WHO/UNAIDS

HIV and Tuberculosis

WHO/UNAIDS

Global Funding for HIV Prevention and Treatment by 2008

Human Immunodeficiency Virus Type 1

HIV reverse transcription doubled-stranded provirus integration

Human Immunodeficiency Virus Type 1 host cell membrane binding

Serologic and Virologic Markers Following HIV Infection

Diagnosis of HIV infection

Enzyme immunoassay for IgG antibodies to HIV1/2: > 99% sensitive and specific positive at varying time after primary infection requires confirmation with Western Blot usually one to two days for positive result Rapid enzyme immunoassay: saliva, blood or plasma results in 20-30 minutes (ED, STD clinics, testing ctr) confirmation (sensitivity/specificity lower ~ 96%) negative result = true negative

HIV Western Blot

Diagnosis of HIV infection

Nucleic acid testing (NAT): Qualitative HIV RNA PCR Quantitative HIV RNA PCR Specific uses: diagnosis of acute HIV in window period diagnosis of maternal-fetal transmission in the baby patients with indeterminate serologic test results monitoring clinical response on antiretroviral therapy

Stages of HIV-1 infection

Viral transmission Primary HIV infection (weeks to months) Seroconversion (weeks to 6 months in > 95%) Clinical latent period (years) Early symptomatic HIV infection (months years) AIDS Advanced HIV infection (CD4 T cell count < 50 cells/mm3)

Conditions defining an AIDS Diagnosis - 71,104 patients in 1997

HIV-1 Transmission Sexual semen, vaginal secretions Parenteral: blood transfusion, contaminated needles, needlestick Maternal fetal: intrauterine, perinatal, postnatal (e.g. breastfeeding) Urine, saliva, stool, sweat not considered infectious body fluids

Risk Factors for HIV-1 transmission

HIV RNA level (viral load) Active sexually transmitted disease (especially ulcerating) Sexual practice (no. sex partners, unprotected receptive anal intercourse) Lack of circumcision

Cases

Primary (Acute) HIV infection

HIV penetrates cervico-vaginal epithelium Free virus binds to tissue macrophages/dendritic cells Transport to regional lymph tissue CD4 cell contact GP120 binds to CD4 conformational change GP120/CD4 complex binds to CCR5 exposing GP41 Internalization of viral receptor complex Uncoating of lipid envelope with release of viral RNA CD4 cells activated, viral DNA integrated, active replication Resting CD4 memory cells Viremia dissemination to multiple lymphoid organs

Primary HIV infection

J. Clin. Invest. 113:937

Host Immune Response to Primary HIV-1

Unrestricted viral replication high viral load Humoral immune response (weeks to months) Cellular immune response: Cytotoxic T lymphocytes (CD8) NK cells T helper cells (CD4) Immune activation Failure to protect and control primary HIV-1 infection Long-term non-progressors Elite controllers

CD4 cell effects of HIV-1 infection

Differential diagnosis of Primary HIV

Epstein Barr virus infection (mononucleosis) Cytomegalovirus infection Syphilis Toxoplasmosis Disseminated gonococcal infection Rubella Other viral exanthems Viral hepatitis

Diagnosis and treatment of primary HIV

Presentation is non-specific (mononucleosis-like) Symptoms usually resolve Public health issues for patient and society Sexual history/drug use Self-perception of risk lack of knowledge about HIV Benefits of treatment not clearly established Risks of early treatment Follow-up test results Increasing risks of transmitted drug resistance

Diagnosis and treatment of primary HIV

Sexual history Drug use Travel history Tests order: heterophile antibody in serum (r/o EBV) RPR lumbar puncture if symptoms of meningitis HIV-1 serology (positive 3 7 weeks post-exposure) HIV RNA PCR in serum Thorough physical exam

Treatment of primary HIV

Counsel on behaviors to prevent transmission ( viral load) Avoid sharing needles IVDU Possible early treatment benefits: preservation of HIV-specific cellular immune responses establish lower viral load set point reduced risk of viral transmission Possible risks: drug toxicities due to longer duration of therapy progressive drug resistance (mutations) Refer to HIV specialist, clinical trial, or treat (indefinitely)

