HIV Prevention Through Early Detection and Treatment of Other Sexually Transmitted Diseases -- United States
Recommendations of the Advisory Committee for HIV and STD Prevention
July 31, 1998
Curable STDs as Cofactors for HIV Transmission
Since the beginning of the AIDS epidemic, researchers consistently have noted a strong epidemiologic association between HIV/AIDS and other STDs in developing and industrialized countries, including the United States. (1,2) The mutually reinforcing nature of these infectious processes has been termed "epidemiological synergy." (1) Diverse observational studies, including cross-sectional studies and cohort studies of HIV seroconvertors, have indicated at least a twofold to fivefold increased risk for HIV infection among persons who have other STDs, including genital ulcer diseases and nonulcerative, inflammatory STDs. (3-12) These "STD cofactor effects" were corroborated for each of the major specific genital ulcer pathogens -- Treponema pallidum (the agent of syphilis), Hemophilus ducreyi (the agent of chancroid), and herpes simplex virus type 2 (HSV-2, the agent of genital herpes) -- as well as for the pathogens principally responsible for nonulcerative STDs -- Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. More recently, evidence has suggested that bacterial vaginosis, which is not strictly an STD but is related to sexual behavior, also can be linked to increased risk for HIV infection. (13)
Several studies have explored potential biologic mechanisms by which other STDs can facilitate sexual transmission of HIV infection by increasing infectiousness or susceptibility. HIV is detected routinely in the exudate of genital ulcers from HIV-infected men and women. (14-17 ) Ulcers bleed easily and can come in contact with vaginal, cervical, oral, urethral, and rectal mucosa during sex. In men and women, inflammatory STDs (e.g., gonococcal and chlamydial infections) appear to increase both the prevalence of HIV shedding and the HIV RNA copy number or "viral load" in genital secretions. ( 17-20) Thus, these STDS are likely indicators of HIV infectiousness. (1,21) In HIV-infected men, gonococcal infection increases shedding of HIV RNA in semen tenfold, but effective treatment of gonorrhea rapidly reduces HIV shedding to background levels. (20) In addition, both ulcerative (e.g., herpes, syphilis, and chancroid) and nonulcerative STDs (e.g., gonorrhea and chlamydia) attract CD4+ lymphocytes to either the ulcer surface (22) or the endocervix, (23) which disrupts epithelial and mucosal barriers to infections and establishes a potential mechanism to increase a person's susceptibility to HIV infection.
To test these epidemiologic and biologic findings, two community-level, randomized controlled intervention trials have been conducted. One trial, in the Mwanza district of Tanzania, documented that continuous provision of improved STD treatment reduces the acquisition of HIV infection. (24) In that study, providing effective drugs for STDs and training health-care providers to treat symptomatic STDs resulted in a 38% lower HIV incidence in six intervention communities compared with six matched control communities. (Figure 1) This lower HIV incidence was not accompanied by changes in sexual behavior or by condom use that might confound the direct association between improved STD treatment and lowered HIV incidence. This randomized controlled trial (RCT) was the first documented intervention that successfully reduced HIV incidence at the population level. This study suggests that treatment of symptomatic STDs is an effective, community-level strategy for HIV prevention in settings and subpopulations in which HIV infection and other STDs are prevalent. Moreover, the program's cost-effectiveness of $217 (U.S.) per HIV infection averted and $10 (U.S.) per disability-adjusted life-year (DALY) saved, compared favorably with other highly effective public health interventions (e.g., childhood vaccinations, which costs $12-$17 [U.S.] per DALY). (25)
The second trial took place in the Rakai District of Uganda and used an alternative approach: intermittent mass STD treatment administered in a blinded fashion every ten months, (26) as opposed to the continuous, enhanced treatment of symptomatic STDs in Mwanza, Tanzania. Early results of the Rakai study indicate no difference in the incidence of HIV infection between intervention and control areas, despite significant reductions in curable STDs in the intervention areas. (27)
Important differences distinguish the two studies. These differences could help the public health community assess which STD interventions are most effective in influencing HIV transmission. An important factor may be continuous efforts compared with intermittent or episodic service delivery, even when the latter is highly intensive. A second could be the stage of an HIV epidemic: at the time of the first trial, Mwanza was experiencing a relatively early HIV epidemic, with community HIV prevalence of 4%, whereas the Rakai study took place in one of the world's most mature epidemics, with a community HIV prevalence of approximately 16%. (28) These factors and others could have contributed to the differing outcomes of these studies, and additional investigation is needed.
