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Transmission of HIV-1 Where Epidemiology Meets Biology

Transmission of HIV-1 Where Epidemiology Meets Biology. Myron S. Cohen, MD J. Herbert Bate Professor Medicine, Microbiology and Immunology and Epidemiology The University of North Carolina at Chapel Hill. Epidemic Spread of HIV. Ro = bDC When Ro >1 epidemic is sustained

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Transmission of HIV-1 Where Epidemiology Meets Biology

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  1. Transmission of HIV-1Where Epidemiology Meets Biology Myron S. Cohen, MD J. Herbert Bate Professor Medicine, Microbiology and Immunology and Epidemiology The University of North Carolina at Chapel Hill

  2. Epidemic Spread of HIV Ro = bDC When Ro >1 epidemic is sustained b = Efficiency of transmission (…a biological event) D = Duration of infectiousness C = Number of people (partners) exposed

  3. Transmission of HIV:Biological Requirements Infectious Susceptibility Inoculum (concentration) Hereditary resistance Phenotypic factors Innate resistance Acquired (immune) resistance …from Cohen and Galvin Nature Microbiology Reviews 2:33-42, 2004

  4. UNC HIV Transmission Group • The Swanstrom Lab (and CFAR) • The Fiscus Lab • The Eron Clinical Research Group (ACTG) • The Kashuba Pharmacology Group • The Hobb’s STD Research Group (CRC) • The Hoffman Malawi Research Team …and most recently the Margolis Lab

  5. NSI HIV (M-tropic) SI HIV (T-tropic) semen lamina propria dendritic cell CD4+ CCR5+ DC-SIGN+ exposure at mucosal epithelium CD4 DC-SIGN CCR5 T cell migration to lymphoid organs

  6. V3 isn't variable for subtype C.

  7. Routes of Exposure and H.I.V. INFECTION ROUTE RISK OF INFECTION Sexual Transmission a. Female-to-male transmission…………1 in 700 to 1 in 3,000 b. Male-to-female transmission……...…..1 in 200 to 1 in 2,000 • Male-to-male transmission………...….1 in 10 to 1 in 1,600 • Fellatio??…………………………….. .0 (CDC) or 6% (SF) Parenteral transmission • Transfusion of infected blood………….95 in 100 • Needle sharing………………………….1 in 150 c. Needle stick…………………………..…1 in 200 d. Needle stick /AZT PEP…………………1 in 10,000 Transmission from mother to infant a. Without AZT treatment………...…….1 in 4 b. With AZT treatment………………….Less than 1 in 10 Royce, Sena, Cates and Cohen, NEJM 336:1072-1078, 1997

  8. Coital Frequency per Month by Age 11 10.02 10 9.11 8.98 9 8 Coital frequency per Month 7.44 7 6 5 4 15-24 25-29 30-34 35-59 Age

  9. HIV Prevalence by Age and Gender among South African youth age 15-24 years 55% 50% 45% Males 40% Females 35% 95% Confidence Interval 31.2% 28.9% 30% 26.3% 25.0% 25% 20% 14.4% 13.8% 15% 12.2% 11.0% 9.4% 10% 7.9% 4.1% 6.0% 5.8% 4.0% 4.1% 5% 3.6% 2.6% 2.3% 2.1% 2.0% 0% Age 15 Age 16 Age 17 Age 18 Age 19 Age 20 Age 21 Age 22 Age 23 Age 24 Pettifor A, et al. AIDS 2005, 19: 1525, Pettifore et al. AIDS 2007 21:2007 862.

  10. Comparison of age of coital debut among young women aged 18-24 years in South Africa (SA) in 2003 and the United States (US) in 2002 (Pettifore et al., submitted)

  11. Hypothesis 1) Estimated transmission rates from earlier studies are too low to explain the epidemic 2) HIV transmission is intermittently AMPLIFIED by increased genital tract shedding 3) AMPLIFIED transmission is critical to the spread of HIV

  12. Factors that Amplify HIV Transmission INFECTIOUSNESS • Stage of Disease … ACUTE INFECTION? • Systemic co-infections -Malaria, Tuberculosis, Helminthic infections (?) • Genital Tract Changes -Bacterial vaginosis, STDs!!! • Circumcision • Hormonal contraception • Genetic factors (HLA B and C) SUSCEPTIBILITY • STDs!!! • Bacterial vaginosis • Inate immunity • Circumcision • Hormonal contraception • Genetic factors (CCR5)

