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Keywords:

  • Acquisition;
  • genital tract;
  • HIV;
  • inflammation;
  • sexually transmitted diseases;
  • transmission

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

Citation Mayer KH, Venkatesh KK. Interactions of HIV, other sexually transmitted diseases, and genital tract inflammation facilitating local pathogen transmission and acquisition. Am J Reprod Immunol 2011; 65: 308–316

Despite several decades of clinical trials assessing the impact of etiological treatment of sexually transmitted diseases (STDs) to decrease HIV acquisition and transmission, almost all of these trials have not proven to be efficacious. Increasing evidence suggests that specific STD treatment alone may not be sufficient to alter the genital tract inflammatory milieu that is created by STDs. This paper examines the associations between STDs and HIV susceptibility and infectiousness, and considers the role of chronic and refractory inflammation to create an environment that potentiates HIV and STD transmission and acquisition by reviewing biological, observational, and clinical trial data


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

Since the earliest days of the HIV epidemic, there was a recognition that people who acquired sexually transmitted diseases (STDs) appeared to be more susceptible to HIV acquisition and transmission.1,2 It has been difficult to disassociate the epidemiologic associations of HIV and STDs with increased sexual activity, contact with core group members who may be at greater risk for STDs, and the trend towards selecting infected partners that enable at risk persons to come in contact with new populations with increased STD prevalence, as opposed to specific biological factors that enhance susceptibility and infectiousness to HIV3–5 (see Fig. 1). With regard to enhanced susceptibility, ulcerative STDs, such as syphilis, Herpes simplex type 2 (HSV-2), and chancroid, result in lesions that cause a breakdown in mucosal integrity and recruit activated target cells containing an enriched population of cells carrying CD4 cell receptors. The consequent lesions elaborate pro-inflammatory cytokines, which in turn increase the number of inflammatory cells in the genital tract milieu that enhance HIV in vivo replication. STDs may also increase the expression of HIV binding ligands which can facilitate HIV acquisition and transmission. Although ulcerative STDs have been associated with the highest rates of enhancing HIV susceptibility, the presence of inflammatory STDs, such as Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, also result in the recruitment of inflammatory cells and potentiate HIV acquisition and transmission.

image

Figure 1.  Biological and epidemiological interactions between HIV and STDs.

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This review examines the association between STDs and HIV susceptibility and will discuss the role of acute, chronic, and residual inflammation in HIV transmission and acquisition by reviewing biological, observational, and clinical intervention data.

Associations between non-ulercative STDs and HIV

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

HIV-infected individuals who are co-infected with STDs are more likely to transmit HIV to their sex partners than mono-infected individuals.6 Before the advent of highly active antiretroviral therapy (HAART), observational data demonstrated an association between non-ulcertaive STDs, such as N. gonorrhoeae and C. trachomatis, and the risk of HIV transmission.7 HIV-infected women who had intercurrent N. gonorrhoeae, C. trachomatis, or T. vaginalis had increased rates of HIV detection in the cervix and vagina compared to HIV-infected women who did not have an STD, and HIV-infected men who had N. gonorrhoeae or C. trachomatis were more likely to have higher levels of HIV in the semen than mono-infected controls.8–11 For women, perturbations of the vaginal microflora associated with bacterial vaginosis have also been associated with increased HIV expression in the genital tract.12 In addition, HIV-infected individuals who experienced reactivations of HSV-2 can have high levels of HIV virus recovered from their genital tract ulcers.13

The effect of STDs on HIV expression in the genital tract and associated increases in infectiousness have been dramatically illustrated by the fact that treatment of acute bacterial infections in the genital tract significantly decreases genital tract HIV concentrations.10,14 In a study of Malawian males attending STD clinics in the pre-HAART era, Cohen et al. demonstrated that the median concentration of HIV RNA in semen among HIV-infected men without urethritis was 1.5 × 104 copies/mL.15 However, HIV RNA concentrations in HIV-infected men with urethritis were almost 10-fold higher at 12.4 × 104 copies/mL, but by 2 weeks post-antiviral therapy, the concentration had decreased more than three-fold to 4.1 × 104 copies/mL. It is notable that although the treatment of these uncomplicated causes of urethritis, including N. gonorrhoeae and C. trachomatis, lasted just a few days, even at 2 weeks following antibiotic treatment the concentration of HIV in genital tract secretions remained several fold greater than that before the onset of the inflammatory bacterial infection. This finding suggests that the genital tract milieu may be perturbed and up-regulated for weeks, and perhaps months or longer, after the treatment of acute bacterial infections, which may result in residual inflammation that can facilitate HIV transmission and acquisition. Similar findings were noted among female sex workers in Kenya, where women who were treated for gonococcal cervicitis experienced a decrease in their cervicovaginal HIV RNA from 3.95 to 3.28 log10 copies/mL and for C. trachomatis from 4.21 to 3.19 log10 copies/mL following treatment.16 The prevalence of HIV-infected cells in genital exudates decreased from 67% to 42%. Thus in these studies, HIV was not completely suppressed with the use of effective antimicrobial therapy but was somewhat diminished, suggesting that after the initial inflammatory response, it may take a much longer time for the genital tract milieu to return to a pre-STD state.

