Natural History of HIV Infection

Dr Farida Amod KZN Provincial ARV Training NRM School of Medicine University of Kwa-Zulu Natal

Module Objectives
Pathogenesis (how HIV infects immune cells) Natural history Acute HIV infection (presentation, diagnosis and treatment) Chronic HIV infection (manifestations and management)

Course of HIV Infection

Primary Infection Seeding of Lymphoid Organs Virus Dissemination

Clinical Latency
CD4 cells/l

HIV RNA copies/ml

Virus RNA

Opportunistic Infections

CD4 Count

Death

Weeks

Years

Pathogenesis of Acute HIV Infection

HIV makes contact with cells located within the genital mucosa

Virus is carried to regional lymph nodes (1-2 days)

Exponential viral replication

There is widespread systemic dissemination to the brain, spleen, distant lymph nodes, etc ( 5-11 days )

Pathogenesis Continued
Following widespread dissemination Development of virus specific T cell responses (CD8 cells) Symptoms of acute infection occur Decrease in plasma viral load Symptoms of acute infection resolve

From Antigen-Presenting Cell to CD4 Cell Destruction

APC CD4 Cell Activated CD4 Cell

HIV

HIV

Picture
DHS/HIV/Pathogenesis/PP

How Does HIV Work?

3. Integration into host cells nucleus HIV 1. Attachment to host cell 4. Reproduction of viral components

2. The virus changes from RNA to DNA

5. Assembly of new HIV viruses

CD4 CELL or T CELL

Course of HIV Infection

Primary Infection Seeding of Lymphoid Organs Virus Dissemination

Clinical Latency
CD4 cells/l

HIV RNA copies/ml

Virus RNA

Opportunistic Infections

CD4 Count

Death

Weeks

Years

Primary HIV: Definition

Refers to new HIV infection Encompasses acute and early HIV Acute infection: days-weeks after infection, during which there are high levels of replicating virus and an attempt by the host immune system to control virus Early infection: variably defined as within 312 months of infection

Epidemiology of Primary HIV Infection

Estimated that 14,000 new infections occur each day in the world, predominantly through sexual contact

Joint United Nations Programme on AIDS. AIDS epidemic update: December, 2001. Geneva: UNAIDS;2001:1-36.

How Often Do People With Primary HIV Infection Seek Health Care?
Swiss cohort
87%

of seroconverters (20/23) in cohort study had symptoms 95% of these patients had medical evaluation Primary HIV Infection considered in only 5 of 19 patients
Primary HIV Infection often leads to medical evaluation, but is under-diagnosed

MACULAR PAPULAR RASH

Case One
Ms J.G- 29 years old domestic worker 1 week history of fever, rash, myalgia and a sore throat. Previously healthy patient. Systemic Enquiry: not on contraception. LNMP: 1/3/04 Has one child- 1year old (breastfeeding). Had an HIV test 1 year ago during her pregnancy negative Unmarried with one partner for the last 4 years. Not using condoms. Unsure if her partner has other casual sexual partners as they do not live together.

Clinical Examination
Temp- 390C, 0.5-1cm posterior and anterior cervical and suboccipital lymph nodes. No evidence of wt loss. Mild pharyngitis. No thrush. Rest of the systems- normal Differential diagnosis includes: viral infections - EBV, rubella secondary syphilis acute hepatitis Is there anything else that you would consider in DD? Acute retroviral syndrome

 The HIV-1 Elisa test done is NEGATIVE Need to either:

Repeat

the test in one month.

P24

antigen test or Quantitative or qualitative viral assays useful for early diagnosis, but not widely available in KZN.

You decide to repeat the HIV-1 Elisa test in 1 month: Result is now POSITIVE

Testing for HIV Infection

Viral Load

Amount of Virus in the Blood

HIV antibody

Level at which antibody can be detected

0 Time when person becomes infected

4-6wks

8-10yrs

Window Period

No Symptoms

HIV Related Symptoms

TIME

Symptoms and Signs of ARS

100% 90%
patients reporting symptoms

80% 70% 60% 50% 40% 30% 20% 10% 0%

fever fatigue rash headache signs and symptoms L/nodes pharyng diarrhoea

Treatment of ARS
Area of much research interest and therapeutic options are not resolved. 2 options: Use of antiretroviral therapy may lower viral set-point and alter the natural history of HIV infection. Early treatment may necessitate the patient being on ARV therapy for an unnecessarily long time. USA guidelines suggest that patients with ARS should be offered treatment.

