THE PREVENTION AND MANAGEMENT of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a challenge for the South; in 2001, over 46% of the individuals with AIDS in the United States lived in that region.1 Similarly, rates of several reportable STDs are also highest in the South; this is true for syphilis, chlamydia, and gonorrhea.2 However, to a large extent, the high regional rates reflect the fact that more blacks live in the South than elsewhere,3 and rates of sexually transmitted diseases (STDs) and HIV are disproportionately high among that group.4 These racial disparities are quite marked: for chlamydia, reported rates and observed prevalence are 2 to 5 times greater among blacks than whites; for gonorrhea, there is at least a 10-fold difference in rates,2,5,6 with similar differences in the reported rates of syphilis2; and antibody to HSV-2 is twice as prevalent among blacks as whites.7,8 In 2003, blacks accounted for 49% of the AIDS cases diagnosed in the United States; the rate of AIDS diagnoses for blacks was almost 10 times the rate for whites and almost 3 times the rate for Hispanics.9 HIV prevalence has been estimated to be more than 1% among 18- to 59-year-old blacks.4 These data clearly highlight a need to revisit HIV and STD prevention approaches among blacks. Since rates of STDs and HIV are both disproportionately high among blacks, it is particularly relevant to consider how control and treatment of STDs can contribute to prevention of HIV, an approach that has been a very attractive concept10 and may have particular relevance for prevention among blacks and for the South. This work reviews the available data about reducing HIV transmission by treating STDs and provides prevention recommendations based on that review.
The idea that preventing and treating STDs may help prevent HIV has resulted in an impressive and convincing body of work that provides powerful arguments for the interplay between HIV and a variety of STDs.11 The relationship between STDs and HIV is complex and synergistic.11,12 STDs may facilitate HIV transmission by increasing infectiousness, susceptibility to HIV acquisition, or both. In addition, HIV may facilitate the transmission of some STDs and alter their natural history.
Three very large, very ambitious community-level randomized trials in Africa attempted to use STD treatment to prevent HIV transmission13–15; and a significant body of work in the wake of these studies has attempted to explain and understand the findings.13,16–23 There have been impressive reviews of relevant literature on this topic, as well as reports and recommendations from federal and international health agencies.10,24,25 A large number of studies have addressed this issue from many different perspectives.18,26–30 Nevertheless, it is not at this time clear just how this accumulated information should be used to improve HIV prevention, or the relevance of the data to the spread of HIV in the United States. For the purpose of identifying how such data are relevant to prevention in the United States, this paper reviews the following: results from the relevant community trials, evidence that STDs increase HIV susceptibility, evidence that STDs increase HIV infectivity, and the evidence that STD treatment reduces these effects.
A community trial in Mwanza, Tanzania,13,16 was a proof-of-concept study that demonstrated that improving access to quality care for symptomatic STDs could impressively reduce HIV incidence31; HIV incidence was initially reported to be 42% less among intervention communities than in experimental ones. However, a trial in Rakai, Uganda, provided a different outcome; this study evaluated the effect of providing mass treatment (i.e., metronidazole, azithromycin, and ciprofloxacin) every 10 months, for a total of three cycles to all residents in the intervention villages.14 However, despite providing mass treatment for STDs, HIV incidence was similar in intervention and control communities. A third community trial, in Masaka, Uganda, was a 3-armed trial in which communities were randomized to a behavioral intervention, an intervention consisting of the behavioral component combined with improved STD care (the latter to be similar to the Mwanza intervention) or to serve as control communities; no effect on HIV incidence was noticed.15
Evaluations of these studies have provided important insights. First, the contribution that STDs play as cofactor for HIV transmission may depend upon the stage of the HIV epidemic.24,32 In the early stages, when HIV prevalence is low, transmission is likely more dependent upon an HIV infected core group with multiple sex partners. STD infections in this population further increase spread of HIV. In Mwanza (initial HIV prevalence of 4.1%; HIV incidence <1 per 100 person-years) interventions that reached the core group may have led to the success observed. However, in areas where the HIV epidemic is more mature such as in Rakai (initial HIV prevalence 15.9%; incidence 1.5–2.0 per 100 person-years), HIV transmission occurred primarily among discordant couples and especially soon after infection is acquired, when viral burden is highest. The role of STDs as a cofactor in this setting may be less critical. Second, not all STDS may be equally important. The prevalence and biology of herpes simplex virus (HSV) suggest that this infection may be of great importance and that incident HSV infection greatly facilitates HIV transmission.24 In Rakai, HSV-2 seroprevalence (31.2% among men; 60.9% among women) was considerably greater than in Mwanza (12.1% among men; 35.6% among women)23; in Rakai, 45% of genital ulcer disease was caused by HSV, whereas in Mwanza, herpes was estimated to account for <10% of genital ulcer disease. Such differences could have had significant effect on outcomes, since none of the three community interventions provided treatment of viral STDs (i.e., herpes).
