia can occur any time during
treatment but elevated lipids requiring intervention are typically seen after six months or
more on ART. This includes hypertriglyceridemia, low levels of high density lipoprotein
(HDL) cholesterol, and elevation of low-density lipoprotein (LDL) cholesterol. This is
primarily reported by patients on protease inhibitors (PIs) but has also been reported
with the NRTIs and NNRTIs, and especially efavirenz. Increases in total cholesterol
are usually due to PIs. NNRTIs are also known to increase total cholesterol but some,
particularly efavirenz, have also been reported responsible for increased HDL. It is
prudent to obtain a fasting baseline serum lipid profile before initiating ART and to take
levels after three months of treatment. Other levels may then be requested as clinically
indicated depending on previous levels, cardiovascular risk factors, or symptoms. Life
style modifications such as increased exercise, proper nutrition, weight loss, avoidance
of illicit drugs and alcohol, and smoking cessation are all important measures to prevent
or to decrease lipid abnormalities.
Dyslipidemia Management
Obtain fasting glucose and lipid profile prior to starting

antiretrovirals (protease inhibitors or efavirenz
containing) & within 3-6 months
of starting new regimen
Count number of CHD risk factors.

If >= 2 risk factors, perform
10-year risk calculation
Intervene for
modifiable non-lipid
risk factors, including diet
and smoking
If above the lipid threshhold based on risk group despite vigorous

lifestyle interventions, consider:
• altering antiretroviral therapy after consultation with expert OR
• using lipid lowering drugs.
If lipid lowering drugs are necessary
Serum LDL cholesterol above threshhold OR

Serum triglycerides greater
triglycerides 2.26-5.65 mm/ L (200-500 mg/dL)
than 5.65 mm/ L (500 mg/dL)
with elevated non- HDL cholesterol
Statin Therapy Fibrate therapy
Notes:
1. Treat patients with hypertriglyceridaemia where the triglyceride level is >10 mmol/l medical
therapy with a fibrate (e.g. Bezafibrate 400mg daily after food). “ The main risk associated with
hypertriglyceridaemia is pancreatitis (usually when level is >15 mmol/l).
2. Major risk factors (exclusive of LDL cholesterol) that modify LDL goals are: cigarette smoking, hypertension
6
(BP >= 140/90 or on antihypertensive medication), low HDL cholesterol (< 1 mmol/L or <40 mg/dL),
family history of premature CHD (CHD in male first degree relative < 55 years; CHD in female first
degree relative < 65 years), age (men>=45 years; women >= 55 years). Diabestes is regarded as a
CHD equivalent.
3. 10-year cardiovascular risk assessment tools (Framingham) available at:
http://cvrisk.mvm.ed.ac.uk /calculator/calc.asp (using mmol/L units)
and http://hp2010.nhlbihin.net /atpiii/calculator.asp (using mg/dL units)
4. Treat patients with a statin if their Framingham risk for MI is calculated to be 20% over 10 years.
5. Simvastatin and most other statins are contra-indicated for use with PIs because of drug interactions.
However, Pravastatin and low dose Atorvastatin are safe.
References:
1. Dube et al. Clinical Infectious Diseases 2003; 37:613–27
& AIDS IN HEALTH FACILITIES (2008). Section 3.10
3. ATP III Guidelines At-A-Glance Quick Desk Reference, available at:
www.nhlbi.nih.gov /guidelines/cholesterol/ atglance.pdf
2.4. Lipodystrophy
Lipodystrophy, commonly known as fat redistribution, has been reported with ART
and typically involves accumulation of visceral fat in the abdomen (central obesity),
dorsocervical area (buffalo hump) and breasts, loss of subcutaneous fat in the face,
extremities and buttocks (lipoatrophy). Both men and women may present with complaints
about increasing breast size and sagging buttocks. Lipodystrophy may also be an
additional risk factor for breast cancer in HIV-infected patients. Fat loss is commonly
presented among patients on NRTI, while fat gain is associated with the PIs.
Patients with fat redistribution should be screened for glucose (i.e., diabetes mellitus
and glucose intolerance) and lipid metabolism (i.e., high levels of triglycerides, total
cholesterol, LDL cholesterol, and low HDL cholesterol) disorders. PI therapy has been
most strongly linked to lipodystrophy syndrome, although NRTIs, especially stavudine
(d4T), have been associated with lipodystrophy. It is important that clinicians monitor
and recommend regular exercise and proper nutrition, and provide psychological
support where necessary. Various treatment strategies should be applied depending on
Dorso-cervical Central Adiposity Fat loss

fat pad (Lipohypertrophy ) (Lipoatrophy)
(Buffalo hump)
7
Wasting and Lipodystrophy Management
Key task is to distinguish morphologic changes

associated with ARV therapy
from wasting due to HIV or OIs
Phenotypes (suggest use

of provider & patient self assessment scale,
anthropometrics)
Wasting Lipodystrophy
Mixed (lipoatrophy
Loss of fat and muscle Fat Loss Fat Gain
and
(lean body mass) (lipoatrophy) (liperhypertrophy)
lipohypertophy )
Due to On thymidine Associated with

Nutritional HIV Wasting
opportunistic analog NRTI therapy both PIs
Syndrome
infections (d4T worse than AZT) and NNRTIs.
Switch to tenofovir
Diet and Exercise
(or abacavir)
References:
1. South Africa National Department of Health.CLINICAL GUIDELINES FOR THE MANAGEMENT OF HIV
& AIDS IN HEALTH FACILITIES (2008). Section 3.12
2. Wohl DA and Brown TT. J Acquir Immune Defic Syndr 2008;49:S93–S100
3. Phillips DR and Hay P. Journal of Antimicrobial Chemotherapy (2008) 62, 866–871
2.5. Gynecomastia
Gynecomastia, (i.e., breast enlargement) with and without other body fat changes has
been reported in men receiving ARVs. Two possible causes of this condition are excess
fat deposition and grandular hypertrophy. Gynecomastia may be unilateral or bilateral
and has no associated lactation. The diagnosis of ARV-induced gynecomastia is one
of exclusion, requiring that other causes such as marijuana or estrogens, prolactinoma,
lymphoma, alcohol use, end-stage liver disease, and breast cancer be considered.
Spontaneous resolution usually occurs.
8
Gynecomastia
Selected Causes of Gynecomastia
Neoplasms
Male Cirrhosis or (Testicular,Adrenal,
Pubertal Medications Uremia Hyperthyroidism
Hypogonadism Malnutrition Ectopic HCG)
Notes:
1. Efavirenz and ddI have been associated with development of gynecomastia. In most cases it resolves
spontaneously over 1-2 years. Switch drugs if its effects are severe (e.g. psychological distress). Nevirapine
could be an option (monitor hepatotoxicity in regard to CD4 levels)
2. Many other drugs have been associated with development of gynecomastia. Commonly used ones
include: spironolactone, isoniazid, cimetidine, ACE inhibitors, calcium channel blockers,anabolic steroids,
estrogens, haloperidol, phenothiazines , tricyclic antidepressants, phenytoin, metoclopramide .
3. Evaluation of hormonal causes would include (when available) measurement of: testosterone, LH, HCG,
estradiol, and TSH. Generally refer to a specialist when hormonal causes are suspected.
References:
1. Mira JA. Antivir There. 2004 Aug;9(4):511-7
2. South Africa National Department of Health CLINICAL GUIDELINES FOR THE MANAGEMENT OF HIV
3. UpToDate (www.uptodate.com)
4. Jover F et al. Breast J. 2004 May-Jun;10(3):244-6
2.6. Lactic Acidosis

Lactic acidosis is a rare but life threatening condition and can occur between 1 to 20
months but typically seen 6 months after the start of NRTI therapy. Clinical symptoms are
non-specific and include, fatigue, nausea, vomiting, abdominal pain, malaise, myalgias
weight loss, and dyspnoea. These symptoms may occur acutely or gradually over time.
A blood test will show elevated levels of lactate with or without metabolic acidosis. This
syndrome may be due to inhibition of deoxlyribonucleic acid (DNA) polymerase gamma
affecting mitochondrial DNA production. Therefore excess lactate production occurs,
resulting in accumulation of toxins and predisposing the patient to the development of
lactic acidosis.
A complete evaluation should include an arterial blood gas, serum amylase and lipase
levels and liver function tests. According to some studies, asymptomatic hyperlactatemia
occurs more frequently, presenting in about 15% of patients on NRTIs. Routine monitoring
of serum lactate is not indicated nor recommended in patients with asymptomatic
hyperlactatemia. Levels should, however, be taken immediately if patient is symptomatic
and complains of fatigue, has sudden weight loss, abdominal disturbances, nausea,
vomiting, and sudden dyspnoea. Potential risk factors include female sex, obesity,
chronic hepatitis C, prolonged exposure to NRTIs (especially D4T, didanosine (ddI), or
zalcitabine (DDC)), acute infection, and pregnancy. Zidovudine, lamivudine (3TC) and
abacavir in contrast, have a lower affinity for DNA polymerase.
Due to the lactic acidosis fatality that has been reported, such cases must be handled by
or referred to experienced clinicians. The high mortality is generally attributable to late
diagnosis as clinicians treat these patients for presumed P. pneumonia and think of lactic
acidosis only when the patient fails to respond to treatment. Therefore, patients suffering
9
Hyperlactatemia and Lactic Acidosis due to NRTI Therapy
Consider spectrum of
symptomatic hyperlactemia -
lactic acidosis in patients on
NRTI therapy (especially d4T, ddI, AZT)
Symptoms may include: non-specific gastrointestinal symptoms with or without mild ALT elevation,
abdominal distention, nausea, abdominal pain, vomiting,
diarrhea, loss of appetite, shortness of breath, ascending neuromuscular weakness,
muscle aches, weight loss, enlarged liver
Measure serum electrolytes

& calculate anion gap
(Na -[Cl + CO2]) AG abnormal if
>16
Measure venous lactate

(drawn without tourniquet, fluoride-oxalate tube,
on crushed ice and measured within 4 hours)
Lactate 5-10 Lactate 5-10 mm/L Lacate 2-5 mm/L

Lactate>10 mm/ L Lactate 2-5 mm/L
mm/L without symptoms without symptoms Lactate <
with or without with symptoms or
with symptoms or or or 2 mm/L
symptoms. anion gap>16
anion gap>16 elevated anion gap elevated anion gap
Repeat lactate. If
Discontinue ARVs Repeat lactate. Monitor for Seek alternative
Repeat lactate. symptoms worsenning &
and Dehydration or development or explanation
Stop ARVs & refer no alternative explanation,
refer immediately to laboratory artifact symptoms, of symptoms or
to hospital stop ARVs and
hospital. likely continue therapy elevated anion gap.
refer to specialist
Notes:
1. In patients with mild hyperlactataemia and minimal symptoms (lactate 2.5-5 and no metabolic acidosis
- standard bicarbonate > 20)
ɶɶ The D4T should be switched to AZT and
ɶɶ The lactate rechecked within 3 days and then weekly until normalized.
ɶɶ Stop ART If the lactate cannot be monitored in the way described
ɶɶ Stop ART and follow the guidelines below if symptoms are severe or the lactate continues to rise
or symptoms get worse despite the switch.
2. Patients with moderately severe hyperlactataemia /moderate metabolic acidosis (lactate 5-10 and/or
standard bicarbonate 15-20)
ɶɶ Stop ART and observe as inpatient for 1-2 days and
ɶɶ Give oral vitamins (vitamin BCo 2 tablets bd and thiamine 100mg bd) ,
ɶɶ Hydrate well (orally or IVI)
ɶɶ Exclude sepsis
ɶɶ Exclude OIs.
ɶɶ Recheck lactate and discharge for outpatient follow-up if clinically stable.
ɶɶ Recommence ART Regimen 1d (Tenofovir , 3TC, EFV) only when lactate and bicarbonate has
normalized (this may take months).
3. Patients with severe hyperlactataemia (lactate > 10 without metabolic acidosis) or significant lactic
acidosis (raised lactate regardless of level and significant metabolic acidosis - standard bicarbonate <
15) The mortality is high in this scenario (up to 60%). These patients should preferably be managed in
a high care facility as such:
ɶɶ Stop ART
ɶɶ IVI Thiamine 100mg 12hrly and BCo 1 amp 12hrly
ɶɶ IVI fluids
10
ɶɶ Blood culture/ urine culture/ septic search AND
ɶɶ Broad-spectrum antibiotic (e.g. third-generation cephalosporin or co-amoxyclav). This is important
because sepsis may mimic or precipitate NRTI-associated lactic acidosis.
ɶɶ IVI NaHCO3 if profound acidosis
ɶɶ Ventilation if respiratory fatigue occurs
ɶɶ Dialysis,
ɶɶ Inotropes and
ɶɶ Other supportive measures as necessary
ɶɶ “ Monitor:
ɶɶ Lactate
ɶɶ Blood gas
ɶɶ Lipase
ɶɶ ALT and
ɶɶ Alkaline Phosphatase.
Recommenced on ART Regimen 1d (Tenofovir , 3TC, EFV) Lopinavir /Ritonavir (Kaletra)when lactate
has significantly decreased and they are clinically improved (this may take weeks to months).
4. Neither d4T nor ddI should be used ever again in any patient who has had symptomatic hyperlactataemia
/lactic acidosis.
References:
& AIDS IN HEALTH FACILITIES (2008). Section 3.1.1
2. Carr, A., Clinical Infectious Diseases 2003; 36( Suppl 2):S96–100
2.7. Gastrointestinal Side Effects (Nausea, Vomiting, Diarrhea, and

Abdominal Pain)
Abdominal discomforts are the most commonly reported side effects with ARVs and may
occur earlier in therapy. Common patient complaints include abdominal discomfort,
nausea and vomiting, loss of appetite, diarrhea, abdominal pain, pancreatitis,
constipation, and heartburn. Patients should be informed that most gastrointestinal
symptoms are self-limiting but some can linger for some time or reappear, which could
be a sign of a serious condition. Gastrointestinal (GI) side effects can be a nuisance
and greatly impact adherence, drug therapy outcome, and the patient’s quality of life.
In addition, GI side effects can cause dehydration, electrolyte imbalances, weight loss,
and malabsorption leading to low plasma drug levels. Coffee, smoking, spicy food,
unknown herbal medicines and non-steroidal anti-inflammatory products should be
avoided as much as possible. A workup should be done to diagnose the underlying
cause or complication of GI problems in order to take proper corrective measures. If
diarrhea occurs, make sure it is not of an infectious origin or due to lactose intolerance.
Nausea and vomiting are commonly associated with all NRTI and all PIs as well as with
the NNRTI, nevirapine. Efavirenz is more commonly associated with nausea rather than
vomiting. Diarrhea is associated with almost all PIs, abacavir and nevirapine.
11
Nausea and Vomiting
Nausea and Vomiting: Differential Diagnosis
Gastrointestinal Cardiac Metabolic:

Medication (myocardial Diabetes
CNS Causes and biliary/ Infectious Pregnancy
related infarction) Uremia
pancreatitis Hepatitis
Serious Usually Not Serious
Symptomatic Abacavir AZT ddI

Hyperlactatemia Hypersensitivity Ritonavir
Notes:
1. Symptomatic hyperlactatemia due to D4T and other NRTIs can present with nausea and vomiting. See
Lactic Acidosis algorithm.
2. Abacavir hypersensitivity (HSR) can present with gastrointestinal symptoms. See Abacavir HSR
algorithm.
3. D4T and ddI can cause pancreatitis, presenting with nausea, vomiting and epigastric pain. See
abdominal pain algorithm.
4. Actively manage nausea due to antiretroviral medication, or adherence will suffer. The common
causative agents are AZT and ddI.
5. Administering anti-emetics half an hour before the antiretroviral dose up to 3 times daily may be helpful.
If the nausea does not settle, refer to a doctor trained on ART.
6. Check for jaundice and take blood for ALT as nausea and vomiting may be the first symptoms of drug-
induced hepatitis.
References:
& AIDS IN HEALTH FACILITIES(2008) Section 3.2
12
Abdominal Pain
Symptomatic Opportunistic Gastrointestinal

hyperlactataemia Hepatitis / intolerance of Unrelated
Pancreatitis infections or IRIS
and lactic acidosis steatohepatitis medication causes
(e.g. abdominal TB)
See Nausea, vomiting, See hepatitis

hyperlactatemia epigastric pain algorithm
algorithm
Check Lipase
If lipase > 4 x
ULN
Stop ART regimen

Admission to hospital
IVI fluids
Notes:
1. Causes of pancreatitis include drug induced (d4T, ddI, 3TC (in children), Kaletra), infectious (e.g. CMV),
alcoholic pancreatitis, hypertriglyceridemia and biliary pathology (e.g. gallstones)
2. NRTI induced pancreatitis may be associated with mitochondrial toxicity. Check lactate after
hemodynamically stabilized.
3. Unrelated causes include: pregnancy, diabetic ketoacidosis, appendicitis, peptic ulcer disease, pelvic
inflammatory disease, and urinary tract infections.
References:
& AIDS IN HEALTH FACILITIES (2008). Sections 3.4 and 3.7
13
ARV-associated Diarrhea Management
Diarrhea may
be associated with ddl & protease
Yes inhibitors. Must distinguish ARV-induced diarrhea from No
other causes. Is diarrhea associated with fever
or mucous / blood in
2 the stool? 3
Not due to ARVs. Evaluate
and treat for infectious Possibly due to
diarrhea. ARVs.
4
Yes Did diarrhea
No
begin within days-weeks of
starting ARVs?
5 7 Evaluate for other causes of diarrhea