Primary HIV Infection: Conclusions

Primary HIV Infection is under-diagnosed May represent a critical opportunity to intervene High index of suspicion, recognition of key signs & symptoms, and lab testing required for the diagnosis HAART may provide opportunity for improved longterm virologic control of HIV Ongoing studies should clarify the role of treatment during PHI

Is Diagnosing Acute HIV Feasible?

Costly!!! No official guidelines regarding treatment

So, what can you do if you suspect Acute HIV Infection?

Feasible Interventions
Assess risk factors for HIV infection Encourage alterations in sexual behavior (positive prevention) Encourage follow up for antibody testing

Chronic HIV Infection

Natural History Clinical Manifestations

Course of HIV Infection

Primary Infection Seeding of Lymphoid Organs Virus Dissemination

Clinical Latency
CD4 cells/l

HIV RNA copies/ml

Virus RNA

Opportunistic Infections

CD4 Count

Death

Weeks

Years

Diagnosis of Chronic HIV Infection

Rapid HIV-1 Testing Pretest counselling Blood obtained via fingerstick Results in approximately 20 minutes Must be confirmed with a second rapid test

Diagnosis

Real Time testing at a HIV Clinic

Diagnosis
HIV-1 antibody ELISA (Enzyme Linked Immunosorbent Assay) test: Requires blood draw Takes approximately 2 weeks for results Must be confirmed with second ELISA test or a Western Blot Test

Laboratory Monitoring of Chronic HIV Infection

Natural History of HIV Infection

Number of CD4 cells / Viral Load
ra i V l ad o L

CD 4 u Co nt

2 weeks

6 years

10

CD4 count and HIV RNA

CD4 count decline is a function of HIV RNA level The higher the HIV RNA, the faster the decline in CD4 cells Typically, CD4 cells decline by approximately 50 cells/year HIV RNA remains stable during intermediate stage of HIV then typically increases dramatically during later stages of disease

CD4 Count and OIs

1000

CD4 Count

Tuberculosis, Herpes zoster (shingles) 500 Oral candida, Herpes simplex, Bacterial pneumonias 200 100 50

Pneumocystis carinii (PCP) Toxoplasmosis, Cryptococcus, Esophageal candida, Histo, Kaposis Cytomegalovirus (CMV), Mycobacteria avium complex Time

Common Clinical Manifestations of Chronic HIV Infection

Constitutional Symptoms
fever weight loss/wasting fatigue

Organ/System Specific

virtually all organ systems can be affected

Consider HIV testing for unexplained syndromes

Wasting

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Skin Manifestations of HIV Infection

 Staphylococcus skin infections Seborrheic dermatitis Genital herpes simplex virus (HSV) Severe chronic, non-healing perianal ulcerative HSV seen in late stage AIDS Human papilloma virus (HPV) infection (warts) Varicella Zoster Virus (VZV) (shingles)

Kaposis Sarcoma

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Anal warts (Human Papilloma Virus)

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Molluscum contagiosum

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Case 2
Mr John Dube, 42 yr old truck driver, presents to MOPD with a productive cough, pleuritic chest pain and fever for 3 days. Previously well with no past history of alcohol use or TB. Married, but admits to occasional casual sexual partners (if away from home for a long time). Inconsistent condom usage O/E: no weight loss, no lymphadenopathy, no thrush chest x-ray: lobar pneumonia

RML Lobar Pneumonia

RML lobar pneumonia RML lobar Pneumonia

Pneumococci with pus cells on sputum

Case 2
A 36 year old HIV positive man presents to OPD with: Increasing shortness of breath dry cough for 2 week. He doesnt know his CD4 count, but he had shingles in 1999.

Case 2 Continued
Vital signs Cyanosed Respiratory rate 30 b/min Pulse 120/min Temperature 39C Oxygen saturation 85% on room air Oral thrush Cervical adenopathy Chest: clear

Case 2 Continued
PCP

Normal Chest X-ray

Diffuse ground glass opacification

Case 2 Continued
What should be included in your differential?

Pneumocystis carini pneumonia? TB? Bacterial pneumonia? Cryptococcus neoformans pneumonia? Pulmonary Kaposis sarcoma?