STDs and HIV Susceptibility
Rottingen et al.25 undertook a systematic evaluation of the role of individual STDS in spread of HIV. Only longitudinal studies were used to estimate HIV susceptibility associated with a particular STD. The results confirm that genital ulcer diseases (i.e., chancroid, syphilis, herpes or unspecified genital ulcer disease) are most strongly associated with increased risk of HIV transmission for both men and women.25 The results with nonulcerative STDs were less compelling. The authors found only 2 relevant studies that addressed HIV susceptibility associated with gonorrhea or chlamydia in men.33,34 Among women, there were 9 studies,35–43 6 of which evaluated female sex workers.
Methodologic issues plague these studies including: (a) limited usefulness of the accuracy of historical data and the sensitivity and specificity of laboratory data; (b) problems with adjusting for risk of HIV exposure (i.e., with similar routes of transmission common to STDs and HIV, residual confounding is nearly unavoidable); (c) the timing of data available, which makes it impossible to determine whether an STD and HIV were cotransmitted (i.e., allowing increases in infectivity to appear as increases in susceptibility). These issues limit the relevance of the usual calculation of attributable risk of an STD for HIV transmission, which focuses on risk for HIV acquisition, and not on effects of increased infectivity.
That genital ulcers increase susceptibility to HIV has great face validity since animal models had suggested that an intact vaginal mucosa is a barrier to infection.44 If the epithelium is intact, for transmission to occur, HIV infection must cross the epithelial barrier to gain access to appropriate target cells45; HIV infection requires fusion of the virus membrane with CD4 on the surface of the target cell and with the CCR5 receptor.46 In women, susceptible cells (e.g., dendritic cells, Langerhans cells, and macrophages) are abundant in the lamina propria.45 In men, although the penile shaft and outer surface of the penis is covered by keratinized stratified epithelium, the inner mucosal surface of foreskin is not and contains Langerhans cells47; in circumcised males, a likely target is the distal penile urethra, which is lined with mucosal epithelium, although containing few Langerhans cells.47 It would be expected that genital ulcers increase HIV susceptibility by facilitating HIV access to such target cells. This expectation is supported by a large number of observational studies25 that have found significant associations between genital ulcer disease and HIV seroconversion. However, as discussed above, such studies are open to numerous methodologic issues, some of which are addressed by discordant-couples study design. Results are available from at least 1 such study: Deschamps et al.,48 studying HIV transmission in Haiti, found history of genital ulcer in the HIV(−) partner highly associated with risk of seroconversion: relative risk (RR) = 6.82 (CI 2.95–15.7). Unfortunately, data from the discordant couples component of the Rakai trial do not address this question directly; recalculation of published data suggests that history of genital ulcer in the HIV-negative partner (regardless of history in the HIV-infected partner) was associated with crude RR = 1.8, with a small number of seroconversions.27
There are also data about the extent to which those with HSV-2 infection (which may be considered a proxy for genital ulceration, whether reported as such or not) are at increased risk of HIV acquisition. HSV-2 causes ulcers and microscopic breaks in the mucosa, which may often be unrecognized and may allow HIV access49; HSV-2 infection may also increase susceptibility to HIV by the influx of CD4+ lymphocytes,50 target cells for HIV infection. (Of note, similar findings are associated with H ducreyi infection51). Longitudinal studies—not only those involving discordant couples—of HIV(−) individuals who have HSV-2 infection are free of some of the methodologic concerns discussed; when HIV seroconversion occurs, the temporal sequence of infection is clear, as is the fact that the 2 infections (i.e., HSV and HIV) were not acquired together so that increased infectivity would not be misclassified as susceptibility. In a meta-analysis, including cohort and nested case-control studies, Wald and Link52 determined that HSV-2 infection was associated with an increased risk of HIV seroconversion, RR = 2.1 (CI 1.4–3.2). However, such results applied primarily to men: there was only 1 study among women, and that did not find an association between HSV-2 infection and HIV seroconversion.42 A recent longitudinal study, not included in the Wald meta-analysis, analyzed the data from the Mwanza trial53 and found similar results; among males, HSV-2 infection at baseline was strongly associated with HIV seroconversion, adjusted odds ratio (OR) = 6.12 (CI 2.52- 14.9); the association among women was weaker, adjusted OR = 1.31 (CI 0.62–2.80).
