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Overview of talk

Link between HSV-2 & HIV or “The Tale of Two Viruses” Connie Celum, MD, MPH University of Washington. Overview of talk. Clinical interactions between HSV-2 & HIV Epidemiologic data: HSV-2 & HIV acquisition  2 fold higher risk of HIV acquisition for HSV-2+

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Overview of talk

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  1. Link between HSV-2 & HIVor “The Tale of Two Viruses” Connie Celum, MD, MPHUniversity of Washington

  2. Overview of talk • Clinical interactions between HSV-2 & HIV • Epidemiologic data: HSV-2 & HIV acquisition •  2 fold higher risk of HIV acquisition for HSV-2+ • Higher risk of HIV acquisition due to incident HSV-2 • Epidemiologic data: HSV-2 & HIV transmission • Higher risk of transmission due to GUD • Intervention trials • What to do now re HSV-2 and HIV?

  3. Genital Herpes: Early AIDS-associated Opportunistic Infection

  4. HSV clinical manifestations in HIV+ man with CD4 40

  5. Chronic gluteal HSV-2 reactivation in HIV+ person

  6. HSV-2 Shedding is Common - Shedding Rates using HSV Culture* - % of Days with HSV Isolation • 4-fold higher rate by HSV PCR than culture • HSV-2 shedding in HIV+ assoc w/CD4<400, PVL >50,000

  7. Yaounde HIV-1: 7% W, 3.6% M HSV-2: 51% W, 27% M Cotonou HIV-1: 2.8% W, 2.8% M HSV-2: 30% W, 12% M Kisumu HIV-1: 29% W, 18% M HSV-2: 68% W 35% M Ndola HIV-1: 32% W, 24% M HSV-2: 55% W, 36% M

  8. Conclusions: Factors related to different HIV prevalence in 4 African cities • Differences in risky sexual behavior are outweighed by cofactors that affect HIV transmission probability: • Lack of male circumcision • HSV-2 infection • Syphilis • Gradual increase in HIV prevalence initially, fueled by risk behavior and biologic cofactors • As #s of HSV-2 /HIV co-infected persons increase, HSV-2 increases per-sex-act transmission of HIV & HSV2 • HIV and HSV-2 epidemics fuel each other Buve AIDS 2001; 15S: S127-131

  9. Etiology of GUD in South Africa (1986-98) Ballard 2001

  10. GUD in U.S. cities: Results of the Multiplex PCR Assay n H. ducrei # (%) T. pallidum # (%) HSV # (%) T. pallidum/HSV # (%) • Birmingham • Chicago • Cincinnati • Dallas • Houston • Los Angeles • Memphis • New York • Philadelphia • St. Louis • Total 50 49 52 52 51 54 50 55 50 53 516* 0 6 (12) 0 0 0 0 10 (20) 0 0 0 16 (3) 13 (26) 4 (8) 1 (2) 6 (12) 1 (2) 0 15 (30) 1 (2) 3 (6) 7 (13) 51 (10) 25 (50) 24 (49) 41 (79) 35 (67) 38 (75) 41 (76) 14 (28) 36 (65) 38 (76) 28 (53) 320 (62) 0 1 (2) 0 2 (4) 1 (2) 0 6 (12) 1 (2) 1 (2) 1 (2) 13 (3) Mertz, JID 1998 *22% of specimens were negative

  11. Results of Metanalysis: HSV-2 and HIV acquisition Estimate of risk for 9 Cohort and Nested Case-Control Studies: 2.1 (1.3, 3.2) Estimate of risk for 18 Case-Control and Cross-sectional Studies : 4.2 (3.1, 5.8) Wald JID 2002

  12. Metaanalysis: Population Attributable Risk % of HIV to HSV-2 • AR% = 51 (based on summary OR of 2.1 from case-control and cohort studies) • If HSV-2 prevalence = 22%, PAR%= 19 • ~ HSV-2 prevalence in general population in U.S. • If HSV-2 prevalence = 50%, PAR%= 35 • ~ HSV-2 prevalence in MSM in Latin America, U.S. • If HSV-2 prevalence = 80%, PAR%= 46 • ~ HSV-2 prevalence in women in Africa

  13. HSV-2 and HIV among high-risk MSM • Assessed HSV-2 as a risk factor among high-risk MSM in Seattle, SF, NY, Boston, Chicago, Denver (1995-97) • Nested case-control study of HIV seroconverters (3 matched non-HIV seroconverters) • O.R. adj 1.8 (95% CI=1.1-2.9) for prevalent HSV-2 infection • O.R. adj 2.8 (95% CI: 0.8, 10.1) for those with recent HSV-2 infection Renzi, JID 2003

