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.
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
Human Immunodeficiency Virus An RNA retrovirus – subfamily Lentivirus Contains: 2 copies of RNA Enzymes: Reverse Transcriptase Integrase Protease Two major envelope proteins: gp120 gp41
Life Cycle of HIV virus 1. Interaction between viral envelope proteins and CD4 receptor and co-receptors leads to binding of the viral envelope and host cytoplasmic membrane 2. Viral reverse transcriptase catalyses the conversion of viral RNA into DNA 3. Proviral DNA enters the nucleus and becomes integrated into chromosomal DNA of host cell (catalyzed by integrase) 4. Expression of viral genes leads to production of viral RNA and proteins. 5. Protease enzyme cleaves proteins into functional mature products. 6. Viral proteins and viral RNA are assembled at the cell surface into the new viral particles and leave the host through budding.
Human Immunodeficiency Virus – Lifecycle in Host Cell
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
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
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
Thrush If plaques wiped off with gauze, erythematous, often bleeding mucosa will be revealed.
Oral Hairy Leukoplakia Associated with EBV infection Does not rub off.
Bacillary Angiomatosis Caused by Bartonella species
Herpes Zoster “Shingles” Caused by Varicella
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.
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!
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)
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 (PaO 2 ) is 70 or less OR If alveolar/arterial (A-a) gradient is 35 mm Hg or more.
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
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/mm 3 Clinical Manifestations: CNS infection: Ring-enhancing cerebral lesions Meningitis Chorioretinitis Pneumonitis Fever, dyspnea, cough Reticulonodular infiltrates (appears similar to pneumocystis) Treatment: Pyremethamine Prophylaxis: Bactrim
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!
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
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
Treatment of HIV Anti-retrovirals Infection prophylaxis
Antiretrovirals – When to Start Therapy Symptomatic HIV DiseaseAntiretroviral therapy recommended Asymptomatic HIV Disease CD4 count ≤ 200Antiretroviral therapy recommended CD4 count > 200 but <350Antiretroviral therapy should be considered and individual decision (if viral load > 100,000) CD4 count ≥ 350Antiretroviral therapy generally not recommended
Human Immunodeficiency Virus – Lifecycle in Host Cell
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
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
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
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!
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
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
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.
Question # 1 The most likely diagnosis is: (A.) Kaposi’s sarcoma (B.) Pyogenic granulomas (C.) Bacillary angiomatosis (D.) Secondary syphilis (E.) Cutaneous cryptococcosis
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.
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.
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.
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
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.
Question # 5 A 34-year old HIV-seropositive man with a CD4 count of 89 comes to your office with a 2-week history of progressive headache and subjective fever. Current medications include dapsone, 200 mg po QDay; Zidovudine, Didanosine, and Nevirapine. A serologic test for antibodies to Toxoplasma gondii obtained 2 years ago was positive (titer 1:32)
Question # 5 Physical examination is remarkable for mild weakness in his left arm and temperature of 39°C; A contrast-enhanced CT scan shows multiple enhancing lesions in the right cerebral hemisphere.
Question # 5 What is the most appropriate next step in management? (A.) Initiate therapy with pyramethamine- sulfadiazine (B.) Obtain an MRI (C.) Consult a neurosurgeon for brain biopsy (D.) Obtain a PET scan (E.) Repeat the serologic test for toxoplasmosis to assess the change in titer.
Question # 6 A 28-year old married woman states at the end of a visit for mild knee pain that she would like an HIV test. Brief review of her HIV risk factors confirms that neither she nor her husband uses drugs. She was last sexually active with a man other than her husband in college. She has had no extramarital relationships and believes her husband also is monogamous.
Question #6 The best response to this patient’s request is to: (A) Explain that the expense of the HIV test is unjustified given her negligible risk. (B) Order a CD4 cell count as a proxy for HIV testing. (C) Order quantitation of viral RNA by polymerase chain reaction (PCR) as a more precise assessment of HIV status. (D) Order an HIV antibody test by enzyme-linked immunosorbent assay (ELISA) with a confirmatory Western blot.