In retrospect, the evidence that nonulcerative STDs increase HIV susceptibility is not as convincing as for genital ulcer disease. There is biologic evidence that the nonulcerative STDs increase recruitment into the genital tract of HIV target cells—CD4+ lymphocytes, monocytes, and Langerhans cells54—and are responsible for superficial cervical ulcers.55 Although such findings provide plausible evidence that nonulcerative STDs increase susceptibility, such evidence is not as convincing as for genital ulcer disease, nor are there as yet supporting animal model data. Furthermore, a randomized clinical trial that provided monthly azithromycin to female sex workers reduced incidence of several treatable STDs but not HIV incidence.56
Similarly, as mentioned, there are methodologic limitations when the observational data addressing susceptibility are examined (i.e., temporal relationship of the diseases acquired and issues of confusing infectivity with susceptibility), even when evaluating discordant couples. Longitudinal data from Rakai27 indicate that history of discharge or dysuria was associated with a nonsignificant increase in risk of HIV seroconversion, adjusted RR = 1.41 (CI 0.89–2.23), although findings differed by sex; this risk was only among men [RR = 2.44 (CI 1.17–5.12)], not women [RR = 1.10 (CI 0.62–1.95)], among whom a report of dysuria or discharge could be caused by a wide variety of clinical entities. This discussion is mainly to highlight how challenging it is to compile truly convincing data measuring the increased susceptibility associated with STDs.
STDs and HIV infectivity
Assessing effects of STDs on infectiousness is also methodologically challenging, and only discordant partnership studies and biologic (i.e., shedding) studies should be considered, since, as Rottingen et al.25 point out, effects on infectiousness cannot be estimated from standard designs. Unfortunately, in reviewing studies of infectiousness, Rottingen et al.25 concluded that the data from these longitudinal studies were “too limited for drawing firm conclusions.”
HIV shedding occurs frequently from ulcers in both men and women (i.e., over 60% for chancroid).57–60 Furthermore, data from at least 1 study suggest that genital ulcer disease is also associated with reversible increase in HIV shedding in semen.61 These results help to interpret observational data from the Rakai study, where a history of genital ulcer disease in the HIV-infected partner among HIV-discordant couples was associated with an increased risk of transmission, RR = 2.58 (CI 1.03–5.69) per sexual act62; in Haiti, such a history was also associated, RR = 2.89 (CI 0.97–9.15), with seroconversion.48 In Pune, India, HSV status affected risk of HIV infection, and incident HSV infection conveyed enormous risk for HIV acquisition (OR = 22.6).24 Surprisingly, discordant-partner studies did not find that history of discharge or dysuria was associated with seroconversion: Haiti, RR = 0.88, when the HIV-infected partner was symptomatic and Rakai, RR = 1.18 [CI 0.54 to 2.59] when either partner was symptomatic.27,48
Although the observational data do not indicate that treating nonulcerative STDs reduces HIV transmission, other data are supportive, particularly with regard to symptomatic urethritis among men; several studies identify the extent to which treatment of symptomatic urethritis reduces HIV shedding.63,64
In terms of evaluating outcomes based on HIV shedding in the genital tract, we should note that a variety of outcomes measures have been used and that this is another area that complicates understanding; various anatomical sites may be assessed (i.e., for males, by urethral swab, or in seminal plasma) and some assessments have considered HIV RNA or HIV proviral DNA, and whether virus is cell-free or cell associated.55 (Although both cell free and cell-associated HIV can cause infection,65 the relative importance of these entities is unknown; animal data suggest that cell-associated virus is less infectious66). Although