Administer antimotility agent (if no by stool examination for WBCs culture,
fever, blood or mucous in stool). and parasite examination).
6 8
If no improvement, evaluate for Treat based on test results or
other causes of diarrhea. syndromically for infectious diarrhea.
Notes:
1. For symptomatic treatment of non-inflammatory diarrhea, use Loperamide, oral, 4 mg immediately,
followed by 2 mg after each loose stool, up to 16 mg/ day for severe diarrhoea. or Codeine syrup/
tablets 15- 30mg po 3-5 times a day (as required).
2. Ensure hydration with home-made sugar and salt solution: 1 level teaspoon of salt and 8 level teaspoons
of sugar dissolved in 1 litre of boiled then cooled water.
References:
& AIDS IN HEALTH FACILITIES (2008). Section 4.11 (Management of Chronic Diarrhea)
14
2.8. Allergies/Rash (Abacavir Hyper-Sensitivity Reaction)
Allergies are a common occurrence with drug therapy. It, however, occurs more
frequently in the HIV population than in the HIV-negative patients. Rashes can occur with
all ARVs but is more common with NNRTI (e.g., nevirapine, efavirenz) and abacavir.
Allergy caused by nevirapine and efavirenz usually occurs within the second or third
week of treatment. It is usually an erythematous, maculopapular, pruritic, and confluent
rash distributed over the trunk and arm. Fever may precede the rash. Further symptoms
include myalgia, fatigue, and mucosal ulceration. Severe but rare reactions such as
Steven Johnson Syndrome, toxic epidermal necrolysis and hepatitis have been reported
and need prompt intervention by an expert. Patients must be told of the possibility of
rashes and clear instructions need to given by the treatment team especially about
the ‘treat through period’ and measures to be taken if systemic symptoms (e.g., fever,
arthralgia, or abnormal liver enzymes) develop or the rash worsens. Nevirapine is more
likely to cause rash than efavirenz but the health-care worker must also ensure that the
rash is not disease related or caused by other drugs used for opportunistic infections. If
a nevirapine rash occurs during the initial two-week dose lead-in period, the dose should
be held at 200mg daily until the rash resolves. It should, however, be discontinued if
rash becomes severe with systemic manifestations.
Abacavir (ABC) causes a hyper-sensitivity reaction (HSR), which can be fatal, in 5 to
10% of patients. HSR is not dose dependent and usually involves multi-organ systems.
It is important to distinguish between ABC HSR and isolated rash. With ABC HSR,
symptoms usually begin after 10 days of therapy and worsen approximately 30-60
minutes after each dose administration. Abacavir HSR is characterized by fever and is
usually accompanied by general malaise, nausea, vomiting, diarrhea, and abdominal
pains. A rash may occur, but this is often mild. Abacavir must be discontinued and re-
challenge is contraindicated as severe symptoms, including life-threatening hypotension
and death, may occur rapidly. In some patients the onset of symptoms may occur within
six weeks, but can also occur any time.
15
ARV Rash Management Flow Chart
Patient is on nevirapine or efavirenz containing
regimen for less than 1 month.
Does patient have any of

Yes the following findings? No
Fever eye discomfort or
blurred vision, mouth
or genital sores, blisters
on skin, rash that is Stop any unnecessary
STOP ALL ARVs and any
hemorrhagic (doesn't medications or traditional
other medications started
blanch) remedies started within
within last month
last month
Refer immediately to Teach patient warming

hospital. signs of severe rash
Administer Benadryl
25-50 mg by mouth
every 6-8 hours
Arrange daily follow-up

until rash either resolves or
becomes severe
Notes:
1. Drug rashes are typically associated with nevirapine (and the abacavir hypersensitivity syndrome
which is covered separately). Less commonly they are associated with efavirenz and rarely with
other antiretrovirals . A number of other drugs used in patients with HIV (e.g. cotrimoxazole and TB
medications) may also result in drug rashes.
2. About 15% of patients started on nevirapine will develop a drug rash. This typically occurs in the
first 3 months. It typically presents with a morbiliform or maculo-papular eruption but may progress to
blistering, desquamation and a Stevens-Johnson syndrome.
3. Most nevirapine skin rashes are mild and will settle despite continuing the drug. However, about 1/3 of
patients require that nevirapine is stopped.
4. Check the following in patients presenting with a nevirapine skin rash: ALT, temperature, ask about
systemic symptoms.
5. Avoid systemic steroids in HIV patients with Stevens Johnson Syndrome unless there is evidence of
adrenal insufficiency.
References:
1. South Africa. National Department of Health. CLINICAL GUIDELINES FOR THE MANAGEMENT OF
HIV & AIDS IN HEALTH FACILITIES (2008). Section 3.3
16
Abacavir Hypersensitivity Reaction (Hsr)
Abacavir (ABC) HSR
1. Incidence ~ 5%
2. 90% within 6 weeks of initiation
3. Symptom complexes
• Fever 80%
• Rash (mild) 70%
• GI (nausea, vomiting, diarrhea, abd pain)
• Fatigue, Myalgias, Arthralgias
• Cough, SOB, sore throat
>= 2 symptoms from

0-1 symptom
2 complexes
• Stop ABC Continue ABC

• Do NOT re-challenge with close monitoring
Notes:
1. Use caution when initiating ABC if Immune Reconstitution Syndome (IRIS) likely (e.g. recent TB
diagnosis) to avoid confusion when fever occurs.
2. ABC HSR symptoms usually worsen daily if ABC continued.
3. ABC HSR can progress to multi-organ failure and death, especially with re-challenge.
4. Rash alone not indicative of ABC HSR.
5. If HLA-B*5701 testing available, do not use ABC if positive.
References:
1. Hughes CA et al. Ann Pharmacother 2008;42:387-96.
2.9. Distal Symmetric Polyneuropathy

Distal Symmetric Polyneuropathy (DSP) usually presents with a distal symmetric distribution
and sensorimotor paralysis. Numbness or burning dysesthesia of the distal extremities
occurs at times with sharp shooting pains or continuous severe burning. Signs of DSP
include depressed ankle reflexes, abnormal vibratory pinprick and cold sensations in
the feet. Risk factors for DSP include vitamin B12 deficiency, diabetes mellitus, history
of alcohol abuse, use of neurotoxic drugs such as isoniazid (INH), dapsone, history of
DSP, and advanced AIDS. DSP is associated with several NRTIs, including zalcitabine,
didanosine, stavudine and zidovudine, especially when combined with ddI and d4T. The
incidence varies by drug, dose, and duration of NRTI and stage of HIV disease. Patients
should therefore be advised about soothing and reducing pressures on hypersensitive
feet or hands. Neuropathy can also result from damage caused by other viruses such as
cytomegalovirus, herpes zoster, or hepatitis B or C.
17
Peripheral Neuropathy
• Don’t start ddI or d4T containing regimen if patient has
symptoms of pre-existing neuropathy
• If pre-existing neuropathic symptoms, determine
causes and treat (nutritional,drug induced e.g. INH,
diabetes, alcohol)
• Neuropathic symptoms due to HIV itself: diagnosis
of exclusion
Symptoms
Peripheral Neuropathy Symptoms:

Burning, tingling pain of feet,
often worse at night.
Occasionally manifest
by leg cramps
Grade the severity of symptoms and relationship

to start d4T or ddI
(e.g. Visual analog scale 0-10; Brief Neuropathy
Screening Tool ( BNST))
Pain Mild Pain moderate or severe (not controlled with NSAIDS,

adjuvants, and vitamin supplementation)
Symptomatic therapy with simple analgesia • Switch to AZT if not contraindicated

Amitriptyline 25-75 mg daily • If AZT contraindicated,switch to Tenofovir
Vitamin supplementation ( B6 and BCo) • Palliate pain with more effective adjuvants and opiates
Selected self care modalities
No relief or worsens
• Switch to AZT if not contraindicated

• If AZT contraindicated, switch to Tenofovir
Notes:
1. Additional adjuvants with some demonstrated efficacy for HIV distal symmetric polyneuropathy include
gabapentin and lamotrigine.
2. Antiepileptic drugs including phenytoin and carbamazepine are both inducers of the cytochrome P-450
enzyme system and can lower levels of antiretrovirals metabolized by that system (NNRTIs and protease
inhibitors) and compromise antiretroviral therapy effectiveness.
3. Self help strategies such as warm baths have been reported in observational studies to palliate HIV-
related neuropathic pain.
References:
1. Gonzalez-Duarte A et al. Diagnosis and Management of HIV-Associated Neuropathy Neurol Clin 26
(2008) 821–832
2. Nicholas PK et al. Symptom management and self-care for peripheral neuropathy in HIV/AIDS. AIDS
Care 2007;19:2,179 - 189
HIV & AIDS IN HEALTH FACILITIES. Section 3.5
4. Cherry CL et al. Neurology 2005;65;1778-1781
18
2.10. Hepatitis (ARV and TB Drugs)
The liver has a central role in drug metabolism and detoxification, and consequently, is
vulnerable to injury. Although the occurrence of drug-induced hepatotoxicity is difficult
to predict, it has been observed that certain patients are at risk during the course of
HIV and TB treatment. The risks factors include high alcohol intake, pre-existing liver
disease, chronic viral infection due to hepatitis B and C, HIV infection, slow acetylation,
advanced TB, female sex, concomitant administration of hepatotoxic drugs, and poor
nutritional status. Elevation of liver enzymes (i.e., alanine aminotransferase and aspartate
aminotransferase) and symptoms of hepatitis (i.e, jaundice, anorexia, and dark urine)
may be associated with all antiretrovirals and occur more frequently in those co-infected
with hepatitis B or C virus.
Hepatotoxicity in the first weeks of therapy is most commonly associated with nevirapine.
It is also associated with nucleosides, especially AZT, d4T and ddI, and PIs, most
commonly ritonavir. Metabolic idiosyncratic reactions appear to be responsible for most
drug-induced hepatotoxicity from the first-line anti-TB medications and fluoroquinolones.
All currently recommended regimens for the treatment of latent TB infection and multidrug-
resistant TB including, isoniazid, rifampicin, pyrazinamide, ethambutol, and quinolones
can cause hepatotoxicity. The use of multiple drug regimens, patient characteristics,
varying definitions of hepatotoxicity, and different monitoring and reporting practices
make it difficult to reach definitive conclusions regarding risks of individual regimens.
19
Pattern, Etiologies, Management of Hepatic Enzyme Elevation
after Initiating Antiretroviral Therapy
Pattern (ALT/ULN)/(ALP/UL N)=R
Hepatocellular R>=5
Cholestatic R<=2 Patterns of Liver Injury
Mixed 2<R<5
Hepatocellular (ALT Mixed Cholestatic (ALP

disproportionately elevated (ALT & ALP proportionately disproportionately elevated
compared to ALP) elevated) compared to ALT)
Extra-hepatic Hepatic mass

Alcoholic Other drugs Drug-induced
Mitochondrial Granulomatous AIDS biliary obstruction lesions (e.g.
Liver (e.g. INH, Viral cholestasis
Nevirapine toxicity (D4T, (e.g. TB) (e.g. gallstones, tumors,
Disease RIF,PZA, hepatitis Cholangiopathy (e.g.
ddI>AZT) hepatitis external bile duct abscesses)
(AST>ALT) fluconazole) thorazine)
compression)
An approach to managing patients with hepatocellular injury pattern on ART:

Consider all possible causes
• if ALT elevated to 50-200 and patient is asymptomatic: continue therapy and repeat ALT in 1 week
• If ALT > 200 (even with no symptom) or if ALT elevated 50-200 with symptoms of hepatitis (nausea and
vomiting, jaundice, right upper quadrant pain): stop ART and other drugs that could be causing hepatitis
(eg. TB treatment) and monitor ALT
• Assess patients with severe ALT derangement for features of liver failure (confusion, metabolic flap and
raised INR). Admit these patients and manage appropriately for liver failure.
• Patients with drug-induced hepatitis have often been on a host of drugs that could possibly cause the hepatitis.
Re-introduction of medication should only be done when ALT has normalized and jaundice has resolved.
Drugs should be rechallenged in the following order as a general rule, while monitoring ALT closely:
ɶɶ Rechallenge treatments of active OIs (e.g. TB drug rechallenge according to local guidelines)
ɶɶ Re-introduce safer ART regimen (e.g. substituting nevirapine with efavirenz if nevirapine was in
the ART regimen when hepatitis occurred).
ɶɶ Rechallenge with prophylactic medication (eg. Co-trimoxazole)
ɶɶ Manage patients with fatty liver/ steatohepatitis according to protocols for the associated
hyperlactaemia
Notes:
1. Nevirapine hepatitis usually, but not always, presents with other signs of hypersensitivity (rash, fever)
2. Mitochondrial toxicity hepatic injury associated with hyperlactatemia and fatty liver (steatosis). ALT
& AST usually only mildly elevated. Other non-specific symptoms include nausea, bloating, diarrhea.
Measure lactate if on NRTIs (d4T, ddI, or AZT)
3. Immune reconstitution syndromes (IRS) may present with cholestatic pattern (e.g. TB IRS) or hepatocellular
pattern (e.g. hepatitis C).
4. Hepatitis B can flare if antivirals active against both HIV and Hepatitis B (i.e. 3TC & tenofovir) are
stopped because of toxicity or HIV resistance.
5. The mixed pattern should prompt consideration of differential diagnoses listed under both the
hepatocellular and cholestatic patterns.
References:
HIV & AIDS IN HEALTH FACILITIES (2008), Section 3.9
2. Inductivu-Yu and Bonacini. Highly Active Antiretroviral Therapy-Induced Liver Injury. Current Drug Safety
(2008) 3:4-13
20
Approach to Anti-Tuberculous Drug Hepatatoxicity
Normal LF Flow chart monitoring the liver function
Check baseline liver No LF monitoring prior to and during tuberculosis (TB)
function in all patients
treatment, and the management of anti-
Increased serum tuberculosis drug-induced hepatotoxicity
Signs or symptoms
transaminasesa (ATDH), based on the American Thoracic
of ATDH
Society guidelines. ALT, alanine amin-
otransferase; INH, isonized; LF, liver func-
tion; PZA, pyrazinamide; RIF, rifampicin;
Pre-existing severe Check LF ULN, upper limit of normal. a In patients
liver disease (2-weekly for 8 weeks) with baseline serum ALT of more than
Normal LF
three times ULN, several regimens without
PZA and, if necessary, with a fluoroqui-
nolone or cycloserine are recommended.
Hepatic B/C serology in risk ALT>2 times ULN Check LF after 1 and 2 weeks, than b Risk groups in which screening for viral
groupsb ALT>5 times ULN or
two-weekly until normal hepatitis is recommended include intrave-
>3 times ULN in presence nous drug users, patients from endemic
of symptoms ares (Asia, Africa, the Pacific Islands, East-
ern Europe or the Amazon region), sexual
or household contacts of infected individu-
In some casesc als, HIV infected patients. c If the patient
Stop all TB drugs! is very sick or still sputum smear positive,
some form of TB treatment should be
given until liver function is normal.
Temporary non-hepatotixic
treatment Normalisation of LF
(ALT<2 time ULN)
Restart with RIF

(with or without ethambutol) Remove last added drug
If RIF is tolerated If symptoms recur or

ALT increases
After 3-7 days:
restart with INH In case of prolonged or
severe ATDH
No LF disorders
Not use PZA, but add other drug

Continue treatment
(ethambutol, fluoroquinoione or
cycloserine).
Source:
Tostmann A et al. Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review. Journal of
Gastroenterology and Hepatology 23 (2008) 192–202
21
2.11. Hyperglycaemia
Disorders of glucose metabolism, which include insulin resistance, impaired glucose
tolerance and diabetes, have been reported with ARVs, especially with PIs and to a
lesser extent, with NRTIs. However, insulin resistance may also be associated with HIV
infection in patients not receiving PIs, perhaps because of direct effects of the virus on
pancreatic cell function and insulin secretion. Today, HIV-infected patients are developing
disorders of glucose metabolism because they are living longer or because they may be
predisposed to developing diabetes. The association between hyperinsulinemia and ART
may result from direct effects on cellular glucose uptake, lipolysis, as well as peripheral
insulin resistance associated with decreased limb fat and/or increased visceral fat.
Lipodystrophy syndrome often accompanies glucose metabolism disorder.
Glucose Intolerance, Diabetes, and Metabolic Syndrome
Definitions of Abnormal Glucose Metabolism
Fasting mmol/L (mg/dL) After OGTT mmol/L (mg/dL) Comments
Normal <5.5 (<100) <7.7 (<140)

Symptoms
Pre-Diabetes IFG: 5.5-6.89 (100-125) 7.7-10.99 (140-199) (polyuria ,polydypsia,
weightloss + random glucose
Diabetes ≥6.9 (≥126) ≥11 (≥200) ≥11 mmol/L
OGTT: Oral Glucose Tolerance Test (75 gm glucose load)

IFG: Impaired Fasting Glucose
Notes:
1. A diagnosis of Metabolic Syndrome diagnosis requires the presence of at least 3 of the following
components: impaired glucose tolerance, hypertension, elevated waist circumference or waist-hip
ratio, and high triglyceride and/or low high-density lipoprotein cholesterol (HDL-C) levels. Metabolic
Syndrome increases risk of diabetes and confers 3-fold increased risk of cardiovascular disease.
2. Effects of protease inhibitors (PIs) on glucose metabolism vary by agent. Among the PIs, atazanavir,
darunavir, and saquinavir have least deleterious effects on glucose metabolism (not currently available
in South African antiretroviral therapy program). Effects of Kaletra appear to be less than indinavir,
which has the greatest impact among the PIs.
3. Non-antiretroviral drugs including niacin, corticosteroids, and thiazide diuretics may impair glucose
metabolism and thereby worsen insulin resistance and diabetes.
4. Abacavir has been associated with increased risk of cardiovascular events in recent epidemiological studies.
Management of abnormal glucose metabolism:

