1. STD-HIV Interactions Peter R. Kerndt, MD, MPH

2. Fundamental questions Do other STDs facilitate sexual transmission of HIV infection? What is role of STD treatment in prevention & control of an HIV epidemic? Do other STDs facilitate sexual transmission of HIV infection? What is role of STD treatment in prevention & control of an HIV epidemic?

3. Sexual Transmission of HIV Depends on: The infectiousness of the index case: Plasma viral load Genital viral load The susceptibility of the uninfected partner: Presence of STDs, genital inflammation Innate host factors (i.e., CCR5 receptors) The infectiousness of the index case: Plasma viral load Genital viral load The susceptibility of the uninfected partner: Presence of STDs, genital inflammation Innate host factors (i.e., CCR5 receptors)

4. Resistance to HIV Infection Chemokine receptor CCR5 important for infection Mutation in CCR5 found to be protective homozygosity = resistance to infection heterozygosity = slowed progression of disease Frequency of mutation varies among different populations Chemokine receptor CCR5 important for infection Mutation in CCR5 found to be protective homozygosity = resistance to infection heterozygosity = slowed progression of disease Frequency of mutation varies among different populations

5. STD-HIV Interactions: Where do we look? Seroconversion studies Susceptibility & infectiousness data Intervention trials  Shifting HIV epidemic  STD services data Where do we look? Seroconversion studies Susceptibility & infectiousness data Intervention trials  Shifting HIV epidemic  STD services data

6. Genital Ulcer Disease Syphilis Herpes Simplex Chancroid

7. Genital Ulcers and HIV Seroconversion *Univariate analysis, **H. ducreyi seropositivity, ***Predominantly herpes

8. Genital Ulcers and HIV Seroconversion *Remained signif. In multivariate analysis; ** Adjusted OR.

9. Non-Ulcerative STDs Gonorrhea Chlamydia BV Trichomonas

10. Nonulcerative STDs and HIV Seroconversion *Univariate analysis

11. HIV incidence by BV status among 1,196 pregnant women in Malawi Source: Taha, et al. AIDS 1998,12:1699-1706 Adj OR for BV 3.68; p=0.04 for linear trend

12. Population Attributable Risk (PAR) of Selected STDs for HIV Seroconversion Site/Population

13. Mechanisms by Which STDs Increase HIV Susceptibility Genital Ulcers Mucosal disruption Target cell recruitment & activation Enhanced viral replication Alteration of chemokine receptors Genital Ulcers Mucosal disruption Target cell recruitment & activation Enhanced viral replication Alteration of chemokine receptors Non-ulcerative STDs Target cell recruitment Enhanced viral replication?

14. Frequency of HIV Shedding* with Non-ulcerative STDs Males Females *By PCR **p < 0.05 for pre-post STD treatment *By PCR **p < 0.05 for pre-post STD treatment

15. Frequency of HIV Shedding* with Genital Ulcers (GUD) Males Female CSWs *By PCR except in Kreiss study which used HIV culture **Univariate risk estimate *By PCR except in Kreiss study which used HIV culture **Univariate risk estimate

16. Median Concentration of HIV-1 RNA in Semen Among 104 Men With and Without Urethritis in Malawi X 10 4 copies/ml

17. Hypothetical Model of Impact of STD on HIV Genital Shedding in Men STD Antibiotic therapy Seroconversion Asymptomatic HIV progression AIDS

18. Impact of Improved STD Control on HIV Infection in Mwanza,Tanzania 12,537 individuals in rural Tanzania followed for 2 years (1000 people from 6 control and 6 intervention communities) Interventions: Established a STD reference clinic and lab Trained staff at health centers on Rx of STDs Regular supply of medications to Rx STDs STD education and free condoms for clients Periodic visits to village by health education team 12,537 individuals in rural Tanzania followed for 2 years (1000 people from 6 control and 6 intervention communities) Interventions: Established a STD reference clinic and lab Trained staff at health centers on Rx of STDs Regular supply of medications to Rx STDs STD education and free condoms for clients Periodic visits to village by health education team

19. HIV Incidence Over 2 Years in 6 Intervention and 6 Control Communities, Mwanza Trial (continuous clinics) Overall reduction of HIV 42% Overall reduction of HIV 42%

