HIV

1. HIV Shelly Ritter, M.D. ARGY Resident

2. HIV/AIDS - History • Cases of Pneumocystis carinii (now jarovecii) pneumonia and Kaposi’s sarcoma first noticed in homosexual males in 1981. • The responsible retrovirus was discovered in 1983. • Serologic testing was started in 1985. • Anti-retroviral therapy was first started in 1987. • Combination anti-retroviral therapy (Highly Active Antiretroviral Therapy – HAART) in 1996.

3. Epidemiology of HIV • 59 million people have been infected worldwide, with 20 million dead. • About 405,926 people living with HIV in U.S. in 2003. • 64% of people with HIV are living in sub-Saharan Africa • though Sub-Saharan Africans only make up 10% of world population

4. Human Immunodeficiency Virus • An RNA retrovirus – subfamily Lentivirus • Contains: • 2 copies of RNA • Enzymes: • Reverse Transcriptase • Integrase • Protease • Two major envelope proteins: • gp120 • gp41

5. Life Cycle of HIV virus • Interaction between viral envelope proteins and CD4 receptor and co-receptors leads to binding of the viral envelope and host cytoplasmic membrane • Viral reverse transcriptase catalyses the conversion of viral RNA into DNA • Proviral DNA enters the nucleus and becomes integrated into chromosomal DNA of host cell (catalyzed by integrase) • Expression of viral genes leads to production of viral RNA and proteins. • Protease enzyme cleaves proteins into functional mature products. • Viral proteins and viral RNA are assembled at the cell surface into the new viral particles and leave the host through budding.

6. Human Immunodeficiency Virus – Lifecycle in Host Cell

7. Human Immunodeficiency Virus – Life Cycle in Host Cell • HIV tends to infect CD4+ T Cells, because CD4 receptor has high affinity for gp120 (HIV viral-envelope protein) • CD4+ T Cells initially die in acute phase due to cytopathologic damage by virus. • CD4+ T Cells then chronically die from: • Chronic activation of T cells • Inhibition of thymic output of T cells • Suppression of the bone marrow • Destruction of lymph-node architecture • Low-level ongoing infection of memory CD4+ T cells

8. Diagnosis of HIV • HIV antibody ELISA – if positive, is always followed by a confirmatory Western Blot • Rapid HIV antibody test • Sensitivity and Specificity 99%! • Results in 5 to 40 minutes usually • Used in: • Occupational Exposure • Pregnant women presenting in labor with no previous HIV testing • Patients who are unlikely to return for results of HIV test • HIV viral load • First choice for diagnosing possible acute HIV • HIV p24 Antigen • Is the first antigen to be elevated in acute HIV • Can be used for diagnosis of primary (acute) HIV

9. Human Immunodeficiency Virus – Stages of Infection • Viral Transmission • Sexual intercourse, exposure to contaminated blood, or perinatal transmission • In U.S., 50% of cases due to male-to-male transmission. • Worldwide, 70-80% caused by vaginal sex, perinatal transmision is 5-10%, and IV drug use is 5-10%. • Acute HIV Infection • A transient, symptomatic period shortly following infection with HIV virus, associated with a high HIV-viral load and robust immune response. • Occurs in 40-90% of new HIV infections. • Symptoms usually develop in days to weeks after initial infection • Include fever, lymphadenopathy, rash, pharyngitis, headache (aseptic meningitis) • HIV antibody will be negative at this point – need to check HIV viral load or p24 antigen level! • Seroconversion • Patient has positive HIV antibody test • Usually occurs 4 to 10 weeks after infection. • Chronic/Latent HIV disease • Viral load tends to increase slowly, CD4 count decreases slowly • “Chronic non-progressors” tend to have little/no decrease in CD4 count • Early Symptomatic HIV Infection • AIDS

10. HIV- Early Symptomatic Infection • Includes: • Thrush • Persistent vaginal candidiasis • Fever • Diarrhea • Oral Hairy Leukoplakia • Herpes Zoster • Bacillary Angiomatosis • Cervical dysplasia/carcinoma in situ • Peripheral neuropathy • Pelvic inflammatory Disease

