Nothing to disclose.

Lisa G. Winston, MD University of California, San Francisco San Francisco General Hospital HIV UPDATE FOR THE PRIMARY CARE PROVIDER Nothing to disclose. 1

Outline Epidemiology Screening / testing for HIV Prevention Evaluation of new adult patients Antiretrovirals Monitoring and ongoing care In the hospital Conclusions 2

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Fast facts CDC: More than 1.2 million people in the U.S. are living with HIV infection About 1 in 7 (14%) are unaware of being infected Youth aged 13-24 years account for 1 in 4 (26%) new HIV infections v Most (72%) occur in males who have sex with males v Almost 60% are unaware of being infected Who should be screened for HIV in the United States? 1. Screen based on risk factors including MSM, persons with sexually transmitted infections, multiple sexual partners, injection drug use 2. Pregnant women 3. 1 & 2 4. 1 & 2 plus all patients ages 13 64 who have ever been sexually active 4

Screening for HIV in the U.S. In 2006, CDC recommended opt- out HIV testing as routine medical care for all ages 13 64 who have ever been sexually active ú Unless the local prevalence is < 0.1% (usually unknown) ú Persons at high risk should be screened at least annually ú Separate written consent should not be required ú Prevention counseling should not be required ú HIV testing routinely provided as early as possible in each pregnancy; rescreening in the third- trimester is recommended in certain areas ú Screening is also reasonable in adults 65 and older who are sexually active MMWR 2006;55(RR- 14):1-17 U.S. preventive Services Task Force April 2013: recommended HIV screening for all persons ages 15 65 ú Similar to CDC recommendations Younger adolescents and older adults at increased risk may also be screened Pregnant women should be screened Data insufficient to recommend interval ú Consider yearly for high risk ú Consider 3-5 years for increased risk 5

Testing for HIV You are seeing a 22 year- old female college student a second time for follow up of fever, sore throat, rash, and anterior cervical lymphadenopathy. Monospot and testing for group A streptococcal pharyngitis were negative, and her symptoms have persisted for five days. She is sexually active with one male partner and does not use condoms. What testing for HIV is appropriate? Testing for HIV 1. Do not test for HIV. A viral diagnosis other than HIV is much more likely. She is at risk for a false positive test. 2. Order a combination antigen/antibody immunoassay. 3. Order a rapid HIV antibody test. 4. Order a rapid HIV antibody test. If it is negative, confirm result with a Western blot. If this is negative, order an RNA PCR assay for HIV. 6

June 2014: http://www.cdc.gov/hiv/pdf/hivtestingalgorithmrecommendation-final.pdf June 2014: http://www.cdc.gov/hiv/pdf/hivtestingalgorithmrecommendation-final.pdf 7

Laboratory testing for HIV HIV- 1/2 antigen/antibody combination assay now recommended ú At least one test with turn around time < 30 minutes for initial result Western blot and immunofluorescence assay (IFA) no longer recommended for confirmation ú False negative or indeterminate results early ú HIV- 2 misclassified as HIV- 1 Clinical Laboratory Improvement Amendments (CLIA) - waived tests Specimen types ú Fingerstick or venous whole blood ú Oral fluids Can be performed by non- laboratorians Quick turn around time Point of care ú Test results delivered Oral fluid tests less sensitive and specific 8

HIV Prevention Male condoms ú With consistent use in heterosexual serodiscordant relationships, likelihood of HIV seroconversion about 80% lower Cochrane Database Syst Rev. 2002;(1) Female condoms about as much protection as male condom against several STIs (? HIV) Clin Infect Dis. 2011;53(S3):S64-78 Male circumcision 3 randomized trials in Africa and observational data - > 50% protective effect for heterosexual HIV acquisition in men Preexposure Prophylaxis Early antiretroviral (ART) treatment of HIV- infected partner with serodiscordant couples ú Enrolled 1763 couples in 9 countries ú Immediate treatment arm had 96% lower risk of acquiring HIV from partner N Engl J Med 2011;365:493-505 (HPTN 052 trial) 9