20. Impact of Improved STD Control on HIV Infection, Mwanza,Tanzania Results: Lower prevalence of all STDs in intervention villages 42% lower incidence of HIV infection in intervention villages (1.2% vs. 1.9%) No significant change in sexual practices (number of partners or use of condoms) Results: Lower prevalence of all STDs in intervention villages 42% lower incidence of HIV infection in intervention villages (1.2% vs. 1.9%) No significant change in sexual practices (number of partners or use of condoms) Grosskurth et al, Lancet 1995, 346:530-6

21. Impact of Intermittent Mass Treatment of STDs in Raki, Uganda Community-based, randomized, controlled trial of mass STD treatment and referral for symptoms or positive syphilis test People seen at home every 10 months, specimens were collected and directly observed therapy was given (intervention = azithro 1g + cipro 250 + metro 2g, placebo = mebendazole + iron-folate + MVI) No change in local STD services Community-based, randomized, controlled trial of mass STD treatment and referral for symptoms or positive syphilis test People seen at home every 10 months, specimens were collected and directly observed therapy was given (intervention = azithro 1g + cipro 250 + metro 2g, placebo = mebendazole + iron-folate + MVI) No change in local STD services

22. HIV Incidence Over 20 Months in Intervention & Control Communities in the Rakai Trial (intermittent clinics) Source: Wawer et al. Lancet 1999; 353:525-35

23. Impact of Intermittent Mass Treatment of STDs in Uganda  Over 10,000 people followed for 1-2 rounds  Initial prevalence of diseases: HIV 16%, GC 1-2%, CT 2-4%, trich 24%, BV 50% syphilis 10% and HSV- 2 30-60%  Results: All curable STDs decreased in intervention groups, but no difference in HIV seroincidence between the groups  Over 10,000 people followed for 1-2 rounds  Initial prevalence of diseases: HIV 16%, GC 1-2%, CT 2-4%, trich 24%, BV 50% syphilis 10% and HSV- 2 30-60%  Results: All curable STDs decreased in intervention groups, but no difference in HIV seroincidence between the groups Wawer, Lancet 1999; 353:525-35

24. STD Intervention Trials Reasons for Different Outcomes Baseline HIV prevalence much higher in Ugandan than in Tanzanian trial (16% vs 4%) High prevalence of difficult to treat STDs (BV, HSV-2) in Ugandan trial Effect of asymptomatic STDs on HIV transmission unclear Conclusion: treatment of symptomatic STDs in areas with early HIV epidemics appears to be effective, but more research needed to establish efficacy in other situations Baseline HIV prevalence much higher in Ugandan than in Tanzanian trial (16% vs 4%) High prevalence of difficult to treat STDs (BV, HSV-2) in Ugandan trial Effect of asymptomatic STDs on HIV transmission unclear Conclusion: treatment of symptomatic STDs in areas with early HIV epidemics appears to be effective, but more research needed to establish efficacy in other situations

25. STD Treatment for HIV Prevention Implications Continuous access to improved STD services is likely to have greater impact than an intermittent mass treatment approach to STD control Untreated symptomatic STDs probably more important than asymptomatic for HIV transmission (asymptomatic key to STD spread & other STD complications) In later stage HIV epidemics, contribution of curable STDs may decline Population impact will be greatest where curable STD rates are substantial Continuous access to improved STD services is likely to have greater impact than an intermittent mass treatment approach to STD control Untreated symptomatic STDs probably more important than asymptomatic for HIV transmission (asymptomatic key to STD spread & other STD complications) In later stage HIV epidemics, contribution of curable STDs may decline Population impact will be greatest where curable STD rates are substantial

26. Role of STDs in HIV Transmission Summary At least 2 to 5-fold increased risk of HIV seroconversion confirmed by data from 4 continents Attributable risk of STDs for HIV transmission substantial in some populations HIV susceptibility likely increased through endocervical CD4 recruitment by nonulcerative STDs, as well as through “portal of entry” created by ulcers At least 2 to 5-fold increased risk of HIV seroconversion confirmed by data from 4 continents Attributable risk of STDs for HIV transmission substantial in some populations HIV susceptibility likely increased through endocervical CD4 recruitment by nonulcerative STDs, as well as through “portal of entry” created by ulcers