11. Thrush If plaques wiped off with gauze, erythematous, often bleeding mucosa will be revealed.

12. Oral Hairy Leukoplakia • Associated with EBV infection • Does not rub off.

13. Bacillary Angiomatosis • Caused by Bartonella species

14. Herpes Zoster • “Shingles” • Caused by Varicella

15. Acquired Immunodeficiency Syndrome (AIDS) • CD4 count < 200/mm3 (regardless of presence or absence of symptoms). • Infection with HIV and one of the following conditions: • Recurrent bacterial pneumonia • Invasive cervical cancer • Candidiasis of esophagus, trachea, bronchi, or lungs • Coccidiodomycosis, extrapulmonary • Cryptococcosis, extrapulmonary • Cryptosporidiosis with diarrhea > 1 month • Cytomegalovirus of any organ other than lymph nodes, liver, spleen • Herpes simplex with mucocutaneous ulcer >1 month, or bronchitis, pneumonitis or esophagitis • Histoplasmosis, extrapulmonary • HIV-associated dementia • HIV-associated wasting (involuntary weight loss of >10%, with diarrhea for > 30 days) • Kaposi’s sarcoma in patient under age 60 • Lymphoma of brain in patient under age 60. • Non-Hodgkins Lymphoma • Disseminated Mycobacterium avium or Mycobaterium kansasii • Disseminated Mycobacterium tuberculosis • Pulmonary tuberculosis • Nocardiosis • Pneumocytis jiroveci pneumonia • Progressive Multifocal Leukencephalopathy • Salmonella septicemia • Strongyloides, extraintestinal • Toxoplasmosis of internal organ.

16. HIV Disease Progression

17. HIV – Initial Visit • Labs • CD4 Count • HIV Antibody Test • HIV Viral Load (need to check this when concerned about Primary HIV!) • HIV Resistance Testing – for selected patient • Hepatitis virus screening (check viral loads) • Tuberculin skin testing • Pap smear • PPD (positive if >/ = 5mm) • Sexually transmitted disease (especially RPR) • Toxoplasma serologic test • CMV serologic test (optional) • Chest radiograph (optional) • Vaccinations • Pneumococcal Vaccine (repeat after 5 years) • Influenza • Hepatitis B • Hepatitis A Don’t give live vaccines – no Varicella, no MMR if CD4 count < 200!

18. HIV - Opportunistic Infections

20. Pneumocystis jiroveci Pneumonia • Protozoa? Fungus? • Used to be most common opportunistic infection, but much less common now that prophylaxis used. • Clinical Findings: • Gradual onset • Fever, chills, weight loss • Cough, SOB • Radiologic Findings Findings • Diffuse interstitial infiltrates (on x-ray) • Cysts • Ground glass infiltrates (on CT scan) • Pleural Effusions • Pneumothorax • Diagnosis: • Positive immunofluorescent staining of sputum or bronchealveolar lavage. • Often elevated LDH (LDH level correlates with severity)

21. Pneumocystis jiroveci Pneumonia

22. Pneumocystis jiroveci Pneumonia • Treatment: • Typically worsen after two to three days of therapy, presumably due to increased inflammation in response to dying organisms • Antibiotics: • Bactrim • Pentamadine • Need to watch for hypoglycemia • Steroids: • Prednisone • If partial pressure of oxygen (PaO2) is 70 or less OR • If alveolar/arterial (A-a) gradient is 35 mm Hg or more.

23. Esophageal Candidiasis • Invasion of esophageal mucosa by Candida. • Symptoms: Odynophagia, dysphagia • Diagnosis: Clinical, EGD • Differential Diagnosis: • Herpes Simplex Virus • Cytomegalovirus • HIV aphthous ulcer (treated with thalidomide!) • Treatment: Fluconazole

24. Toxoplasmosis • Toxoplasma gondii • Intracellular protozoan parasite • Felines are the only animals in which it can complete its reproductive cycle. • Usually in AIDS patients with CD 4 count < 100/mm3 • Clinical Manifestations: • CNS infection: • Ring-enhancing cerebral lesions • Meningitis • Chorioretinitis • Pneumonitis • Fever, dyspnea, cough • Reticulonodular infiltrates (appears similar to pneumocystis) • Treatment: Pyremethamine • Prophylaxis: Bactrim

25. Toxoplasmosis

26. Cryptococcosis • Cryptococcus neoformans • An encapsulated yeast • Often found in soil containing droppings/guano of pigeons, canaries, parrots, turkeys. • Infection usually occurs with CD4 counts less than 100. • Frequently results in: • Meningoencephalitis • Lung nodules • Skin findings • Symptoms: • Mental status changes • Vision loss, hearing loss • Diagnosis: • Elevated serum cryptococcal antigen • Lumbar Puncture • Elevated opening pressure • Elevated CSF cryptococcal antigen • India Ink Stain showing encapsulated yeast • Treatment: • Serial lumbar punctures, ventriculostomy, VP shunt • Amphotericin, fluconazole, flucytosine

