Preventing and Controlling Chlamydia -- the Silent STI -- in People With HIV
Table of Contents
- Chlamydia Risk Factors in People With and Without HIV
- How Chlamydia Sets Up Infection and Spreads
- Chlamydia Raises Risk of HIV Infection and Progression
- Screening and Testing for Chlamydia: Urine Is Not Enough
- Chlamydia Prevention That Works: Condoms and Beyond
- Benefits Reaped With Better Partner Notification
- Treating Chlamydia in People With HIV
Every year nearly 3 million people in the United States get infected with Chlamydia trachomatis, the most frequently reported bacterial sexually transmitted infection (STI ) in this country. An international review and a US study determined that about 5% of HIV-positive people have chlamydia infection. Because chlamydia -- the silent STI -- often causes no symptoms, regular screening of sexually active people is essential. Risk factors for chlamydia infection include prior chlamydia, multiple sex partners, unprotected sex, drug use during sex, younger age, and a CD4 count below 200 cells/mm3. Rectal chlamydia infection can boost the risk of HIV infection in MSM nearly 9 times, and chlamydia doubles the risk of HIV shedding in the genital tract. Treating chlamydia significantly lowers cervical HIV shedding. Various strategies for getting antibiotics to sex partners of people diagnosed with chlamydia -- without requiring partners to visit a clinic for an exam -- have proved effective in treating more partners and preventing reinfection in index cases. But such strategies have some drawbacks. Chlamydia treatment guidelines are the same for people with and without HIV. Some research suggests that the simplest regimen -- single-dose azithromycin -- may be less than optimal for people with asymptomatic rectal chlamydia.
Chlamydia poses an insidious and ongoing threat to HIV-positive people -- insidious because it usually causes no symptoms and so can easily go undetected, ongoing because people with HIV often remain sexually active and so risk picking up or passing along another STI.
Chlamydia trachomatis accounts for the highest proportion of reported bacterial STIs in the United States, about 3 million new infections yearly,1 representing about 2.7% of adults between 18 and 44 years old. And people with HIV do their share in sustaining that high rate. A systematic review of HIV-positive people across the world (but mostly in North America and Europe) figured that 5% have chlamydia.2 Chlamydia proved the fourth most prevalent STI in this review, following Trichomoniasis (at 18.8%) and syphilis and gonorrhea (tied for second at 9.5%).
Chlamydial urethritis usually does provoke symptoms in men,3 but most women with chlamydia-induced pelvic inflammatory disease have symptoms so mild or nonspecific that they never seek medical care.4 (A handout for patients at the end of this article lists chlamydia symptoms and other chlamydia prevention and care pointers.) Yet 20% of women with pelvic inflammatory disease become infertile, 18% succumb to "debilitating, chronic pelvic pain," and 9% face life-threatening tubal pregnancy.4 C trachomatis infection during pregnancy can lead to postpartum endometritis in mothers and to conjunctivitis or pneumonia in infants.4
Gay and bisexual men with and without HIV run a risk of asymptomatic rectal chlamydia if they practice receptive anal intercourse. A 3076-man study in Britain charted a 38% prevalence of HIV and rectal chlamydia coinfection, and two thirds of rectal infections caused no symptoms.5 Those findings prompted the investigators to call rectal chlamydia "a reservoir of undiagnosed infection" in men who have sex with men (MSM).
Besides causing pelvic inflammatory disease in women and epididymitis in men, chlamydia can trigger conjunctivitis or sexually acquired reactive arthritis in adults.4 And as with most STIs, chlamydia heightens the risk of acquisition or transmission of HIV and other sexually transmitted pathogens.
|Chlamydia Care Reminders for HIV Providers|
Although the CDC and other agencies and professional groups offer lengthy and detailed advice on chlamydia screening, diagnosis, and treatment in people with and without HIV, chlamydia experts acknowledge big holes in understanding the natural history of this pervasive infection. In 2008 the CDC gathered an advisory group to sort out what's known -- and not known -- about the course of chlamydia in infected people.6 They homed in on four "key questions" whose answers bear heavily on chlamydia prevention and care guidelines. After parsing available data, the panel agreed that no one knows the answers (Table 1).