Preexposure Prophylaxis (PrEP) Tenofovir + emtricitabine (Truvada) orally once daily in HIV- negative men who have sex with men ú 2499 people randomized in 6 countries ú 44% reduction overall in incidence of HIV NEJM 2010;363:2587-99 (iprex trial) Tenofovir orally once daily in HIV- negative injection drug users in Thailand ú 49% reduction in incidence of HIV Lancet 2013;381:2083-90 Tenofovir vaginal gel studies with mixed results Preexposure Prophylaxis (PrEP) Identify those who may benefit ongoing high risk ú MSM with condomless receptive anal sex ú MSM with multiple anal sex partners ú MSM with syphilis or rectal gonorrhea or chlamydia ú MSM with one or more HIV- positive sex partners ú Heterosexual men and women with one or more HIV- positive sex partners ú Selected injection drug users 10

Postexposure Prophylaxis A 20- year old man without known HIV infection presents 12 hours after participating in oral sex with another man without a condom. The other man s mouth contacted this man s penis. The other man is known to have HIV infection. Would you provide post exposure prophylaxis? 1. Yes 2. No Postexposure Prophylaxis Post exposure prophylaxis recommended for persons seeking care after significant non- occupational exposures to blood, genital secretions, or other infectious body fluids of a person known to be HIV infected ú 28- day course ú Initiate as soon as possible ú 3- drug regimen in most cases: new - tenofovir + emtricitabine (Truvada) + raltegravir MMWR 2005;54(RR02):1-20 New York State Dept of Public Health AIDS Institute http://www.hivguidelines.org/clinical- guidelines/post- exposure- prophylaxis/hiv- prophylaxis- following- non- occupational- exposure/ 11

MMWR 2005;54(RR02):1-20 Postexposure Prophylaxis - occupational Revised guidelines for occupational postexposure prophylaxis Key changes from previous guidelines: ú Use 3 drugs for all exposures ú Usual preferred regimen is tenofovir + emtricitabine (Truvada) + raltegravir No change from previous: start as soon as possible, continue for 28 days Infect Control Hosp Epidemiol 2013;34:875-92 12

Number of confirmed cases (N = 58) of occupationally acquired HIV infection among health care workers reported to CDC United States, 1985 2013 *150 possible cases Laboratory technician needle puncture working with live HIV culture MMWR 2015 / 63(53):1245-6 Evaluation of new patients In addition to measurements of CD4 cell count and HIV viral load, should all newly diagnosed patients undergo HIV genotype testing to evaluate for resistance to antivirals? 1. Yes 2. No 13

Evaluation of new patients Routine laboratory testing ú HIV antibody if not previously documented ú CD4 cell count and percentage ú HIV RNA viral load ú Genotype 10-12% transmitted primary resistance ú CBC, serum chemistries, blood sugar, lipids, urinalysis ú Hepatitis serologies ú Screening for syphilis Evaluation of new patients Other routine tests ú Tuberculosis screening (PPD or interferon- gamma release assay) ú Toxoplasma IgG ú Gonorrhea and chlamydia sites based on sexual practices ú Pap smear in women twice in first year and annually thereafter if initial testing normal Colposcopy for ASC- US or higher grade abnormality Obstet Gynecol 2010;116(6):1492-509 14

Evaluation of new patients Other tests to consider ú HLA B*5701 before abacavir use; only once ú Co- receptor tropism assay before CCR5 entry inhibitor use (maraviroc) ú G6PD level particularly before certain drugs, e.g. dapsone, and in at risk racial or ethnic groups ú Varicella zoster virus screening if no history of chickenpox or shingles ú Anal Pap smear, especially for MSM recommended by some experts HIV Primary Care Guidelines, Clin Infect Dis 2013;1-35 Antiretrovirals (ARVs) 15