the level of genital HIV shedding in any one individual seems influenced by a variety of factors,55,67,68 the majority of studies have indicated that shedding in the genital tract, for both men and women, is positively correlated—but not invariably69—with blood plasma HIV RNA viral load.55,68–71 The Rakai data demonstrated that transmission risk is directly associated with level of plasma viral load and that no HIV transmissions occurred if HIV-1 RNA level was under 1500 copies/mL; furthermore, each log increment in the plasma viral load was associated with 2.45-fold increase in the risk of seroconversion.72 Because of the correlation between viral load in blood and semen, changes in seminal viral load have important implications for HIV infectivity. In this regard, studies have been able to demonstrate the potential benefit for HIV prevention that may result from treating STDs: among males treated for urethritis, HIV-1 concentration in semen decreased from 12.4 × 104 copies/ml to 4.12 × 104 copies/mL after 2 weeks; the decrease was greater among those treated for gonococcal urethritis and less for urethritis associated with other etiologies (i.e., chlamydial or trichomoniasis).63 Reductions in HIV shedding in the genital tract should be associated with decreased HIV transmission. In fact, a mathematical model has suggested that a 1 log reduction in seminal HIV load could be associated (depending upon other factors) with approximately a fivefold decrease in infectivity (i.e., probability of HIV transmission per sexual contact).73 Importantly, an analysis of discordant-couple data from Rakai did not find that a history of STD symptoms in the HIV-infected partner, aside from genital ulcer disease, was associated with an increased risk of transmission per sex act.62 These data address only symptomatic urethritis; the few available and relevant studies suggest that asymptomatic urethritis in men is not associated with elevation of seminal viral load.63,74
Studies have evaluated HIV shedding among women with cervicitis (gonococcal, chlamydial, or nonspecific) or with vaginal discharge diseases.55,70,75–83 Just as for men, there are multiple approaches for measuring HIV shedding in the female genital tract, i.e., use of endocervical swabs, or cervicovaginal lavage, with variations in volume and considerations of whether RNA, DNA, cell-free, or cell-associated HIV is assessed.55 Nevertheless, it seems that the results from these approaches do correlate and may be quite comparable (i.e., endocervical swab and cervicovaginal lavage).84 However, there are only 2 longitudinal studies that have evaluated the effect of treatment of STD-specific cervicitis (i.e., chlamydial or gonococcal), and these have demonstrated that treatment is associated with significant decreases in HIV shedding.85,86 These studies have included women who presented with symptoms and those whose STD was identified by screening; reduction in HIV shedding does not seem associated with symptomatology. However, the one study evaluating treatment of vaginal discharge (i.e., trichomoniasis, candidiasis, and bacterial vaginosis) involved primarily women with symptoms. Decrease in HIV shedding is associated with treatment for candidiasis and trichomoniasis; HIV shedding did not decrease after treatment for bacterial vaginosis86 (Table 1).
Despite the positive findings, there are methodologic limitations to these studies; it is clear that for many individuals genital shedding of HIV is intermittent71,87 and so evaluations should include a control group, ideally matched for stage of disease and blood viral load; depending upon the type of evaluation used, more than 1 measurement is desirable since use of cervicovaginal lavage is associated with large intrasubject variation.71
Lastly, studies have demonstrated that infectious syphilis88 and genital herpes activation89 are associated with elevations in HIV plasma viral load, which tend to decrease with STD treatment, indirect evidence that STD treatment may reduce infectivity.