  14. HIV Acquisition Risk highest among those with Incident HSV-2 in India 22.6% 7.5% 7.5% Adjusted hazard ratio 3.6% Reynolds et al JID 2003:187;1513

  15. Probability of HIV Acquisition in 174 Monogamous Couples: Rakai HIV Acquisition Risk per 1000 Exposures HSV-2 Antibody in HIV- Partner • Viral Load in HIV+ SP • <1700 • 1700-12,499 • 12,500-38,499 • >38,500 HSV-2 Neg 0. 04 0.5 0.2 0.7 HSV-2 Pos 1.0 2.3 1.8 3.6

  16. Summary: HSV-2 and HIV acquisition • HSV-2 increases risk of HIV acquisition 2-fold • Regardless of HSV-2 symptom recognition • Hypothesis: HSV-2 increases HIV susceptibility through portal of entry and recruitment of activated CD4 cells • Concern about unmeasured confounding • Higher risk of HIV acquisition among those with recent HSV-2 infection • Hypothesis: More frequent & longer HSV-2 reactivation

  17. HSV-2 and HIV Transmission Data from Rakai HIV-discordant couples HSV-2 and HIV infectiousness

  18. Mechanisms of herpes increasing the risk of HIV transmission • Mucosal or epithelial break • “Portal of exit”: Larger inoculum of HIV through sexual exposure • Higher infectious “unit” • Upregulation of HIV replication inHSV-2/HIV co-infected cells • Increased frequency of HSV-2 reactivation in HIV-infected persons • Associated with low CD4 (<200) and higher plasma viral load (>50,000)

  19. Detection of HIV & HSV in genital lesion swabs during genital herpes outbreak • Schacker JAMA, 1998

  20. GUD treatment and Lesional HIV Shedding • 79 consecutive HIV+ patients with GUD in South Africa • Treatment tailored to suspected etiologic agent HIV detection in lesional fluid Baseline7 days14 days Typical HSV lesions* N=16 9 (56%) 2 (13%) 0 (0%) Atypical HSV lesions** N=16 3 (81%) 12 (75%) 6 (38%) * Treated with valacyclovir 500 mg bid **Treated for chancroid only Ballard 2001

  21. HSV-2 and Natural History of HIV • 7 of 8 studies have shown survival benefit for HIV+ persons on acyclovir[Ionnadis JID 1998] • Mechanism: Decreased expression of HSV proteins that upregulate HIV replication? • Increased plasma HIV RNA during HSV-2 reactivation • 48% decrease in plasma HIV RNA during acyclovir suppression[Schacker, JID 2003]

  22. Does herpes facilitate HIV acquisition? HIV transmission?

  23. Summary of why to focus on HSV-2 in HIV prevention • Desperately need new prevention strategies • HSV-2 is highly prevalent in high-risk HIV-uninfected and HIV-infected populations • HSV-2 appears to increase HIV acquisition and transmission • Widely available serologic tests for HSV-2 • Generic, low cost, well-tolerated treatment (acyclovir) • Clinical benefits, particularly in HIV-positive persons

  24. HSV-2 & HIV: Priorities for research • Proof-of concept trial: HSV-2 & HIV susceptibility • Does suppressive therapy in HSV-2 populations with high HIV incidence prevent HIV acquisition? • Proof-of concept trial: HSV-2 & HIV infectiousness • Does suppressive therapy in HIV+, HSV-2+ coinfected persons prevent HIV transmission? • Impact of acyclovir in syndromic management of genital ulcer disease on HIV shedding

  25. HPTN 039: HSV-2 suppressive therapy to prevent HIV Acquisition Harare, Zimbabwe Lusaka, Zambia Johannesburg, SA 1823 HIV- HSV-2+ heterosexual women and 1823 high-risk, HIV- HSV-2+ MSM Lima & Pucallpa, Peru Seattle San Francisco New York Randomize Acyclovir 400 mg bid Placebo 1° endpoint: HIV infection (estimated to be 3.5%/yr in placebo arm)