27. United States vs. international settings STD epidemiology is different HIV/AIDS epidemiology is different STD clinical services are stronger United States vs. international settings STD epidemiology is different HIV/AIDS epidemiology is different STD clinical services are stronger

28. STDs in the USA U.S. has highest rates of STDs in the industrialized nations Heterosexual transmission of HIV increasing STD control in U.S. likely to be beneficial because of early HIV epidemic and substantial rates of STDs U.S. has highest rates of STDs in the industrialized nations Heterosexual transmission of HIV increasing STD control in U.S. likely to be beneficial because of early HIV epidemic and substantial rates of STDs

29. Syphilis and Gonorrhea Rates in the U.S. Are the Highest in the Industrialized World

30. STDs … Are Common Most commonly reported infections in U.S. True burden many fold higher Estimated 15 million new cases annually 25% in teens (approximately 1 in 8 aged 13-19 infected) Highest rates for most common STDs in teen- aged girls, especially minority teens Gonorrhea - rates rival those in developing world Chlamydia - 5-12% infected Most commonly reported infections in U.S. True burden many fold higher Estimated 15 million new cases annually 25% in teens (approximately 1 in 8 aged 13-19 infected) Highest rates for most common STDs in teen- aged girls, especially minority teens Gonorrhea - rates rival those in developing world Chlamydia - 5-12% infected

31. Prevention Implications of Advances in HIV Treatment Potential substantial decrease in average infectiousness Longer duration of life Increased well-being and diminished fear of HIV leading to increased sex Potential increase in proportional role of intermittent factors that increase infectiousness (e.g., STDs) Potential substantial decrease in average infectiousness Longer duration of life Increased well-being and diminished fear of HIV leading to increased sex Potential increase in proportional role of intermittent factors that increase infectiousness (e.g., STDs)

32. Syphilis Outbreaks in MSM Since 1997 STD rates have risen dramatically among MSM Seattle, San Francisco, Los Angeles and Miami have all reported increasing syphilis rates, especially among MSM Up to 70% have been co-infected with HIV in some cities Complacency secondary to new HIV therapies and treatments is thought to be the cause of increased unsafe sex practices Since 1997 STD rates have risen dramatically among MSM Seattle, San Francisco, Los Angeles and Miami have all reported increasing syphilis rates, especially among MSM Up to 70% have been co-infected with HIV in some cities Complacency secondary to new HIV therapies and treatments is thought to be the cause of increased unsafe sex practices

33. STD Trends Among MSM Doubling in proportion of MSM with GC in STD clinics in 8 large cities (12% to 23.5%, 1993-96) - MMWR Increases in male rectal GC in San Francisco (21 to 38 per 100,000, 1994-97) after declines (42 to 20 per 100,000, 1990-93) - MMWR Increases in syphilis, GC (125%) & chlamydia (50%) rates among MSM in Seattle/King Co. (1997-98) - AJPH 60% of MSM with syphilis HIV-infected 25% of MSM with GC or chlamydia HIV-infected Doubling in proportion of MSM with GC in STD clinics in 8 large cities (12% to 23.5%, 1993-96) - MMWR Increases in male rectal GC in San Francisco (21 to 38 per 100,000, 1994-97) after declines (42 to 20 per 100,000, 1990-93) - MMWR Increases in syphilis, GC (125%) & chlamydia (50%) rates among MSM in Seattle/King Co. (1997-98) - AJPH 60% of MSM with syphilis HIV-infected 25% of MSM with GC or chlamydia HIV-infected

34. Percentage of MSM Reporting Selected Sexual Behaviors & Male Rectal Gonorrhea Rates - San Francisco, 1990-1997 *Per 100,000 men aged > 15 years +Condoms always used during anal sex during the previous 6 months **Unprotected anal sex with two or more partners during the previous 6 months *Per 100,000 men aged > 15 years +Condoms always used during anal sex during the previous 6 months **Unprotected anal sex with two or more partners during the previous 6 months

35. Early Syphilis by HIV Status Los Angeles County, 2000-2005 6 in 10 MSM Early Syphilis Cases Report Being HIV Infected