ARVs available in the U.S. nucleoside/ nucleotide reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors Generic Trade Class Year Zidovudine, AZT Didanosine, ddi Retrovir NRTI 1987 Videx NRTI 1991 Stavudine, d4t Zerit NRTI 1994 Lamivudine, 3TC Epivir NRTI 1995 Generic Trade Class Year Nevirapine Viramune NNRTI 1996 Delavirdine Rescriptor NNRTI 1997 Efavirenz Sustiva NNRTI 1998 Etravirine Intelence NNRTI 2008 Rilpivirine Edurant NNRTI 2011 Abacavir, ABC Ziagen NRTI 1998 Tenofovir, TDF Viread NRTI 2001 Emtricitabine, FTC Emtriva NRTI 2003 ARVs available in the U.S. nucleoside/ nucleotide reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors combinations Trade Composition Class Year Combivir Zidovudine + lamivudine NRTI 1997 Trizivir Zidovudine + lamivudine + abacavir NRTI 2000 Truvada Tenofovir + emtricitabine NRTI 2004 Epzicom Abacavir + lamivudine NRTI 2004 Atripla Tenofovir + emtricitabine + efavirenz Complera Tenofovir + emtricitabine + rilpivirine NRTI + NNRTI 2006 NRTI + NNRTI 2011 16

ARVs available in the U.S. protease inhibitors Generic Trade Class Year Saquinavir Invirase PI 1995 Ritonavir Norvir PI 1996 Indinavir Crixivan PI 1996 Nelfinavir Viracept PI 1997 Lopinavir + ritonavir Kaletra PI 2000 Atazanavir Reyataz PI 2003 Fosamprenavir Lexiva PI 2003 Tipranavir Aptivus PI 2005 Darunavir Lexiva PI 2006 ARVs available in the U.S. fusion inhibitors, entry inhibitors CCR5 co-receptor antagonist, integrase strand transfer inhibitors Generic Brand Class Year Enfuvirtide, T- 20 Fuzeon Fusion inhibitor 2003 Maraviroc Selzentry CCR5 antagonist 2007 Raltegravir Isentress Integrase inhibitor Elvitegravir + cobicistat + emtricitabine + tenofovir Stribild Integrase inh + booster + NRTI + NRTI Dolutegravir Tivicay Integrase inhibitor 2007 2012 2013 17

When to start antiretroviral therapy (ART)? Recommended for all persons with HIV strength varies based on CD4 count ú AI: < 350 cells/mm 3 ú AII: 350 500 cells/mm 3 ú BIII: > 500 cells/mm 3 Regardless of CD4 count, patients with an AIDS- defining illness, HIV- associated nephropathy, hepatitis B virus requiring treatment, pregnancy Panel on Antiretroviral Guidelines for Adults and Adolescents. http:// aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Updated 11/13/14 What to start for ART-naïve patients? Most common recommended regimens: tenofovir + emtricitabine plus one of the following 1. efavirenz 2. atazanavir + ritonavir 3. darunavir + ritonavir 4. raltegravir 5. dolutegravir 6. elvitegravir + cobicistat Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf 18

What to start for ART-naïve patients? Recommended regimens continued: ú abacavir + lamivudine + dolutegravir For HIV RNA < 100,000 copies/ml and CD4 > 200: ú tenofovir + emtricitabine + rilpivirine Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf What to start for ART-naïve patients? All preferred regimens have three drugs: 2 NRTIs and 1 drug from another class ú ritonavir and cobicistat don t count Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf 19

A few key issues with common ARVs: Abacavir test for HLA- B*5701 prior to use; don t use abacavir if positive Efavirenz more side effects Tenofovir and rilpivirine caution with renal insufficiency Atazanavir and rilpivirine acid suppressing drugs interfere with absorption Review drug interactions Treatment goals Viral load undetectable less than 20 copies/ml ú Should occur by 24 weeks with rapid early decrease ú Achieved by 85 90% of naïve patients in clinical trials Treatment is life long Some patients may not have robust CD4count increases with undetectable viral load, e.g. older, starting at lower CD4 count 20

