I. HIV Epidemiology. HIV Infection A Primer. Objectives. Disclosures 7/18/2014

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1 Objectives HIV Infection A Primer Discuss the worldwide and domestic epidemiology of HIV infection Review HIV Biology Review HIV Transmission and Prevention Review HIV diagnosis Describe the approaches to clinical treatment of HIV Oluwaseun Falade Nwulia MD, MPH Medical Director Baltimore City Health Department Early Intervention Initiative Disclosures None I. HIV Epidemiology 1

2 Adults and children estimated to be living with HIV 2011 North America 1.4 million [1.1 million 2.0 million] Caribbean [ ] Latin America 1.4 million [1.1 million 1.7 million] Western & Central Europe [ million] Middle East & North Africa [ ] Sub-Saharan Africa 23.5 million [22.1 million 24.8 million] Eastern Europe & Central Asia 1.4 million [1.1 million 1.8 million] East Asia [ million] South & South-East Asia 4.0 million [3.1 million 5.2 million] Oceania [ ] Estimated number of adults and children newly infected with HIV 2011 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe [ ] Middle East & North Africa [ ] Sub-Saharan Africa 1.8 million [1.6 million 2.0 million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania 2900 [ ] Total: 34.0 million [31.4 million 35.9 million] Total: 2.5 million [2.2 million 2.8 million] 5 6 Estimated adult and child deaths from AIDS 2011 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe 7000 [ ] Middle East & North Africa [ ] Sub-Saharan Africa 1.2 million [1.1 million 1.3 million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania 1300 [< ] Total: 1.7 million [1.5 million 1.9 million] 7 Source: 8 2

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4 BESURE Study Baltimore City Cross sectional behavioral study and HIV testing at MSM identified venues in Baltimore City (n=645) Overall prevalence HIV+ 37.7% Black MSM 51.4% (4.0X as likely as non Hispanic white MSM) Unrecognized infection 54.8% overall; 63.8% black MSM 2008 (n=448) Overall prevalence HIV % Black MSM 68.8% (2.5X as likely as non Hispanic white MSM) Unrecognized infection 63.8% overall; 76.9% black MSM High HIV Prevalence Among Young MSM in 5 US Cities Pooled analysis of serial cross sectional data from young MSM (18 29 yrs) from 5 cities (Baltimore, Miami, LA, NYC, SF) included in 4 different cohorts over various periods from HIV prevalence yrs of age: 11% (stable) yrs of age: 16% (slightly increasing) HIV testing increased significantly over time in both age groups (P <.0001) German D et al. J Acquired Immune Deficiency Syndrome 2011; 57:77-87 Oster AM, et al. AIDS Abstract MOAC0104. II. HIV Biology 4

5 HIV Biology An enveloped RNA virus Uses reverse transcriptase, an RNA dependent DNA polymerase to create a linear double stranded DNA Survival advantages Genetic diversity Latency Reduces effectiveness of host immune response Types of HIV Virus HIV 1 Most common in sub Saharan Africa and throughout the world Groups M, N, and O Pandemic dominated by Group M Group M comprised of subtypes A J HIV 2 Most often found in West Africa 18 Structure of HIV Envelope Core p24 Reverse Transcriptase III. HIV Transmission and Prevention RNA 19 5

6 How is HIV Transmitted? HIV Transmission Most infectious body fluids are genital secretions and blood (also present in breast milk) Potentially infectious: Cerebrospinal, synovial, pleural, pericardial and amniotic fluid Non infectious: Feces, nasal secretions, saliva, sputum, sweat, tears, urine, vomitus (unless they contain blood) 21 HIV Transmission Sexual Transmission Risk of transmission highest with acute infection Unaware of HIV status Very high viral loads Increased risk with concomitant STD infection Significantly decreased risk with undetectable HIV viral load Decreased risk with use of condoms HIV Transmission Blood Transmission Injection Drug Use (needle exchange programs very effective prevention) Health Care Worker occupational exposure (rates reduced with post exposure prophylaxis) Blood transfusion (essentially eliminated with screening of blood products) 6