The results of these two intervention trials reinforce the importance of ongoing operational research to identify the strategies most effective for HIV prevention. (29) Public health officials should assess the epidemiologic context of the HIV and STD epidemics based on the available data (i.e., epidemiologic associations, biologic mechanisms, and intervention trial results) to plan and monitor implementation of early detection and treatment of STDs to prevent HIV infection in the United States.
Other Strategies for Reducing STDs for HIV Prevention
Mathematical modeling of the biologic effects of other STDs on HIV infectiousness and susceptibility has documented that standard epidemiologic measures of effect (e.g., odds ratios or relative risks) might substantially underestimate the effect of STDs on HIV transmission. (30,31) This underestimation occurs because standard measures do not consider the effects of STD cofactors on ongoing HIV transmission. Models suggest that STD incidence and prevalence could be critical determinants of whether sustained heterosexual HIV epidemics can persist in subpopulations with different levels of risky sexual behavior. (32)
Modeling also suggests other findings relevant to the role of STD treatment in a comprehensive approach to HIV prevention. First, models have demonstrated a substantially greater effectiveness and cost-effectiveness when STD prevention is implemented early in an HIV epidemic, before widespread dissemination of infection. (33-36) The greater impact of the Tanzania study (24) compared with the Ugandan study (27) appears to corroborate this prediction. Second, directing STD interventions toward persons at highest risk for acquiring and transmitting infection with HIV and other STDs will generate a greater impact on the subsequent course of an epidemic. ( 34,36,37) Empiric evidence of these findings is available from interventions that improved STD services for female sex workers in countries where HIV transmission was strongly associated with commercial sex. (10,38)
Intersecting Epidemics of HIV Infection and Other STDs
As discussed previously, concurrent STDs increase the transmission probability for HIV infection. In addition to this STD cofactor effect, the impact of other STDs on HIV transmission will depend on a) the magnitude of the epidemics of other STDs in the population and b) the extent to which the epidemiology of curable STDs overlaps that of HIV infection.
Magnitude of STD Epidemics in the United States
The United States has the highest rates of STDs in the industrialized world. (39) In 1996, approximately 400,000 genital C. trachomatis infections were detected and reported to CDC, (40) making this infectious disease the most commonly reported in the United States, (41) despite continuing evidence that screening is limited even among the highest risk groups. (42,43) Although gonorrhea incidence in the United States declined nearly 60% during 1980-1996, (40,44 ) the 1996 rate of 124/100,000 was 26 times greater than the rate in Germany (4.7) and 50 times the rate in Sweden (2.4). The total rate of syphilis in the United States in 1996 was 20.2/100,000 -- 13 times higher than the rate in Germany (1.5) and 33 times higher than the rate in Sweden (0.6). Although it is not a curable STD, the prevalence of infection with HSV-2 (a chronic, persistent viral infection) actually increased by 30% during the first 15 years of the AIDS epidemic in the United States; by 1991, a total of 22% of all U.S. adults, an estimated 45 million persons, were infected with HSV-2. (45) This often underrecognized burden of STDs in the United States led the Institute of Medicine to issue a landmark report on STDs and their prevention in the United States. (39) In this report, the Institute of Medicine estimated the 1994 cost of sexually transmitted HIV infection at $6.7 billion and the cost of other STDs and their immediate sequelae at $10 billion. (39)
Against this backdrop of high overall STD rates and costs, some subpopulations experience even higher-than-average incidence and prevalence of STDs. Sexually active adolescents in most parts of the United States, regardless of race or socioeconomic status, have a point prevalence for chlamydial infection of 5%-10%. (46) In 1996, routine notifiable disease reporting alone indicated a gonorrhea case rate of 3% for African-American women aged 15-19 years and men aged 20-24 years in the United States. (40) Reported rates of primary and secondary syphilis in the United States are approximately fiftyfold higher among African Americans than whites. (40) Men who have sex with men (MSM), especially young MSM, continue to have high rates of STDs. (47,48) STD prevalence rates also are typically high among persons who use illicit drugs, including both injecting-drug users (IDU) and noninjecting-drug users. In terms of geographic variation, bacterial STD rates are higher in many large cities and sharply higher in the southeastern United States than for the country as a whole. (40,49 ) Superimposed on the high prevalence of STDs overall in the United States, the higher rates within these demographic or geographic subgroups suggest that the potential for reducing STD prevalence in these groups could be especially large.
Intersecting Epidemiology of HIV Infection with Curable STDs
The potential impact of STDs in facilitating HIV transmission depends not only on the magnitude of the STD cofactor effects and the overall STD prevalence rates, but also on the extent to which other STDs are concentrated disproportionately among persons and subpopulations likely to be exposed to HIV infection. STD/HIV coinfection rates can be one indicator of this epidemiologic interaction, which heightens the potential contribution of curable STDs to the sexual transmission of HIV infection.
