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Introduction to HIV AIM • • • • • • • • Epidemiology Testing for HIV infection Natural history of disease When to start ART (guidelines/trends in the field) Antiretroviral agents Common toxicities Opportunistic infections OI prophylaxis Global summary of the AIDS epidemic, 2008 Number of people living with HIV in 2008 People newly infected with HIV in 2008 AIDS-related deaths in 2008 December 2009 Total Adults Women (aged 15 and above) Children under 15 years 33.4 million [31.1 – 35.8] 31.3 million [29.2 – 33.7] Total Adults Children under 15 years 2.7 million [2.4 – 3.0] 2.3 million [2.0 – 2.5] 430 000 [240 K – 610K] Total Adults Children under 15 years 2.0 million [1.7 – 2.4] 1.7 million [1.4 – 2.1] 280 000 [150 K – 410 K] 15.7 million [14.2 – 17.2] 2.1 million [1.2 – 2.9] Case • 23-year old woman presents to Emergency Department with one week history of fever, malaise, myalgias, headache and sore throat • Five days PTA she noted the onset of a new non-pruritic rash, on her face, torso, extremities • Two days PTA developed mouth sores that were so painful she was unable to eat or drink • PMH- negative • Soc Hx- sexually active, single, in grad school Case • Physical Examination in ED T 40oC. BP 104/76 P 108 R 20 Appears unwell HEENT: Multiple oral ulcerations Non-exudative pharyngitis Multiple cervical nodes (slightly tender) Diffuse maculopapular Rash Case • Laboratory data in ED • H/H12/36 • WBC 3100 (65 segs, 25 lymphs, 6 atyp lymphs, 4 monos) • Platelets 71,000 • ALT 124, AST 75 • Urine drug screen negative • All other labs normal Differential Diagnosis • • • • • • • • Infectious Mononucleosis CMV HIV Enterovirus- Coxsackie Adenovirus Streptococcal pharyngitis Arcanobacterium hemolyticum Syphilis Principles of testing • HIV infected patients produce antibodies which recognize HIV proteins • • • • ELISA Western Blot Immunofluorescence Radioimmunoprecipitation Figure 6 Proteins Detected by HIV Western Blot R tat pol 5’ U5 IN PRO p17 p24 gag HIV-1 }gp160/120{ p61POL p55GAG p51POL gp41ENV rev 3’ RT vif vpr vpu env gp120 env gp41 nef U3 R HIV-2 }gp135/120ENV{ p61POL p55GAG p51POL p24GAG gp36ENV p31POL p30GAG p17GAG p18GAG p31POL Interpretation of Western Blot – Positive: ANY Two: p24, gp41, gp160/120 – Negative: NO positive bands – Indeterminate: the remainder • Isolated p24 band most common indeterminate • Isolated gp160/120 band suspicious for early infection • A 38 year old multiparous nurse is evaluated because of an abnormal ELISA for HIV when she attempted to donate blood. A follow up Western Blot analysis has an indeterminate result. The patient is asymptomatic. She and her husband have a monogamous relationship and neither have used illicit drugs. Patient has never received a blood transfusion, and reports a needle stick injury approximately 8 years ago from an HIV negative individual. Her physical examination is normal, her CD4 count is normal, but her plasma viral load is 82 copies/ml. Which of the following is the most appropriate management at this time? – – – – Recheck the plasma viral load now Recheck the HIV serologic study in 3 months and 6 months Begin HAART Begin HAART if her CD4 count drops to <350/µL WB Interpretation Indeterminate False Negative • Window period • • Common variable immunodeficiency NOT Subtype – Newest assays should identify even O • • • • • • • • • • • Infections (HIV-2 , HTLV-I, schisto) Neoplasms Dialysis Ethnicity-Africans Thyroiditis Elevated Bilirubin Rheumatologic diseases Multiple pregnancy Immunization (Tetanus, HIV) Nephrotic proteinuria (massive) Error in laboratory HIV Infection Profile rev 5’ R tat pol U5 IN PRO p17 p24 gag 3’ RT vif vpr vpu env gp120 env gp41 nef U3 R Anti-Env antibody Relative Level HIV RNA Detection limit P24 antigen Time Post-Infection Natural history of the disease • Seroconversion- Median time from exposure to antibody-63 days (4 -10 wks) • Clinical latent period • Average rate of decline of CD4 cells after 1 yr is 50 cells (range- 30-90)- correlated with the viral load • PGL • Early symptomatic HIV infection • AIDS HIV Transmission Factors • • • • • • Stage of the disease Viral load STD Genital lesions Frequency of unprotected sex Circumcision Case • A 35 year old asymptomatic male with a CD4 count of 325, viral load of 15,000 presents to the clinic for routine evaluation. Hepatitis testing reveals that the patient has a positive HBsAg, AST-80 and ALT of 85. Which of the following is the most appropriate ART regimen – – – – Delay treatment till he is symptomatic Begin azt/3tc/efv Begin abc/3tc/efv Begin tfv/ftc/efv Response To Therapy • • • • Potency of antiretroviral therapy Lower viral load Higher CD4 count Rapid reduction in plasma viral load in response to therapy • Approximately 70% achieve this goal and 80% of patients in clinical trial settings achieve this goal Indications to start ART CD4 BASED IRRESPECTIVE OF CD4 COUNT • ART is recommended for patients with CD4 counts between 350 and 500 • History of an AIDS defining illness • HIV associated nephropathy • Concomitant hep B with indications to initiate hep B treatment • Pregnancy • 50% of the panel members would start ART in patients with CD4 counts greater than 500 Probability of AIDS/Death Life Cycle of HIV Furtado MR et al. NEJM 1999;340:1614-22. Life Cycle of HIV Maturation inhibitors Fusion Inhibitor CCR5 INHIBITORS PI NRTI NNRTI INTEGRASE INHIBITORS Furtado MR et al. NEJM 1999;340:1614-22. Current Antiretroviral Medications NRTI • • • • • • • • Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zidovudine Zalcitabine Tenofovir NNRTI PI • • • • • • • • – soft gel – hard gel First • • • Delavirdine Efavirenz Nevirapine Second • Etravirine Amprenavir Fosamprenavir Atazanavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir • • Tipranavir Darunavir Fusion inhibitor Enfurtivide Integrase inhibitor Raltegravir CCR5 inhibitor Maraviroc Drugs in the pipeline • NNRTI inhibitors Rilpivirine •Integrase inhibitors • CXCR4 inhibitors • Maturation inhibitors Elvitegravir • CD4 blockers •CCR5 inhibitors Vicriviroc Initial Treatment: Preferred Components NNRTI • Efavirenz PI • Boosted Atazanavir • Boosted Darunavir INTEGRASE • Raltegravir NRTI • Tenofovir • Emtricitabine Initial Treatment: Alternative Components NNRTI • Nevirapine PI • Lopinavir/Ritonavir • Boosted Fosamprenavir •Boosted Saquinavir NRTI • Abacavir • Zidovudine • Lamuvidine Drugs with activity against hepatitis B and HIV activity • • • • Tenofovir Emtricitabine Lamuvidine Entecavir NRTI • Toxicities – Bone marrow toxicity, macrocytic anemia, neutropenia GI-nausea, vomiting-AZT – General-headache, insomnia, asthenia-AZT – Lactic acidosis-D4T>DDI>AZT>TFV/ABC – Pancreatitis-DDI& D4T – Peripheral neuropathy-DDI/D4T>AZT>TFV – Lipoatrophy/lipodystrophy-D4T – Myopathy (including cardiomyopathy)-AZT – Hyperlipidemia-D4T>AZT>TFV/ABC – Rapidly progressive ascending muscle weakness-D4T NRTI • Abacavir – – – – Abacavir hypersensitivity reaction Fever, Rash HLA type association with abacavir hypersensitivity CAD • Tenofovir – – – – – Fanconi syndrome Renal insufficiency Dosage adjustment for Crcl<50 Bone abnormalities in monkeys and ?fetal risks ? osteopenia Non-Nucleoside Reverse Transcriptase inhibitors (NNRTI) • Efavirenz – – – – CNS toxicity Rash Teratogenicity False positive cannabinoid reaction • Nevirapine – Hepatotoxicity – Highest risk in women whose CD4 count was greater than 250 at the time of NVP initiation (11.0% vs 0.9%) – Men with CD4 counts greater than 400 (6.3%vs 1.2%) – Rash, with reports of TEN and SJS Protease inhibitors • Metabolic toxicities – – – – – – – – – – – Hyperlipidemia/Hypertriglyceridemia-RTV Hyperbilirubinemia-ATZ and IDV Nephrolithiasis-IDV (a few case reports with ATZ) Pyuria and Interstitial nephritis-IDV Hyperglycemia-IDV and LPV/RTV Diarrhea-LPV/RTV (cap)& NFV CAD Lipodystrophy Drug drug interactions Increased bleeding among hemophiliacs PR interval prolongation-ATZ Life threatening toxicities • • • • Abacavir hypersensitivity