36. HIV Seroconversion Among Early Syphilis Using Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS), Los Angeles, Jan 2002 – April 2004 * Total Early Syphilis1721 All Male ES Cases1426 Specimen banked212 HIV positive by standard testing a logarithms 74 (35%) STARS Non-reactive (early /recent infection) 12 STARS Reactive (Late Infection)62 * JAID, Taylor, M, Volume 38, Number 5, April 15 2005

37. New HIV Infection Among Men with Early Syphilis Los Angeles County, Jan 2002- April 2004, N=212 Source: Taylor, M.M. et al., JAIDS: 38(5), 2005 Estimated Recent HIV Infection Among Early Syphilis Cases Per Year Males MSM 17 26 12 - 22% 19 - 33% %95% CI

38. STD Co-infection Among Acute HIV Patients in Los Angeles County

39. Objective To examine the prevalence of STDs among a cohort of acutely infected HIV patients in Los Angeles County

40. HIV Viremia and Antibody Response HIV RNA (plasma) 11 0102030405060708090100 22 Acute HIV Infection (Window Period) HIV Antibody Days

41. Detection of HIV 0 1 2 3 4 5 6 7 8 9 10 Symptoms p24 Antigen HIV RNA HIV EIA* Western blot Weeks Since Infection *3 rd generation, IgG & IgM After Fiebig et al, AIDS 2003; 17(13):1871-9 *2 nd generation EIA IgG *1 st generation EIA IgG

42. 1 Screening Pool Individual specimens 10 Pools of 10 A B C D E F G H I J A B C D E F G H I J 100 (HIV antibody negative) Pooled NAAT Screening for Early HIV Infection

43. Multistage pooling Quinn et al [AIDS 2000] 1 Master Pool 2-Stage Pooling Individual specimens N=100 10 Intermediate Pools A B C D E F G H I J A B C D E F G H I J A B C D E F G H I J A B C D E F G H I J

44. EIA non-reactive Pooled NAAT HIV Negative Presumptive AHI Neg. Pos. HIV Testing Roche Amplicor® Monitor HIV-1 or GenProbe Aptima assay Vironostika® HIV1 antibody test

45. Background STDs in HIV-positive individuals increases the risk of HIV transmission HIV RNA in Semen (Log 10 copies/ml) Acute Infection 3 wks STD Episode AIDS Cohen, Pilcher, UNC Center for AIDS Research

46. Background In acute HIV infection, individuals are highly infectious Studies have suggested over 40% of new infections may be caused by persons with primary HIV infection Treatment of STD in HIV co-infected may reduce HIV transmission After people become aware they are HIV-positive, the prevalence of high-risk sexual behavior is reduced substantially – reduced number of partners and sero-sorting

47. Study Population 13 Public Health Department STD clinics Mobile Testing Unit (MTU) 2 community STD clinics, majority of clients are MSM (sites A&B) Jail Unit for MSM and transgenders

48. Data Collection STD/HIV Intake form Public Health Laboratory testing database STD surveillance database

49. Results

50. Pooled Testing - Acute HIV Detection Studies Los Angeles, 02/06 – 01/08 Site EIA +/Total EIA (%) NAAT pos. EIA neg. (n) % increased HIV infection detected (%) Site A Site B 140 / 7,830 1.8% 61 / 1,793 3.4% 28 4 20% 7% Jail 172 / 1,595 10.8%00% STD Clinics 236 / 27,861 0.8%94% MTU ---------- 31 / 2,708 1.1% ---------------- ------- 1 false+ -------- 0% ------ Total640 / 41,787 1.5%416%

51. Pooled Testing - Acute HIV Detection Studies Los Angeles, 02/06 – 03/08 Site EIA +/Total EIA (%) NAAT pos. EIA neg. (n) % increased HIV infection detected (%) Site A Site B 178 / 8,528 2.1% 72 / 2,129 3.4% 30 4 17% 6% Jail 186 / 1,718 10.8%00% STD Clinics 289 / 30,098 1.0%94% MTU ---------- 39 / 2,882 1.4% ---------------- ------- 1 false+ -------- 0% ------ Total764 / 45,355 1.7%436%