|Table 1. Key Questions About the Course of Chlamydia Remain Unanswered|
|Key Question||What Data Say So Far|
|What is the duration of untreated, uncomplicated genital chlamydial infection in humans?||"Ethical considerations are a major challenge in studying the natural history of untreated chlamydia. ... Taking these ethical challenges into consideration, designing longitudinal studies on the natural history of chlamydia will be difficult."|
|Which clinical factors influence resolution of untreated, uncomplicated genital chlamydial infection in humans?||"... we have limited knowledge about the clinical factors that influence the duration of untreated, uncomplicated genital chlamydial infections in humans."|
|Which host immune responses occur in uncomplicated genital chlamydial infections in humans, and which genetic determinants of the host modulate these immune responses?||"... there are few studies of host immune responses in humans with uncomplicated genital chlamydial infections."|
|Which biological properties of C trachomatisinfluence resolution of uncomplicated genital chlamydial infections in humans?||"... we have very limited knowledge of the impact of biological characteristics of C trachomatis on outcomes of uncomplicated genital chlamydial infection in humans, including most importantly, the duration of infection."|
Source: Geisler et al.6
With those limits in mind, this review analyzes chlamydia risk factors, prevalence, and incidence in people with HIV; the impact of chlamydia on HIV risk and progression; screening for and diagnosing chlamydia in people with HIV; preventing chlamydia; and treating chlamydia in people with HIV. The article is limited to C trachomatis serovars that cause urethritis, pelvic inflammatory disease, and the other conditions mentioned above. Three C trachomatis serovars can cause lymphogranuloma venereum, a lymphatic system infection that spawned a concerning spate of outbreaks among MSM over the past decade,7,8 but this article will not cover lymphogranuloma venereum.
CDC case counters tallied 1,307,389 chlamydia infections in 2010.1 They note that this number underestimates the actual total because most people with chlamydia don't know they're infected, so their case doesn't get reported. The CDC estimates the actual number of new chlamydia infections yearly (chlamydia incidence) at 2.8 million.1 Among women and girls, chlamydia rates are highest among teens (2536 per 100,000) and 20- to 24-year-olds (2447 per 100,000), while among men and boys prevalence peaks in the 20-to-24 age group (605 per 100,000).4 Because the cervix of teenage girls and young women is not fully matured and is probably more susceptible to chlamydia, the CDC notes, this age group runs a higher risk of infection than older sexually active women.1
In 2011 a 37-study systematic review of STIs acquired after people became infected with HIV figured chlamydia prevalence at 5%.2 The analysis embraced 708,296 HIV-positive people, and 27 of the studies were from North America, Europe, or Australia. The highest STI coinfection prevalence came among people with newly diagnosed HIV, a result possibly reflecting a heightened HIV acquisition risk in people with an STI. Overall STI prevalence did not differ between men and women or between people taking or not taking combination antiretrovirals. The latter finding, these researchers cautioned, "suggests that STI co-infections could undermine efforts to use HIV treatments for prevention by increasing genital secretion infectiousness."2
A study of 235 HIV-positive gay men seen in Sydney in 2004 and 2005 found that 2% had urethral chlamydia and 6% had anal chlamydia, and these rates did not differ from prevalence in an HIV-negative cohort of gay men.9 At four HIV/STI clinics in London, a study of 3076 MSM seen in 2005 and 2006 recorded rectal and urethral chlamydia rates of 8% and 5%.5 Rectal rates reflected chlamydia variants causing lymphogranuloma venereum (LGV) as well as non-LGV variants. Of the 247 rectal infections, 171 (69%) evoked no symptoms and so would have been missed without screening.
Although chlamydia and most other STIs reach their highest prevalence in teens and young adults, an eye-opening 1996-2003 study of people attending genitourinary medicine clinics in the British Midlands shows that people over 44 years old contribute their share to STI prevalence.10 These investigators counted 4445 STI episodes in people 45 and older during the study period, including 801 chlamydia diagnoses (18%). Compared with 1996, the chlamydia rate was 3.6 times higher in 2003 (95% confidence interval [CI] 2.55 to 5.06, P < 0.0001). That jump was bigger than the overall 2.27 times rise in STI prevalence. Over the study period, the overall STI rate rose more in men (rate ratio [RR] 2.51, 95% CI 2.14 to 2.94, P < 0.0001) than in women (RR 1.85, 95% CI 1.50 to 2.28, P < 0.0001). The researchers did not report HIV rates.
Chlamydia incidence remains poorly studied in HIV populations. The largest recent study involved 4461 HIV-positive people in the US Military Natural History cohort monitored 6 months or later after their positive HIV test.11 Through an average follow-up of 7.08 years, 278 people (6%) picked up chlamydia, a rate similar to the 5% chlamydia prevalence recorded in the 37-study systematic review of 708,296 people with HIV.2 In the military study, chlamydia or gonorrhea rates were significantly higher in younger, male African Americans with a history of either STI.
A 2004-2006 study of 557 HIV-positive people in four US cities detected new chlamydia infections only in 365 MSM, not in 73 men who have sex with women or 119 women.12 In MSM, incidence 6 months after they entered the cohort stood at 5% for anorectal chlamydia and at 2% for oropharyngeal chlamydia (Table 2).
|Table 2. Chlamydia Prevalence and Incidence in 527 HIV-Positive U.S. Adults|
|Baseline Prevalence||Incidence at 6-Month Visit|
|MSM (n = 365)||MSW (n = 73)||Women (n = 119)||MSM (n = 365)||MSW (n = 73)||Women (n = 119)|
MSM, men who have sex with men; MSW, men who have sex with women.