HIV Shedding and STDs: Effect of Antiretroviral Therapy
It is also important to consider how antiretroviral therapy might influence recommendations related to STD treatment as an HIV prevention strategy since highly active antiretroviral therapy (HAART) has a substantial effect by reducing HIV shedding in semen and the female genital tract.90 For example, Cu-Uvin et al.91 found that among antiretroviral-naïve women, cervicovaginal HIV shedding decreased by 0.7–2.1 logs within 1 to 14 days of starting on HAART, and Pereira et al.92 reported almost complete suppression of HIV shedding in semen more than 8 months after starting treatment with lamivudine and zidovudine. In general, if blood plasma viral load is undetectable, the viral load in semen is usually undetectable also.93 However, some individuals still shed HIV in the genital tract, despite having suppressed HIV concentrations in blood,68 suggesting that the genital tract can represent a separate compartment for HIV replication. From the few studies that evaluated the effect of STDs on genital shedding of HIV among infected individuals on antiretroviral therapy, the following observations can be made:
- For the most part, even individuals with urethritis who have nondetectable levels of HIV in blood plasma will still have undetectable levels in semen.93
- Urethritis may still play a role in increasing seminal viral load in some patients. Sadiq et al.93 describe how, with treatment of gonococcal urethritis, the seminal viral load was reduced 20-fold in a patient whose blood viral load was poorly controlled; this suggested that antiretroviral therapy may not always control the potentiating effects of urethritis on viral replication. Winter et al.94 found that urethritis was associated with HIV shedding in semen, adjusting for blood plasma load, and antiretroviral therapy, among other factors. There are few studies among women addressing viral shedding while on ART.
Implications for Prevention Activities
The community trials would suggest that the Mwanza experience may be more relevant for the United States, with its comparatively low prevalence of HIV and continuing importance of core group transmission, than Rakai or Masaka95; if control and treatment of STD does offer some promise for HIV prevention in the United States, we must consider what makes sense for this country. (The Mwanza model introduced rudimentary care into a context where appropriate STD care was nearly nonexistent.) In general, STD prevention approaches to reduce STD rates among those at risk for HIV should be strengthened, and in particular among blacks, given the marked disparities in STD/HIV rates; the issue is about specifics.
The strongest evidence supports treatment of symptomatic STDs and cervical infection among HIV-infected individuals to reduce HIV shedding and infectivity. The effectiveness of such a recommendation is dependent upon the identification of a large proportion of those who are HIV infected, consistent with the new initiative taken by CDC96 to increase the identification of HIV-infected individuals, using rapid testing, implemented in nontraditional settings, approaches recently demonstrated to be cost-effective97; effectiveness also requires strengthening prevention efforts carried out by HIV-care providers, also consistent with recent recommendations.98 However, many individuals have delayed or avoided care despite recognition of STD symptoms99 because of disappearance of the symptoms or lack of appreciation of the importance of such symptoms or cost and availability of care.99,100 Although the effectiveness of such recommendations would be more limited among those well controlled on HAART, all health care providers—and especially those caring for HIV-infected individuals—should be advising patients about the importance of obtaining prompt care when even mildly symptomatic.
HIV care providers should address these specific issues with their patients and inquire about symptoms at each visit. Such counseling and review of risk behavior is consistent with the recommendations made by IDSA/CDC.98 In this regard, clinicians should be prepared to diagnose and treat the following symptomatic conditions, which should reduce HIV shedding and infectivity:
- Urethritis among men: addressing chlamydia, gonorrhea, and regarding trichomoniasis as a possible cause74,101
- Genital ulcer disease among men and women: addressing primarily syphilis and herpes; chancroid should always be kept in mind, but its occurrence has become quite rare in the United States2
- Symptomatic vaginal discharge disease and cervicitis: since treatment of trichomoniasis, candidiasis, chlamydial and gonococcal cervicitis is associated with decreased shedding of HIV78,85,86; treatment of bacterial vaginosis has not been demonstrated to reduce HIV shedding.
- Such recommendations may be particularly important for individuals who have not yet been started on antiretroviral therapy or whose CD4 levels do not warrant antiretroviral treatment but who have detectable plasma viral load; these recommendations are also relevant for those on antiretroviral therapy who are not well controlled.