CD4 monitoring Every 3-6 months ú During first 2 years ART ú If viremia develops on ART ú CD4 < 300 After two years on ART with suppressed viral load ú CD4 300-500: every 12 months ú CD4 > 500: monitoring optional Monitoring and ongoing care HIV RNA every 3 6 months, depending on stability Chemistry panel, BUN, Cr, CBC, AST, ALT, total bilirubin every 3 6 months Lipids and fasting glucose (if normal) annually Urinalysis every 6 months if taking tenofovir ú Protein, glucose 21

What about prophylaxis for opportunistic infections (OIs)? Your patient had a CD4 count of 89 cells/mm 3 when he started ART one month ago. He is tolerating ART well. Prophylaxis also should be given for which OIs? 1. Pneumocystis pneumonia (PCP) 2. PCP and toxoplasmosis (if IgG positive) 3. PCP, toxoplasmosis, and Mycobacterium avium complex (MAC) 4. PCP, toxoplasmosis, MAC, and cytomegalovirus (CMV) retinitis OI primary prophylaxis indicated PCP: CD4 count < 200 cells/mm 3 Toxoplasma gondii encephalitis: toxoplasma IgG positive and CD4 count < 100 cells/mm 3 Mycobacterium avium complex (MAC): CD4 count < 50 cells/mm 3 Primary prophylaxis not routinely recommended for other OIs in the U.S. based on CD4 count Specific recommendations for stopping primary prophylaxis, and sometimes secondary prophylaxis, when CD4 count rises http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent -oi-prevention-and-treatment-guidelines/0 22

Immunizations for HIV-infected adults: most common Pneumococcal vaccines: Prevnar- 13 and Pneumovax Influenza vaccine and Tdap/Td as for non- HIV infected Hepatitis A for MSM, persons with or at risk for hepatitis B or C, liver disease Hepatitis B all susceptible patients, check for hep B surface antibody after series, may need double dose Zoster and varicella vaccines as for non- HIV infected, if CD4 > 200 Counseling A person diagnosed with HIV at age 25 has an estimated median survival of > 35 years Annals of Int Med 2007;146:87-95 (Danish study) Safer sex condoms still key message ú Prevent many new sexually transmitted infections Partner notification Contraception Pre- conception counseling 23

Acute illness: when to start ART? AIDS Clinical Trials Group (ACTG) 5164 study: enrolled non- TB OIs and invasive bacterial infection ú Benefit to starting early (median 12 days) PCP: start within 2 weeks Most OIs have limited data ú Start within 2 weeks Acute illness: when to start ART? Tuberculosis ú Start within 2 weeks if CD4 < 50 ú Start within 4 weeks if CD4 > 50 and severe disease ú Start within 12 weeks if CD4 > 50 and no severe disease ú With meningitis, consider deferring for 8 weeks Cryptococcal meningitis ú Consider starting after 2 weeks, probably after 5 weeks in resource limited setting Other CNS or CMV retinitis ú Consider starting after 2 weeks http://hivinsite.ucsf.edu/insite?page=md-ward86-art-oi 24

Conclusions There are data linking improved patient outcomes, including survival, with greater provider experience and expertise ú At least 6 studies from 1996 2005 Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Where to get help? http://nccc.ucsf.edu/ Conclusions: free assistance HIV/AIDS Management ú M F, 9AM 8PM Eastern time ú 800-933- 3413 Post Exposure Prophylaxis (PEP) ú 7 days per week, 9AM 2AM Eastern time ú 888-448- 4911 Perinatal HIV/AIDS ú 7 days per week, 24 hours/day ú 888-448- 8765 25