Sexually Transmitted InfectionTreatment and HIV Prevention

Toye Brewer, MDCo-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+/HIV-persons 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

• 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

Genital viral load and Plasma Viral load

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 ?

0%5%

10%15%20%25%30%35%40%45%

cured notcured

none incident

visit 1follow up

Increased Infectiousness in the HIV+ STI status and HIV-1 genital shedding

in HIV+ women (Ghys et al. AIDS.1997)

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 foldCohen 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 STIsEtiology

• 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 IncidenceGrosskurt 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 HSVHigher 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 InteractionsHIV+ / 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

Reynolds SJ, et al. J Infect Dis. 2003;187:1513-1521. Serwadda D, et al. J Infect Dis. 2003;188:1492-1497.

HSV+ / HIV-• 2X increased risk of HIV

seroconversion• Influx of CD4 +

lymphocytes in the genital tract

• Macro and micro abrasions in the genital tract

HIV Seroconversion associated with GUD: Case Control study from Rakai

• 248 seroconverting men and 496 controls

• HSV-2 seropositivitywas 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+/HSV-2+

HIV+

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. 4th International AIDS Society Conference, MOAC104, Sydney, 2007.

HSV-2 Suppressive Therapy for Prevention of HIV Acquisition: II

Results of HPTN 039Cellum 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 — Male-to-female rate ratios: United States,

1981–2004

Male-Female rate ratio

0

2:1

4:1

6:1

8:1

10:1

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*

*2003 data are preliminary.

00.5

11.5

22.5

33.5

44.5

55.5

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

*

Per

cent

of i

sola

tes

Resistance 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)

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+/HIV-persons 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’m sorry, I did not learn.