1. Diet and exercise are important in all patients with abnormal glucose metabolism. Patients should be
referred to a dietician for nutritional counseling.
2. Monitor fasting glucose in patients on Kaletra at baseline, 6 months then annually.
3. Check glucose if symptoms of diabetes occur.
4. Manage the diabetes as per standard protocols. Metformin may cause lactic acidosis, especially in
patients with elevated serum creatinine.
5. Consider switching d4T to tenofovir if diabetes develops on d4T.
22
Effects of ARVs on Glucose Metabolism
Direct Indirect (mainly via lipoatrophy and

mitochondrial toxicity)
Protease Inhibitors Patterns of Liver Injury
References:
1. Tebas P. J Acquir Immune Defic Syndr. 2008 Sep 1;49 Suppl 2:S86-92
3. D-A-D Study Group. Lancet. 2008 Apr 26;371(9622):1417-26
2.12. Tenofovir-Related Nephrotoxicity

Tenofovir is the first nucleotide analogue approved for treatment of HIV infection. Although
its potential for mitochondrial dysfunction is comparatively lower, it is postulated that
tenofovir may induce kidney damage as a result of mitochondrial DNA depletion in
kidney tubular cells. Although clinical trials have not been conclusive on the extent and
relevance of tenofovir-induced nephrotoxicity, cases of acute renal failure and Fanconi
Syndrome (renal tubular necrosis with hypophosphataemia) have been reported. It
should, however, be noted that nephrotoxic drugs may be only one of several causes of
renal dysfunction in HIV patients. Generally from a urinalysis, a glomerular dysfunction
is indicative of HIV-Kidney disease (proteinuria alone or combined with hematuria) and
tubular dysfunction is usually associated with drug toxicity (cast in urine and/or specific
gravity of 1.010). It is therefore recommended that prior to starting tenofovir, patients’
creatine clearance should be calculated (Cockcroft-Gault method) and this should be
repeated monthly thereafter for up to 6 months. Tenofovir can also cause nausea,
diarrhoea, vomiting, and flatulence.
23
Reported Forms of Tenofovir Nephrotoxicity
Fanconi Syndrome (glyosuria,

Acute renal failure Nephrogenic diabetes insipidus
phosphaturia, aminoaciduria)
Antiretroviral drug, dosing category

Dosage
Tenofovir
Usual dosage 300 mg po q.d.
Dosage for patients with CKD or ESRD
Creatinine clearance ≥ 50 mL/min No adjustment
Creatinine clearance 30-49 mL/min 300 mg po q48h
Creatinine clearance 10-29 mL/min 300 mg po q72h
Receiving hemodialysis 300 mg po every 7 daysc
Receiving peritoneal dialysis Unknown, use with caution
Cockcroft-Gault
CrCl (mL/min)
[140 - age (years)] x weight (kg) [x 0.85 if female]
=
72 x serum creatinine (mg/dL)
Notes:
1. Clinically significant nephrotoxicity in patients with normal underlying renal function is rare.
2. Patients receiving tenofovir who have a GFR !90 mL/min per 1.73 m2, patients receiving other
medications eliminated via renal secretion (e.g., adefovir , acyclovir, ganciclovir, or cidofovir), patients
with other comorbid diseases (e.g., diabetes or hypertension), or patients receiving ritonavir boosted
protease inhibitor regimens should be monitored at least biannually for measurements of renal function,
serum phosphorus,and urine analysis for proteinuria and glycosuria.
3. Avoid concomittant use of nephrotoxic medications with tenofovir (e.g. aminoglycosides , amphotericin
B, foscarnet).
4. Dosing of tenofovir should be based on estimated creatinine clearance (CrCl) using the Cockcroft-
Gault formula above. The following website can be used to calculate CrCl:
http://nephron.com/cgi-bin/CGSI.cgi
5. Fanconi Syndrome, a proximal tubular disorder, should be suspected when normoglycemic glycosuria,
hypophosphatemia , and proteinuria are persistently present.
References:
1. Gupta et al. Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients:
Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America
Clinical Infectious Diseases 2005; 40:1559–85
2. Fine at al. Renal Disease in Patients with HIV InfectionDrugs 2008; 68 (7): 963-980
24
References
1. AIDS Education Training Centers. Adverse Reactions to HIV Medications.
<www.aidsetc.org> (Accessed February 2009)
2. Barrios, A, Garcia-Benayas, T, Gonzalez-Lahoz, J, et al., “Tenofovir-related
Nephrotoxicity in HIV-infected Patients.” AIDS 18 (6) (2004): 960-963
3. Bartlett, JG, Gallant, JE. Medical Management of HIV Infection. Johns Hopkins
Medicine, Health Publishing Group, 2004
4. Duncombe, C. “Managing Antiretroviral Side Effects – A Practical Guide”. The
western Pacific Regional Office of the WHO, 2003
5. Montessori, V, Press, Haris, et al. “Adverse Effects of Antiretroviral Therapy for HIV
infection.” Canadian Medical Association Journal. 170 (2) (January 20, 2004)
6. New York State Department of Health, AIDS Institute. Long-term Complications of
Antiretroviral Therapy. <www.hivguidelines.org> (Accessed February 2009)
7. Saukkonen, JJ, Cohn, DL, Jamer, RM, et al. “Hepatotoxicity of Antituberculosis
Therapy” (official American Thoracic Society Statement). AM J Resp Crit Care Med,
174 (2006): 935-952
8. South Africa. National Department of Health. National Antiretroviral Treatment
Guidelines, 2009
9. Stenger, M, Szczech, L. “Renal Dysfunction and Tenofovir Toxicity in HIV-infected
Patients.” Topics in HIV Medicine (International AIDS Society, USA.) 2008
10. Tostmann, A et al., “Anti-tuberculosis Drug-induced Hepatotoxicity: Concise Up-to-
Date Review.” Journal of Gastro and Hepatology 23 (2008): 192-202
11. Yimer, G, Getachew, A, Wondwossen, A. Anti-Tuberculosis therapy – Induced
Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients.
25
26
SECTION B
Drug Interactions
27
3.1. Drug-Drug Interactions
Drug interactions have become an increasingly complex challenge for health-care
workers treating HIV-infected patients.
Generally, drug interactions can be classified into two broad categories:
• Interactions altering pharmacokinetics, and
• Interactions affecting pharmacodynamics.
Although both interactions have the potential to be problematic in patients receiving
highly active antiretroviral therapy (HAART), pharmacokinetic interactions are more
common and more difficult to predict due to the complex nature of drug metabolism.
Most interactions are minor and may not be noticeable or of any clinical significance;
however, there are an equally significant number of interactions that can cause a decrease
in patient or clinical outcomes, therapeutic failures, mild to moderate toxicity, and severe
to life threatening toxicities. Clinically significant drug interactions are generally those
that produce at least a 30% change in pharmacokinetic parameters.
Drug interactions occur in almost all patients who are being treated for HIV/AIDS due
to the average number of drugs for HIV and opportunistic infections, food interactions,
vitamins, complementary, and herbal or traditional medicines that may be taken by the
patient.
A. Pharmacokinetic Interactions
Pharmacokinetic drug interactions can be classified according to whether they affect
the absorption, distribution, metabolism, or elimination of other drugs. Most common
drug interactions encountered in HIV infection involve those that affect metabolism or
absorption.
Metabolism
Drug interactions involving metabolism are the most common and the most difficult to
predict. Drugs used in HAART, especially non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors (PIs), are metabolized via the cytochrome P450 enzyme
system (CYP450). The CYP450 enzyme system is responsible for drug metabolism. The
enzyme responsible for the majority of drug metabolism is CYP3A4, although 2C19 and
2D6 are also common and, to a lesser extent, CYP1A2. Drugs interact with CYP450
enzymes in one of three ways:
• Through inhibition,
• Through induction, and
• By acting as a substrate.
Some drugs may interact in more than one way, and act as an inhibitor and inducer
of different CYP450 enzymes. CYP450 enzymes are expressed both in the liver and in
the enterocytes of the small intestine. These can produce inhibition or induction of drug
metabolism within the gastrointestinal tract. A common example of this type of interaction
is concurrent use of saquinavir and grapefruit juice. As a result of CYP450 inhibition in
the gasterointestinal (GI) tract, grapefruit juice significantly increases the bioavailability
28
of saquinavir. Similarly, ritonavir may inhibit CYP3A4 in the intestine, which is one of the
proposed mechanisms that contribute to this drug acting as a pharmacokinetic “boost.”
Drugs that inhibit CYP450 enzymes generally lead to decreased metabolism of other drugs
that are metabolized by the same enzyme. The decreased metabolism can result in higher
drug levels and increased potential for toxicity. Although inhibition is usually reversible,
irreversible inhibition of CYP450 can occur, requiring new CYP450 enzymes to be
synthesized to overcome the inhibition. Inhibition of drug metabolism tends to occur quickly
(based on drug half-life), with maximal effect occurring when the highest concentrations of
the inhibitor are reached. Inhibition could be used therapeutically; for example, ritonavir
is a very potent inhibitor of CY3A4, thus it used in combination with lopinavir (Kaletra) to
increase lopinavir blood levels. It is important to note that grapefruit juice contains various
substances that inhibit CYP3A4-mediated metabolism in the gut wall.
Induction of the CYP450 system results in the increased clearance of concomitant
medications metabolized by the same enzyme. When drugs that induce CYP450 enzymes
are administered to a patient, the body responds by increasing the production of specific
enzymes of the CYP450 system. The increased enzyme production could lead to increased
metabolism and decreased concentrations of drugs metabolized via the same pathway. In
general, the maximal effect of enzyme induction is apparent within 7 to 10 days, although
with drugs with a relatively long half-life, such as methadone, the full effect of induction
may take even longer. Drugs may also undergo a phenomenon termed “autoinduction”,
whereby a drug has the capability of inducing its own metabolism. For example, nevirapine,
which is why it is dosed 200 mg daily for the first 14 days of treatment, then 200 mg twice
daily thereafter. A drug may act as a substrate by occupying the active site of a specific
CYP450 enzyme. This drug’s metabolism is then affected by other medications that either
induce or inhibit the CYP450 enzyme system.
Absorption
Drug interactions that affect absorption occur when one drug reduces the bioavailability
of a second drug. Reduced absorption is caused by one of four mechanisms:
• Alterations related to the presence or absence of food,
• Alterations in gastric pH caused by antacids, H2-blockers, or proton-pump
inhibitors,
• Chelation of drugs caused by calcium, magnesium, or iron, and
• Inhibition of the P-glycoprotein or other transport pump.
B. Pharmacodynamic Interactions
Pharmacodynamic interactions occur when one drug causes an alteration in the
pharmacological response (drug effect) of a second without a resultant change in
drug concentrations or pharmacokinetic parameters. In this type of interaction, the
pharmacological response from the drug can be antagonistic, additive, or synergistic.
• Antagonistic effects result in the drug’s pharmacological effect being reduced
due to concurrent therapy, such as is seen when zidovudine and stavudine are
co-administered.
29
• Additive effects occur when the use of two drugs leads to enhanced
pharmacological activity.
• Synergy occurs when the concurrent use of two or more drugs results in an effect
that is greater than the addition of all of the drugs together (i.e., the effect is
exponential, not additive).
Table 1. Routes of elimination of haart and the effect

on cyp450
DRUG ELIMINATION EFFECT ON CYP450 SYSTEM
Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
Abacavir (ABC) Hepatic Insignificant
Didanosine (ddI) Renal excretion 50% None
Emtricitabine (FTC) Renal excretion 86% None
Lamivudine (3TC) Renal excretion 70% None
Stavudine (d4T) Renal excretion 50% None
Tenofovir (TDF) Renal excretion 70-80% None
Hepatic metabolism with renal
Zidovudine (AZT, ZDV) None
excretion
Non-Nucleoside Reverse Transcriptase Inhibitors
Efavirenz (EFV) Hepatic CYP3A4 inducer (inhibitor in vitro)
Nevirapine (NVP) Hepatic CYP3A4 inducer
Protease Inhibitors
Amprenavir (APV), Fosamprenavir
Hepatic CYP3A4 inhibitor/inducer
(FPV)
CYP3A4 inhibitor, CYPIA2, CYP2C9
Atazanavir (ATZ) Hepatic
inhibitor
Indinavir (IDV) Hepatic CYP3A4 inhibitor
CYP3A4 inhibitor
CYP2D6 inhibitor
Lopinavir/ritonavir (LPV/r) Hepatic
(3A4 inhibition >2D6)
3A4 and CYPIA2 inducer
Nelfinavir (NFV) Hepatic CYP3A4 inhibitor/inducer
CYP3A4 inhibitor
CYPD6 inhibitor
Ritonavir (RTV) Hepatic
(3A4 inhibition>2D6)
3A4 and CYPIA2 inducer
Saquinavir (SQV) Hepatic Weak CYP3A4 inhibitor
30
3.2. Drug-Food Interactions
Food intake or meals can enhance or inhibit the absorption, metabolism, distribution,
and excretion of drugs. Dietary management to improve the efficacy of a drug includes
taking it with food, on an empty stomach, taking it with particular foods, or avoiding
particular foods. (See drug information section for each individual drug.)
3.3. Herb/Traditional/Complementary-Drug Interactions
According to the Comprehensive HIV and AIDS Care, Management and Treatment Plan
for South Africa, about 90% of HIV-positive patients take some form of complementary or
herbal medicine. This implies that a majority of patients on ART will also be taking some
form of herbal, traditional or complementary medicine. Research on herbal or traditional
medicines is very limited and thus has not been regulated for purity and potency. There
is inadequate clinician experience combining herbal, traditional or complementary
medicines with ARVs. It is however prudent that clinicians document, as much as possible,
the name, source, and quantity of any other medicines that may be taken by the patient.
Clinicians should counsel patients on the possibility of drug interactions that may result to
therapeutic failure or toxicities. (See below tabling common drug-drug interactions.)
31
Table 2. Common Drug-Drug Interactions Among ARV
DRUGS Registered in South Africa
Table 2.1. Protease Inhibitors