reaction Lactic Acidosis with NRTI Nevirapine related hepatotoxicity Steven Johnson’s syndrome Fusion inhibitors • Injection site reaction almost universal • Hypersensitivity reaction <1%- do not rechallenge • Increased rate of bacterial pneumonia • A 35 year old female with HIV infection presents to the office. She was diagnosed with PCP and at that time had a CD4 count of 92/µL, viral load105,000 copies/ml. AZT/3TC/EFV was initiated and 6 months post therapy her CD4 count was 323/µL and her VL was ND. Approximately 1 year ago she started missing appointments and 4 months prior her VL was 878 copies/ml and today her CD4 count is 300/µL and her VL is 5375 copies/ml. She remains asymptomatic. Which of the following is the most appropriate management? – – – – – Continue the current regimen Substitute Nevirapine for Efavirenz Add Nevirapine to the current regimen Order an HIV genotype resistance assay Recommend a drug holiday until she becomes symptomatic. DHHS guidelines • Monitoring of therapy – Average gains- 50-150 cells/first year and 50- 100 cells/year (assuming viral control) thereafter until a set point is reached – Viral load suppression to below undetectable should be achieved in 16-24 weeks in an ARV naïve patient – A 1 log decline in viral load in 2-8 weeks – Viral suppression in 12-24 weeks Pathogen Indication Preferred Alternative PCP CD4<200, oropharyngeal candidiasis Bactrim DS qd Bactrim SS qd Bactrim 1 DS triweekly Dapsone Aero-pentamidine Atovaquone Toxoplasmosis CD4<100 Pos Toxo serology Bactrim DS qd Bactrim 1 SS qd Dapsone+pyrimethamine and leucovorin Atovaquone/pyrimethamin e/leucovorin M.tuberculosis TST>5mm INH-300 mg po Exposure to active TB qd Prior pos untreated TST Rifampin-600 mg po qd M.Avium intracellulare CD4<50 Rifabutin-300 qd Azithro-1200 q weekly Claritho-500 bid Opportunistic Infections • • • • Fever and Pulmonary infiltrate CNS manifestations Ophthalmologic manifestations Diarrhea Fever and Pulmonary infiltrate • A 32 year old male presents to the clinic with a 2 week history of non-productive cough, worsening SOB and fever. The patient was recently diagnosed with HIV and his CD4 count is 150 cells/µL. • O/E- HR-100, RR-22, T-100, Pulse ox-85% RA. • RS- examination reveals a few scattered rales and rhonchi. Differential Diagnosis • • • • • • • • • • • • PCP- the most commonly diagnosed OI in North America M.tuberculosis Community acquired pneumonia C.neoformans H.capsulatum C.immitis R.equi Atypical Mycobacteria (M.kansasii) HSV CMV KS Malignancies Case • A 40 year female is bought in by her family. Over the past few weeks her family has noticed that she has been forgetful, lethargic and confused. The patient has a CD4 count of 35 and has not been on ART or prophylaxis. • Examination reveals a right sided hemiparesis and VII nerve palsy Differential Diagnosis By Presenting Symptoms, Exam Findings Focal - Toxoplasmosis Lymphoma PML Cryptococcoma VZV Meningovascular syphilis Other (TB, fungal) Nonfocal - Cryptococcal meningitis CMV encephalitis AIDS dementia Lymphomatous meningitis - Other (TB, fungal) Is This CNS Toxoplasmosis? Factors that lessen the likelihood: - On TMP-SMX or other prophylaxis CD4 count > 100/μl Negative serologies Solitary lesion on MRI (multiple and bilateral lesions more c/w toxo) - No contrast enhancement - No MRI improvement on 2-3 weeks of therapy - Uptake on SPECT Primary AIDS-Related CNS Lymphoma Mean CD4 = 30/μl EBV associated RARE among HIV negative patients about 2% of AIDS patients Evolution: 2-8 weeks Survival after diagnosis is usually limited to months PCR of CSF is usually positive for EBV Case • 32 year old african american male last documented CD4 count of 10 presents to the clinic with symptoms of lethargy, headache and a skin rash. O/E- he is awake, but appears minimally lethargic, there is no neck stiffness. CSF exam-reveals a WBC count of 3, protein100, glucose-30. Case • A 35 year old AA male with a CD4 count of 65 presents to the clinic with c/o progressive loss of