Factors associated with HIV progression

CD4 cell count: normal > 500 cells/mm3 average decline in HIV ~ 50/mm3/year HIV RNA levels: higher levels may correlate with more rapid CD4 decline Symptoms during primary infection Viral fitness and replication capacity Co-receptor use: CCR5 versus CXCR4 Viral phenotype: syncytium vs. non-syncytium-producing Co-infection with other organisms: HCV, Tuberculosis Injection drug use

Course of untreated HIV-1 infection

Fauci et al. Annals. I.M 1996

CDC and WHO staging of HIV infection

Stage 1: CD4 > 500 cells/mm3 asymptomatic, +/- lymphadenopathy Stage 2: WHO = CD4 350 500 cells CDC = CD4 200 500 cells Stage 3: WHO = CD4 200 350 cells CDC = CD4 < 200 cells Stage 4: WHO = CD4 < 200 cells

Stage 2 (CDC)/Stage 2-3(WHO) CD4: 200 500 cells

Seborrheic dermatitis Herpes zoster Papular pruritic dermatitis Oropharyngeal candidiasis Weight loss Anemia, neutropenia, thrombocytopenia Bacterial pneumonias tuberculosis

Group A Strep culture negative, probably viral, pharyngitis

Group A Streptococcal Pharyngitis

Stage 3 (CDC)/Stage 4 (WHO) CD4 < 200 cells/mm3

Risk of specific opportunistic infections CD4 count < 50 cells: Cytomegalovirus retinitis, colitis, encephalitis Toxoplasma encephalitis Progressive multifocal leukoencephalopathy (PML) Disseminated mycobacterium avium (MAI) HIV encephalopathy Geography: Cryptococcus and tuberculosis in Africa Histoplasmosis in U.S. Midwest Leishmania in Central, South America, Mediterramean

Case

Pneumocystis pneumonia in HIV patient

Silver stain of cysts of Pneumocystis jirovecii in lung tissue

Treatment and Prevention of PCP

Treatment: 1. Not acutely ill; PO2 >70mmHg trimethoprim/sulfa oral 2. Ill with PO2 < 70mmHg IV trimethoprim/sulfa steroids 3. Alternate regimens: pentamidine IV atovaquone oral Prophylaxis: 1. Trimethoprim/sulfa one double strength tablet daily 2. dapsone 100 mg oral daily 3. atovaquone 1500 mg oral daily

Pulmonary manifestations of HIV infection

Common: bacterial, pneumocystis, tuberculosis Less common: Mycobacterial MAI, Fungal Cryptococcus, Histoplasma, Coccidioides, Penicillium marneffei, Blastomycosis Viral Cytomegalovirus, Herpes simplex Non-infectious Kaposis sarcoma, non-Hodgkins lymphoma, lung cancer

Neurological complications of HIV

Meningeal syndromes: aseptic meningitis; syphilis; cryptococcal meningitis Cognitive and motor syndromes: HIV-associated neurocognitive disorder (HAND) (AIDS dementia, AIDS encephalopathy) Central Nervous System mass lesions: Toxoplasma encephalitis; primary CNS lymphoma; PML Peripheral nervous system syndromes: distal sensory polyneuropathy; polyradiculopathy

38 yo male with HIV infection and toxoplasma encephalitis

Primary central nervous system lymphoma in 45 yo with HIV

Diagnostic evaluation of CNS mass lesion(s) in HIV patients

Management of CNS mass lesions in HIV

Toxoplasma: no diagnostic test except biopsy (rarely done) positive serum serology (anti-toxoplasma IgG) CNS lymphoma: CSF Epstein Barr virus DNA PCR Biopsy Treatment decisions: Multiple lesions treat for toxoplasma and monitor Single lesion and no LP biopsy/empiric toxo treatment Steroids if mass effect Pyrimethamine/sulfa plus leucovorin for toxoplasma Secondary prophylaxis with P/S after recovery and until CD4>200

CMV retinitis in HIV infection

CMV retinitis in HIV

AIDS-defining condition; CD4< 50 cells/mm3 Pre-HAART: 20 40% incidence Post-HAART: rare in patients on therapy Pathogenesis: CMV reactivation; viremia Pathology: full-thickness retinal necrosisscar Symptoms: floaters, blurring, flashing lights Complications: blindness; retinal detachment; second eye involvement Diagnosis: direct exam Treatment: IV ganciclovir or oral valganciclovir ocular implant slow release ganciclovir(8mths) ocular injection Foscarnet