A single-center nurse-led self-screening program for chlamydia and gonorrhea in Brighton, UK, involved 976 screens done over 8 months in HIV-positive people with no STI symptom.13 Screening detected 143 infections that would have been missed without this program. In MSM incidence measured 9.8% for rectal chlamydia, 2.6% for urethral chlamydia, and 1.7% for pharyngeal chlamydia. Chlamydia incidence in heterosexual men and women was 2.1%.
In the general US population, yearly chlamydia case rates among women vaulted 54% from 2000 to 2010 (Figure 1).14 The CDC cautions that this inexorable case-rate inflation could reflect more intense screening, more sensitive diagnostic tests, or improved surveillance and reporting systems,4 but "persistently high infection rates" probably figure heavily in the equation.
A prospective study of 1427 HIV-negative MSM recruited from 2001 through 2004 in Sydney recorded urethral and anal chlamydia incidence rates of 7.43 and 4.98 per 100 person-years, higher than the 3.49 and 2.96 rates for urethral and anal gonorrhea.15 Chlamydia incidence in these HIV-negative MSM far outstripped incidence in the general population of US women in 2010 -- 610.6 per 100,000 in the US women14 and 7430 and 4980 per 100,000 for urethral and anal chlamydia in the Australian MSM. In these men unprotected anal intercourse with HIV-positive partners and frequent insertive oral sex raised the risk of urethral gonorrhea or chlamydia, and receptive unprotected anal intercourse made anal infections more likely.
Researchers have not directly tried to gauge the impact of active chlamydia infection on HIV incidence, though evidence from a systematic review described above supports that intuitive association.2 One should not assume, however, that wider chlamydia control measures will necessarily trim HIV incidence. A 2011 Cochrane Database review of four trials "failed to confirm the hypothesis that STI control [through biomedical intervention] is an effective HIV prevention strategy" in the general population.16 However, all these trials took place in rural Africa. The Cochrane team did find "other compelling reasons why STI treatment services should be strengthened."
Several big studies identified independent predictors of chlamydia and other STIs in HIV-positive people and the general population (Tables 3 and 4).12,17-21 Being young raises the risk of chlamydia. Having lots of sex -- and lots of risky sex -- raises the risk. But these are obvious indicators; a few risk factors are less evident.
|Table 3. Risk Factors for Chlamydia and Other STIs in People With HIV|
|First Author||Location(s)||Year(s)||No. of Participants||Risk Factors (95% CI)|
|Mayer12||SUN Study participants in Denver, Minneapolis, St. Louis, Providence||2004-2006||365 MSM, 73 MSW, 119 women||For prevalent STIs* in MSM:|
> 4 partners: OR 4.81 (2.59-9.13)
For incident STIs* in MSM:
> 4 partners: OR 3.44 (1.82-7.56)
Polysubstance abuse (not marijuana): OR 5.0 (1.82-13.2)
|Heiligenberg17||Netherlands, academic hospital outpatient clinics||2007-2008||659 MSM||For CT, NG, or SY:|
Age < 40: OR 2.5 (1.3-5.0)
Sex with > 2 sex partners: OR 2.1 (1.2-3.5)
Sharing sex toys: OR 2.2 (1.0-4.9)
For CT or NG:
Age 40-44 vs older: OR 2.4 (1.1 5.3) Age < 40: OR 2.4 (1.1-5.4)
Enema before sex: OR 2.4 (1.3-4.4)
Drugs during sex: OR 2.4 (1.4-4.0)
|Landes18||Western Europe and Ukraine||1999-2005||1050 pregnant women||For CT, SY, or TV:|
Being single: OR 3.9 (1.2-12.7)
Sex partner of IDUs:OR 3.8 (1.4-10.4)
CD4 count <200: OR 5.4 (1.0-28.1)
CT, Chlamydia trachomatis; MSM, men who have sex with men; MSW, men who have sex with women; NG, Neisseria gonorrhoea; OR, odds ratio; SY, syphilis; TV, Trichomonas vaginalis.