52. Pooled Testing - Acute HIV Detection Studies Los Angeles, 02/06– 01/08 HIV NAAT testing led to: 6% increase in HIV detection 20% increase (Site A) 7% increase (Site B) 1 in 1000 1 in 275 (Site A) 1 in 433 (Site B)

53. Patients with Acute HIV Infection (AHI) VL (cp/ml) at time of initial HIV-1 Ab negative test: 6 500,000 in 9 days) 10 >100,000 19 >500,000 6 w/ invalid quantitative assay 1 <75 (false positive) 25/41 (61%) patients presented with symptoms 10 AHI symptoms only (flu-like &/or rash &/or fever) 4 AHI and STD symptoms 10 STD symptoms 1 cervical lymphadenopathy N=41

54. Gender of Cases and Sex Partners Gender of sex partner 27 (66%) MSM only 11 (27%) MSMW/W 2 (5%) MSW only 1 (2%) WSM 28112 malefemale N=41 Gender of AHI cases 39 male 1 transgender M to F 1 female

55. Number of Sex Partners 3 months prior to diagnosis N=41, range=1 to 72 partners *6 with no information on gender of sex partner

56. Anal Intercourse & Condom Use 3 months prior to diagnosis 38 (93%) reported anal intercourse –29 insertive & receptive (incl. 2 who reported vaginal sex) – 5 receptive only (incl. 1 who reported vaginal sex) – 4 insertive only N=41 11 (30%) never used condoms for anal intercourse – 5 (13%) always use condoms –21 (57%) sometimes / mostlyN=37

57. Sex Partner Risks 30 (73%) reported having ever met anonymous sex partners: –14 internet – 9 bar/clubs – 6 bathhouse/sex club 5 (12%) reported sex with IDU in the year prior to diagnosis 8 (20%) reported sex with HIV positive partner(s) in the year prior to diagnosis N=41

58. Drug Use 1 year prior to diagnosis 20 (56%) used one or more drugs 15 (41%) methamphetamines –9 used meth with at least 1 other drug (ecstasy, nitrates, viagra, ketamine, poppers) 5 viagra –All used in combination with at least one other drug (meth, ecstasy, nitrates, ketamine, cocaine, marijuana) 4 marijuana 3 alcohol only 3 nitrates only N=41

59. 39 / 41 AHI were tested for at least one STD –37 Males (24 MSM, 11 MSMW, 2 MSW) –39 tested for CT/GC –37 tested for syphilis 18/39 (46%) co-infected on lab tests –4/37 (11%) early syphilis –7/39 (18%) CT –14/39 (36%) GC 6 co-infected with more than 1 STD –3 CT/GC –2 early syphilis/GC –1 early syphilis/CT/GC AHI and STD Co-infection

60. STD Prevalence *MSM visiting 12 LAC STD Clinics in 2006 **All visits to 12 LAC STD Clinics in 2006

61. Conclusion STD co-infection in the acute stage of HIV infection is common. Increased likelihood of AHI among MSMs w/ –Diagnosis of an STD –Recent high risk sexual exposures (eg. anonymous parters, sex with IDU, sex with HIV positive partner) –Other risk history, including methamphetamine use, viagra use and meeting of partners from the internet –Individuals with acute HIV and an STD co- infection provide a target for intervention to reduce HIV transmission.

62. Recommendations Any MSM presenting for evaluation of an STD with a negative HIV Ab. test should be tested for acute HIV infection. Any individuals with acute HIV should be tested for other STD’s.

63. Where Do People Go for STD Treatment? Population-based estimates from NHSLS Private provider59% Other clinic15% Emergency room10% STD clinic 9% Family planning clinic 7% Population-based estimates from NHSLS Private provider59% Other clinic15% Emergency room10% STD clinic 9% Family planning clinic 7% Source: Brackbill, 1997

64. Physician’s Risk Assessment and Screening Practices, 1996 Source: Abt, 1997

65. STD Treatment for HIV Prevention in the US - Where Do We Start? Access to & quality of STD clinical services Early & effective STD-related health care behaviors Surveillance systems to monitor STD/HIV trends & interrelationships Access to & quality of STD clinical services Early & effective STD-related health care behaviors Surveillance systems to monitor STD/HIV trends & interrelationships