A subsequent meta-analysis of 48 studies evaluating the interactions of STDs and HIV corroborated an increase in genital tract HIV RNA and DNA in the presence of STDs, which included bacterial pathogens like N. gonorrhoeae and C. trachomatis, viruses like HSV-2, as well as protozoal infections like T. vaginalis.17 The aggregate findings of HIV detection decreasing from 39% to 29% again supported the concept that treating and managing bacterial STDs could decrease HIV infectiousness, but in and of itself might not be sufficient to eliminate the potential for enhanced HIV transmission even after the treatment of the STD.

Molecular mechanisms have been studied that may help explain how non-ulcerative STDs may mediate enhancement of HIV infection. N. gonorrhoeae has been shown to enhance the activity of resting CD4 positive T cells in facilitating HIV infection through toll-like receptor 2 (TLR-2) activation, which both increased the susceptibility of primary CD4 positive T cells to HIV infection and enhanced HIV-infected CD4 positive T cells at an early stage of the HIV life cycle after viral entry.18N. gonorrhoeae also enhanced the ability of HIV to infect activated dendritic cells,19 which can present virus to other susceptible cells.

In the case of T. vaginalis, genital tract infection may potentiate HIV transmission and acquisition because of the activity of its lipophosphoglycan, which is highly prevalent on the surface of the parasite and does not undergo stereotypic structural changes during parasitic development.20,21 It has been hypothesized that this lipophosphoglycan exploits galectin binding to induce responses favoring parasite survival, but at the same time this inflammatory process alters genital tract microflora in women at risk for HIV infection so that women with T. vaginalis are more likely to have bacterial vaginosis, and are also more susceptible to HIV acquisition and transmission.

Data from clinical trials of treating bacterial STDs to prevent HIV

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

Over the last decade and a half, there have been several large, multi-center clinical trials conducted in sub-Saharan Africa to evaluate whether the treatment of bacterial STDs could result in decreasing the incidence of HIV transmission and acquisition (see Table I).22 In the Mwanza trial, the only clearly successful STD intervention study, multiple communities in Tanzania were randomized to receive syndromic management of acute bacterial STDs with a regimen that was effective against N. gonorrhoeae, syphilis, and C. trachomatis.23,24 The study was initiated in communities with an average HIV prevalence of 1%, and by the end of the study HIV prevalence was approximately 4% across the sites. By the end of the study, the syndromic management approach resulted in a 29% decrease in syphilis and a 49% reduction in incident urethritis. Although there were no changes in condom use or sexual risk behaviors, there was a statistically significant 38% reduction in HIV incidence. However, several subsequent large interventional STD trials conducted in East Africa were not successful in demonstrating that STD treatment could decrease HIV incidence. In the Rakai study conducted in rural Uganda, the investigators randomized communities to receive periodic mass treatment with a regimen that was effective against N. gonorroheae, C. trachomatis, T. vaginalis, and bacterial vaginosis, as well as syphilis.25 Intervention teams went into villages every 9–10 months to offer the mass treatment. The investigators were able to demonstrate a 20% reduction in syphilis and a 41% reduction in incident T. vaginalis, both of which were statistically significant. However, there was no reduction in HIV incidence in the intervention communities. In contrast to the Mwanza study, the HIV epidemic was already much more well-established in this part of rural Uganda, with an HIV prevalence at the beginning of the study of over 16% in the male population.26,27 Subsequent analyses by researchers in the Rakai group found that the two largest predictors of incident HIV infection among HIV discordant couples were the level of circulating plasma HIV RNA in the infected partner28 and, independently, also the presence of prevalent and incident HSV-2 infection.27 Similar to the Rakai trial, two other large scale clinical trials of STD interventions, one involving syndromic management of STDs as part of a community randomized trial in Masaka, Uganda, and one involving monthly antibiotic chemoprophylaxis conducted among Kenyan female sex workers, did not lead to a decrease in HIV incidence.29,30