27. Cryptococcosis

28. Mycobacterium avium intracellulare • Usually occurs when in HIV people with CD4 count less than 50. • Disease is usually disseminated. • Symptoms: • Fever • Lymphadenopathy • Night sweats • Abdominal pain • Diarrhea • Weight loss • Diagnosis: • Positive blood culture • Positive bone marrow biopsy • Treatment: • Rifabutin, clarithromycin, azithromycin • Prophylaxis: • Azithromycin – 1250 mg po Q week • Start when CD4 count < 50!

29. HIV-Associated Malignancies • Kaposi’s Sarcoma • Due to excessive proliferation of spindle cells thought to have an endothelial cell origin. • Associated with Human Herpesvirus-8 (HHV-8), which is also known as Kaposi’s Sarcoma Virus (KSV). • Found in 90% of cases • Most common malignancy in HIV • Clinical Findings: • Skin: Deep purple/red lesions; Can appear anywhere on skin (sometimes on soles of feet, causing pain with walking) • Gastrointestinal: Nausea, vomiting, abdominal pain, odynophagia, dysphagia, bowel obstruction, • Pulmonary: cough, dyspnea, shortness of breath, chest pain • Diagnosis: Biopsy • Treatment: Antiretrovirals, Local therapy (radiation, topicals), Systemic Chemotherapy

30. Kaposi’s Sarcoma

31. HIV-Associated Malignancy • AIDS defining malignancies: • Non-Hodgkin’s Lymphoma • Usually B Cell lymphomas • Includes primary CNS lymphoma and body cavity lymphoma (primary effusion lymphoma • Often associated with Epstein Barr Virus (EBV) • Treatment: Anti-retrovirals, chemotherapy, steroids (for CNS) • Kaposi’s Sarcoma (Human herpesvirus- 8 – HHH-8) • Cervical/Anal Cancer (Human papillomavirus - HPV) • Non-AIDS defining malignancies: • Hodgkin’s Lymphoma • Multiple myeloma • Leukemia • Lung Cancer • Basal Cell Carcinoma of the skin • Seminoma

32. Treatment of HIV • Anti-retrovirals • Infection prophylaxis

33. Antiretrovirals – When to Start Therapy

34. Human Immunodeficiency Virus – Lifecycle in Host Cell

35. Antiretrovirals • Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTI’s) • Block reverse transcriptase activity by incorporating themselves into the viral DNA and acting as chain terminators in the synthesis of proviral DNA. • Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTI’s) • Bind directly and non-competitively with reverse transcriptase, blocking its activity • Protease Inhibitors • Inhibit HIV-1 protease, resulting in release of structurally disorganized and non-infectious viral particles. • Fusion Inhibitors • Inhibit fusion of initial virus with CD4 cell • Only member is Enfuvirtide (T20) • Only used in salvage therapy

36. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI’s) • Include: • Abacavir (ABC) • Didanoside (ddI) • Emtricitabine (FTC) • Lamivudine (3TC) • Stavudine (d4T) • Tenofovir (TDF) • Zalcitabine (ddC) • Zidovudine (AZT, ZDV) • Side Effects: • Lactic Acidosis • Hepatic Steatosis • Peripheral neuropathy • ***Hypersensitivity reaction with Abacavir

37. Non-nucleoside reverse transcriptase inhibitors (NNRTI’s) • Include: • Nevirapine (NVP) • Side effects: • Rash (can cause Stevens Johnson) • Hepatotoxicity in women with CD4 ≤ 250 • Efavirenz (EFV) • Side Effects: • CNS side effects: dizziness, insomnia, hallucinations • Can cause fetal malformations, neural tube defects • Dilavirdine (DLV) • Side Effects • Rash • Increased transaminases

38. Protease Inhibitors • Include: • Amprenavir (APV) • Atazanavir (ATV) • Fosamprenavir (f-APV) • Indinavir • Lopinavir + Ritonavir (Kaletra) • Nelfinavir • Ritonavir • VERY IMPORTANT – Is able to boost levels of other protease inhibitors! • Saquinavir • Side Effects • Inhibit CYP450 system • Hyperlipidemia • Hyperglycemia • GI upset • Kidney stones -- Indinavir

39. Choosing Antiretroviral Regiment • Need Protease Inhibitor or NNRTI + 2 – NRTI’s • Most popular initial regimens: • Efavirenz + (lamivudine or emtricitabine) + (zidovudine or tenofovir) • Lopinavir/Ritonavir + (lamivudine or emtricitabine) + zidovudine • Tenofovir, Emtricitabine and Lamivudine also treat Hepatitis B!