Drug ATV FPV IDV LPV NFV RTV SQV
Analgesics
Aspirin + + + + + + +
Buprenophine - - - + - - -
Codeine/Dihydrocodeine - - - - - - -
Dextropropxyphene - - - - - - -
Diclofenac + + + + + + +
Fentanyl - - - - - - -
Ibuprofen + + + + + - +
Methadone + - - - - - -
Morphine - - - - - - -
Paracetamol + + + + + + +
Pethidine - - x - - - -
Piroxicam - - x - - x -
Tramadol - - - - - - -
ANTIARRHYTHMICS
Amiodarone - x x x x x x
Quinidine x x x - x x x
Disopyramide - - - - - - -
Flecainide x x x x - x x
Lidocaine/(Lignocaine) - - - - - - -
Mexiletine - - - - - - -
Propafenone x x x - - x x
– Potential interaction – may require close monitoring, alteration of drug dosage or timing of administration
+ No clinically significant interaction expected
x These drugs should not be co-administered
o There are no clear data, actual or theoretical, to indicate whether an interaction will occur
ATV-Atazanavir; FPV-Fosamprenavir; NFV-Nelfinavir; IDV-Indinavir; LPV-Lopinavir; RTV-Ritonavir; SQV-Saquinavir;
EFV-Efavirenz; NVP-Nevirapine; ABC-Abacavir; DDI-Didanosine; D4T-Stavudine; FTC-Emtricitabine; 3TC-Lamivudine;
ZDV-Zidovudine
32
ANTIBACTERIALS
Azithromycin + + + + + - +
Ciprofloxacin + + + + + + +
Clarithromycin - + + - + - +
ANTIFUNGALS
Amphotericin B + + + + + + +
Fluconazole + + + + + + +
Flucytosine + + + + + + +
Itraconazole - - - - + - +
Ketoconazole - + - - + - +
Miconazole - o o - o - +
Terbinafine + + + + + + +
ANTIHISTAMINES
Cetirizine + + + + + + +
Fexofenadine - - - - + - -
Loratadine - - - - - - -
Terfenadine x x x x x x x
ANTIMIGRAINES
Ergotamine & Ergot derivatives x x x x x x x
Sumatriptan - - - - - - -
ANTINEOPLASTICS
Cyclophosphamide - - - - - - -
Cytarabine; Doxorubicin + + + + + + +
Etoposide; Irinotecan - - - - - - -
Paclitaxel - - - - - - -
ZDV-Zidovudine
33
ANTINEOPLASTICS
Vinblastine; Vincristine - - - - - - -
ANTI-PLATELET AND ANTI-COAGULANT
Clopidogrel - - - - - - -
Warfarin - - - - - - -
ANTIPROTOZOALS
Artemisinins - - - - - - -
Atovaquone - + + - + - +
Chloroquine + + + + + - +
Halofantrine x x x x x x x
Mefloquine - - - - - - -
Pentamidine + + + + + - +
Primaquine o o o o o o o
Proguanil + + + + + - +
Pyrimethamine + + + + + - +
Quinine - - - - - - -
Sulfadoxine/pyrimethamine + + + + + - +
ANTIPSYCHOTICS / NEUROLEPTICS
Chlorpromazine - - - - - - -
Clozapine - - x - - - -
Haloperidol - - - - - - -
Olanzapine - - - - - - -
Perphenazine + + + + + - +
Pimozide x x x x x x x
Quetiapine - - - - - - -
ZDV-Zidovudine
34
Risperidone + + + + + - +
Sulpiride + + + + + + +
ANTIRETROVIRALS
NRTIs Abacavir + + + - + + +
Didanosine - - - - - - -
Emtricitabine + + + + + + +
Lamivudine + + + + + + +
Stavudine + + + + + + +
Zidovudine + + + + + + +
NNRTIs Efavirenz - - - - - - -
Nevirapine - - - - - + -
PIs Atazanavir - x - - - -
Fosamprenavir - + - + - -
Indinavir x + - - - -
ANTIVIRALS
Aciclovir, Valaciclovir + + + + + + +
Adefovir + + + + + + -
Cidofovir + + + + + + +
Entecavir + + + + + + +
Famciclovir + + + + + + +
Foscamet + + + + + + +
Ganciclovir + + + + + + +
Ribavirin + + + + + + +
ZDV-Zidovudine
35
ANXIOLYTICS / HYPNOTICS / SEDATIVES
Alprazolam - - x - - - -
Chlordiazepoxide + + + + + + +
Clorazepate - - x - - - -
Diazepam - - x - - - -
Estazolam - - x - - - -
Flurazepam - - x - - - -
Lorazepam + + + + + + +
Midazolam (oral) x x x x x x x
Oxazepam, Temazepam + + + + + + +
Triazolam x x x x x x x
Zolpidem - - - - - - -
BETA BLOCKERS
Atenolol - + + - + - +
Bisoprolol - + + - + - +
Carvedilol - - - - - - -
Metoprolol - - + - + - +
Propranolol - + + - + - +
BRONCHODILATORS
Theophylline - + + - + - +
CALCIUM CHANNEL ANTAGONISTS
Amilodipine; Ditazem - - - - - - -
Nicardipine; Nifedipine - - - - - - -
Nisoldipine; Verapamil - - - - - - -
ZDV-Zidovudine
36
ERECTILE DYSFUNTION AGENTS
Apomorphine - - - - - - -
Sildenafil/Tadalafil - - - - - - -
GASTROINTESTINAL AGENTS
Antacids - + - + o o +
Cimetidine - - + + + + +
Cisapride x x x x x x x
Domperidone + + + + + + +
Lansoprazole x + + + x + -
Loperamide - + + - + - -
Metoclopramide + + + + + + o
Omeprazole x + - + x + -
Ondansetron + + + + + + +
Pantoprazole x + - + x + +
Prochlorperazine + + + + + - +
Ranitidine - - + + + + +
GENERAL ANAESTHETICS
Enflurane/Halothane + + + + + + +
Ketamine + + + + + + +
HERBALS/NUTRACEUTICALS
Echinacea - - - - - - -
Garlic - - - - - - x
Grapefruit juice + + + + + + +
Milk thistle - - + - - - -
Quercetin o o o o o o +
ZDV-Zidovudine
37
Seville orange juice + + + + + + +
St John's Wort x x x x x x x
Valerian + + + + + + +
Vitamin E + + + + + + +
ILLICIT/RECREATIONAL
Alcohol + + + + + + +
Gamma-hydroxybutyrate - - - - - - -
Marijuana - + + - + - -
MDMA ("Ecstasy") - - - - - - -
Methamphetamine - - - - - - -
IMMUNE MODULATORS
Hydroxyurea + + + + + + +
Interferons + + + + + + +
Interleukin 2 + + + + + + +
IMMUNOSUPPRESSANTS
Ciclosporin, Mycophenolate - - - - - - -
Sirolimus, Tacrolimus - - - - - - -
LIPID LOWERING AGENTS
Atorvastatin - - - - - - -
Clofibrate + + + + + + +
Fenofibrate + + + + + + +
Fish Oils + + + + + + +
Fluvastatin + + - + + + +
Gemfibrozil + + + - + + +
ZDV-Zidovudine
38
Pravastatin + + - + - + -
Simvastatin x x x x x x x
IMMUNOSUPPRESSANTS
Ciclosporin, Mycophenolate - - - - - - -
Sirolimus, Tacrolimus - - - - - - -
Atorvastatin - - - - - - -
Clofibrate + + + + + + +
Fenofibrate + + + + + + +
Fish Oils + + + + + + +
Fluvastatin + + - + + + +
Gemfibrozil + + + - + + +
Pravastatin + + - + - + -
Simvastatin x x x x x x x
ORAL ANTI-DIABETICS
Gliclazide-Glipizide - - - - - - -
Metformin + + + + + + +
Rosiglitazone + + + + + + +
Tolbutamide - - - - - - -
OTHERS
Allopurinnol + + + + + + +
Candesartan + + + + + + +
Diogoxin - - - - - - -
Irbesartan - - - - - - -
ZDV-Zidovudine
39
OTHERS
Ramipril + + + + + + +
Valsartan + + + + + + +
STEROIDS
Budesonide - - - - - - -
Dexamethasone - - - - - - -
Ethinylestradiol - - - - - - -
Fluticasone - - - - - - -
Megestrol acetate + + + + + + +
Nandrolone + + + + + + +
Prednisolone - - - - - - -
Progesterone/Progestogen - - - - - - -
Testosterone - - - - - - -
ZDV-Zidovudine
40
Table 2.2. Non-Nucleoside Reverse Transcriptase Inhibitors
DRUG EFV NVP
ANALGESICS
Aspirin + +
Buprenophine - -
Codeine; Dihydrocodeine - -
Dextropropxyphene + +
Diclofenac + +
Fentanyl - -
Ibuprofen + +
Methadone - -
Morphine + +
Paracetamol + +
Pethidine + +
Piroxicam + +
Tramadol - +
ANTIARRHYTHMICS
Amiodarone - -
Quinidine - -
Disopyramide - -
Flecainide - -
Lidocaine (Lignocaine) - -
Mexiletine - -
Propafenone - -
ZDV-Zidovudine
41
DRUG EFV NVP
ANTIBACTERIALS
Azithromycin + +
Ciprofloxacin + +
Clarithromycin - -
Clavulanic acid + +
Clindamycin + +
Dapsone + +
Erythromycin + -
Ethambutol + +
Isoniazid + +
Metronidazole + +
Pyrazinamide + +
Rifabutin - -
Rifampicin - x
Rifapentine - -
Streptomycin; Tetracyclines + +
Trimethoprim/Sulfamethoxazole + +
ANTIFUNGALS
Amphotericin B + +
Fluconazole + -
Flucytosine + +
Itraconazole - -
Ketoconazole - x
Miconazole + -
Terbinafine + +
ZDV-Zidovudine
42
DRUG EFV NVP
ANTIHISTAMINES
Cetirizine + +
Fexofenadine - -
Loratadine - +
Terfenadine x -
ANTIMIGRAINES
Ergotamine & Ergot derivatives x -
Sumatriptan + +
ANTINEOPLASTICS
Cyclophosphamide - -
Cytarabine; Doxorubicin + +
Etoposide; Irinotecan - -
Paclitaxel - -
Vinblastine; Vincristine - -
ANTI-PLATELET AND ANTI-COAGULANT
Clopidogrel - -
Warfarin - -
ANTIPROTOZOALS
Artemisinins - -
Atovaquone + +
Chloroquine + +
Halofantrine - -
Mefloquine + +
Pentamidine + +
Primaquine o o
ZDV-Zidovudine
43
DRUG EFV NVP
ANTIPROTOZOALS
Proguanil + +
Pyrimethamine + +
Quinine - -
Sulfadoxine/pyrimethamine + +
ANTIPSYCHOTICS/NEUROLEPTICS
Chlorpromazine + +
Clozapine + +
Haloperidol + +
Olanzapine - -
Perphenazine + +
Pimozide x -
Quetiapine - -
Risperidone + +
Sulpiride + +
ANTIRETROVIRALS
NRTIs Abacavir + +
Didanosine (ddI) + +
Emitricitabine (FCT) + +
Lamivudine (3TC) + +
Stavudine (d4T) + +
Zidovudine (AZT/ZDV) + +
NNRTIs Efavirenz -
Nevirapine -
PIs Atazanavir - -
ZDV-Zidovudine
44
DRUG EFV NVP
ANTIRETROVIRALS
Fosamprenavir - -
Indinavir - -
Lopinavir - -
Nelfinavir - -
Ritonavir - +
Saquinavir - -
ANTIVIRALS
Aciclovir, Valaciclovir + +
Adefovir + +
Entecavir + +
Famciclovir + +
Foscamet + +
Ganciclovir + +
Ribavirin + +
ANXIOLYTICS/HYPNOTICS/ SEDATIVES
Alprazolam - -
Chlordiazepoxide + +
Clorazepate - -
Diazepam - -
Flurazepam/Estazolam - -
Lorazepam + +
Midazolam (oral) x -
Oxazepam, Temazepam + +
Triazolam x -
ZDV-Zidovudine
45
DRUG EFV NVP
ANXIOLYTICS/HYPNOTICS/ SEDATIVES
Zolpidem - -
BETA BLOCKERS
Atenolol + +
Bisoprolol + +
Carvedilol - -
Metoprolol + +
Propranolol + +
CALCIUM CHANNEL ANTAGONISTS
Amilodipine; Ditazem - -
Nicardipine; Nifedipine - -
Nisoldipine; Verapamil - -
BRONCHODILATORS
Theophylline + +
ERECTILE DYSFUNTION AGENTS
Apomorphine - -
Sildenafil; Tadalafil - -
Antacids + +
Cimetidine - +
Cisapride x -
Domperidone + +
Lansoprazole + +
Loperamide + +
Metoclopramide + +
ZDV-Zidovudine
46
DRUG EFV NVP
Omeprazole + +
Ondansetron + +
Pantoprazole + +
Prochlorperazine + +
Ranitidine + +
GENERAL ANAESTHETICS
Enflurane; Halothane + +
Ketamine - -
Echinacea - -
Garlic - -
Grapefruit juice + +
Milk thistle - -
Quercetin o o
Seville Orange Juice + +
St John's Wort x x
Valerian + +
Vitamin E + +
ILLICIT/RECREATIONAL
Alcohol + +
Gamma-hydroxybutyrate + +
Marijuana + +
MDMA ("Ecstasy") + +
Methamphetamine + +
ZDV-Zidovudine
47
DRUG EFV NVP
IMMUNE MODULATORS
Hydroxyurea + +
Interferons + +
Interleukin 2 + +
IMMUNOSUPPRESSANTS
Ciclosporin, Mycophenolate - -
Sirolimus, Tacrolimus - -
Atorvastatin - -
Clofibrate + +
Fenofibrate + +
Fish Oils + +
Fluvastatin - -
Gemfibrozil + +
Pravastatin - +
Simvastatin - -
ORAL ANTI-DIABETICS
Gliclazide-Glipizide - -
Metformin + +
Rosiglitazone + -
Tolbutamide - -
OTHERS
Allopurinnol + +
Candesartan + +
Diogoxin - -
ZDV-Zidovudine
48
DRUG EFV NVP
OTHERS
Irbesartan - -
Ramipril + +
Valsartan + +
STEROIDS
Budesonide + +
Dexamethasone - -
Ethinylestradiol - +
Fluticasone + +
Megestrol acetate + +
Nandrolone + +
Prednisolone - -
Progesterone/Progestogen - -
Testosterone - -
ZDV-Zidovudine
49
Table 2.3. Nucleoside Reverse Transcriptase Inhibitors
DRUG ABC DDI FTC 3TC D4T ZDV
ANALGESICS
Buprenophine - + + + + +
Codeine; Dihydrocodeine - + + + + -
Diclofenac + + + + + +
Methadone - - + + - -
Paracetamol + + + + + +
ANTIBACTERIALS
Azithromycin + + + + + +
Ciprofloxacin + + + + + +
Clarithromycin + + + + + -
Clavulanic acid + + + + + +
Dapsone + + + + + -
Rifabutin + + + + + +
Rifampicin - + + + + -
Rifapentine + + + + + +
Streptomycin; + + + + + +
Trimethoprim/Sulfamethoxazole + + - - - -
ANTICONVULSANTS
Levetiracetam + + + + + +
Oxcarbazepine + + + + + +
Phenobarbital - + + + + -
Phenytoin - + + + + -
Valproate - + + + + -
ANTIDEPRESSANTS
Trazodone + + + + + +
ZDV-Zidovudine
50
Venlafaxine + + + + + +
ANTIFUNGALS
Amphotericin B + - - - - -
Fluconazole + + + + + +
Flucytosine + - - - - -
Itraconazole + + + + + +
Ketoconazole + + + + + +
ANTINEOPLASTICS
Cytarabine; + + + + + +
Doxorubicin + - - - - -
Etoposide; + + + + + +
Irinotecan + + + + + -
Vinblastine; + - - - - -
Vincristine + - - - - -
ANTIPROTOZOALS
Atovaquone + + + + + +
Pentamidine + - - - - -
Pyrimethamine + - - - - -
Quetiapine + + + + + +
Sulpiride + + + + + +
ANTIRETROVIRALS
NRTIs Abacavir - + - + +
ZDV-Zidovudine
51
Didanosine (DDI) - + - x +
Emitricitabine (FCT) + + x + +
Lamivudine (3TC) - - x + +
Stavudine (d4T) + x + + x
Zidovudine (AZT/ZDV) + + + + x
NNRTIs Efavirenz + + + + + +
Nevirapine + + + + + +
PIs Atazanavir + - + + + +
Fosamprenavir + - + + + +
Indinavir + - + + + +
Lopinavir - - + + + +
Nelfinavir + - + + + +
Ritonavir + - + + + +
Saquinavir + - + + + +
ANTIVIRALS
Aciclovir, + + + + + +
Adefovir + + + + + +
Entecavir + + + + + +
Famciclovir + + + + + +
Foscamet + + - x + +
Ganciclovir - - - x + -
Ribavirin - x - - - x
Valaciclovir + + + + + +
ANXIOLYTICS / HYPNOTICS/ SEDATIVES
Oxazepam + + + + + +
ZDV-Zidovudine
52
Cimetidine + + + + + +
Loperamide + + + + + +
Metoclopramide + + + + + +
Pantoprazole + + + + + +
Ranitidine + + + + + +
HERBALS / NUTRACEUTICALS
Cyanocobalamin + + + + + +
Valerian + + + + + +
ILLICIT / RECREATIONAL
Alcohol + + + + + +
IMMUNE MODULATORS
Hydroxyurea + x + + x +
Interferon alpha + - - - - -
Interleukin 2 + - - - - -
IMMUNOSUPPRESSANTS
Mycophenolate - + + + + -
Tacrolimus + + - - + +
Fish Oils + + + + + +
ORAL ANTI-DIABETICS
Gliclazide + + + + + +
OTHERS
Allopurinol + - + + + +
ZDV-Zidovudine
53
Candesartan + + + + + +
Digoxin + + + + + +
Disulfiram - + + + + -
Irbesartan - + + + + -
Ramipril + + + + + +
Spirinolactone + + + + + +
Valsartan + + + + + +
STEROIDS
Ethinylestradiol + + + + + +
Megestrol acetate + + + + + +
Progesterone/Progestogen + + + + + +
ZDV-Zidovudine
54
TABLE 3. Selected ARVs with Mechanisms of Drug
Interactions and Management Recommendations

Interacting Clinical
ARV Drug Effect of Interaction Management
Drug Significance
Abacavir Alcohol Decreased abacavir No dose adjustment necessary
metabolism by alcohol
dehydrogenase. Abacavir
+
area under the curve (AUC):
increased 41%; half-life:
increased 26%
Abacavir Zidovudine Abacavir decreases the No dose adjustment necessary
absorption of zidovudine.
+
Reduced maximum
concerntration (Cmax)
Abacavir Lamivudine Abacavir decreases the No dose adjustment necessary
absorption of lamivudine. +
Reduced Cmax
Didanosine (ddI) Tetracyclines Magnesium and calcium ions Administer ddI at least two
contained in the tablet’s buffer - hours after or six hours before
chelate with the antibiotics tetracycline
Didanosine (ddI) Atazanavir The buffer in didanosine Didanosine buffered tablets
neutralizes the acid should be taken two hours
environment needed for after or one hour before
-
atazanavir absorption taking atazanavir to minimize
the interaction or use enteric
coated tablets
ZDV-Zidovudine
55
Drug Significance
Didanosine (ddI) Tenofovir The ddI area under the curve Patients taking drugs
(AUC) increases by 60% concurrently require dosage
reductions according to their
- weight: >60kg: 250mg;
<60kg:200mg;if severely
underweight give 125mg ddI
once daily
Didanosine (ddI) Allopurinol Inhibition of presystemic Monitor patient for ddI side
metabolism by allopurinol. effects
AUC of ddI increased between
-
113%-122%. Cmax increased
69-116%. Increased ddI effects
(pancreatitis, neuropathy)
Didanosine (ddI) Foods Decreased didanosine Administer ddI at least 2 hours
effects due to a reduction in apart with meals
-
bioavailability by 20-25%
when given with any food
Didanosine (ddI) Itraconazole Decreased itraconazole Administer itraconazole
absorption due to decreased capsules at least 2 hours
gastric acidity resulting from after ddI tablets/suspension.
antacid buffer contained - Itraconazole solution as
within ddI tablets/suspension. suggested alternative
Decreased itraconazole effects
Didanosine (ddI) Ranitidine Inhibition of gastric acid No dose adjustment necessary

slightly enhancing didanosine
bioavailability by reducing acid
+
degradation. Ranitidine AUC:
decreased 16%; Cmax: no
significant change
Didanosine (ddI) Metroclopramide No significant change to No dose adjustment necessary
+
didanosine levels
ZDV-Zidovudine
56
Drug Significance
Didanosine (ddI) Loperamide Didanosine AUC: no significant No dose adjustment necessary
+
change; Cmax: decreased 23%.
Didanosine (ddI) Ketoconazole Decreased ketoconazole Administer ddI tablets/
absorption due to decreased suspension at least 2 hours
gastric acidity resulting from apart
antacid buffer contained within -
didanosine tablets/suspension.
Possibly decreased didanosine
effects.
Didanosine (ddI) Ganciclovir Decreased oral ganciclovir Administer didanosine tablets/
(21%) absorption due to suspension at least 2 hours
decreased gastric acidity apart of oral ganciclovir
resulting from antacid buffer - administration
contained within didanosine
tablets/suspension. Didanosine
AUC: increased 111%.
Emtricitabine Indinavir No significant change to either No dose adjustment necessary