Table I.   Clinical Trials of STD Treatment Aimed at Decreasing HIV Acquisition and Transmission
Primary author, referenceSiteTime periodInterventionStudy populationResults
  1. Table data adapted from a meta-analysis of HIV prevention interventions by Padian et al.22

RCTs of non-viral STDs
 Grosskurth et al.23Mwanza, Tanzania1991–1994Community randomized trial involving syndromic management of curable STDsMen and women (N = 12,537)Significant decrease in HIV incidence
 Wawer et al.25Rakai, Uganda1994–1998Community randomized trial, treatment included azithromycin, ciprofloxacin, and metronidazoleMen and women (N = 12,726)No significant decrease in HIV incidence
 Kamali et al.29Masaka, Uganda1994–2000Community randomized trial involving syndromic management of curable STDsMen and women, youth (N = 13,598)No significant decrease in HIV incidence
 Kaul et al.30Kenya1998–2002AzithromycinFemale sex workers (N = 416)No significant decrease in HIV incidence
RCTs of HVS-2 suppressive therapy
 Watson-Jones et al.47Tanzania2004–2007AcyclovirHSV-2 positive women (N = 821)No significant decrease in HIV incidence
 Celum et al.48Peru, South Africa, Zambia, Zimbabwe, USA2003–2007AcyclovirHSV-2 positive women, MSM (N = 3,172)No significant decrease in HIV incidence
 Celum et al.49Southern and Eastern Africa2004–2008AcyclovirHIV discordant couples (N = 3,408)No significant decrease in HIV incidence

Given the collective findings of these clinical trials, the question arises: why did effective antibacterial therapy not prove to be effective in all but one of these STD treatment intervention studies? There may be several answers. Although antibacterial and anti-protozoal agents were effective in treating specific infections, they may not have been sufficiently potent to alter the inflammatory genital tract milieu that was established once these STDs developed in the study participants. In settings where the HIV epidemic is highly established, so that any new sexual partner has a high likelihood of being HIV-infected, STD treatment may result in a modest decrease in HIV infectiousness or susceptibility, but this intervention alone cannot override the residual infectiousness of HIV-infected partners, particularly those with untreated or acute HIV infection. Lastly, HSV-2 was highly co-prevalent in the African settings where the STD interventions were studied; and epidemiological studies have repeatedly identified HSV-2 to be associated with increased HIV susceptibility and infectiousness.31–33 The Mwanza, Rakai and Masaka studies did not include anti-HSV-2 suppressive agents in the STD treatment regimens; and, therefore, one of the more prevalent and significant STDs with the largest population attributable risk fraction for facilitating HIV infection was not part of the intervention in these treatment packages.34 In a meta-analysis of the role of STD interventions to decrease HIV transmission, a Cochrane Review noted, ‘There is limited evidence from randomized controlled trials for sexually transmitted infection control as an effective HIV prevention strategy’.35 They surmise that treatment services may sometimes reduce HIV incidence in environments characterized by emerging epidemics (i.e. low and slowly rising) and particularly in settings where treatment services in the past were poor and where STDs were highly prevalent, but in many settings around the world where the HIV epidemic is already well-established and specific STDs might not be as prevalent, the effects of STD treatment alone may be limited. Moreover, the question was raised as to whether STD interventions to prevent HIV infection could be truly effective without treating or preventing HSV-2.

Synergy between HSV-2 and HIV: From observational studies to clinical trials

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

HSV-2 and HIV are synergistic co-pathogens.36 Up to 90% of people living with HIV in some settings also are infected with HSV-2, and the lower limit of HSV-2 prevalence has been about 33%.31,37 Patients who are HSV-2 and HIV co-infected appear to have a longer duration of HSV-2 lesions with greater shedding of HSV-2, particularly if they are immunodeficient, and HIV can be recovered from their genital tract lesions.38 Individuals who are infected with HSV-2 may have microscopic re-activation and viral shedding up to several times a day, and this is more frequent in individuals who are HIV co-infected.13,39 Among African men, the prevalence of foreskin inflammation was associated with both HIV and HSV-2 infections, and stromal and epithelial inflammation were highest in those co-infected with HIV and HSV-2.40

Individuals who engage in sexual risk behaviors who have serologic evidence of HSV-2 are much more likely to acquire HIV, whether they have clinically significant genital ulcer disease or not.41 The prevalence of HSV-2 in populations engaging in high levels of sexual risk behaviors is very similar to that of HIV-infected individuals.42 Both among high-risk women in Africa,43 as well as men who have sex with men (MSM) in the developed world,44 incident HSV-2 infection has been shown to be independently associated with a marked increase in HIV acquisition.

