Sexually Transmitted Infection Treatment and HIV Prevention

Sexually Transmitted Infection Treatment and HIV Prevention Toye Brewer, MD Co-Director, Fogarty International Training Program University of Miami Miller School of Medicine

STI Treatment and HIV Prevention. Which of the following is false? a) STIs cause increased HIV RNA in genital secretions, even if the plasma viral load is undetectable. b) Epidemiologic evidence suggests genital herpes contributes significantly to HIV transmission worldwide. c) Acyclovir for suppression of HSV-2 in HSV- 2+/HIVpersons did not decrease HIV transmission in randomized controlled trials. d) No randomized controlled trial has suggested that control of STIs can decrease HIV transmission. e) I do not know, I m coming to learn.

Sexual Transmission of HIV depends on The infectiousness of the index case (HIV+ partner) Plasma viral load (amount of virus in the blood) Genital viral load (amount of virus in genital secretions) The susceptibility of the uninfected (HIV-) partner Presence of STIs or other genital inflammation

Genital viral load and Plasma Viral load The concentration of HIV in blood can be directly (but imperfectly) correlated with HIV in semen and genital secretions However, increased levels of HIV in genital secretions caused by STIs results from local (genital) replication Hart CE 1999

Role of STIs in HIV Transmission Syndrome Risk estimate Median Range Genital ulcers 4.7 3.3-18.2 Syphilis 3.0 2.0-9.9 Genital herpes 3.3 1.9-8.5 Chlamydial infection 4.5 3.2-5.7 Gonorrhea 4.7 3.5-8.9 Trichomoniasis 2.7? Anogenital warts 3.7?

Increased Infectiousness in the HIV+ STI status and HIV-1 genital shedding in HIV+ women (Ghys et al. AIDS.1997) 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% cured not cured none incident visit 1 follow up

STIs and genital shedding in HIV+ men HIV-RNA in the semen of HIV infected men increases over 8 fold in the presence of gonorrhea Concentrations of >1,000,000 seen in HIV infected men with gonorrhea Effective antimicrobial treatment decreases RNA in genital secretions about 10 fold Cohen et al. Lancet.1997, Schacker et al. JAMA 1998

Increased Susceptibility in the HIV - Partner STIs increase the number of cells receptive to HIV infection in the HIV- partner STIs create mucosal micro and macro abrasions in the HIV- partner

Classification of STIs Etiology Bacterial (Curable) Gonorrhea, Chlamydia, Syphilis, Chancroid Viral (Uncurable, but generally suppressible) Genital herpes, Genital Warts, HIV Pathophysiology Mucosal inflammatory diseases- Gonorrhea, Chlamydia, Trichomonas Ulcerative diseases- Genital herpes, Syphilis, Chancroid, Others- Genital Warts, Hepatitis B

Gonorrhea Infection

Genital Herpes Infection (HSV)

STIs and HIV Transmission Ulcerative diseases are believed to increase transmission risk more than mucosal diseases (macro-abrasions) Bacterial diseases, because they can be cured and controlled, are not currently believed to be as important in HIV transmission as viral diseases A reactivating viral disease is particularly important in HIV transmission

Treatment of STDs for HIV Prevention: Mwanza vs. Rakai Community randomized trials Mwanza-Improved management of symptomatic bacterial STDs 40% reduced HIV incidence over two years Rakai- Mass treatment for bacterial STIs q 6 months No significant reduction in HIV Incidence Grosskurt et al.1995.

Why the Difference? Different Prevalences of Genital Herpes and bacterial STIs 38% of GUD in Rakai due to HSV <10% of GUD in Mwanza due to HSV Higher rates of bacterial STIs in Mwanza Genital Herpes was not affected by the antibiotics used in the trials

HSV-2 Seroprevalence in Various Countries

Genital Herpes Most common STI worldwide Causes recurrent genital ulcerations Symptoms may be very subtle and unrecognized Cannot be cured but can be suppressed with medications

HSV/ HIV Interactions HIV+ / HSV+ More severe, extensive, persistent HSV More frequent reactivations 3-7X increased shedding Increased HIV plasma viral load in the absence of treatment HIV RNA present in herpetic ulcers HSV+ / HIV- 2X increased risk of HIV seroconversion Influx of CD4 + lymphocytes in the genital tract Macro and micro abrasions in the genital tract Reynolds SJ, et al. J Infect Dis. 2003;187:1513-1521. Serwadda D, et al. J Infect Dis. 2003;188:1492-1497.