66. STD Treatment for HIV Prevention Access to Quality Clinical Services  Public & private settings serving HIV-infected or high risk persons  Timely access to quality STD diagnosis & treatment for symptomatic people at high risk (e.g.: HIV C/T sites, schools, drug treatment centers, jails)  Training for clinicians & program managers  Public & private settings serving HIV-infected or high risk persons  Timely access to quality STD diagnosis & treatment for symptomatic people at high risk (e.g.: HIV C/T sites, schools, drug treatment centers, jails)  Training for clinicians & program managers

67. STD Treatment for HIV Prevention Early, Effective Health Care Behavior Sexual risk reduction counseling PLUS… Messages for at-risk persons & providers Other STDs increase HIV spread Recognize & act on symptoms/sign Most STDs asymptomatic; regular screening critical Specific information on sources of care Sexual risk reduction counseling PLUS… Messages for at-risk persons & providers Other STDs increase HIV spread Recognize & act on symptoms/sign Most STDs asymptomatic; regular screening critical Specific information on sources of care

68. STD Treatment for HIV Prevention Linked STD/HIV Surveillance Systems  Capacity & linkages at local level  Monitoring of extent of overlap of STD- & HIV- infected populations; relative importance of STD treatment as HIV prevention strategy  Monitoring of etiological spectrum of STDs  Timely analysis & dissemination to policy makers, program managers, providers  Capacity & linkages at local level  Monitoring of extent of overlap of STD- & HIV- infected populations; relative importance of STD treatment as HIV prevention strategy  Monitoring of etiological spectrum of STDs  Timely analysis & dissemination to policy makers, program managers, providers

69. STD Treatment to Enhance HIV Prevention Implementation of Advisory Committee for HIV & STD prevention recommendations [MMWR 1998; 47 (No. RR-12)] Augmentation of HIV Community Planning Groups to focus on STD data issues, detection, & treatment in areas with syphilis or GC rates > HP 2010 targets Local cross-training for STD & HIV staff in project areas with syphilis or GC rates > HP 2010 targets Demonstration projects of on-site STD screening, treatment & related services in setting serving HIV infected & at-risk individuals HIV-STD data systems & surveillance linkages Evaluation & applied research capacity to answer critical operational questions Implementation of Advisory Committee for HIV & STD prevention recommendations [MMWR 1998; 47 (No. RR-12)] Augmentation of HIV Community Planning Groups to focus on STD data issues, detection, & treatment in areas with syphilis or GC rates > HP 2010 targets Local cross-training for STD & HIV staff in project areas with syphilis or GC rates > HP 2010 targets Demonstration projects of on-site STD screening, treatment & related services in setting serving HIV infected & at-risk individuals HIV-STD data systems & surveillance linkages Evaluation & applied research capacity to answer critical operational questions

70. STDs as Cofactors of HIV infection STDs increase genital HIV RNA concentration in the HIV+ partner- independent of plasma viral load STDs increase the number of cells receptive to HIV infection in the HIV- partner STDs create mucosal micro and macro abrasions in the HIV- partner STDs increase genital HIV RNA concentration in the HIV+ partner- independent of plasma viral load STDs increase the number of cells receptive to HIV infection in the HIV- partner STDs create mucosal micro and macro abrasions in the HIV- partner

71. STDs as Cofactors of HIV infection Mucosal inflammatory disease increases HIV acquisition 5 fold in the HIV- partner Ulcers increase HIV acquisition 10-12 fold in the HIV- partner Mucosal inflammation and ulcers increase HIV shedding in genital secretions of the HIV- partner Mucosal inflammatory disease increases HIV acquisition 5 fold in the HIV- partner Ulcers increase HIV acquisition 10-12 fold in the HIV- partner Mucosal inflammation and ulcers increase HIV shedding in genital secretions of the HIV- partner

72. “Improved prevention of STDs should be an essential component of a national strategy for preventing sexually transmitted HIV infection.” The Hidden Epidemic: Confronting STDs Institute of Medicine, 1997 “Improved prevention of STDs should be an essential component of a national strategy for preventing sexually transmitted HIV infection.” The Hidden Epidemic: Confronting STDs Institute of Medicine, 1997