Based on accumulating biological and epidemiological data, it is reasonable to think that interventions that should suppress HSV-2 expression with the use of thymidine kinase inhibiting agents, such as acyclovir, might be beneficial in reducing HIV acquisition and transmission.45,46 In 2008, a large randomized controlled trial conducted among HIV uninfected, HSV-2 antibody-positive African women to prevent HIV acquisition, comparing acyclovir to placebo, had no impact.47 Later that year, another large multi-center study among high-risk North and South American MSM and African women who were HIV-uninfected, HSV-2 seropositive failed to show a benefit of acyclovir prophylaxis in decreasing HIV incidence, but unlike the earlier study, this study did show a 47% reduction in genital ulcers.48 More recently, a study of HSV-2 suppressive therapy among HIV-infected and HSV-2 seropositive Africans who were in HIV discordant relationships did not demonstrate a decrease in HIV transmission to their uninfected partners, but did show a decrease in genital ulcers by 73% and plasma HIV viral load by 0.25 log10.49,50 A reason for the failure of acyclovir to prevent HIV acquisition and transmission could be due to the relatively low dosage that was used (400 mg/twice daily), while in some settings a drug concentration several times higher may be used for optimal HSV-2 suppression, particularly in individuals who are already HIV co-infected.51,52 Another reason for the lack of efficacy may be that although acyclovir decreases active clinical shedding of HIV, it may not be sufficiently potent to alter the inflammatory genital tract milieu, including micro-ulcerations, recruitment of cells that can bind or transmit HIV, or other mucosal changes that may potentiate HIV transmission.53

The mechanism for chronic HSV-2 enhancing HIV susceptibility, even after active HSV-2 suppression, may be partially explained by recent work that evaluated biopsied lesions from HIV-uninfected, HSV-2-seropositive individuals.54 The investigators assessed the presence of CD4+, CD8+, and dendritic cells, including those expressing DC-SIGN, and biopsies were performed in the same areas of these patients several times over a period of months after healing, including after receiving daily antiviral therapy. The cells that persisted reacted to HSV-2 antigens, suggesting that they were still recognizing the presence of virus even though it was being actively expressed, and these cells expressed the HIV co-receptor CCR5 and were contiguous to dendritic cells that expressed DC-SIGN. These findings suggest that cells from healed genital sites might be more readily infected ex vivo by HIV than control specimens. Another mechanism by which HSV-2 continues to alter the genital tract milieu may be because it is associated with altered vaginal microflora.55 In this study, Kenyan female sex workers were evaluated every 6 months, and women who were HSV-2 seropositive were more likely to also have bacterial vaginosis and, even after stratifying for sexual risk behaviors, antibiotic use, and prevalent reproductive tract infections, a very close association between N. gonorrhoeae, T. vaginalis, and syphilis with HSV-2 was observed. This study highlights the epidemiological synergy between persistent viral infections, altered genital microflora, and chronic genital tract inflammation.

Future of STD clinical trials to prevent HIV

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

The inability to find scalable STD interventions to decrease HIV acquisition and transmission has been disappointing in light of the lack of efficacy seen in several large clinical trials over the past decade.35,56,57 Moreover, because of lowered drug costs and improved safety profiles, interest has grown in the potential efficacy of HAART in suppressing HIV in the genital tract of infected individuals and/or offering antiretroviral chemoprophylaxis to high-risk HIV-uninfected individuals.14,58 However, it is also possible that a more comprehensive approach that addresses frequently co-prevalent bacterial, viral, and other genital tract infections might be more successful in decreasing genital tract inflammation and protecting individuals from acquiring or transmitting HIV.59 This comprehensive genital tract hygiene approach might synergize with a decrease in host HIV burden in individuals initiating HAART.

The high co-prevalence of STDs and HIV is not only a phenomenon of the developing world,60 but is also common in some populations in the United States and other developed countries.61 In a recent study of HIV-infected patients in care in five cities in North America, the presence of any STD was 18% at baseline and 4% after 6 months of follow-up despite initial comprehensive therapy.62 The most common infections were diagnosed among MSM in care, including a high prevalence of rectal C. trachomatis at baseline (7%) and a relatively high incidence of almost 5% at 6 months. N. gonorrhoeae and C. trachomatis at other mucosal sites as well as syphilis were also prevalent in this population. Among HIV-infected women, T. vaginalis was the most common genital tract infection at baseline (14%), with approximately 1% incidence at 6 months.