7 HIV Transmission Mother to child transmission Can occur during pregnancy, labor and delivery and through breast feeding Without treatment: 15 30% risk during pregnancy or labor and delivery 5 20% risk through breast feeding Virtually eliminated in high income countries HIV Prevention A (abstinence) B (be faithful monogamy) C (condoms & circumcision) D (diagnosis) E (exposure prophylaxis) F (female controlled methods) G (genital tract factor treatments i.e. microbicides?) H (HAART) I (immunity and vaccine?) Prevention Studies Pre exposure prophylaxis with ART Trial Population N Efficacy P iprex MSM % <0.001 Partners DC* %** <0.001 TDF 2 DC* % 0.03 Topical microbicide (ART) CAPRISA 004 Male circumcision Test, link to care, plus early initiation of ART (TLC Plus) Vaccines *DC-Discordant couples ** TDF -67%, TDF/FTC -75% The iprex Study HIV ve men and transgender women who have sex with men Randomized 1:1 to daily PrEP FTC/TDF vs placebo Prevention service provided to all HIV testing Risk reduction counseling Condoms STD testing and treatment Grant et al, NEJM

8 The iprex study Efficacy (Modified intention to treat) 44% reduction in FTC/TDF arm (P=0.005) Sites 11 Participants 2499 San Francisco Boston Chiang Mai Guayaquil Lima Iquitos Sao Paulo Rio de Janeiro Cape Town New England Journal of Medicine, online Nov 23, 2010 Grant et al, NEJM 2011 CDC Guidance for PreP Use 8

9 HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: cells/mm 3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count cells/mm 3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count 250 cells/mm 3 * (n = 877 couples) *Based on 2 consecutive values 250 cells/mm 3. Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Couples received intensive counseling on risk reduction and use of condoms Cohen MS, et al. N Engl J Med. 2011;365: HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Delayed Arm: 27 Linked Transmissions: 28 Total HIV 1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Immediate Arm: 1 P <.001 Cohen MS, et al. N Engl J Med. 2011;365: Unlinked or TBD Transmissions: 11 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV 1 RNA suppression HIV Prevention Science Mathematical model: test and immediate treatment to virtually eliminate transmission Pre exposure prophylaxis (44% reduction) 73% reduction in those who took FTC/TDF Antiretroviral therapy (96% reduction) Vaginal Microbicide (39% reduction) Circumcision (50 60% reduction) Condoms, condoms, condoms!!! From Granich RM, et al, Lancet 2009, 373:

10 US HIV Care Cascade What About A Cure The Mississippi baby Baby born to mother found to be HIV +ve during labor No antenatal care ART started at 30 hours of age; even before HIV infection in confirmed in baby From MMWR December 2, 2011 / 60(47); ; Accessed 1/10/12 Persaud D et al. NEJM 2013 The Mississippi Baby Mother stopped ART at age 18 months Baby returned to care at age 23 months No replicating virus found in blood Initially termed functional cure then termed remission Virus rebounded at age 46 months IV. Diagnosis Persaud D et al NEJM

11 HIV Testing 3 Types of HIV screening tests Antibody tests Detect antibodies proteins the body makes agaians HIV Antigen/ Antibody tests 4 th Generation HIV Tests Nucleic acid RNA tests Detect HIV directly 4 th Generation HIV tests Detect p24 antigen as well as conventional HIV antibodies. Higher sensitivity Picks up HIV infection earlier than routine ELISA (as soon as 3 weeks after exposure to HIV) HIV Testing Algorithm, Initial Test Antibody or Antibody/Antigen test Laboratory Based Test Rapid Test Multiple settings Hospitals, clinics, fairs, home. Confirmatory/Follow up testing antibody differentiation tests distinguish HIV 1 from HIV 2 antibodies HIV 1 nucleic acid tests detects viral RNA directly Western blot and indirect immunofluorescence assay detects antibodies HIV Western Blot Updated HIV Testing Algorithm Possible results: Negative: no bands Positive: reactivity to gp120/160 plus either gp41 or p24 Indeterminate: presence of any band pattern that does not meet criteria for positive results Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at 11