drug +
Emtricitabine Stavudine No significant change to either No dose adjustment necessary

drug +
Emtricitabine Tenofovir No significant change to either No dose adjustment necessary

drug +
Emtricitabine Zidovudine No significant change to either No dose adjustment necessary

drug +
ZDV-Zidovudine
57
Drug Significance
Lamivudine Abacavir Delayed lamivudine No dose adjustment necessary
absorption. Lamivudine
+
Cmax: decreased 35%; AUC:
decreased 15%
Lamivudine Amprenavir No significant change to either No dose adjustment necessary
+
drug
Lamivudine Atazanavir No significant change No dose adjustment necessary
on lamivudine. Effect on +
atazanavir not studied.
Lamivudine Efavirenz No significant change on No dose adjustment necessary
lamivudine. Effect on efavirenz +
not studied.
Lamivudine Cotrimoxazole Lamivudine AUC: increased No dose adjustment necessary
44%. Increased lamivudine +
effects
Lamivudine Methadone No significant effect on No dose adjustment necessary
methadone. Effect on +
lamivudine not studied
Stavudine Zidovudine Intracellular activation of Avoid concurrent use
x
stavudine is inhibited.
Stavudine Didanosine Concurrent use increases risk Avoid concurrent use
x
of neuropathy
Stavudine Ethambutol Concurrent use increases risk Avoid concurrent use
x
of neuropathy
Stavudine Ethionamide Concurrent use increases risk Avoid concurrent use
x
of neuropathy
Stavudine Isoniazid Concurrent use increases risk Avoid concurrent use
x
of neuropathy
Stavudine Dapsone Concurrent use increases risk Avoid concurrent use
x
of neuropathy
ZDV-Zidovudine
58
Drug Significance
Stavudine Zalcitabine Concurrent use increases risk Avoid concurrent use
x
of neuropathy
Tenofovir Atazanavir Tenofovir AUC: increased Co-administer atazanavir/
37%; Cmax: increased 34%; ritonavir together with
Minimum concerntration - tenofovir
(Cmin): increased 29%;
Increased tenofovir effects
Tenofovir Rifampin No significant change to either No dose adjustment necessary
+
drug
Tenofovir Stavudine No significant change to either No dose adjustment necessary
+
drug
Tenofovir Methadone No significant change to either No dose adjustment necessary
+
drug
Tenofovir Nevirapine Potential early virologic failure Use caution when co-
administering tenofovir,
- didanosine and either efavirenz
or nevirapine in treatment
naive patients
Zidovudine Stavudine The thymidine analogues Avoid concurrent use
both compete for the same
phosphorylation sites in the x
growing chain of HIV DNA
Zidovudine Fluconazole Zidovudine AUC: increased by No dose adjustment necessary

74%; Half-life: increased by
+
128%. Increased zidovudine
effects.
Zidovudine Rifampicin Avoid if possible; may consider No dose adjustment necessary
saquinavir 400 mg BID with +
ritonavir 400 mg BID
ZDV-Zidovudine
59
Drug Significance
Zidovudine Phenytoin Zidovudine clearance: No dose adjustment necessary
+
decreased by 30%
Zidovudine Clarithromycin Zidovudine Cmax: increased No dose adjustment necessary
by 50%; AUC: no significant +
change
Zidovudine/ Stavudine The thymidine analogues Avoid concurrent use
Lamivudine both compete for the same
phosphorylation sites in the x
growing chain of HIV DNA
Zidovudine/ Valproic acid Zidovudine AUC: increased Monitor and adjust dose as
Lamivudine 19.5%; Cmax: increased by required
-
effects
Zidovudine/ Ganciclovir Zidovudine AUC: increased by Monitor and adjust dose as
Lamivudine 19.5%; Cmax: increased by required
-
effects
Zidovudine/ Cotrimoxazole Lamivudine AUC: increased by No dose adjustment necessary
Lamivudine 44%. Increased lamivudine +
effects
ZDV-Zidovudine
60
Table 3.2. Non-Nucleoside Reverse Transcriptase Inhibitors.
Clinical
ARV Drug Interacting Drug Effect of Interaction Management
Significance
Efavirenz Midazolam and In vitro studies suggest that Caution required.
triazolam derivatives efavirenz is a potent inhibiter of Monitor patients
CYP3A4.There is a potential for for side effects of
increased drug concentrations of - midazolam
these medications and associated
toxicity.
Efavirenz Clarithromycin Concurrent use causes the Avoid concurrent use

clarithromycin AUC and Cmax to of the two drugs.
be decreased by 39% and 26% Clinicians may consider
respectively using azithromycin
x
instead, as CYP450
drug interactions are
unlikely with this
medication
Efavirenz Methadone Efavirenz is a CYP3A4 inducer When using the two
therefore leading to reduced drugs concurrently
methadone levels as methadone monitor the patients for
is metabolized by the same signs and symptoms of
isoenzyme. Effects are seen after - methadone withdrawal.
about one to two weeks or longer. Any change in ART
regimens should
be reported to the
providers
ZDV-Zidovudine
61
Clinical
Significance
Efavirenz Rifampicin Concurrent use of efavirenz Consult with experts
with rifampicin has been shown before considering
to reduce the AUC and CMax the options below.
of efavirenz by 26% and 20% Increase efavirenz
respectively. dosage to 800mg daily.
Substitute rifampicin
- with rifabutin. Current
guidelines suggest
that rifabutin dose be
increased to 450mg
daily and the efavirenz
should remain 600mg
once daily
Efavirenz Phenytoin Phenytoin induces the CYP450 Concurrent use of the
system, blood drug levels of - two drugs should be
efavirenz maybe reduced. avoided if possible
Efavirenz Phenobarbital Induces the CYP450 system. Concurrent use of the
Reduced drug levels of efavirenz - two drugs should be
avoided if possible
Efavirenz Amprenavir The amprenavir and the efavirenz Standard dose for
have an antagonistic effect on the efavirenz. Increase
CYP3A4 system. Reduced doses of - amprenavir dosage to
the amprenavir occur 1,200mg three times
daily
Efavirenz lopinavir The lopinavir and efavirenz have Consult experts before
an antagonistic effect on the considering the options
CYP3A4 system. The lopinavir below: Standard dose
levels may be reduced - for efavirenz. Increase
lopinavir dose to
533mg/133mg (four
capsules) twice daily
ZDV-Zidovudine
62
Clinical
Significance
Efavirenz Ritonavir The ritonavir and efavirenz have Consult experts before
an antagonistic effect on the considering the options
CYP3A4 system. The ritonavir below: Standard dose
levels may be reduced - for efavirenz. Increase
ritonavir dose to
533mg/133mg (four
capsules) twice daily
Efavirenz Antacids No significant effects No dosage adjustment
+
is necessary
Efavirenz Carbamazepine Not studied. Induction of CYP450 Avoid concurrent use.
and CYP3A4 by both drugs may Consider alternative
lead to decreased efavirenz agents. Monitor
-
carbamazepine levels
and adjust dosage
accordingly
Efavirenz Ergotamine Inhibition of CYP450 3A4 by Do not co-administer
efavirenz would result in increased x
ergotamine effects (e.g., ergotism)
Efavirenz Fluconazole Inhibition of CYP450 3A4 by No dose adjustment
fluconazole. Efavirenz AUC: necessary
increased 16%; Cmax: no +
significant change
Efavirenz Itraconazole Induction of CYP450 3A4 by Do not co-administer

efavirenz results in decreased x
itraconazole effects
Efavirenz Lorazepam Lorazepam AUC: no significant No dose adjustment
+
change; Cmax: increased 16% necessary
ZDV-Zidovudine
63
Clinical
Significance
Efavirenz Phenobarbital Induction of CYP450 3A4 by Avoid combination
phenobarbital results in decreased if possible; consider
efavirenz effects alternative agents;
monitor phenobarbital
- levels and adjust
dosage accordingly.
Suggested alternatives:
gabapentin,
lamotrigine, topiramate
Efavirenz St John’s Wort Induction of CYP450 3A4 by St. Do not co-administer
John's Wort results in decreased x
efavirenz effects
Efavirenz Warfarin Possible inhibition or induction of Monitor INR or PT
CYP450 by efavirenz resulting in and adjust warfarin’s
increased or decreased warfarin - dosage accordingly
effects (altered INR, increased risk
of bleeding or clotting)
Efavirenz Phenytoin Induction of CYP450 3A4 by both Avoid combination

drugs. Decreased efavirenz and if possible; consider
phenytoin effects. alternative agents;
monitor phenytoin
x levels and adjust as
indicated. Suggested
drug substitutes
are: gabapentin,
lamotrigine, topiramate
Efavirenz Ketoconazole Induction of CYP450 3A4 by Avoid concomitant
efavirenz. Decreased ketoconazole x administration
effects
Efavirenz Azithromycin Azithromycin AUC: no significant No dose adjustment
+
change; Cmax: increased 22%. necessary
ZDV-Zidovudine
64
Clinical
Significance
Efavirenz Clarithromycin Inhibition of CYP450 3A4 by Dose adjustment not
efavirenz. Clarithromycin AUC: established
decreased 39%; Cmax: decreased
-
26%; 14-hydroxy clarithromycin
AUC: increased 34%; Cmax:
increased 49%
Efavirenz Ethinyl Oestradiol Ethinyl estradiol AUC: increased No dose adjustment
+
37%; Cmax: no significant change. necessary
Nevirapine Methadone NVP is a CYP3A4 inducer When using the two
(NVP) therefore leading to reduced drugs concurrently
methadone levels as methadone monitor the patients for
is metabolized by the same signs and symptoms of
isoenzyme. Effects are seen after - methadone withdrawal.
about one to two weeks or longer An increase in
methadone levels may
be necessary after the
addition of NVP
Nevirapine Oral contraceptives Contraceptive failure may occur Use an alternative birth
(NVP) due to induction of CYP3A4 by NVP control method
which increases metabolism of the -
oral contraceptive
Nevirapine Rifampicin Rifampicin and rifabutin are potent Inpatients taking anti-
(NVP) CYP3A4 inducers which reduce NVP mycobacterial therapy
trough levels by 37% and 16% substitute rifampicin
-
respectively with rifabutin to
minimize reduction in
NVP drug levels
Phenytoin induces the CYP450 Concurrent use of the
Nevirapine
Phenytoin system. Reduced drug levels of x medication should be
(NVP)
NVP may occur avoided if possible
ZDV-Zidovudine
65
Clinical
Significance
Carbamazepine induces the Concurrent use of the
Nevirapine
Carbamazepine CYP450 system. Reduced drug x medication should be
(NVP)
levels of NVP may occur avoided if possible
Concurrent use of the
Nevirapine Induces the CYP450 system.
Phenobarbital x medication should be
(NVP) Reduced drug levels of NVP
avoided if possible
Consult experts before
considering the options
The indinavir and NVP have an below:
Nevirapine
Indinavir antagonistic effect on the CYP3A4 -
(NVP) Increase indinavir
system
dosage to 1000mg
every eight hours
The amprenavir and NVP have an
Standard dose for NVP;
Nevirapine antagonistic effect on affect the
Amprenavir - Increase amprenavir
(NVP) CYP3A4 system. Amprenavir's
dosage to 1,200mg TID
levels may be reduced
Dosages have not yet
Nevirapine Probable drug interactions may
Atazanavir - been established with
(NVP) occur although no data is available
NVP
Nevirapine Induction of CYP450 3A4 by St. Avoid concurrent
Sir John’s Wort x
(NVP) John's Wort administration
Possibly decreased warfarin effects Monitor INR or PT
Nevirapine
Warfarin (e.g., altered INR, increased risk - and adjust warfarin’s
(NVP)
of clotting) dosage accordingly
Induction of CYP450 3A4 by

nevirapine. Ketoconazole AUC:
Nevirapine Avoid concurrent
Ketoconazole decreased 63%; Cmax: decreased x
(NVP) administration
40%. Decreased ketoconazole
effects
ZDV-Zidovudine
66
Clinical
Significance
Nevirapine Inhibition of CYP450 3A4 by No dose adjustment
Cimetidine +
(NVP) cimetidine. necessary
NVP Cmin: no significant change.

Clarithromycin AUC: decreased
Nevirapine No dose adjustment
Clarithromycin 29%; Cmax: decreased 20%; +
(NVP) necessary
Cmin: decreased 46%; 14-hydroxy
clarithromycin AUC: increased 27%
Induction of CYP450 3A4 by NVP.

Ethinyl estradiol: AUC decreased Avoid co-administration;
Nevirapine 23%; half-life: decreased 44%; additional contraceptive
Ethinyl estradiol x
(NVP) Norethindrone: AUC decreased measures may be
18%; half-life: decreased 15%. needed
Possible contraceptive failur
ZDV-Zidovudine
67
Clinical
Significance
Atazanavir Clarithromycin Clarithromycin AUC: increased Reduce clarithromycin
94%; Cmax: increased dose by 50%
50%; Cmin: decreased 62%;
14-hydroxyclarithromycin
-
AUC: decreased 70%; Cmax:
decreased 72%; Cmin: increased
164% Increased clarithromycin
effects
Atazanavir Rifabutin Atazanavir AUC: increased Reduce rifabutin dose to
191%; Cmax: increased 81%. - 150 mg QOD or 3x/week
Increased atazanavir effects
Atazanavir Fluconazole No significant change No dose adjustment
+
necessary
Atazanavir Ketoconazole No significant change No dose adjustment
+
necessary
Indinavir Itraconazole Indinavir AUC: similar to AUC of Decrease indinavir to
800 mg Q8H alone. - 600 mg Q8H
Increased indinavir effects
Indinavir Ketoconazole Indinavir AUC: increased 68%. May consider decreasing
-
Increased indinavir effects indinavir to 600 mg Q8H
Indinavir Amlodipine Increased amlodipine effects Use lower starting dose
-
(e.g., hypotension, heart block) and titrate to effect
Indinavir Rifampin Decreased indinavir and Do not co-administer
x
ritonavir effects
Fosamprenavir Efavirenz No significant effects No dose adjustment
+
necessary
Fosamprenavir Paroxetine Decreased paroxetine effects Titrate paroxetine to
-
effect
Nelfinavir Omeprazole Decreased nelfinavir effects x Do not co-administer
ZDV-Zidovudine
68
Clinical
Significance
Nelfinavir Rifapentine Decreased nelfinavir effects x Do not co-administer
Ritonavir / Efavirenz Efavirenz is a potent inducer of Consult experts before
Lopinavir the CYP3A4 system. Significant considering the following
reductions in ritonavir levels option. Ritonavir/
may occur when using these two - lopinavir dosage may
drugs concurrently. The AUC is need to be increased
reduced by about 15%.
Ritonavir / Nevirapine NVP is a potent inducer of the Consult experts before

Lopinavir CYP3A4 system. Significant considering the following
reductions in ritonavir levels option. Ritonavir /
may occur when using these two - lopinavir dosage need to
drugs concurrently. The AUC is be increased
reduced by about 33%
Ritonavir Alprazolam , Ritonavir inhibits the CYP3A4 Avoid concurrent use.

midazolam, system that metabolises the Substitute with zolpidem,
triazolam benzodiazepams. Potential for x oxazepam, temazepam
prolonged or increased sedation or lorazepam
or respiratory depression
Ritonavir Simvastatin, Ritonavir inhibits the CYP3A4 Use pravastatin or

lovastatin, high dose enzymes responsible for the fluvastatin instead as
atorvastatin extensive metabolism of the they have minimal effects
statins. Statins’ levels are on CYP450
-
markedly increased. Risk
of toxicity is increased (i.e.,
myopathy, renal failure and
even death)
ZDV-Zidovudine
69
Clinical
Significance
Ritonavir Rifampicin Rifampicin is a potent inducer of Consider rifabutin as an
CYP3A4, leading to significant alternative
reductions in PI levels potentially
leading to virologic failure or -
resistance. May use with full
dose ritonavir
Ritonavir Carbamazepine Reduction in ritonavir and Avoid concurrent

increase in carbamazepine use. Consider
blood levels alternative agents for
carbamazepine. Monitor
- carbamazepine levels
and adjust dosage
accordingly
Ritonavir Cotrimoxazole Induction of CYP450 3A4 by No dose adjustment

ritonavir. Sulfamethoxazole necessary
AUC: decreased 20%; +
trimethoprim AUC: increased
20%
Ritonavir Digoxin Increased digoxin effects Monitor digoxin
concentrations closely
- and adjust dosage
accordingly
Ritonavir Ergotamine Increased ergotamine effects Do not use concurrently.

