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Case 4: Discussion

Impact of STDs and HIV Transmission

Although early cross-sectional studies revealed an overlap between populations with a high incidence of sexually transmitted diseases (STDs) and those with HIV infection, they did not establish a causal relationship between STDs and HIV[1]. More recent studies have demonstrated that STDs significantly increase the risk for both HIV acquisition and transmission[2]. Mathematical models have estimated that routine screening and treatment of STDs in HIV-infected individuals could avert a significant number of new HIV infections in the United States[3,4]. Thus, the Centers for Disease Control and Prevention (CDC), the Health Resources and Services Administration (HRSA), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA) have recommended that all HIV-infected persons undergo routine STD screening in order to reduce the risk of HIV transmission (see Case 3: STD Screening in HIV-Infected Individuals in this Prevention for Positives Module)[5].

STDs and HIV Transmission: Potential Mechanisms

Several plausible biologic mechanisms may explain how STDs increase the risk of HIV transmission (Figure 1). Genital ulcer disease and inflammatory STDs may facilitate HIV infection through both mechanical and immune-mediated mechanisms[5]. In the HIV-negative partner, genital ulcers break down the mechanical barrier to infection, potentially allowing HIV easier access to deeper tissues and the vasculature. Furthermore, inflammatory STDs and genital ulcer diseases recruit activated CD4 cells to the surface of the genital tract, increasing the pool of cells susceptible to HIV infection[6,7]. Cytokine release due to STDs may also facilitate HIV entry into cells[1]. In the HIV-infected partner, the STD may manifest as an eroded genital ulcer or friable mucosa, either of which would be prone to bleeding during intercourse. With this scenario, HIV-laden blood could easily penetrate small breaks in a partner's oral, vaginal, or rectal mucosa[6]. Moreover, genital ulcer disease can increase plasma HIV RNA levels[8,9,10]. Both genital ulcer disease and inflammatory STDs increase shedding of HIV from genital ulcers, semen, and genital secretions[2]. The mechanism by which this occurs remains unclear, but experts hypothesize that both large numbers of HIV-infected cells recruited to the site of an STD and high rates of HIV replication secondary to cytokine release from the inflammatory response to an STD may contribute[11].

STDs and Susceptibility to Acquiring HIV

The presence of an inflammatory STD significantly increases susceptibility to HIV, with a relative increased risk of acquiring HIV of 1.5 to 2.2 (Figure 2); the risk effect is greater for men than for women (Figure 3)[1,12]. Multiple studies have also demonstrated that genital ulcer disease increases the risk of HIV acquisition, with active clinical lesions increasing the risk by about 2.1 to 2.7 fold (Figure 4). Overall, a more pronounced difference in risk effect by gender is noted with genital ulcer disease than with non-ulcerative disease (Figure 3)[12]. The association between HSV infection and HIV susceptibility is particularly well-established, with at least a two-fold increased risk of acquiring HIV among individuals infected with HSV[13]. Susceptibility to HIV is even higher among individuals who have recently acquired HSV-2 (incident versus prevalent infection) (Figure 5)[14].

STDs and Risk of Transmitting HIV (Infectiousness)

The risk of transmitting HIV is affected when an HIV-infected person has either an inflammatory or ulcerative STD. Gonorrhea, chlamydia, and trichomoniasis significantly increase HIV shedding from the genital tract[1,15,16]. Furthermore, the treatment of non-specific, gonococcal, or chlamydial urethritis) reduces the semen HIV RNA levels in HIV-infected men (Figure 6) [16,17]. Similarly, treating cervicitis caused by gonorrhea, chlamydia, or trichomonas reduces HIV RNA levels in cervical or vaginal secretions in HIV-infected women (Figure 7)[18,19]. Given that higher HIV RNA levels in semen are associated with an increased risk of HIV transmission[20], and treatment of urethritis in a HIV-infected man reduces semen HIV RNA levels, it is logical to conclude that treatment of urethritis in an HIV-infected man should reduce sexual transmission of HIV. In one study of genital ulcer disease in HIV-infected persons in India, HIV was detected in more than one-third of all active ulcers and almost two-thirds of ulcers caused by chancroid (Figure 8). In a separate study, investigators detected HIV levels greater than 10,000 copies/mL in genital ulcers associated with recurrent HSV infection[22]. Importantly, even subclinical HSV also appears to increase HIV shedding in the genital tract[7]. Longitudinal studies of HIV serodiscordant partnerships have revealed an increased risk of HIV transmission from HSV-infected partners[23,24]. Overall, the presence of a recent genital ulcer in an HIV-infected individual increases the per-contact rate of HIV transmission almost 4-fold[7]. Treatment of HSV reduces both HSV and HIV viral shedding[13]. A randomized controlled trial is underway to evaluate whether use of acyclovir therapy by HIV-infected individuals with HSV-2 can effectively prevent HIV transmission within HSV and HIV serodiscordant couples[7].