12 Case 1 A 20 year old man presents to your clinic with a 3 day history of fever, sore throat, headache, myalgias, and fatigue On examination he has a diffuse maculopapular, erythematous rash Social History: MSM. Multiple anonymous sexual encounters with men in the last year What is in your differential diagnosis? What tests would you order? Clinical Manifestations of Primary HIV Infection N =160 V. HIV Staging and Initial Evaluation Vanhems P, et al. AIDS. 2000;14:

13 HIV Time Course CD4 count and HIV RNA ( viral load ) The CD4 count provides a real time estimate of the risk that a patient has for developing complications The viral load set point provides a clue as to how quickly HIV disease is likely to progress HAART: Then and Now VI. Antiretroviral Treatment ARV Therapy Cocktail Atripla 13

14 Virologic Response to HAART CD4 Recovery Battegay et al. Lancet Inf Dis 2006 Current ARV Medications NRTI Abacavir (ABC) Didanosine (ddi) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4t) Tenofovir (TDF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir (EVG) Dolutegravir(DTG) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) Goals of Treatment Reduce HIV associated morbidity and mortality Reduce risk of HIV transmission to others 14

15 Markers of treatment success HIV RNA below the limit of detection Improving immune system as evidenced by stable or rising CD4 counts Case 2 A 21year old man diagnosed with HIV 4 months ago. His CD4 counts have been 680 and 700 cells/mm 3. He has no active medical, mental health, or substance abuse issues. He is sexually active with other men and uses condoms some of the time. Would you start him on antiretroviral therapy? US Health and Human Services Antiretroviral therapy Guidelines DHHS Guidelines, May 2014: When to Start Antiretroviral therapy recommended for all HIV infected pts; strength of recommendation varies according to CD4+ cell count or condition Downloaded from on 7/17/

16 Rating Scheme for Recommendations Strength of recommendation: A: Strong B: Moderate C: Optional Quality of evidence: I: 1 randomized controlled trials II: 1 well designed nonrandomized trials or observational cohort studies with long term clinical outcomes III: Expert opinion DHHS Guidelines, May 2014: When to Start CD4+ Cell Count or Clinical Condition CD4 + count < 350 cells/mm³ (AI) CD4 + count cells/mm³ (AII) CD4 + count > 500 cells/mm³ (BIII) History of AIDS-defining illness (AI) Pregnancy (AI) HIV-associated nephropathy (AII) HBV coinfection (AII) At risk of transmitting HIV to sexual partners (AI, heterosexuals; AIII, others) Downloaded from on 7/17/2014. DHHS Guidelines, May 2014: When to Start Recommended for HIV infected individuals for the prevention of transmission of HIV. The strength and evidence for this recommendation vary by transmission risks: perinatal transmission (AI) heterosexual transmission (AI) other transmission risk groups (AIII) DHHS Guidelines, May 2014: When to Start Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence (AIII) Patients may choose to postpone therapy, and providers, on a case by case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors. Downloaded from on 7/17/2014 Downloaded from on 7/17/

17 DHHS Guidelines, May 2014: What to Start Clinical Case 3 A 24 year old man presents with sore throat, a fever, generalized lymph nodes, and a faint rash on his body. He had unprotected sex 10 days ago. Which test is the most appropriate to confirm your diagnosis? A. HIV RNA PCR B. HIV p24 antigen detection C. HIV ELISA D. HIV Western Blot Downloaded from on 7/17/2014 Thank You QUESTIONS????? 17