x Replace with 5-HT
agonists ("triptans")
ZDV-Zidovudine
70
Clinical
Significance
Ritonavir Fluconazole Inhibition of CYP450 3A4 by No dose adjustment
fluconazole. Ritonavir Inhibition necessary
of CYP450 3A4 by fluconazole +
Ritonavir Itraconazole Inhibition of CYP450 3A4 Dose adjustment not

by itraconazole resulting in - established, consult
increased ritonavir effects experts
Ritonavir Metronidazole Disulfiram-like reaction (e.g., Avoid concurrent use
headache, hypotension,
flushing, vomiting) as a reaction x
with alcohol in the ritonavir oral
solution
Ritonavir Phenobarbital Induction of CYP450 3A4 by Avoid combination
phenobarbital resulting in if possible; consider
decreased ritonavir effects alternative agents;
- levels and adjust
accordingly. Possible
substitutes are
gabapentin, lamotrigine,
topiramate
Ritonavir Sir John’s Wort Induction of CYP450 3A4 by Avoid concurrent use
St. John's Wort resulting in x
decreased ritonavir effects
Ritonavir Warfarin Possible inhibition of CYP450 Monitor INR or PT and
3A4, 2C9 and 1A2 by ritonavir. adjust warfarin’s dosage
Resulting in decreased warfarin - accordingly
effects (e.g., decreased INR,
increased risk of clotting)
ZDV-Zidovudine
71
Clinical
Significance
Ritonavir Sildenafil Inhibition of CYP450 3A4 by Consult with experts and
ritonavir resulting in Sildenafil initiate therapy at 25 mg
increased blood levels and dose; do not exceed 25
effects such as hypotension, - mg in 48 hour period.
priapism.
Ritonavir Phenytoin Increased phenytoin blood levels Avoid concurrent use;

and effects. consider alternative
agents such as
gabapentin, lamotrigine,
x
topiramate. Monitor
phenytoin levels and
adjust its dosage
accordingly
Ritonavir Nifedipine Inhibition of CYP450 3A4 by Monitor and adjust
ritonavir. Increased nifedipine nifedipine dosage
effects (e.g., hypotension, - accordingly
cardiac arrhythmias)
Ritonavir Fluoxetine Inhibition of CYP450 2D6 by No dose adjustment

both drugs. AUC: increased 19%; necessary
Cmax: no significant change.
+
Increased ritonavir effects;
possibly increased fluoxetine
effects
Ritonavir Theophylline Possible induction of CYP450 Monitor and adjust
1A2 by ritonavir. Theophylline theophylline as indicated
AUC: decreased 43%; Cmax: -
decreased 32%; Cmin: decreased
57%; half-life: decreased 57%
ZDV-Zidovudine
72
Clinical
Significance
Ritonavir Amitriptylline Inhibition of CYP450 3A4 and Monitor and adjust
2D6 by ritonavir. Increased amitriptyline dosage
amitriptyline effects (e.g., accordingly
-
dry mouth, hypotension,
and confusion). Increased
amitriptyline levels.
Ritonavir Clarithromycin Inhibition of CYP450 3A4 by No dose adjustment
ritonavir. Clarithromycin AUC: necessary
increased 77%; Cmax: increased +
31%; Cmin: increased 182%.
Increased clarithromycin effects
Saquinavir Simvastatin, Saquinavir inhibits the CYP3A4 Select pravastatin or

lovastatin, high dose enzymes responsible for the fluvastatin as they have
atorvastatin extensive metabolism of the minimal effects on
statins. Statins’ levels are CYP450 or use low dose
-
markedly increased. Risk of artovastatin with close
of toxicity is increased (i.e., follow-up for potential
myopathy, renal failure and hepatotoxicity
even death)
Saquinavir Alprazolam , Saquinavir inhibits the CYP3A4 Avoid concurrent use.
midazolam, system that metabolises the Consider substitution with
triazolam benzodiazepams. There is a zolpidem, oxazepam,
potential for prolonged or temazepam or lorazepam
x
increased sedation or respiratory
depression. It is the least
potent protease inhibitor on the
CYP3A4 isoenzyme
ZDV-Zidovudine
73
Clinical
Significance
Saquinavir Rifampicin Rifampicin is a potent inducer Consider rifabutin as
of CYP3A4 and CYP450, leading an alternative. Avoid if
to significant reductions in possible; may consider
saquinavir levels potentially x saquinavir 400 mg BID
leading to virologic failure or with ritonavir 400 mg
resistance. AUC: decreased 84%; BID
Cmax: decreased 79%
Saquinavir Garlic Garlic induces the CYP3A4 Avoid concurrent use

enzymes resulting in significant particularly when
decrease in saquinavir levels. x saquinavir is the sole PI
Potential virologic failure or in the regimen
resistance
Saquinavir Carbamazepine Induction of CYP450 and Avoid concurrent use;

CYP3A4 by carbamazepine may consider alternative
reduce saquinavir levels agents; monitor
- carbamazepine levels
and adjust dosage
accordingly
Saquinavir Fluconazole Inhibition of CYP450 3A4 by Dosage adjustments

fluconazole. Saquinavir AUC: necessary
increased 50%; Cmax: increased -
56%
Saquinavir Itraconazole Inhibition of CYP450 3A4 by No dose adjustment

+
itraconazole necessary
ZDV-Zidovudine
74
Clinical
Significance
Saquinavir Phenobarbital Induction of CYP450 3A4 by Avoid combination
phenobarbital. May decrease if possible; consider
saquinavir effects alternative agents;
x
levels and adjust dosage
accordingly. Suggested
alternatives are
gabapentin, lamotrigine
Saquinavir Sir John’s Wort Possible induction of CYP450 Avoid concurrent use
3A4 by St John's Wort resulting x
in decreased saquinavir effects
Saquinavir Warfarin Possible inhibition of CYP450 by Monitor INR or PT and
saquinavir. Increased warfarin adjust warfarin as
effects (e.g., increased INR and - indicated
risk of bleeding)
Saquinavir Sildenafil Inhibition of CYP450 3A4 Initiate sildenafil at

by saquinavir. Sildenafil 25 mg daily; adjust
AUC: increased 200-1100%. dose as indicated; not
-
Increased sildenafil effects (e.g., recommended to exceed
headache, flushing, priapism) 25 mg in a 48 hour
period
Saquinavir Ranitidine Inhibition of CYP450 3A4 by No dose adjustment
ranitidine. Saquinavir AUC: necessary
increased 67%; Cmax: increased +
74%
ZDV-Zidovudine
75
Clinical
Significance
Saquinavir Phenytoin Induction of CYP450 3A4 Avoid combination
by phenytoin. May decrease if possible; consider
saquinavir levels alternative agents;
monitor phenytoin levels
x and adjust as indicated.
Suggested alternative
agent are gabapentin,
lamotrigine, tiagabine,
Topiramate
Saquinavir Ketoconazole Inhibition of CYP450 3A4 Dose adjustment not
by ketoconazole. Increased - established
saquinavir effects
Saquinavir Grape-fruit Juice Inhibition of gastrointestinal Separate grapefruit
CYP450 3A4 by grapefruit juice. juice from saquinavir
Saquinavir AUC: increased 50%; - administration by at least
increased saquinavir effects 2 hours
Saquinavir Clarithromycin Inhibition of CYP450 3A4 by Dose adjustment not

clarithromycin. Clarithromycin - established
AUC: increased by 45%
Saquinavir Dexamethasone Possible induction of CYP450 No dose adjustment
3A4 by dexamethasone. May + necessary
decrease saquinavir levels
Saquinavir Erythromycin Inhibition of CYP450 3A4 Dose adjustment not
by erythromycin. Increased - established
saquinavir effects
ZDV-Zidovudine
76
SECTION C
The Role of Laboratory Services in
Preventing and Managing Side Effects
77
Introduction
Prior to the commencement of ARVs, certain laboratory parameters are recommended
at baseline, and subsequently at the prescribed follow-up visits. Laboratory support in
patient follow-up visits is pivotal in monitoring ART toxicity and/or clinically relevant
laboratory anomalies, which will assist the clinicians in the overall management of
the patient. Thus, through laboratory analysis, any suspicion of toxicity, adverse drug
reactions, and other side effect can be specifically identified and accurately linked to
the underlining cause. This also allows adequate and timely tracking of intervention
measures. Such timely interventions lead to maximum use of limited resources, better
management of the patient, and overall, ensure a better quality of life.
In monitoring of ARV drug toxicity or pharmacovigilance, the laboratory should:
• Liaise with management and other technical staff when developing a
pharmacovigilance strategy,
• Ensure that the testing methods and instruments are optimal,
• Provide timely reliable baseline test results before the commencement of ARV,
• Provide timely reliable follow-up test results on request,
• Provide timely warning on abnormal test results and deviations,
• Confirm suspicion based on analysis,
• Assist in result interpretation and utilization thereof,
• Instill quality particularly in laboratory process and other medical analytical
processes,
• Play a leadership role in the introduction and training in the use point of care testing
options to monitor drug toxicity, and
• Occupy a permanent seat in the ARV pharmacovigilance team.
The table on page 83 shows some clinically relevant laboratory anomalies (i.e., adverse
events) associated with ART that must be monitored periodically as indicated.
78
79
Clinically Relevant Laboratory Anomalies (Adverse Events) Associated with ART
Abnormal
Indication
Values that
for Lab Test/ Common ARVs Routine Monitoring
Test Parameter Normal Value Trigger Change
Clinical Implicated Frequency
in ART
Manifestation
Management
Baseline, then monthly for
Hemoglobin level 10.5 -18.0 g/dl <6.5 g/dL Anaemia AZT, d4T 3 months, at 6 months,
6-monthly

NVP, ABC, AZT, ddI,
Neutrophil count 2.0 – 7.5 x109/L <0.5 x 109 /L Neutropenia 3 months, at 6 months,
dT4, 3TC
Hematology Complete 6-monthly
blood
count (CBC) Mostly by drugs for OIs,
HIV Disease process but
Platelets count 100 – 450 x 109/L <29 x 109/L Thrombocytopenia 3 months, at 6 months,
not clear if some ARVs are
6-monthly
implicated.
Leukocytes count 4.0 – 11.0 109/l <1.0 x 109/L Leukopenia AZT, ddI 3 months, at 6 months,
6-monthly
ALT Alanine Baseline then monthly for 3

LPV, RTV, ABC, ddI,
aminotransferase 5.0 – 50U/L >5 x normal value Hepatotoxicity months then at 6 months then
d4T, 3TC
serum triaminase 6-monthly
Liver panel
Baseline then monthly for 3
AST Aspartate LPV, RTV, ABC, ddI,
5.0 – 38U/L >5 x normal value Hepatotoxicity months then at 6 months then
aminotransferase d4T, 3TC
6-monthly
Abnormal
Indication
Values that
in ART
Manifestation
Management
Baseline then monthly for 3

Alkaline
40-130U/L >5 x normal value Hepatotoxicity RTV, ddI months then at 6 months then
Phosphatase
6-monthly
Liver panel
« Baseline then monthly for 3
Bilirubin 0-1.3 mg/dl >2.5 x normal value Hyperbilirubinaemia RTV, NVP, ddI, d4T, 3TC months then at 6 months then
6-monthly
Baseline, then monthly for 3

Kidney panel Serum creatinine 80-115 umol/L >3 x normal value Nephrotoxicity RTV, ddI
months, 6 months, 6 monthly
Baseline,6 months and

Lipid panel Fasting Triglycerides 0.5 – 1.5mmol/L >13.56 mmol/L Hypertriglyceridaemia LPV, RTV
thereafter every 12 months
Baseline, 6 months and

Lipid panel Fasting Cholesterol 3.0 – 4.8mmol/L >13.56 mmol/L Hypercholesterolemia LPV, RTV, EFV
thereafter every 12 months
80
81
Abnormal
Indication
Values that
in ART
Manifestation
Management
<39mg/ml or >251 Baseline, 6 months and

Fasting Glucose 4-6mmol/l Hyperglycemia ABC, LPV, ddI
mg/ml thereafter every 12 months
Serum /Pancreatic Baseline, 3 months and

Chemistry 28-100U/L 4 x upper normal limit Pancreatitis ddI, dT4
amylase thereafter every 12 months
Indicated based on clinical

Serum lactate <2mmol/l >5mmol/l Lactic acidosis NRTIs (3TC,TDF, ABC)
signs
d4T = Stavudine 3TC = Lamivudine EFV = Efivarenz
NVP = Nevirapine AZT = Zidovudine TDF = Tenofovir
ddI = Didanosine RTV = Ritonavir LPV = Lopinavir
ABC = Abacavir Ab = Antibodie
When indicated in bold, the drug has been shown to have effect in above 5% of people in clinical trials. When indicated
in ordinary character, the drug has been shown to have effect in less thane 5% of people in clinical trials.
South African National Antiretroviral Treatment Guidelines 2009
HIV/AIDS, Antiretroviral 2003 Newsletter. Issue No. 10. WHO Regional Office for the Western Pacific.
82
SECTION D
Drug Information for ARVs
Registered in South Africa
83
TABLE 5. ARVS REGISTERED IN SOUTH AFRICA
ABACAVIR (ABC)
300 mg tablets
20 mg/ml oral solution
Dosage and Directions Adults:
300 mg twice daily or 600 mg once daily
Children:
(3 months to 16 years) 8 mg/kg bid max 300 mg twice daily
1-3 months (investigational) - 8 mg/kg q12h
Hepatic Dose Adjustments:
Child-Pugh Score 5-6: 200 mg twice daily
Child-Pugh Score 7-12: Not recommended by manufacturer
Contraindicated with moderate to severe impairment
Oral Bioavailability 83%
Serum Half-life 1.5 hours
Intracellular Half-life 21 hours
Route of Metabolism • Metabolized by alcohol dehydrogenase and glucuronyl transferase
• Renal excretion of metabolites 82%
Pregnancy and Lactation Contraindicated in pregnancy and lactation
(FDA Pregnancy Category C)
Common Drug Interactions Absolute Contraindications: Hypersensitivity to abacavir
As part of the ARV regimen: tenofovir + lamivudine
Drugs that may be co-administered under supervision:
methadone, retinoid compounds
Natural/Traditional/ Insufficient data available
Homeopathic Medicines
Drug-Food Interactions • May be taken with or without food.
• Alcohol increases ABC levels by 41%.
Adverse Effects Serious: Lactic acidosis, hepatic steatosis, pancreatitis, hypersensitivity reaction
Signs and symptoms of this hypersensitivity reaction include: high fever, diffuse
skin rash, GI intolerance, fatigue or malaise, nausea, vomiting, myalgia,
respiratory distress, lactic acidosis, hepatomegaly, diarrhea, loss of appetite.
Abacavir should never be restarted following hypersensitivity reaction.
Storage • Store the tablets and oral solution between 20ºC and 25 ºC
• Avoid freezing the oral solution
84
Other Drug Information • Abacavir should not be restarted after a hypersensitivity reaction as it will
lead to life threatening hypotension and death possibly within hours.
• No clinically significant interaction between abacavir, lamivudine, and
zidovudine
DIDANOSINE (ddI)
250 mg EC capsules, 400 mg EC capsules
25 mg / 50 mg/ 100 mg /150 mg buffered tablets
2 g/100 ml pediatric powder
EC Capsules:
>60 kg: 400 mg qd
<60 kg: 250 mg qd
Children:
(2 weeks – 8 months): 100 mg/m2/dose po bid
8 months and older: 120 mg/m2 twice daily
Renal Dose Adjustments:
≥ 60 kg:
CrCl 30-59: (EC) 200 mg qid
CrCl < 10: (EC) 125 mg qid
< 60 kg:
CrCl < 10: Formulation not suitable
Oral Bioavailability 30-40%
Serum Half-life 1.6 hours
Intracellular Half-life 25-40 hours
Route of Metabolism • Metabolism of ddI in man has not been evaluated
• Renal excretion 50%
Pregnancy and Lactation • Safety in pregnant women not established
• Contraindicated in lactating women (FDA Pregnancy Category B)
Common Drug Interactions Absolute contraindication: Hypersensitivity to ddI
Drugs to avoid:
Stavudine
Tenofovir + Lamivudine
Tenofovir + Delavirdine
Tenofovir + Efavirenz
Tenofovir + Nevirapine
Zalcitabine
85
Common Drug Interactions Drugs that may be co-administered under supervision:
• Itraconazole and ketoconazole should be taken 2 hours before buffered
ddI or enteric coated ddI should be used.
• ddI should be taken 2 hours after or 6 hours before fluoroquinolones
• Other drugs requiring close monitoring include: allopurinol, ganciclovir,
methadone, delavirdine, darunavir, tenofovir and atazanavir.
Drug-Food Interactions • Take on an empty stomach at least 2 hours after, and 1 hour before a
meal
• Avoid alcohol as it will increase the risk of pancreatatis.
Adverse Effects Serious: Lactic acidosis, hepatomegaly with steatosis, hepatotoxicity (clinical
hepatitis or asymptomatic serum transaminase elevation), pancreatitis, cases of
Steven-Johnson Syndrome and toxic epidermal necrosis
Other: Rash, lipodystrophy, shivering, GI intolerance, asthenia, headache,
fever, optic neuritis, retinal disorder, peripheral neuropathy
Storage Store under controlled room temperature
Other Drug Information • Not to be used with stavudine during pregnancy due to increased risk of
lactic acidosis
• Fatal lactic acidosis has been reported among pregnant women who
received a combination of ddI and stavudine with other antiretroviral
combinations
• Didanosine should be withheld if pancreatitis is suspected and
discontinued if pancreatitis is confirmed
• Didanosine and stavudine combination should only be used during
pregnancy if the potential benefit clearly outweighs the potential risks
EFAVIRENZ
50 mg capsules, 100 mg capsules, 200 mg capsules, 600 mg tablets
600 mg once daily at night
Children:
Use in pediatric patients less than 3 years of age has not been studied
Hepatic/Renal Dose Adjustments: Not recommended for hepatic
impairment
Renal: Dosage adjustment for renal insufficiency does not appear necessary
Oral Bioavailability Data not available
Serum Half-life 40-55 hours
86
Route of Metabolism Metabolized by cytochrome P450 (3A4 mixed inducer/inhibitor), 14%-34%
excreted in urine (glucuronidated metabolites, <1% unchanged), 16%-61% in
feces
Pregnancy and Lactation Animal studies have shown teratogenesis and it is not recommended in lactating
mothers (FDA Pregnancy Category C)
Common Drug Interactions Absolute Contraindications: Hypersensitivity to efavirenz
As Part of the ARV Regimen:
• Atazanavir (for therapy-experienced patients)
• Fosamprenavir without ritonavir
Drugs that may be co-administered under supervision: midazolam,
methadone, rifampin, rifabutin, diltiazem, ethinyl estradiol
Natural/Traditional/ • St John’s Wort is an absolute contraindication
Homeopathic Medicines • Avoid garlic supplements
Drug-Food Interactions Take on an empty stomach. Avoid high fat foods
Adverse Effects Serious: Stevens-Johnson Syndrome, toxic epidermal necrosis, skin rash,
hepatotoxicity (clinical hepatitis or asymptomatic serum transaminase
elevation), aggressive behavior, delusion of persecution, manic behavior,
mental disorder, seizure, suicidal thoughts
Other: dizziness, insomnia, somnolence, depression, paresthesia, headache