Intervention Trials

Based on the substantial evidence that STDs contribute to HIV transmission, three randomized controlled trials were performed in Africa to evaluate the efficacy of population-based STD treatment on community HIV prevalence. The studies, one performed in the Mwanza district of Tanzania and two performed in the Rakai and Masaka districts of Uganda, produced conflicting results[25,26,27]. In Mwanza, improved infrastructure for the continuous evaluation and treatment of STDs, including serosurveillance for syphilis and STD syndromic management, significantly lowered the community prevalence of HIV[25]. In contrast, periodic mass STD screening and treatment in Rakai had insignificant impact on HIV prevalence[26]. Experts have proposed that several differences between study populations and the interventions used in the Rakai and Mwanza trials may have contributed to the disparate outcomes. These factors included (1) the stage of HIV epidemic, (2) the proportion of symptomatic versus asymptomatic STDs treated (3), the prevalence of incurable STDs such as genital herpes, and (4) sustained versus intermittently available STD services[28]. In a subsequent trial in Masaka, Uganda, syndromic STD management did not reduce HIV-incidence[27]. The striking differences in results between the Ugandan and Tanzanian studies are probably best explained by the earlier stage of the HIV epidemic and the greater prevalence of both high-risk sexual behavior and curable STDs in Malawi compared with Masaka and Rakai. Similar trials have not been performed in a resource-rich setting, but mathematical models suggest that STDs contribute to more than 5,000 new HIV cases in the United States each year (Figure 9)[3,29]. Based on such mathematical modeling, one study determined that routine screening for STDs in HIV-infected individuals is a cost-effective means of preventing HIV transmission in the United States, with a maximum cost of ,000 per averted HIV infection[4].

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    Figure 1. Proposed Mechanisms for the Effects of STD on HIV Transmission

    Risk of human immunodeficiency virus type 1 (HIV-1) acquisition, by herpes simplex virus type 2 (HSV-2) infection status, in a cohort of patients at 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000.

    Adapted from: Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis. 2003;187:1513-21.

    Reproduced with permission from University of Chicago Press.


    Figure 1
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    Figure 2. Pooled Risk Effect of Non-Ulcerative STDs on Susceptibility to HIV

    Combined risk effects from studies of the effects of STDs on HIV susceptibility. NUD= non-ulcerative disease *Includes a variety of clinical presentations, including vaginal discharge, vulvitis, cervicitis, pelvic inflammatory disease, urethritis, and urethral discharge.

    Data from: Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. 2001;28:579-97.


    Figure 2
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    Figure 3. Differences in Risk Effect of STDs on Susceptibility to HIV by Gender

    This graph depicts the risk effects of ulcerative and non-ulcerative STDs on HIV susceptibility. GUD= genital ulcer disease, NUD= non-ulcerative disease *includes a variety of clinical presentations, including vaginal discharge, vulvitis, cervicitis, pelvic inflammatory disease, urethritis, and urethral discharge.

    Data from: Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. 2001;28:579-97.


    Figure 3
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    Figure 4. Pooled Risk Effect of Genital Ulcer Diseases on Susceptibility to HIV

    Combined risk effects from studies of the effects of genital ulcer disease on HIV susceptibility.

    Data from: Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. 2001;28:579-97.


    Figure 4
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    Figure 5. Risk of HIV Acquisition by Herpes Infection Status

    Risk of human immunodeficiency virus type 1 (HIV-1) acquisition, by herpes simplex virus type 2 (HSV-2) infection status, in a cohort of patients at 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000.

    Adapted from: Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis. 2003;187:1513-21.

    Reproduced with permission from University of Chicago Press.


    Figure 5
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    Figure 6. Effect of Single Dose of Ceftriaxone on Seminal HIV Levels in Men with Urethritis

    This graph shows the effect of one dose of ceftriaxone (Rocephin) on the seminal HIV levels in 86 men who had urethritis. The bars indicate the median values. Reproduce from: Cohen MS. HIV and sexually transmitted diseases: lethal synergy. Top HIV Med. 2004;12:104-7. This figure is based on data from Cohen MS, Hoffman IF, Royce RA, Kazembe P, Dyer JR, Daly CC, Zimba D, Vernazza PL, Maida M, Fiscus SA, Eron JJ Jr. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. AIDSCAP Malawi Research Group. Lancet. 1997;349:1868-73.


    Figure 6
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    Figure 7. Decrease in HIV Viral Shedding after Treatment of Cervicitis and Vaginitis

    A significant reduction in cervical and vaginal HIV-1 shedding is observed after treatment of gonorrhea, chlamydia and trichomonas in women.

    NSC = non-specific cervicitis

    Data from: McClelland RS, Wang CC, et al. Treatment of cervicitis is associated with decreased cervical shedding of HIV-1. AIDS. 2001;15:105-10 and Wang CC, McClelland RS, Reilly M, Overbaugh J, et al. The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1. J Infect Dis. 2001;183:1017-22.


    Figure 7
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    Figure 8. Percentage of Genital Ulcers PCR Positive for HIV RNA

    Data from: Gadkari DA, Quinn TC, Gangakhedkar RR, et al. HIV-1 DNA shedding in genital ulcers and its associated risk factors in Pune, India. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:277-81.


    Figure 8
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    Figure 9. Estimate of Annual HIV Infections in the United States Attributable to STDs

    Estimate of annual HIV infections attributable to STDs by type of STD, based on mathematical modeling.

    Data from: Chesson HW, Pinkerton SD. Sexually transmitted diseases and the increased risk for HIV transmission: implications for cost-effectiveness analyses of sexually transmitted diseaseprevention interventions. J Acquir Immune Defic Syndr. 2000;24:48-56.


    Figure 9