  13. A. Fauci, 2006

  14. Why is Acute HIV Important?Pilcher and Cohen, J Clin Invest, 2005 • Vaccine Development (CHAVI) • Prevention Opportunities (HPTN) • Treatment -for secondary prevention (HPTN) -for viral load reduction (ACTG) - to attack “persistance” (ACTG)

  15. The acute retroviral syndrome • 49-89% of patients “symptomatic” within 3 mos. SchackerKinloch-de Loes Fever 93% 87% Fatigue 93 26 Pharyngitis 70 48 Weight loss 70 13 Myalgias 60 42 Headache 55 39 ….BUT LESS THAN 1,000 subjects with acute/early HIV have been reported out of 60,000,000 infected!!

  16. Fiebig Classification of HIV-1 Infection Eclipse Phase I II III IV V VI (Fiebig, AIDS 2003) v RNA+ * Western blot +/- Western blot + (p31-) Western + (p31+) * Env SGA sequence analysis of plasma virus population Transmitted virus

  17. Pooling Serum Specimensto Detect HIV RNA(Pilcher et al JAMA288:216-221, 2002) A Individual testing on 10 specimens 10 pools of 10 screened 20 Screening Pools Tested N=2000

  18. HIV Testing in North Carolina (n=109,250)(Pilcher, Cohen et al NEJM 352: 1873, 2005 EIA/WB + - NAAT Long Term HIV Positive + - LS-EIA at UNC + F/U Testing (Ab+NAAT) - + - Likely recent “Detuned” Unknown duration HIV Negative Acute HIV 106 477 23

  19. Viral Loads at Initial Detection 10 9 8 median 209,183 7 6 Log HIV RNA cp/ml 29,347 5 4 3 2 1 0 Established HIV+ (n=66) Acutely HIV + (n=21)

  20. ADDED BENEFIT OF ROUTINE AHI SCREEING 1PILCHER, 2KLAUSNER, 3PATEL, 4STEKLER, 5PRIDDY, 6STEVENTS, 7PILCHER, 8FISCUS, 9 deSOUZA

  21. Infection by testing site: NC(Pilcher et al. NEJM, 2006) 250 Acute Recent Unknown Duration 16/23 Acute Infections from STD Clinics 200 150 100 50 Not shown: Prenatal/OB FP Drug Treatment General Medical TB Field visits 0 STD HIV Testing “Other” Prison, Jail N= 44656 11688 7575 3053

  22. STDs Amplify HIV-1 Transmission • Reducing physical/mechanical barriers • Increasing HIV in genital lesions, semen or both • Evoking a more infectious HIV variant • Increasing the number of receptor cells or the density of receptors per cell …and co-transmission of HIV and STDs leading to clusters of subjects with acute HIV infection

  23. Malawi Overview • Population 10 million • 90% rural • Per Capita income $190 AIDS impact • 900,000 people living with HIV • 15% adult prevalence • STD Clinic: 47% prevalence

  24. The Tidziwe Center Lilongwe Central Hospital Lilongwe, Malawi

  25. Dean Roper Visits Malawi

  26. Acute HIV Infection and STDsPilcher et al. AIDS 18:1-8, 2004 • 1,361 men screened in STD and Dermatology Clinics in Lilongwe Malawi • 47% antibody + (chronic HIV Infection) • 2.1% (28) with acute HIV (antibody -, RNA +) Inguinal nodes: 11.4% acute HIV Genital ulcer (HSV): 7.8% acute HIV CSW exposure: 9.1% acute HIV Acute HIV was detected ONLY in symptomatic STD patients (!!) implying co-transmission or “staged” transmission of an STI followed by HIV, or vice-versa.

  27. Viral Loads in Malawi: Chronic and Acute HIV Infection 10 8 6 Log HIV RNA cp/ml 4 2 0 HIV Ab+ HIV Ab- (acute)

  28. HIV-1 viremia (grey) and Semen (black)Pilcher et al. AIDS August 2007Grey=Blood and Black=semen (95% CI) 9 7 5 log10 HIV-1 RNA copies per mL 3 1 0 4 8 12 16 20 24 28 Weeks Since HIV infection

  29. HIV-1 Viremia and SheddingPilcher et al. AIDS August 2007

  30. 7 5 3 0 AIDS Acute Infection 3 wks Asymptomatic Infection HIV Progression Sexual Transmission of HIV(Cohen and Pilcher, JID May 2005) Risk of Transmission Reflects Genital Viral Burden 1/30- 1/200 HIV RNA in Semen (Log10 copies/ml) 1/100- 1/1000 1/500 - 1/2000 1/1000 - 1/10,000