At the core of the enhanced residual infectiousness of HIV-infected individuals after being treated for STDs is the fact that a major mode by which HIV is transmitted is through intracellular virus.63 In several studies of HIV-infected men and women, when HIV in semen and cervical vaginal secretions was quantified, the investigators noted that genital tract leukocytes were a major source of residual HIV, including individuals who were on effective HAART whose cell-free virus was more consistently suppressed.63–65 Many HIV-infected individuals may have been more sexually active prior to their infection and acquired non-HIV genital tract infections, resulting in maintaining a large number of persistent genital tract leukocytes which can potentiate their infectiousness to sex partners. In some individuals, genital tract leukocytosis can result in as many as 1 million HIV-infected genital tract mononuclear cells per mL of semen.66 Ironically, some immunosuppressed individuals can experience a paradoxical effect with initiating effective HAART since the treatment may suppress extracellular viral replication, but the consequent immune reconstitution can greatly increase the seminal concentrations of CD4 and CD8 bearing T cells by as much as a 25-fold, potentially rendering them more infectious to others.67

The future success of biologically-based HIV prevention interventions will need to build on the brake in HIV replication afforded by the use of HAART, which has been touted in ‘test and treat’ recommendations.68,69 However the efficacy of early initiation of HAART may be mitigated by the residual effects of untreated STDs and the chronic inflammatory milieu that they potentiate. Next generation STD clinical trials aimed at decreasing HIV spread will need to integrate recent molecular developments suggesting the important role of inflammation in the genital tract that may not be fully resolved with current STD treatment regimens. Future study designs may need to offer treatment for bacterial, viral, and protozoal genital tract pathogens, and integrate these interventions with early identification and HAART for HIV-infected persons who may continue to transmit HIV to others. Additional research is needed to understand how to downregulate genital tract inflammation after acute STDs, and to suppress upregulation of HIV expression by co-prevalent chronic genital viral infections. The emerging insights regarding the complexity of the genital tract milieu and the synergistic interactions between HIV and other local infections may ultimately lead to combination interventions that result in having an appreciable impact in the slowing the global pandemic.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

STDs facilitate HIV transmission and acquisition through both ulceration and inflammation. Bacterial and protozoal STD treatment can cause a statistically significant decrease in genital tract HIV concentrations; however, this may not be consistent or sufficient to have a public health impact on the spread of HIV via sexual transmission.70 The lack of a robust effect of treating STDs on HIV acquisition and transmission may be partially due to residual genital tract inflammation, and the fact that many individuals with STDs have multiple co-pathogens, including asymptomatic viral STDs, that are not always treated. Although the initiation of HAART will decrease HIV expression both in the plasma and genital tract, the presence of residual STDs and HIV-bearing genital tract leukocytes may mitigate this benefit. Moreover, as part of the immune reconstitution following HAART initiation, immunosuppressed HIV-infected individuals can experience a repopulation of the genital tract with HIV-infected leukocytes that could make some of these individuals potentially more infectious to their partners. In summary, strategies to decrease STD-related potentiation of HIV acquisition and transmission will need to be based on a better understanding of host immune responses that can specifically downregulate genital tract inflammation and may need to include primary prevention of STD acquisition, such as the development of vaccines against HSV-2 and other STD pathogens.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References

This research has been facilitated by the infrastructure and resources provided by the Lifespan/Tufts/Brown Center for AIDS Research (grant# P30 AI42853; PI, Charles Carpenter) and the Brown/Tufts/Miriam Fogarty AIDS International Training and Research Program (grant# D43TW000237; PI, Kenneth Mayer). K.K. Venkatesh is supported by NIMH Ruth Kirschstein National Research Service Award (NRSA; grant # F30 MH079738-01A2). Funding agencies had no involvement in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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  2. Abstract
  3. Introduction
  4. Associations between non-ulercative STDs and HIV
  5. Data from clinical trials of treating bacterial STDs to prevent HIV
  6. Synergy between HSV-2 and HIV: From observational studies to clinical trials
  7. Future of STD clinical trials to prevent HIV
  8. Conclusions
  9. Acknowledgments
  10. Author Contributions
  11. Conflict of interest
  12. References
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