Storage Store the capsules in an air tight container under controlled room temperature.
Other Drug Information • Monitor Liver Function Tests (LFTs) and lipids
• Not be used as a single agent to treat HIV or added on as a sole agent to
a failing regimen
• CNS effects are common but severity usually decreases within two weeks.
Effects may be decreased by giving the drug at bed-time
FOSAMPRENAVIR
700 mg tablets, 50 mg/ml oral suspension
Single PI (unboosted): 1,400 mg BID
Fosamprenavir 700 mg BID + ritonavir 100 mg BID (for treatment experienced

patients)
Fosamprenavir 1,400 mg QD + ritonavir 200 mg QD
Fosamprenavir 1,400 mg QD + ritonavir 100 mg QD
87
Dosage and Directions Children:
Age 2-5 years and treatment naïve: 30 mg/kg BID (oral suspension), not to
exceed 1,400 mg BID
Age ≥6 years, Boosted PI: fosamprenavir 18 mg/kg (oral suspension) BID +

ritonavir 3 mg/kg BID, not to exceed fosamprenavir 700 mg BID + ritonavir
100 mg BID
Wt >39 kg: may give adult dose, using tablet formulation of fosamprenavir
Dosage Adjustment:
• No dose adjustment is necessary in renal insufficiency
• Dose adjustment is necessary in hepatic insufficiency
Oral Bioavailability The absolute oral bioavailability of amprenavir after administration in humans
has not been established
Serum Half-life The plasma elimination half-life of amprenavir is approximately 7.7 hours
Intracellular Half-life Data not available
Route of Metabolism After oral administration, fosamprenavir is rapidly and almost completely
hydrolyzed to amprenavir and inorganic phosphate prior to reaching the
systemic circulation. This occurs in the gut epithelium during absorption.
Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4)
enzyme system
Pregnancy and Lactation Safety in human pregnancy has not been determined
Common Drug Interactions Absolute contraindications: Hypersensitivity to fosamprenavir or
amprenavir, triazolam, dihydroergotamine, ergonovine, ergotamine,
methylergonovine, cisapride, midazolam, pimozide
Amiodarone, bepridil, lidocaine (systemic), quinidine, warfarin, diltiazem,
felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine,
nisoldipine, dexamethasone
Natural/Traditional/ No data available
Drug-Food Interactions Take with or without food
Adverse Effects Serious: Skin rash, Swelling of the face, lips, and tongue (angioedema)
Other: Diarrhea, rash, nausea, vomiting, headache
Storage Tablets should be stored at room temperature in a tightly closed container. Oral
suspension may be stored at room temperature or refrigerated. Refrigeration of
oral suspension may improve taste for some patients. Do not freeze.
88
Other Drug Information Patients should inform their health-care provider if they have a sulfa allergy.
The potential for cross-sensitivity between drugs in the sulfonamide class and
fosamprenavir is unknown.
The health-care provide should instruct patients to shake the bottle of the oral
suspension vigorously before each use. Inform patients that refrigeration of the
oral suspension may improve the taste.
INDINAVIR
200 mg capsules, 400 mg capsules
800 mg orally every 8 hours
Indinavir 800 mg + ritonavir 100-200 mg BID
Children:
The optimum dose has not been established. Warn the doctor to watch out for
nephrolithiasis.
Consider 350-500 mg/m2 every 8 hrs
600 mg indinavir every 8 hrs + delavirdine 400 mg every 8 hrs
Hepatic dose adjustments:
Mild to moderate insufficiency with cirrhosis: 600 mg q8h; no data in severe
hepatic impairment
Hepatic impairment with concomitant delavirdine. dosing:
Oral Bioavailability 65% (on empty stomach)
Serum Half-life 1.5-2 hours
Route of Metabolism P450 cytochrome
3A4 inhibitor and substrate
Common Drug Interactions Absolute Contraindications: Hypersensitivity to indinavir.
As part of the ARV regimen:
Atazanavir (potential for additive increased indirect bilirubin)
Tipranavir/ritonavir
midazolam, carbamazepine, antifungals, sildenafil, atorvastatin, rifabutin,
nevirapine, didanosine
Natural/Traditional/ St John’s Wort and garlic are absolutely contraindicated.
89
Drug-Food Interactions • Take on empty stomach with water one hour before or two hours after
meals
• Drink at least 1.5 l of water daily to reduce the risk of developing renal
side effects
Adverse Effects Serious:
• Nephrolithiasis/urolithiasis/ crystalluria, nephrotoxicity hemolytic
anemia, insulin resistance/diabetes mellitus, hepatotoxicity (clinical
hepatitis or asymptomatic serum transaminase elevation)
• Bleeding episodes are increased in hemophiliac patients
• Cases of Stevens-Johnson Syndrome and toxic epidermal necrosis have
been reported
Other: Cardiovascular effects, abdominal pain, nausea and vomiting, back
pain, hyperbilirubinemia, asthenia, headache, alopecia, dry skin, ingrown
nails, insomnia, dizziness, rash, dislipidemia, hypertriglyceridemia
Storage Store at room temperature in a tightly closed container. Protect from moisture
Other Drug Information: May require increased use of Factor VIII products when used in hemophiliac
patients
LAMIVUDINE
150 mg tablets, 300 mg tablets, 10 mg/ml solution
HIV infection in combination with other agents.
150 mg orally bid or 300mg once daily
Children:
3-16 yrs : 4mg/kg bid Max dose: 150mg bid
Neonates: birth - 30 days 2mg/kg/dose po bid
Renal Dose Adjustments:
CrCl 30-49: 150 mg qd; CrCl 15-29: 150 mg x 1 then 100 mg qd;
CrCl 5-14: 150 mg x 1 then 50 mg qd; CrCl < 5 or Dialysis: 50 mg x 1 then 25

mg qd
Route of Metabolism Metabolism of lamivudine is a minor route of elimination. In man, the only
known metabolite of lamivudine is the trans-sulfoxide metabolite. Renal
excretion
90
Common Drug Interactions Absolute contraindications:
abacavir + tenofovir
tenofovir + didanosine
zalcitabine
Drugs that may be administered under close supervision include emtricitabine
Drug-Food Interactions Give without regard for food
Adverse Effects Serious Adverse Effects: hepatomegaly with steatosis, lactic acidosis,
pancreatitis, especially children; some fatal cases, relapsing type B viral
hepatitis
Other: nausea, dizziness, fatigue or malaise, headache, dry mouth, dreams,
insomnia and other sleep disorders
Storage Store lamivudine oral solution and tablets at controlled room temperature in a
tightly closed container
Other Drug Information Extreme caution should be taken when administering lamivudine to patients
with a history of prior antiretroviral nucleoside exposure, pancreatitis or other
risk factors for developing pancreatitis
NELFINAVIR
625 mg tablets, 50 mg/g oral powder solution
750 mg tid or 1 250 mg bid
Children:
25 to 30 mg/kg/dose bid with food
Hepatic Dose Adjustment: Use with caution as no dosing information is
available
Oral Bioavailability 20-80%
Serum Half-life 3.5-5 hours
3A4 inhibitor (less than ritonavir)
Pregnancy and Lactation Adequate well-controlled studies of pregnant women have not been conducted.
Contraindicated in lactating women (FDA Pregnancy Category B)
91
Common Drug Interaction Absolute contraindication: Hypersensitivity to nelfinavir.
Etravirine
Drugs that may be used concomitantly under close monitoring include:
midazolam, fentanyl, garlic, atorvastatin, azithromycin, sildenafil
Drug-Food Interactions Take with meal or light snack
Adverse Effects Serious: Hepatotoxicity (clinical hepatitis or asymptomatic serum
transaminase elevation), bleeding episodes may increase in hemophiliac
patients
Other: Lipodystrophy, nausea, hyperglycemia/diabetes mellitus, new onset
and exacerbation, raised cholesterol, raised triglycerides, gastrointestinal
discomfort/diarrhea, elevated liver function tests, fatigue, osteonecrosis,
cardiac effects
Storage Store at room temperature after mixing oral solution. Solution stable for up to
6 hours
Other Drug Information If there is trouble swallowing, there is a powder formulation that can be
dissolved in water
Diarrhea is very common and can be managed with antidiarrheals such as
loperamide or diphenoxylate/atropine
NEVIRAPINE
200 mg tablets, 50 mg/5 ml oral suspension
Dosage and Directions Adults: 200 mg once a day for 14 days then 200 mg bid in combination with
other antiretrovirals
Neonatal dose: 5 mg/kg qid for 14 days, then 120mg/m2/dose q12h for
14 days, then 200 mg/m2/dose q12h
Children: ≥ 2 months to < 8 years 4 mg/kg once daily for 14 days, then 7
mg/kg twice daily. Max 400 mg for any patient
8 years and older: 4 mg/kg po qd for 14 days, then 4 mg/kg po bid (max
200mg bid)
Renal:
No dosing adjustment for CrCl ≥ 20 mL/min
Hepatic Dose Adjustment:

Avoid use with moderate to severe hepatic impairment
92
Oral Bioavailability >90%
Route of Metabolism Metabolized by cytochrome P450 (3A4 inducer); 80% excreted in urine
(glucuronidated metabolites, <5% unchanged), 10% in feces
Contraindicated in lactating women. (FDA Pregnancy Category B)
Common Drug Interactions Absolute contraindications: Hypersensitivity to nevirapine.
As part of ARV regimen: atazanavir, other NNRTIs, rifampin, rifapentine,
ketoconazole.
Drugs that may be used concomitantly under close supervision include
cyclophosphamide, fluconazole, itraconazole, amprenavir, atazanavir
Natural/Traditional/ St. John’s Wort and garlic supplements are an absolute contraindication
Drug-Food Interactions Take with or without food
interactions:
Adverse Effects Serious: Skin reaction with or without pruritus, Stevens-Johnson syndrome,
toxic epidermal necrosis, hepatitis, liver failure, life-threatening hepatotoxicity,
rash, abrupt onset of flu-like symptoms (nausea, vomiting, myalgia, fatigue),
abdominal pain, jaundice, or fever with or without skin rash; may progress to
fulminant hepatic failure with encephalopathy
Storage Nevirapine tablets and oral solution should be stored at controlled room
temperature
Other Drug Information: • ***Patients should be monitored closely during first 18 weeks of therapy,
especially the first 6 weeks for Black Box ADRs***
• Mild to moderate rash may be managed by symptomatic treatment with
antihistamine and continuing of offending agent
• Discontinue therapy if skin rash progresses to severe in nature
(accompanied by blisters, fever, mucous membrane involvement) or in
the presence of systemic symptoms.
• Initial dose of 200 mg per day for the first 14days, then 200 mg twice
daily decreases frequency of rash.
• Hepatotoxicity may be life threatening. It is more common at higher CD4
cell counts, in women, and in patients with Hepatitis B or C.
• Nevirapine should not be initiated in women with CD4 >250 cells/µl
or men with CD4 >400 cell/µl, unless the benefit outweighs the risk.
Monitor liver tests closely for the first 16 weeks of treatment for signs of
liver toxicity.
93
RITONAVIR
100 mg capsules, 80mg/ml oral solution
Dosage and Directions Adults: 600 mg bid. Start with 300 mg bid and increase to full dose over 14
days
Note: full dose is rarely used, ritonavir is used at much lower dose to “boost”
the levels of other protease inhibitors
Children: Safety and efficacy not established in children under 18 years
Hepatic Dose Adjustments: No adjustment for mild impairment; no data
for moderate/severe impairment-use with caution
Oral Bioavailability Not determined
Route of Metabolism P450 cytochrome 3A4 substrate (3A4 >2D6; potent 3A4 inhibitor)
Contraindicated in lactating women (FDA Pregnancy Category B)
Common drug Interactions Absolute contraindication: Hypersensitivity to ritonavir, alfuzosin,
amiodarone, astemizole, bepridil, cisapride, ergot derivatives.
alprazolam
Natural/Traditional/ St John’s Wort is an absolute contraindication
Drug-Food Interactions Take with food, high-fat snacks may reduce side effects
Adverse Effects Serious: hepatotoxicity (clinical hepatitis or asymptomatic serum transaminase
elevation), bleeding episodes may increase in hemophiliac patients, skin rash,
pancreatitis, hepatitis
Other: paresthesia, hyperglycemia, new onset/exacerbation of dislipidemia,
fat maldistribution, nausea and vomiting, elevations in liver function enzymes,
asthenia, abdominal pain/diarrhoea, taste perversion, oardiovascular effects,
osteonecrosis
Storage • Store the capsules in the refrigerator between 2 to 8 degrees celsius.
• Solution does not need refrigeration if used within 30 days.
• Avoid exposure to extreme heat. Dispense in the original container
Other Drug Information Shake well before each use. Avoid exposure to excessive heat. Solution
can be mixed with chocolate syrup or ice cream, or Ensure to mask taste.
Coadministration of ritonavir with certain non-sedating antihistamines, sedative
hypnotics, antiarrhythmics, or ergot alkaloids may result in potentially serious
and life-threatening adverse events due to possible effects of ritonavir on
hepatic metabolism of certain drugs.
94
SAQUINAVIR
200 mg hard gelatin capsules, 500 mg tablets
Dosage and Directions Adults: Recommended dosage and directions is 1000 mg of saquinavir to be
taken with 100 mg of ritonavir every 12 hours.
Children: Safety and efficacy in patients younger than 16 years have not been
established
Hepatic: Use with caution; no dosing information available
Oral Bioavailability 4% erratic
3A4 inhibitor and substrate (weak inhibitor)
Pregnancy and Lactation Adequate well controlled studies of pregnant women have not been conducted.
Contraindicated in lactating women.
(FDA Pregnancy Category B)
Common Drug Interactions Absolute Contraindications:
Hypersensitivity to Saquinavir.
Darunavir/ritonavir
amprenavir, atorvastatin, sildenafil, clarithromycin
Natural/Traditional/ St. John’s Wort and garlic supplements are an absolute contraindication
Drug-Food Interactions It is to be taken within 2 hours after food.
Adverse Effects Serious: Hepatotoxicity (clinical hepatitis or asymptomatic serum
transaminase elevation). Bleeding episodes may increase in hemophiliac
patients
Other: Headache, GI intolerance, LFTs, nausea, asthenia, abdominal
pain, ocular effects, hyperlipidemia, hyperglycemia, diabetes mellitus,
hypertriglyceridemia, osteopenia/ osteoporosis
Storage Saquinavir mesylate should be stored at room temperature
Other Drug Information: • Hard gelatin capsules and tablets and soft gelatin capsules are not
bioequivalent and cannot be used interchangeably
• Liver function tests, renal function tests, complete blood counts with
differential and routine blood chemistry (every 2 to 4 weeks)
• Saquinavir is not recommended as a single protease inhibitor, it is to be
used in conjunction with ritonavir
95
STAVUDINE
15 mg capsules, 20 mg capsules, 30 mg capsules, 40 mg capsule,
1 mg/ml powder for oral solution
Dosage and Directions Adults: >60 kg: 40mg bid
<60 kg: 30 mg bid
Children:
< 30kg: 1 mg/kg/dose every 12 hours
Weighing 30 kg or greater: use the recommended adult dosing:

<60kg: 30 mg bid
Renal:
≥ 60 kg:
CrCl 26-50: 20 mg q12h, CrCl 10- 25 or
HD : 20 mg qd
< 60 kg:
CrCl 26-50: 15 mg q12h, CrCl ≤ 25 or HD: 15 mg qd

Serum Half-life 1.0 hour
Intracellular Half-life 3.5 hours
Route of Metabolism This has not been extensively researched. Renal excretion 50%
Common Drug Interactions Absolute Contraindication: Hypersensitivity to stavudine.
Zalcitabine
Zidovudine
Didanosine: Peripheral neuropathy, lactic acidosis, and pancreatitis have been
reported with this combination. Use only if benefits clearly outweigh risks
Drug-Food Interactions Stavudine may be taken without regards for food
96
Adverse Effects Serious: lactic acidosis, hepatomegaly, hepatic steatosis, pancreatitis, rapidly
progressive ascending neuromuscular weakness
Other: lipodystrophy, hyperlipidemia, peripheral neuropathy, rash, nausea
and vomiting, headache, diarrhea, anorexia, anemia, thrombocytopenia,
insomnia, myalgia
Storage Store capsules at room temperature in tightly closed bottles.
Suspensions after reconstitution with water should be stored in a refrigerator
for about 30 days
Other Drug Information: • Use with caution and only if potential benefit
• Reinstitution of stavudine is not recommended after confirmed lactic
acidosis
• Increased risk of lactic acidosis when combined with didanosine; this
combination should be avoided in pregnant women
• Consider dosage and directions adjustment for peripheral neuropathy
TENOFOVIR
300 mg tablets
Dosage and Directions Adults: 300 mg once daily taken orally without regard for food.
Children: Safety and efficacy not established
8 mg/kg/dose qd (investigational)
Renal dose adjustments:
CrCl (mL/min) Dose
30-49 300 mg q48h
10-29 300 mg bi wk
ESRD 300 mg q wk
Oral Bioavailability 25% in fasting state; 39% with high fat meal
Serum Half-life 17 hours