Diagnosing PCP
Difficult to do at most centers Gold standard: bronchoalveolar lavage Alternative: induced sputum Often diagnosis is presumptive based on xray and symptoms
Fever Progressive exertional dyspnea Cough oftentimes non-productive

Evaluation of a hospitalised HIV + patient with CAP Chest Radiograph

Diffuse Infiltrate

Focal Consolidation

Suspect PCP and consider TB

Suspect usual bacterial pathogens

Investigate and treat for PCP

Investigate and treat for CAP

Response and resolution

SAMJ Aug 2002

No response Refer for special investigations

Pneumocystis pneumonia

Severe Infection

DUAL INFECTIONS (N = 11 )

PCP PCP 44

H.influenae H.influenae 11

S.aureus S.aureus 22

Other pairs PCP + CMV S. aureus + HSV 1 Triple Infections (n=3)

TB = 9
C.albicans C.albicans 11 CMV CMV 11

Treating PCP
Start treatment empirically Preferred Treatment Bactrim 15/75 mg/kg/day i.v. or p.o. for 21 days Prednisone: If pO2 <70 mmHg or A-a gradient >35 mm Hg Oxygen to maintain O2 saturation

Preventing PCP
Cotrimoxazole SS 2 tablets per day Prevention Indication: CD4 < 200 or WHO clinical 2/3/4 When to stop: CD4 > 200 for > 3 mo When to restart: CD4 falls to < 200

Case 3
A 55 y.o. woman presents to the emergency department in a post ictal state. Her daughter says that she witnessed her mother have what she described as a generalized seizure. Vitals arousable but not alert BP 150/90 Respiratory Rate 12 Temperature 340C

Case 2 Continued
You admit her and obtain a CT scan the next day

Case 2 Continued
What would you include your differential? Tuberculoma? Toxoplasmosis? Primary central nervous system lymphoma? Cryptococcoma?

Toxoplamosis
Usually limited to patients with CD4 counts <100 Symptoms Focal neurological deficits Seizure Fever Headache Altered mental status Typical radiological findings Multiple ring enhancing lesions

Toxoplasmosis
Treatment

Bactrim: 10/50 mg/kg/d orally for 30 days

Primary Prophylaxis (No previous episode of toxoplasmosis)

Cotrimoxazole 2 SS per day when CD4 <100 Can discontinue when CD4 > 200 for > 3 months
Secondary Prophylaxis (previous episode of toxoplasmosis)

CD4 count >200 for > 6 months and completed initial toxoplasmosis therapy and is asymptomatic

Other CNS Lesions

Primary CNS lymphoma with enhanced lesion and slight mass effect

Other CNS Lesions

Tuberculomas visualized as small, ring enhancing lesions

Patient Presentation
26 year old male with Class C3 AIDS (history of cryptococcal meningitis and CD4+ T-cell count 40 presents with non-healing anal ulcer On examination:

Non-healing anal ulcer in a patient with AIDS

What is the differential? How would you assess the patient?

Patient Presentation
Ulcer is swabbed for HSV culture and DFA. Patient is treated empirically for anal herpes with acyclovir 400 mg three times daily. Results return positive for HSV-2 by DFA and culture. Ulcer resolves after 4 weeks.

Case 3
A 20year old man presents to your HIV clinic. He was diagnosed positive 3 years ago and his CD4 count at that time was 450. He has been lost to follow-up. Now he presents to resume his care.

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Case 3
On exam you discover the following:

What is this?

Is this the same infection?

No, its oral hairy leukoplakia

Treating Candidiasis
Oral thrush clotrimazole troches 5 times per day for 14 day Oesophageal thrush fluconazole 200 mg/day for10-14 days Vaginal: Miconazole 200mg vaginal suppositories or oral fluconazole 150 mg (one dose only)

Case 4
A 37 year old man presents with intense, burning pain on his shoulder. The pain began two days prior. Clinical examination reveals:

Case 4
On exam you find:

Case 4
What is it? Should you treat it? Why? Herpes Zoster Maybe Helps healing and helps post herpetic neuralgia Acyclovir

How?

Complications of HZ Infection
Post-herpetic neuralgia Aseptic Meningitis Encephalitis Bacterial skin infections Herpes zoster ophthalmicus Retinal necrosis Herpes zoster oticus

Case 5
A 26 year old woman presents to OPD with headache and just not feeling well for 1 week. When her mother leaves the room she tells you that she is HIV positive. On exam she has no neurological deficits.