The effect on HIV shedding of treating asymptomatic infection is less well documented, and therefore the rationale for STD screening among HIV-infected individuals is not to reduce HIV infectivity. In this regard, clinicians should be aware that the CDC/IDSA Guidelines recommended the following screening guidelines for identification of asymptomatic STD among HIV-infected individuals: at initial visit, all patients should be screened for syphilis; among women, all should be tested for trichomoniasis and those ≤25 years of age, tested for C trachomatis. Subsequent screening or testing of other individuals (i.e., men) should be based on risk behavior.98 Since a high proportion of syphilis cases occurred among those with HIV-infection, screening for syphilis has been recommended by CDC/IDSA98; such screening for syphilis makes sense for syphilis control and may contribute to preventing HIV transmission.102 Similarly, asymptomatic chlamydia and gonococcal cervicitis should be identified and treated, as already recommended.95,101 In addition, the CDC STD Treatment Guidelines101 recommend that women with chlamydia infection be rescreened in 3 to 4 months.
STD treatment may help reduce HIV susceptibility, but, for the most part, either supporting evidence is limited, or, aside from efforts to control syphilis, practical and specific implementation strategies are as yet lacking. The evidence is weak that HIV susceptibility can be reduced by treating asymptomatic chlamydia or gonorrhea, the 2 common inflammatory STDs already addressed by public health programs. Nevertheless, the large racial disparities that exist for these diseases are unacceptable; addressing these problems should be a national priority, regardless of the impact on HIV transmission. Although reducing rates of cervical chlamydia and gonorrhea, especially among blacks, is already a priority and efforts to increase screening coverage are being developed,103 clearly more needs to be done; recommendations to improve prevention of gonorrhea have recently been addressed.104 Unfortunately, since the health care system in the South already faces challenges in terms of capacity,105 the need to strengthen STD prevention services there constitutes both an imperative and a challenge.
The evidence is stronger that preventing ulcerative STDs can decrease HIV susceptibility, and here there is some good news: programmatic efforts in the South to address syphilis, an ulcerative STD, have had some success, since the rate of syphilis has decreased in the South while increasing in all other regions.106 However, given the increases in syphilis that have occurred among gay and bisexual males, it is important that such prevention efforts targeting minority populations in the South be continued.107
However, the STD-HIV relationship that may be most relevant for HIV prevention among blacks, and thus for the South, may involve HSV-2. As discussed, the evidence that HSV-2 increases susceptibility to HIV is particularly compelling and probably relevant for the South. Wald and Link52 have estimated that 35% of HIV infection among blacks could be attributed to HSV. In fact, a recent evaluation among black women found that one of the strongest risk factors for new HIV infection was a history of genital herpes.108 Based on such observational data, several large randomized trials are being implemented, evaluating if HSV-2 suppressive treatment (i.e., acyclovir) of HIV-uninfected individuals who are HSV-2 seropositive can decrease their HIV acquisition. Results from such studies can inform future recommendations that are relevant for the South and elsewhere. Nevertheless, it would seem prudent for clinicians to advise individuals diagnosed with genital herpes that they are at increased risk for HIV acquisition and to encourage HIV testing if status is uncertain and to emphasize established HIV strategies (i.e., abstinence, mutual monogamy, condoms, etc.).
Lastly, an STD diagnosis may offer the potential for HIV prevention by helping to identify individuals who are particularly infectious for HIV, those with a symptomatic STD and recently acquired HIV. Clearly, HIV testing should be offered to individuals with symptomatic STDs.101,109 More generally, in light of the prevalence of unrecognized HIV infection among STD clinic attendees,109 point of care testing for HIV in those settings should be a priority.110 In addition, recent studies have demonstrated that individuals with acute HIV may present with symptomatic STDs and that lymphadenopathy may be a important clinical clue of early infection111; such individuals may be particularly contagious because of the elevated plasma viral load associated with primary HIV,112 although routine HIV testing may be negative. In a recent study of 109,500 subjects in North Carolina, the majority of patients with previously unrecognized early HIV (acute or recent) were detected in public STD clinics.113
In summary, control and treatment of STDs can definitely contribute to HIV prevention. Treatment of symptomatic STDs among those with HIV infection is clearly warranted, syphilis prevention activities targeting minorities in the South must be maintained, and the racial disparities in some STDs must be addressed. Improved and increased HIV testing in patients with STDs has the potential to identify many people with unrecognized HIV infection, including those with acute HIV infection who are most contagious.
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