Intracellular Half-life 10-50 hours
Route of Metabolism In vitro studies indicate that neither tenofovir disoproxil nor tenofovir
are substrates of CYP enzymes. Following IV administration of tenofovir,
approximately 70–80% of the dose is recovered in the urine as unchanged
tenofovir within 72 hours of dosing
Contraindicated in lactating women. (FDA Pregnancy Category B)
97
Common drug Interactions Absolute Contraindication: Hypersensitivity to tenofovir.
As part of the ARV regimen, the following must be avoided:
Atazanavir without ritonavir
didanosine + delavirdine
didanosine + efavirenz
didanosine + nevirapine
lamivudine + abacavir
lamivudine + didanosine
Tenofovir should be used with caution when taken with drugs that are actively
secreted renally or primarily excreted by the kidneys, including acyclovir,
valacyclovir, ganciclovir,
Drug-Food Interactions A high fat meal increases oral absorption
Adverse Effects Serious: fatal lactic acidosis, hepatomegaly with steatosis, pancreatitis, Acute
renal insufficiency, Fanconi syndrome
Other: diarrhea, flatulence, nausea, vomiting, osteopenia, asthenia,
lipodystrophy, hypophosphatemia, dizziness, headache, proteinuria, asthenia
Storage Store under controlled room temperature
Other Drug Information • Gastrointestinal symptoms may be worse in lactose intolerant patients
since tenofovir is formulated with lactose.
• Monitor hepatic function closely for at least several months when patients
discontinue tenofovir and are coinfected with HBV.
• If taken with ddI (Videx or Didanosine), it can increase ddI levels in the
blood by as much as 60%, causing increased ddI side effects
98
ZALCITABINE
0.375 mg tablets, 0.750 mg tablets
0.750 mg tablet orally every 8 hours in combination with other antiretroviral
agents
Children:
limited data on safety and efficacy
N/A
Renal:
Based on preliminary data, the recommended zalcitabine dosage reduction for
patients with impaired renal function is creatinine clearance 10 to 40 mL/min:
0.750 mg of zalcitabine every 12 hours; creatinine clearance < 10 mL/min:
0.750 mg of zalcitabine every 24 hours.
Route of Metabolism Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate.
Zalcitabine does not undergo a significant degree of metabolism by the liver.
Common Drug Interactions Absolute Contraindications: Hypersensitivity to zalcitabine
As part of the ARV regimen the following drugs should be avoided:
Didanosine
Lamivudine
Stavudine
Zidovudine
The concomitant use of HIVID with drugs that have the potential to cause
peripheral neuropathy should be avoided where possible. Drugs that have
been associated with peripheral neuropathy include antiretroviral nucleoside
analogues, chloramphenicol, cisplatin, dapsone, disulfiram, ethionamide,
glutethimide, gold, hydralazine, isoniazid, metronidazole, nitrofurantoin,
phenytoin, ribavirin, and vincristine.
Drug-Food Interactions The optimum dosing has not been adequately researched.
99
Adverse Effects Serious: Peripheral neuropathy, pancreatitis, lactic acidosis and severe
hepatomegaly with steatosis
Other: abnormal weight loss, asthenia, cachexia, chest tightness or pain,
chills, cutaneous/allergic reaction, debilitation, difficulty moving, dry eyes/
mouth, edema, facial pain or swelling, flank pain, flushing, increased sweating,
lymphadenopathy
Storage Store at room temperature in a tightly closed container, away from light and
moisture
Other Drug Information: • The use of zalcitabine has been associated with significant clinical adverse
reactions, some of which are potentially fatal. Zalcitabine can cause
severe peripheral neuropathy and because of this should be used with
extreme caution in patients with preexisting neuropathy.
• Zalcitabine may also rarely cause pancreatitis and patients who develop
any symptoms suggestive of pancreatitis while using zalcitabine should
have therapy suspended immediately until this diagnosis is excluded.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of antiretroviral nucleoside
analogues like zalcitabine, either used alone or in combination with other
drugs.
• Rare cases of hepatic failure and death considered possibly related to
underlying hepatitis B and zalcitabine have been reported.
ZIDOVUDINE
100 mg capsules, 300 mg tablets, 50 mg/5 ml syrup, 10 mg/ml injection
Dosage and directions Adults: One 300 mg tablet bid or 200 mg tid
Children: 6 weeks -12 years: 160mg/m2 every 8hrs
Neonates for prevention of perinatal transmission:
Less than 6 weeks age: 2mg/kg po q6 hours (starting within 12 hours after
birth)
No dose adjustment recommended, monitor for toxicity
Renal: CrCl < 15 or HD: 100 mg TID
Route of Metabolism Metabolized by the liver and renal excretion
Pregnancy and Lactation Safety in human pregnancy has not been determined (FDA Pregnancy Category C)
100
Common Drug Interactions Absolute Contraindication: hypersensitivity to zidovudine
As part of the ARV regimen: the following should be avoided:
Stavudine
Zalcitabine
Doxorubicin (additive bone marrow suppression)
Ganciclovir: Additive bone marrow suppression
Ribavirin: Additive anemia, which may require use of EPO
Drug-Food Interactions Taking with food may minimize stomach discomfort
Adverse Effects Serious: Neutropenia, anaemia in advanced HIV patients, drug induced
myopathy, lactic acidosis, hepatic steatosis, hepatomegaly , Stevens-Johnson
Syndrome and toxic epidermal necrosis have been reported in some cases
Other: Constipation, loss of appetite, nausea and vomiting, asthenia,
headache, insomnia, malaise, myalgia, myopathy, hyperpigmentation of skin
and nails
Storage • Store all dose and directions formulations between 15 and 25 degrees
celsius.
• Protect zidovudine capsules from moisture.
Other Drug Information • In cases of neutropenia or anemia discontinue until marrow recovery.
• Fatigue, nausea, headache, and myalgia usually resolve 2-4 weeks after
initiation.
LAMIVUDINE/STAVUDINE
Lamivudine 150 mg Stavudine 30 mg tablets
Lamivudine 150 mg Stavudine 40 mg tablets
1 tablet twice daily for patients weighing < 60 kg
1 tablet twice daily for patients weighing > 60 kg
Children: Lamivudine/stavudine is not intended for use in pediatric patients
Renal Dose Adjustment: Reduction of the dosage and directions of both
stavudine and lamivudine is required in patients with a creatinine clearance of
50 ml/min or less
101
Common Drug Interactions: Absolute Contraindication:
Lamivudine/stavudine is contraindicated in patients with clinically significant
hypersensitivity to any of the components contained in the formulation.
See the drug information on lamivudine and stavudine

Trimethoprim 160 mg/sulphamethoxazole 800 mg once daily has been shown
to increase lamivudine exposure (AUC)
See the drug information on lamivudine and stavudine
Natural/Traditional/ See the drug information on lamivudine and Sstavudine
Adverse Effects Serious: See the drug information on lamivudine and stavudine
Other: See the drug information on lamivudine and stavudine
Storage: Store at room temperature in a tightly closed container, away from light and
moisture
Other Drug Information: • Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination, including lamivudine and stavudine.
• Because it is a fixed-dose combination, lamivudine/stavudine should not
be prescribed for patients requiring dosage and directions adjustment,
such as those with reduced renal function (creatinine clearance < 50
ml/min), those with low body weight (< 50 kg or 110 lbs), or those
experiencing dose-limiting adverse events.
• Patients should be monitored for the development of neuropathy that is
usually characterized by numbness, tingling or pain in the feet or hands.
LAMIVUDINE/ ZIDOVUDINE
Zidovudine 300 mg/Lamivudine 150 mg tablets
One tablet (Zidovudine 300 mg/Lamivudine 150 mg) twice a day
Children:
Not recommended under 12
Renal and Hepatic Dosage Adjustment:
• Not recommended CrCl < 50 mL/min
• Not recommended for severe hepatic impairment
Pregnancy and Lactation Mothers are recommended not to breastfeed while taking lamivudine/
zidovudine.
102
Common Drug Interactions Absolute Contraindications:
Lactic acidosis, renal failure,
• Drugs that can alter the levels of zidovudine and lamivudine blood
concentrations although insignificantly include: ritonavir, Pprobenecid,
fluconazole, nelfinavir, ritonavir, methadone
• The use of products also containing lamivudine and zidovudine is not
recommended.
Drug-Food Interactions Take with or without food, however taking with food may minimize upset
stomach
Adverse Effects Serious: Lactic acidosis, anemia and neutropenia, severe hepatomegaly
with steatosis, myopathy, acute flares of hepatitis B upon discontinuation of
lamivudine
Other: Other side effects include diarrhea, nausea and vomiting,
musculoskeletal pain, headache, neuropathy
Storage Store between 2ºC and 30ºC
LOPINAVIR (LPV)/RITONAVIR (RTV)

LPV 200 mg/RTV 50 mg film-coated tablets
LPV 80 mg/RTV 20 mg per mL oral solution (contains 42% alcohol)
For therapy-naïve patients:
LPV 400 mg/RTV 100 mg (2 tablets) bid with or without food
or
LPV 800 mg/RTV 200 mg (4 tablets) once daily with or without food
or
LPV 400 mg/RTV 100 mg (5 mL) bid with food
or
LPV 800 mg/RTV 200 mg (10 mL) once daily with food
For therapy-experienced patients:

LPV 400 mg/RTV 100 mg (2 tablets) bid with or without food
or
LPV 400 mg/RTV 100 mg (5 mL) bid with food
Children:
No data available
Use with caution in patients with hepatic impairment
Oral Bioavailability Not determined in humans
103
3A4 inhibitor and substrate
Pregnancy and Lactation Do not breastfeed while taking therapy
Common Drug Interactions Absolute Contraindications: Hypersensitivity to lopinavir and ritonavir
As part of the ARV regimen: the following should be avoided:
Darunavir/ritonavir
See drug information on lopinavir and ritonavir

See drug information on lopinavir and ritonavir
Natural/Traditional/ Garlic supplements and St. Johns’ Wort are an absolute contraindication
Drug-Food Interactions Tablets: May take with or without food; swallow whole
Oral solution: Must take with food. To increase absorption by 50%-80%, take
with a meal containing >15 g of fat
Adverse Effects Serious: See drug information on lopinavir and ritonavir
Other: GI intolerance, nausea, vomiting, diarrhea, asthenia, elevated serum
transaminase, hyperglycemia, fat redistribution and Lipid abnormalities,
possible increased bleeding episodes in patients with hemophilia
Storage Tablets: store at room temperature. Do not expose to high humidity outside
original container for longer than 2 weeks
Refrigerated oral solution: stable until expiration date on label. If stored at
room temperature, stable for 2 months
Other Drug Information See drug information on lopinavir and ritonavir
LAMIVUDINE/NEVIRAPINE/STAVUDINE
Stavudine 30 mg Lamivudine 150 mg Nevirapine 200 mg tablets
Stavudine 40 mg Lamivudine 150 mg Nevirapine 200 mg tablets
Stavudine 30 mg Lamivudine 150 mg Nevirapine
200 mg tablets
1 tablet twice daily for patients weighing < 60 kg
Stavudine 40 mg Lamivudine 150 mg Nevirapine

200 mg tablets
1 tablet twice daily for patients weighing > 60 kg
Children: The combination is not intended for use in pediatric patients
104
Pregnancy and Lactation Mothers are recommended not to breastfeed
Absolute Contraindications See the drug information on stavudine, lamivudine and nevirapine
Common drug interactions See the drug information on stavudine, lamivudine and nevirapine
Natural/Traditional/ See the drug information on stavudine, lamivudine and nevirapine
Adverse Effects Serious: See the drug information on stavudine, lamivudine and nevirapine
Other: See the drug information on stavudine, lamivudine and nevirapine
Hepatic/Renal Dose Because it is a fixed-dose combination, it should not be prescribed for patients
Adjustments: requiring Dosage and directions adjustment, such as those with low body weight
Storage Store at room temperature in a tightly closed container, away from light and
moisture
Other Drug Information • The combination should not be used for patients who are initiating
therapy with nevirapine. It should be administered only to patients who
have received stavudine + lamivudine (standard doses) + nevirapine
(200 mg once daily) for 2 weeks and have demonstrated adequate
tolerability to nevirapine.
• The combination should be discontinued if patients experience
severe rash or a rash accompanied by constitutional findings. It
is contraindicated for patients who are just initiating therapy with
nevirapine. These patients require a lead-in dose of nevirapine 200 mg
once daily, which has been shown to reduce the incidence of rash and
development of hypersensitivity.
• Administration should be interrupted in patients experiencing moderate
or severe liver function tests abnormalities (excluding GGT), until the
liver function test elevations have returned to baseline.
105
Definition of FDA Pregnancy Categories:
• A = Adequate and well-controlled studies of pregnant women fail to demonstrate

a risk to the fetus during the first trimester of pregnancy (and no evidence exists of
risk during later trimesters).
• B = Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate
well-controlled studies of pregnant women have not been conducted.
• C = Safety in human pregnancy has not been determined; animal studies are either
positive for fetal risk or have not been conducted, and the drug should not be used
unless the potential benefit outweighs the potential risk to the fetus.
• D = Positive evidence of human fetal risk that is based on adverse reaction data
from investigational or marketing experiences, but the potential benefits from the
use of the drug among pregnant women might be acceptable despite its potential
risks.
• X = Studies among animals or reports of adverse reaction have indicated that the
risk associated with the use of the drug for pregnant women clearly outweighs any
possible benefit.
Creatinine clearance calculation equation
Cockcroft-Gault Equation
CrCl = (140-age) x (IBW in kg) x (0.85 if female)

Serum Cr x 72
Estimate Ideal Body Weight (IBW) in kg: IBW = 50kg (male) or 45kg (female) + 2.3kg
for each inch >5 ft.
In SA: IBW = 50kg (male) or 45kg (female) + 2.3kg x (Actual height in cm – 152.4cm)
2.5cm
Note: If Actual Body Weight (ABW) is < IBW, use ABW for calculation.
106
Assessment of Liver Function: Child-Pugh Score system (Add score for
each category)
Points Scored for Observed Findings

1 2 3
Encephalopathy none 1 or 2 3 or 4
grade*
Ascites absent slight moderate
Serum bilirubin, <2 2 to 3 >3
mg/dL
Serum albumin, >3.5 2.8 to 3.5 <2.8
g/dL
Prothrombin time, <4 4 to 6 >6
sec prolonged
*Grade 0: normal consciousness, personality, neurological examination,

electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5
cps waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic
waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower
waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta
activity
Assessment as good operative risk (A or mild) if 5 or 6 points; moderate risk (B or
moderate) if 7 to 9 points; and poor operative risk (C or severe) if 10 to 15 points.
(Developed for surgical evaluation of alcoholic cirrhotics.)
107
References:
1. Cipla. Therapeutic Index. 12 Feb. 2009. <http://www.cipladoc.com>
2. Gibbon CJ (ed), South African Medicines Formulary. 7th Edition 2005.
3. New York State Department of Health AIDS Institute. HIV Clinical Resource. 12
Feb. 2009 <http://www.hivguidelines.org>
4. Rxlist. The Internet Drug Index. 12 Feb. 2009 <http://www.rxlist.com>
5. US Food and Drug Administration. Guidance for Industry
Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data
Analysis, and Impact on Dosing and Labeling. 12 Feb. 2009. <http://www.fda.
gov>
6. South Africa. National Department of Health. National Antiretroviral Treatment
Guidelines. 2009
7. Valcyte package insert. (2001). Switzerland: Roche Laboratories.
108

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Antiretroviral Therapy

Dr. Henry Fomundam

Prof. Christopher Mathews

Second Edition, 2009

Dr. Henry Mbah

Mr. Thami Mseleku

Dr. David Kalombo

2. Flow Charts for Most Common or Severe Adverse Drug

Educate patient regarding

If symptoms are moderate-

Side effects and

Evaluate potential causes (psych, Adjust efavirenz administration

Ensure patient access to

Provide close patient

Psychiatric referral and antidepressant therapy

Anemia (usually macrocytic) Neutropenia

Correct other causes Calculate absolute neutrophil

• ANC < 0.75 • ANC < 0.75

• Replace AZT with Tenofovir • Obtain blood cultures

Replace AZT Replace AZT Refer

Obtain fasting glucose and lipid profile prior to starting

Count number of CHD risk factors.

If above the lipid threshhold based on risk group despite vigorous

If lipid lowering drugs are necessary

Serum LDL cholesterol above threshhold OR

Statin Therapy Fibrate therapy

Dorso-cervical Central Adiposity Fat loss

Key task is to distinguish morphologic changes

Phenotypes (suggest use

Due to On thymidine Associated with

2.6. Lactic Acidosis

Measure serum electrolytes

Measure venous lactate

Lactate 5-10 Lactate 5-10 mm/L Lacate 2-5 mm/L

2.7. Gastrointestinal Side Effects (Nausea, Vomiting, Diarrhea, and

Nausea and Vomiting: Differential Diagnosis

Gastrointestinal Cardiac Metabolic:

Serious Usually Not Serious

Symptomatic Abacavir AZT ddI

Symptomatic Opportunistic Gastrointestinal

See Nausea, vomiting, See hepatitis

Stop ART regimen

5 7 Evaluate for other causes of diarrhea

Does patient have any of

Refer immediately to Teach patient warming

Arrange daily follow-up

>= 2 symptoms from

• Stop ABC Continue ABC

2.9. Distal Symmetric Polyneuropathy

Peripheral Neuropathy Symptoms:

Grade the severity of symptoms and relationship

Pain Mild Pain moderate or severe (not controlled with NSAIDS,

Symptomatic therapy with simple analgesia • Switch to AZT if not contraindicated

• Switch to AZT if not contraindicated

Hepatocellular (ALT Mixed Cholestatic (ALP

Extra-hepatic Hepatic mass

An approach to managing patients with hepatocellular injury pattern on ART:

Restart with RIF

If RIF is tolerated If symptoms recur or