vision and left sided hemiparesis. A LP and MRI are performed. PCR of the CSF is positive for JC virus. Which of the following is the most appropriate treatment for this patient – – – – 1-Start acyclovir 2-Start radiation and dexamethasone 3- Start sulfadiazine and pyrimethamine 4-Start HAART • A 40 year old male with AIDS presents with a 1 days history of blurred vision and a several hour history of acute loss of vision in the right eye. On physical examination, vitals signs are normal. Pupils are equal and readily reactive to light. Examination of the right fundus shows a localized area of hemorrhagic necrosis of the fovea. The remainder of the examination is normal. There are no exudates and no uveal disorders. After hospitalizing the patient, which one of The following intravenous agents is most appropriate? Bactrim Acyclovir Gancyclovir Penicllin A corticosteroid Case • A 35 year old male with a CD4 count of 45 presents to the clinic with a 1 week history of blurred vision, floaters in his right eye. There is no pain or photophobia, external examination is normal, fundoscopy reveals. http://hivinsite.ucsf.edu/InSite Case • Which one of the following antivirals would you like to use – Valgancyclovir – Gancyclovir – Acyclovir – Valacyclovir Case • A 45 year old HIV positive male whose CD4 count is 78 presents to the clinic with c/o diarrhea. The diarrhea is non-bloody, painless. He denies fevers. He states that his he recently acquired a puppy. His labs reveal normal electrolytes and a Hb-12.5. His serum alkaline phosphatase is also within normal limits. Stool cultures are negative Protozoal Agents positive on AFB staining Isospora Cyclosp Cryptospo Microsporid ora ridium ium Size (μ) 20-30 Mod afb Positive Positive Positive Therapy Tmp-smx, 8-10 Tmp-smx, cipro, cipro pyrimetha mine 4-6 HAART, paromomycin, nitazoxinide 1-5 Negative albendazole Case • A 18 year old male previously treated for TB with ATT was recently diagnosed with HIV. He is started on an AZT/3TC/Nevirapine based regimen. Approximately 3 weeks after starting ART he presents to the clinic with worsening SOB. His CD4 count at ART initiation was 55 cells/µL and viral load is 85,000 copies/ml. His viral load at presentation was 85 copies/ml. Immune Reconstitution Inflammatory Syndrome (IRIS) – Seen after HAART with immune recovery – M.tuberculosis, Cryptococcus, CMV, MAC, PML, – Manifest with rheumatologic manifestations as well as Graves disease – Continue HAART and treat underlying infection if possible – Sometimes need steroids to decrease inflammation References • Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services.. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentsGL.pdf. • • Clotet B et al Lancet 2007;369:1169-1178Efficacy and safety of darunavir-ritonavir at week 48 in treatment experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials. The stages and natural history of HIV infection J. Bartlett-Uptodate • SMART study group NEJM 2006;355:2283-2296 CD4+ Count-Guided Interruption of Antiretroviral Treatment • Cooper D et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB. • Steigbigel R et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB. • Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104. References • • • • • • • • Selzentry- prescribing information http://media.pfizer.com/files/products/uspi_maraviroc.pdf, accessed aug 21,2007 HIV drug resistance database http://hivdb.stanford.edu accessed Aug 18,2007 Shafer RW Clinical Microbiology Reviews Apr 2002;15: 247-277 Genotype testing for Human Immunodeficiency Virus type I drug resistance Slides from the Personal Collection of Dr. Maldarelli Principles and Practices of infectious Diseases MKSAP 14 2002 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons infected with the HIV virus http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2009 Treating opportunistic infections among HIV infected adults and adoloscents- December 17,2004 http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2008