40. HIV Prophylaxis • When CD4 count < 200: • Pneumocystis (PJP) prophylaxis • Trimethroprim/Sulfamethoxazole (Bactrim) – one DS tab po QDay If allergy, or unable to tolerate: • Dapsone (need to check G6PD first!) • Pentamadine (aerosolized) • Atovaquone • When CD4 count < 100 • Toxoplasma gondi prophylaxis: • Trimethoprim/Sulfamethoxazole – one DS tab po QDay • Dapsone (Qday) + pyramethamine (Q week) + leucovorin (Q week) • When CD4 count < 50 • Mycobacterium avium intracellulare prophylaxis • Azithromycin – 1200 mg po Qweek Or • Clarithromycin – 500 mg po q12h

41. Immune Reconstitution Inflammatory Syndrome (IRIS) • Following the initiation of antiretroviral therapy, patient may have exaggerated immune response to underlying opportunistic pathogens. • Most patients develop symptoms one week to a few months of the initiation of antiretrovirals. • Most commonly: • Cryptococcus • Mycobacterium tuberculosis • Mycobacterium avium intracellulare • Toxoplamosis • Patient should undergo testing for cryptococcus, toxoplasmosis, tuberculosis (PPD) prior to starting therapy. • Treatment: • Treat infection! • Continue antiretrovirals • Administer steroids • Hold antiretrovirals

42. Question # 1 • A 27-year old HIV-positive male presents with multiple purple pedunculated nodules on his sin. He says that these lesions have spread rapidly and have a tendency to bleed. In the previous 2 weeks, he has had intermittent fevers and general malaise.

43. Question # 1 • The most likely diagnosis is: (A.) Kaposi’s sarcoma (B.) Pyogenic granulomas (C.) Bacillary angiomatosis (D.) Secondary syphilis (E.) Cutaneous cryptococcosis

44. Question # 2 • A 36-year old male with a history of HIV infection for the past 5 years comes to your office for a second opinion about starting antiretroviral therapy. He had varicella zoster infection 1 year ago, and recently noticed some white plaques on the inside of his cheeks. The only medications he is taking are vitamins. Physical examination reveals diffuse adenopathy, which appears unchanged from previous examinations.

45. Question # 2 • Labs: • Hct: 36% • Leukocyte count: 2.2 • Platelet count: 125 • CD4 cell count: 345 • HIV RNA level: 5,000 copies/mL

46. Question # 2 • Which is the most appropriate recommended antiretroviral therapy? (A) No therapy (B) Zidovudine (C) Zidovudine in combination with didanosine and zalcitabine or lamivudine (D) Efavirenz in combination with lamivudine and zidovudine.

47. Question # 3 • An 32-year old man is seen for an initial visit after the diagnosis of HIV infection. The patient believes his infection was sexually acquired. He works at a nursing home, and two years ago had a positive tuberculin skin test, for which he received 1 year of isoniazid therapy. His physical examination is unremarkable.

48. Question #3 • In addition to a CD4 count, viral load testing, and a blood chemistry profile, what additional clinical and laboratory testing should be ordered? (A) Rapid plasma reagin (B) HIV-1 p24 antigen (C) Hepatitis C antibody (D) Tuberculin skin testing (E) Beta-2 microglobulin

49. Question # 4 • A 23-year old HIV-infected woman comes to your office because she has noticed painless white lesions in her mouth when brushing her teeth. She is taking no medications. Her last CD4 count 2 months earlier was 520/microliter. On physical examination, she has patches of white, linear, frondlike lesions along both lateral surfaces of the buccal mucosa; the lesions do not scrape off with a tongue blade. Scraping from the surface of the buccal mucosa reveal a few yeast forms in a microscopic wet mount prepared with potassium hydrochloride.

50. Question # 4 • The likeliest diagnosis is: (A) Hairy oral leukoplakia (B) Oral candidiasis (C) Aphthous stomatitis (D) Acute necrotizing ulcerative gingivitis