Management of HIV: treatment naive patient

Accurate diagnosis Screening for opportunistic infections and malignancy Assessment for non-HIV co-morbidities Health insurance Family/partner issues Substance abuse Immigration status Communication language barriers Mental health Pregnancy and childhood HIV Work-related limitations (appointments for follow-up)

Introduction of protease inhibitors in patients with HIV and < 100 CD4 cells N. Engl. J. Med. 338 (1998)

Decision to begin antiretroviral therapy

All patients or according to CD4 cell count (early vs. delayed) Goal: improve disease-free survival suppress viral replication improve immunologic function prevent resistance prevent transmission Arguments favoring early initiation: many treatment options more potent drugs decreased drug toxicity fewer pills improved adherence improvement in overall health earlier treatment improves immunologic recovery (higher CD4 counts) decreased transmission (public health benefit)

Decision to begin antiretroviral therapy

Arguments against early treatment: long-term toxicity development of drug resistance effects on quality of life cost of HIV care Current recommendations: (DHHS expert committee) 1. Start ART in all patients with CD4 < 500 cells/mm3 2. No consensus yet on patients with CD4 > 500 cells/mm3 3. All pregnant patients regardless of CD4 count

Initiating HAART
CD4 count, HIV RNA PCR quantitative Drug resistance genotype or phenotype Screen for hepatitis B,C, tuberculosis, sexually-transmitted disease Pregnancy test Complete physical exam Selection and discussion of specific drugs, schedule, adherence Assurance of availability if side effects or questions Follow-up plan

Antiretroviral drug classes

Nucleoside (nucleotide) reverse transcription inhibitors Nonnucleoside reverse transcription inhibitors Protease inhibitors Integrase strand transfer inhibitors CCR5 antagonists

Target sites for anitretroviral drugs in HIV infection

Choosing a ART regimen

1. three active drugs of 2 or more different classes 2. standard is: backbone = two NRTI drugs base = NNRTI or PI or integrase inhibitor 3. PI drug is boosted with low dose ritonavir (PI) four drugs but ritonavir at subtherapeutic dose 4. Barrier to drug resistance higher with PI vs. other drug classes

Currently recommended regimens

1. PI-based: tenofovir + emtricitabine one tablet daily (Truvada) darunavir 800mg once daily or 600mg twice daily ritonavir 100mg once daily or 100mg twice daily or tenofovir + emtricitabine one tablet daily (Truvada) atazanavir 400mg once daily or 300mg once daily ritonavir 100mg once daily (with 300mg atazanavir)

Currently recommended regimens

2. NNRTI-based: Efavirenz 600mg tablet oral once daily tenofovir + emtricitabine one tablet oral daily or Atripla combination of three drugs in one tablet 3. Integrase inhibitor-based: tenofovir + emtricitabine one tablet oral daily raltegravir 400mg tablet oral twice daily

Expected side effects of standard regimens

NRTIs: GI nausea, vomiting, diarrhea anemia (zidovudine) peripheral neuropathy (didanosine, stavudine) lactic acidosis (rare) renal injury (tenofovir) metabolic syndrome NNRTIs: (with efavirenz) insomnia, bad dreams, dizziness hepatic necrosis (nevirapine)

Expected side effects of standard regimens

Protease inhibitors: GI nausea, diarrhea (especially ritonavir, lopinavir) metabolic syndrome weight gain, glucose intolerance - lipid abnormalities elevation of indirect bilirubin (atazanavir)

Special indications for HAART

Pregnancy: Protect mother and prevent maternal-fetal transmission All pregnant HIV infected women should be treated Choice of drugs limited by safety concerns for the fetus Limited pharmacologic data for newer drugs Antepartum, intrapartum and post-partum HAART for child (zidovudine, +/- other) Breastfeeding: resource-rich countries defer resource-poor maternal and/or infant antiretroviral prophylaxis for entire breastfeeding period + one week

Special indications for HAART

Pre-exposure prophylaxis: animal studies show protection by all routes human study results in MSM and uninfected women not conclusive CDC interim guidelines apply only to high-risk MSM tenofovir-emtricitabine recommended drug combination risks: drug resistance non-adherence increased high-risk behaviors