  31. 7 5 3 0 AIDS Acute Infection 3 wks STD Episode STD Episode Acute HIV and STD episodes(Cohen and Pilcher, JID, 2005 HIV RNA in Semen (Log10 copies/ml)

  32. Prevention of HIV • STD control, behavior change, condoms • Vaccines (Trials Ongoing) • Treatment of Bacterial Vaginosis (Planning) • Topical microbicides (Trials Ongoing) • The diaphragm (Trial Completed) • Male circumcision (Trials Ongoing) 7. HSV-2 treatment/prevention (Trials Ongoing) 8. Antiretroviral therapy (Trials Ongoing) 9. Societal (structural) interventions: needle exchange, poverty reversal, etc…ALL WORK

  33. 15 Overall 58 ( 66, 48) Impact of MC on HIV : Evidence from observational studies and RCTs Reduction of risk (95% CI) Weiss et al. AIDS 2000, 14:2361-70 7 1 Auvert et al. PLoS Med 2005(11): e298.2006 South Africa (RCT) 60 ( 76, 33) 1 Bailey et al. Lancet 2007; 369: 643–56 59 ( 76, 30) Kenya (RCT) 1 Gray et al. Lancet, 2007, 657–66 51 ( 82, 14) Uganda (RCT) 60 85 80 70 .50 1 Reduction of risk (0%)

  34. Antiviral TherapyCohen et al. Annals Internal Med. 2007 Effect on Sexual Transmission of HIV ?

  35. ART to Prevent Sexual Transmission of HIV • Treatment of the infected person? • Post-exposure prophylaxis (PEP)? • Pre-Exposure Prophylaxis (PREP)?

  36. 0 50% 100% 150% 200% 500% 600% ABC (150%) ZDV (200%) TDF (500%) 3TC (600%) APV (20%) NVP (70%) IDV (100%) ENF (ND) d4T (2%) EFV (3%) SQV (3%) RTV (3%) LPV (5%) NFV (5%) Male Genital Tract Exposurepercent of blood plasmaKashuba et al. and CROI 13 Abstract 569 (Vourvahis), 13th CROIAbstracts 396 (Stekler), Abstract 618 (Katzenstein) NRTI PI NNRTI FI

  37. 3TC (400%) FTC (600%) TDF (400%) ddI (100%) IDV (200%) SQV(ND) ZDV (200%) EFV (0.6%) ABC (150%) d4T (4%) RTV (20%) DLV (20%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Female Genital Tract Exposure(percent of blood plasma)Dumond et al. Abstract 129, 13th CROI 0 200% 400% 600% NRTI PI NNRTI

  38. 100 80 60 detectable HIV in semen Patients (%) with 40 20 0 HIV-RNA HIV-DNA ART Suppresses HIV in Semen: Biological Plausability Controls (drug naive) n=55 Potent ART n=114 p<0.0001 p=0.025 Vernazza, Cohen et al., AIDS, 2000

  39. 100 Injectable FTC/Tenofovir (n = 6) 75 Oral truvada (n = 6); p = 0.0004 [HR = 7.8] 50 % Uninfected animals Injectable FTC (n = 6); p = 0.005 [HR = 3.9] 25 Oral TDF (n = 4); p = 0.095 Controls (n = 18) 0 0 2 4 6 8 10 12 14 Number of rectal exposures

  40. Potential end-points of HIV-vaccine efficacy trials protection against HIV sterilizing immunity protection against disease (modification of the course of HIV infection in vaccine recipients) no protection establishment of chronic infection with low viral load “normal” infection with variable levels of viral load initial infection “controlled” no infection UNAIDS–97100 1 August 1998

  41. This CHAVI web site is at http://www.chavi.org

  42. Interdisciplinary CHAVI 001 Studies B Cell Discovery Antibody Studies Mucosal Immunity Innate Immunity Cytokines Apoptosis CHAVI 001 Acute HIV-1 Infection T Cell Discovery Good vs. Bad T cells Genetic Data Computational Biology Ro Analyses Sexual Behavioral Sexual Networks Sexual Dynamics Transmitted Sequences Viral Biology Structural Biology

  43. The Consequences of Acute Infection HIV- Acute HIV • Massive reduction in mucosal CD4+ T cells even in acute infection Douek and Schacker 2004 J Exp Med

  44. Onset of Innate Immune Responses During Acute HIV-1 Infection

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