What do you think is wrong?

Just a headache? CNS lesion? Meningitis? Something else?

Symptoms of Cryptococcal Meningitis

Most Common Fever Headache Malaise Less Common Altered Mental Status Stiff neck Vomiting Usually subacute onset

Diagnosis
Lumbar puncture Obtaining an opening pressure is key!!! Usually markedly elevated >20 cmH20 on the initial tap India ink preparation to visualize organisms and/or measurement of cryptococcal antigen Culture is definitive WBC typically low with mononuclear predominance (<50/microliter) Total protein and glucose only slightly abnormal

Recommended Treatment
Initial Therapy Amphotericin B 0.7 mg/kg/day (starting dose) for 14 days Fluconazole 800 mg stat, then 400mg/day for 8-10 weeks Follow-up Fluconazole 400 mg/day for 8 weeks Maintenance Fluconazole 200 mg/day lifelong ( if not on ARVs) Fluconazole 200 mg/day until immune reconstitution occurs (CD4 >100-200 for >6 months)

Management of Intracranial Hypertension

Majority of the deaths in studies were associated with increased intracranial pressure, likely reflecting cerebral edema Repeat lumbar puncture with any sign of increased pressure Headache Altered mental status (may be slight)

What is This?

Severe Kaposis Sarcoma

Kaposis Sarcoma
Most common tumor in HIV infection Etiologic factor human herpes virus 8 Many manifestations Skin lesions Oral lesions Gastrointestinal tract involvement Pulmonary involvement

Treatment for Kaposis Sarcoma

Cured by antiretroviral therapy in many cases Local therapy (i.E. Topical retinoic acid and radiation) for extensive dermatologic disease Interferon alpha and chemotherapy for patients with widespread disease

Case 7
A 47 y.o. woman presents to the clinic with fever, night sweats, and overwhelming fatigue. She is HIV positive with a CD4 count of 45. Her symptoms have been present for approximately 2 weeks.

Case 7 Continued
On exam the patient has an enlarged liver Lab studies reveal a hemoglobin of 5 and leukopenia Thinking that the patients constitutional symptoms indicate TB you send sputum for AFB They are negative X 2 What is wrong with this patient?

Case 7 Continued
Disseminated Mycobacterium Avium Complex (MAC) Usually limited to patients with CD4 counts less than 50 Often presents with non-specific symptoms Enlargement of the liver, spleen and abdominal lymph nodes are common Anemia, neutropenia, and thrombocytopenia are also common with bone marrow involvement

Diagnosis of MAC
Culture of organism Blood Lymph node Bone marrow

Treatment of MAC Infection

Formulary limitations may limit intervention Preferred therapy Clarithromycin 500 mg po bid and ethambutol 15 mg/kg/day for 12 months Alternative Azithromycin 600 mg/day and ethambutol 15 mg/kg/day (may add rifabutin 300 mg per day)

Conclusion

Acknowledgements
Contributors:

Dr Stephen Tabet Dr. Bisola Ojikutu Dr. Michael Klompas Dr. Janet Giddy

Oral Manifestations of HIV/AIDS

Candida angular chelitis

Oral Hairy Leukoplakia

Epstein-Barr virus (EBV) induced benign epithelial thickening

Apthous ulcers in HIV-infected patient

Oral warts (HPV) in patient (CD4 lymphocyte count 120)

By Salvatore Marra, from AIDS imaging

http://members.xoom.it/Aidsimaging

Case 6
A 17 year old woman presents to clinic for pre-ARV screening The medical officer does all of the following:
Discusses adherence and disclosure Performs baseline blood tests (i.e. FBC, U&E, screen for syphilis) Screens for TB Discusses antiretroviral therapy in detail

What did they forget to do?

Importance of the Pap Smear

Significantly increased risk for invasive cervical cancer in HIV positive women
Added to CDC list of AIDS defining conditions in 1993 Higher incidence of all stages of cervical intraepithelial neoplasia (CIN) Faster progression to invasive disease Most frequent cause of cancer in women with HIV in many developing countries

Screening
Recommended screening
Perform baseline Pap smear If normal, then repeat yearly If low grade abnormalities, repeat after 6 months If high grade squamous intraepithelial lesion or invasive cancer is reported by pathology, then refer immediately to GYN for colposcopy, biopsy and treatment