For example, a much higher prevalence of HIV coinfection exists among persons with any STDs than among those without STDs or a history of STDs. (1,50-52) Consequently, interventions directed toward any person with an STD are targeted intrinsically to persons with a higher prevalence of and at higher risk for HIV infection.
Among persons with STDs, the likelihood of HIV coinfection typically is high among persons with ulcerative STDs, reflecting shared risk factors and the strong, mutually reinforcing effects of ulcerative STDs and HIV infection on ulcer persistence and HIV transmissibility. (1) For example, a recent multicenter study of syphilis therapy in the United States documented an 18% prevalence of HIV infection among patients with early syphilis in several large cities in the United States. (53) A study from New York (city), which has a longstanding HIV/AIDS epidemic, reported a tendency toward increasing HIV prevalence over time among genital ulcer disease patients, even in an STD clinic setting with declining overall rates of HIV infection. (50) A newly reemerging syphilis epidemic in Baltimore was concentrated among HIV-infected persons, with HIV/syphilis coinfection rates of 18% -- higher than the 3% HIV prevalence observed among other STD clinic patients. (54) These examples reinforce the need to detect, treat, and prevent bacterial ulcerative STDs wherever they persist (55) or reemerge (56) in a community.
Although HIV coinfection rates typically are higher-than-average among persons with ulcerative STDs, the high incidence and prevalence of the major nonulcerative STDs, especially chlamydia and gonorrhea, (40) suggests that their population-attributable risk for promoting sexual transmission of HIV infection could be even greater. (1) Moreover, data from the Supplement to HIV/AIDS Surveillance (SHAS) project and other studies demonstrate that, despite the markedly high prevalence of HIV infection among genital ulcer disease patients, the incidence of nonulcerative STDs among HIV-infected persons could be higher than the incidence of genital ulcer disease. (57,58)
In addition to these considerations related to persons infected with different STD pathogens, subpopulations at increased risk for HIV transmission typically have higher rates of STDs. For example, despite substantial declines since the beginning of the AIDS epidemic, MSM continue to have high rates of bacterial and other STDs, (48,59) and outbreaks of gonorrhea continue to occur. (47) Notably, the occurrence of other STDs continues to be an important predictor of HIV seroconversion among young MSM. (59) Also, although parenteral exposure through contaminated injection equipment is paramount among IDUs, they are at risk for sexual HIV transmission, as well. In one study of female IDUs, for example, syphilis was identified as a prominent risk factor for acquiring new HIV infection, a finding that suggests sexual transmission could account for an underrecognized subset of new HIV infections in this group. (60)
Recent Shifts in the HIV/AIDS Epidemic in the United States
The U.S. HIV/AIDS epidemic has evolved recently in three ways that suggest that STD cofactor effects are becoming increasingly important. First, heterosexual HIV transmission is responsible for the most rapidly increasing subset of U.S. AIDS cases, having increased both proportionately and absolutely, (61) despite recent evidence that the epidemic is leveling off within some other subpopulations. (62) Heterosexual HIV transmission is particularly important among women (61) As noted previously, evidence exists for a prominent STD cofactor effect related to heterosexual HIV transmission. (1,2,24,63,64)
Second, the most striking recent subpopulation increase in AIDS in the United States is among women, particularly young African-American women, (61,62) among whom the prevalence of other STDs also is disproportionately high. (40) The shift in the HIV/AIDS epidemic toward African Americans reflects, and could in part be attributable to, the longstanding disproportionate burden of other STDs in this group. It also is closely related to the increasing prevalence of heterosexual HIV transmission, which reinforces the importance of routine screening for asymptomatic STDs, because the proportion of STDs that are asymptomatic is higher among women than men.
Third, an increasing proportion of all AIDS cases (62) and AIDS cases among young women (61) are being reported in the southeastern United States, a trend that reflects the geographic distribution of notifiable STDs (e.g., gonorrhea and syphilis) nationwide. (Figure 2) (40,44,49) Like other trends, the geographic overlap between U.S. regions (e.g., the South) that have the highest STD rates and those with the most rapidly expanding epidemic of heterosexual AIDS and HIV infection (61,64) suggests a need to strengthen early STD detection and treatment among persons at risk for HIV infection.