  26. HSV-2 suppressive therapy to prevent HIV Transmission 3646 HIV- discordant couples HSV-2/HIV co-infected persons Randomize HIV/HSV-2 + persons w/ CD4 >250 Acyclovir 400 mg bid Placebo bid 1° endpoint: HIV infection in HIV-negative partners at 1 yr, estimated to be 4% in placebo arm - Both arms receive episodic ACV for GUD -

  27. Prospective sites for Gates HSV-HIV Transmission Trial Nairobi, Eldoret, Kisumu, Kenya Kitwe & Ndola, Zambia Kampala, Uganda Gabarone, Botswana Moshi, Tanzania • Other potential sites: • Chennai,India • Haiti Johannesburg, Durban Capetown, RSA

  28. HSV-2 & HIV: Relevance for HIV prevention • Provides proof-of-concept about HSV-2 & HIV • Guides priorities for HSV-2 prevention (vaccines, condoms, serologic testing) and treatment • Is suppressive acyclovir for HIV prevention feasible, if effective? • Applicable to more HIV+ persons in sub-Saharan Africa than antiretrovirals based on CD4 <200 or symptoms, given ~70% HSV 2+ seroprevalence • Acyclovir is cheaper ($45/yr), needs less infrastructure than antiretrovirals

  29. So… what to do now regarding HSV-2 and HIV in the U.S.??? • As HSV-2 infection may be implicated in the transmission of HIV, HIV-positive individuals should be offered HSV serological testing • Counsel HIV+/ HSV-2+ persons re. clinical issues, potential for increased infectiousness Suppressive antiviral therapy should be routinely offered to HIV-positive patients with frequent clinical HSV-2 reactivation • Consider for HIV/HSV2+ persons with CD4 <400 in whom HSV-2 reactivation is frequent & often subclinical

  30. HSV-2 testing for high-risk HIV-negative persons • Persons at risk for sexual acquisition of HIV infection (e.g., MSM & partners of HIV+) should be routinely offered HSV-2 serological testing • Educate re HSV-2 • Counsel HSV-2+ persons that HSV-2 confers a substantially increased risk of HIV • Encourage condom use & ↓ no of partners

  31. Hello herpes our old friend. Will be with us ‘til the end. ‘Cause the virus softly creeping, Left its genes while we were sleeping. Not integrated into our genome, It’ll roam, that episome. The DNA of herpes Herpes simplex 1 and 2 Will forever be with you On our gums, lips, eyes, or down there, too And there isn’t much that we can do But there is acyclovir to help And we’ll want help From herpes hurting you Herpes Simplex 1 & 2-Adapted by Brian Flatt and Dr. Helen Davies, Univ of Pennsylvania-

  32. Acknowledgments:“It takes a team …” • Anna Wald, MD, MPH • Larry Corey, MD • Jai Lingappa, MD, PhD • Jim Hughes, PhD • Rhoda Ashley, PhD • Julie McElrath, MD, PhD • Scott Rose and Gray Davis, FHI • Wendy Stevens, MD, Univ of Wits • DAIDS, NIH • Bill and Melinda Gates Foundation • Participants in previous and future studies

  33. Partners in Prevention Research

  34. Thanks to our talented & hard-working colleagues: HPTN 039 Lima, Peru:A Lucchetti, J Lama, P Goicochea, A Ortiz, J Sanchez San Francisco:J Fuchs, S Buchbinder New York:B Koblin, L Strich Seattle:N Ocbamichael, D Somera, C Pope, D Jameson, E Lennon, J Price, G Froehle, P Farley Harare, Zimbabwe:F Cowan, T Chipato, J Brown, N Padian Lusaka, Zambia:S Reid, T Ito, L Rice, S Vermund Johannesburg, SA:S Delaney, H Rees

  35. More thanks: Investigators and sites for Gates HSV-HIV Transmission trial Kampala, Uganda: A. Ronald Nairobi, Kenya: G. John-Stewart, J. Kiarie, C. Farquhar Eldoret, Kenya: K. Wohls, J. Sidel, K. Fife Kisumu, Kenya: E. Bukusi, C. Cohen Moshi, Tanzania: S. Kapiga, W. Nkya Ndola & Kitwe, Zambia: M. Inaweda, W. Kamenga, S. Allen Johannesburg PHRU: N. Bandezi, G. Gray, J. McIntyre Johannesburg RHRU: S. Delaney, F. Vetter, H. Rees Gabarone, Botswana: P. Ndase, M. Essex Durban, SA: A. Robinson Chennai, India: K. Kumarsamy, K. Mayer,S. Solomon

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