HIV Seroconversion associated with GUD: Case Control study from Rakai 248 seroconverting men and 496 controls HSV-2 seropositivity was associated with increased risk of HIV acquisition (OR 1.7, 95% CI 1.2-2.4) Gray et al., presentation 0498, ISSTIR

Risk of HIV-1 acquisition by HSV-2 infection status Reynolds et al. JID. Vol. 187.

HIV Seroconversion associated with HSV-2 infection Can the use of Acyclovir and other anti virals with activity against HSV-2 suppress HSV-2 shedding and reactivation leading to a decrease in HIV transmission?

Studying the Effect of Suppressive Treatment of Herpes on Transmission HSV-2+ /HIV- HIV+ HIV+/HSV-2+ HSV-2-, HIV-

HSV 2 Suppressive Therapy to Reduce HIV Acquisition: I 30 month randomized, placebo controlled trial enrolling 820 HIV-, HSV-2+ high risk women Daily Acyclovir 400 mg or placebo Endpoints of HIV infection, pregnancy or completion of 30 months of therapy 60% of women who completed the study; 8% in each arm Adherence was problematic; among women who took at least 75% of their medications, there was a non statistically significant reduction in incident HIV infections Watson-Jones, D et al. 4 th International AIDS Society Conference, MOAC104, Sydney, 2007.

HSV-2 Suppressive Therapy for Prevention of HIV Acquisition: II Results of HPTN 039 Cellum et al. 3251 HSV-2+, HIV- participants: MSM and women from the US, Peru and African sites. Adherence to study drug by self-report and pill count was excellent HIV incidence was 3.9/100 person-years in the acyclovir arm (75 events) and 3.3/100 person-years in the placebo arm (64 events), HR = 1.16 (95%CI 0.83 to 1.62).

HSV-2 Suppressive Therapy for Prevention of HIV Transmission: Celum et al.. Ongoing study of > 3000 discordant heterosexual couples, one of whom is HIV+, HSV-2+ and the other of whom is HIV-, HSV-2- Results expected in 2009

Recent Trends in the US: Increases in STIs among MSM Syphilis LGV Quinolone Resistance Neisseria Gonorrhoeae

Atypical Presentations of Primary Syphilis

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

Primary and secondary syphilis Maleto-female rate ratios: United States, 1981 2004 Male-Female rate ratio 10:1 8:1 6:1 4:1 2:1 0 1981 83 85 87 89 91 93 95 97 99 2001 03

HIV Syphilis Co-Infection, Florida

LGV Caused by serovars L1,L2 and L3 serovars of C. trachomatis Proctitis among MSM, increasing among MSM In Europe and the US, but still rare Cell culture, which is technologically difficult, is the only US FDA approved method of diagnosis Must be treated with longer courses of doxycycline (three weeks)

LGV: The Groove Sign

LGV Proctitis

Quinolone Resistant Gonorrhea Gonorrhea has a long history of evolving resistance to commonly used antibiotics- sulfanilimide, penicillin, tetracycline Resistance to fluoroquinolones began in SE Asia and have rapidly spread in the US to Hawaii and California. MSM in the US have a higher prevalence than heterosexual men (18% vs. 2%).

Percentage of GISP isolates with intermediate resistance or resistance to ciprofloxacin, 1990-2003* Percent of isolates 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003* Resistance *2003 data are preliminary. Intermediate resistance

Conclusions STIs increase the transmission and acquisition of HIV The presence of a new bacterial STI in an HIV+ patient is evidence of unsafe sex practices HIV + patients are subject to more frequent and extensive reactivations of incurable viral STIs which increase infectivity Whether or not suppressive therapy of HSV-2 in HIV+ patients will reduce transmission is not known

Clinician s Responsibility: The CDC s Message* Ongoing Risk Reduction Counseling to HIV+ patients STI screenings in sexually active HIV + patients Prompt and adequate treatment of STIs * Incorporating HIV Prevention into the Medical Care of Persons Living with HIV (MMWR, July 18 2003)