Current Status of STD Clinical Services in the United States
Access to and Quality of Care in STD Clinics
Widespread availability of good-quality clinical STD services is essential to ensuring that infections are detected and treated to help reduce the risk for STD and HIV transmission. (39) However, persons living in the United States currently have limited awareness of their need for STD services, as well as limited access to these services. Nearly one out of five persons living in the United States think that all STDs are curable, and more than half do not know that other STDs facilitate HIV transmission. (39) Only half of local public health departments in the United States provide STD preventive services, compared with 96% that provide vaccinations. (Figure 3) (65) Even where STD services are provided, access to care often is restricted by limited hours of operation and the lack of timely services. (66) Nearly 40% of local health departments that provide STD services cannot see potentially infected (and infectious) new patients the same day they seek care, and 15% cannot see such patients for 3 days or more. (65)
STD Services Outside Public Health Clinics
As a result of changing health-care systems in the United States, most patients with STDs, especially women, are not examined in public STD clinics. In primary-care settings, even if persons are examined by a clinician, most providers do not routinely obtain a sexual history or ask about or screen for STDs. (42,67 )
To address this problem, innovative approaches to delivering STD clinical care outside of categorical STD clinics are being explored. Integration of STD care and family-planning services within a broader reproductive health model provides efficient health care for women and has been highly successful as a primary strategy for reducing chlamydial infections in the United States. (68) Prenatal and obstetrical-care settings also provide a venue for STD/HIV screening and prevention, while enhancing the potential for prevention of perinatal HIV transmission (69) and other STD-related adverse outcomes of pregnancy. (70,71) Recognition that public-sector STD services cannot reach all persons who need them has prompted additional efforts to reach private providers. (72,73) Specific strategies include promoting improved STD services within managed care organizations (MCOs), (74) which are emerging as a dominant medical-care system in much of the United States, (75) particularly for the more disadvantaged subset of the population at higher risk for HIV infection. For example, the role of MCOs was specifically considered in the development of the Institute of Medicine report, The Hidden Epidemic, and MCO representatives helped develop the 1998 Guidelines for Treatment of Sexually Transmitted Diseases, which is used to set STD practice standards in the United States. (76) Additional efforts have been undertaken with providers who care for other critical subpopulations with high rates of STDs (e.g., adolescents), (73) but these efforts need to be increased substantially.
Establishing STD clinical services in nonclinical, institutional, or community settings typically is more expensive than clinic-based approaches but could yield substantial benefits if services are extended to persons at higher-than-average risk for acquiring or transmitting STDs within communities. (77,78) New STD diagnostic methods that use urine, self-collected swabs, or other noninvasive specimens will permit direct outreach to persons who might not effectively access any formal health-service setting. (79,80) In addition, the recent approval of rapid HIV tests and tests that use oral fluids as a specimen (81-83) could facilitate the widespread use of HIV testing and counseling in STD care settings, particularly nontraditional ones. Community outreach for STD prevention is limited in many jurisdictions (Figure 3), (65) particularly outside dedicated STD clinics or in other venues where there are persons at higher-than-average risk for STD or HIV infection. For example, although U.S. prisons have expanded screening programs for HIV infection in recent years, STD screening and prevention remains less common. (84) Fewer than half of U.S. jails (85) offer routine STD detection and treatment programs, despite their documented high yield and impact. (77,86)
Importance of Asymptomatic Infections
An often unrecognized aspect of STDs, including bacterial STDs, is how frequently persons with these infections have no symptoms or do not recognize symptoms. Most studies of STDs are conducted in health-care settings specifically for persons who do recognize symptoms; therefore, these studies usually overestimate the proportion of infected persons who are symptomatic. Studies of STD screening in nonhealth-care settings (e.g., jails, workplaces, and communities) or health-care settings where STD treatment is not the primary function (e.g., family-planning clinics) suggest that most persons with gonorrhea or chlamydia are asymptomatic. Among women seeking contraceptive or other gynecologic services, 52% of those with gonorrhea and at least 70% of those with chlamydial infection exhibited neither symptoms nor signs of infection. (87,88) Four population-based studies of men documented that 68%-92% of those with gonorrhea reported no symptoms, (89-92) and one study reported that 92% with chlamydia reported no symptoms. (92)
This common lack of symptoms for gonorrhea and chlamydia has important implications for treatment of these STDs, as well as for the way in which STD treatment can be used for HIV prevention. Providing access to treatment for persons with STD symptoms is an essential aspect of STD and HIV prevention, but most curable STDs will go unrecognized and untreated without increased efforts to detect and treat persons without symptoms. Opportunities to identify and treat asymptomatically infected persons include screening in health-care settings when persons are present for other problems (e.g., in emergency rooms or family-planning clinics, during routine or annual physical examinations, and during vaccination visits for adolescents and adults) and in nonhealth-care settings (e.g., schools and jails). Screening also can be conducted through sex-partner-notification programs.
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