* STIs include syphilis and oropharyngeal, rectal, or genitourinary tract N gonorrhoea and/or C trachomatis.
|Table 4. Risk Factors for Chlamydia and Other STIs in the General Population|
|First Author||Location(s)||Year(s)||No. of Participants||Risk Factors (95% CI)|
|Holtgrave19||48 contiguous United States||1999||Not stated||For CT:*|
Poverty: r 0.358, r2 0.128, P < 0.01
Social capital:† r -0.532, r2 0.283, P < 0.01
Income inequality: r 0.395, r2 0.156, P < 0.01
|Wand20||Sydney, Australia, sexual health clinics||1998-2009||3805 MSM, 5313 MSW, 7084 women||For CT in MSM:‡|
Age < 25 vs 40+: OR 1.47, P = 0.005
Age 25-29 vs 40+: OR 1.58, P < 0.001
Age 30-39 vs 40+: OR 1.42, P = 0.006
Current vs never smoker: OR 1.19, P = 0.05
Genital or anal vs no symptoms: OR 2.86, P < 0.001
Inconsistent condom use: OR 1.51, P < 0.001
CT for women:‡
Never married: OR 1.25, P = 0.05
Minority: OR 1.33, P < 0.001
Inconsistent condom use: OR 1.51, P < 0.001
|Peterman21||STI clinics in Denver, Long Beach, Newark||1999-2000||1236 women, 1183 men attending STI clinic||For recurrent CT:|
15-25 vs older: OR 2.2 (1.7-2.9)
Black vs white: OR 2.0 (1.3-3.1)
Hispanic vs white: OR 1.9 (1.2-2.9)
Infection at initial visit: OR 1.6 (1.2-2.2)
2-4 partners vs 1: OR 1.7 (1.3-2.3)
CT, Chlamydia trachomatis; MSM, men who have sex with men; MSW, men who have sex with women; NG, Neisseria gonorrhoea; OR, odds ratio; SY, syphilis; TV, Trichomonas vaginalis.
* Stated as Pearson product moment correlation coefficients.
† The central features of social capital are "trust, reciprocity, and cooperation among members of a social network that aims to achieve common goals."19
‡ Other variables -- including 1, 2, or 3 or more sex partners in the last months versus none, STI symptoms, and contact with an STI case -- were also associated with higher odds for chlamydia in MSM and women. Risk factors for heterosexual men were being single, minority status, being unsure about HIV status, inconsistent condom use, increased number of female sex partners in the past 3 months, anal/genital symptoms, and presenting for STI screening or being a contact of an STI case.
For starters, "young" doesn't necessarily mean under 25, at least not among gay and bisexual men. A study of 659 HIV-positive MSM in the Netherlands found that being 40 to 44 rather than older more than doubled the odds of chlamydia, gonorrhea, or syphilis17 (Table 3). In Australia a study of 3805 MSM seeking care at STI clinics found that those 30 to 39 had a 42% higher risk of chlamydia than older men20 (Table 4). In this study the heightened risk was similar in MSM under 25 and MSM 25 to 29.
Analysis of HIV-positive US SUN Study participants found that MSM who had 4 or more sex partners in the 6 months before STI testing ran a higher risk of both prevalent and incident chlamydia, gonorrhea, or syphilis12 (Table 3). Multiple substance abuse inflated the odds of incident STIs 5 times in these MSM. Among HIV-positive MSM in the Netherlands, sharing sex toys or having an enema before sex (a signal of receptive anal intercourse) more than doubled the odds of chlamydia, gonorrhea, or syphilis17 (Table 3). In these MSM using drugs during sex also more than doubled the STI risk. Among Australian MSM seen in STI clinics, smoking cigarettes boosted the odds of chlamydia 19%20 (Table 4). In the same study inconsistent condom use in the past 3 months made chlamydia 50% more likely in both MSM and women.
A study of HIV-positive pregnant women in Western Europe and Ukraine (Table 3) determined that a CD4 count below 200 cells/mm3, being single, and having an injection drug user (IDU) sex partner made chlamydia, syphilis, or Trichomonas vaginalis more likely.18
A 48-state US study of the general population found significant links between poverty or income inequality and chlamydia (Table 4).19 These associations are reflected in two other general-population studies that traced ties between chlamydia risk and minority status in US MSM22 or Australian men and women20 (Table 4). Sociodemographic variables must also figure in consistent correlations between childhood sexual abuse and risk of HIV and other STIs. A 2004-2005 analysis of the US National Epidemiologic Survey on Alcohol and Related Conditions found that women or men reporting abuse during childhood ran a higher risk of HIV or other STIs as adults.22 Compared with people not abused as children, the STI risk was higher in abused men or women who also reported same-sex partners or attractions than in those who did not.
A study of 485 girls and 51 boys who were 13 or younger and evaluated for sexual abuse at four US centers found that 3% of girls had chlamydia and 3% had gonorrhea.23 No children tested positive for HIV and no boys had any STI, but 40 of 485 girls (8%) had one or more STIs. Girls with vaginal discharge had higher STI rates than girls without discharge (24.5% versus 6%), but 10 girls with STIs had normal physical exams. And 27 of 40 girls with an STI (67.5%) had normal or nonspecific anogenital exams. One expert in this field counsels that "specific [sexually transmitted] infections in prepubertal children, such as Neisseria gonorrhoeae or Chlamydia trachomatis, are due to abusive contact and should be reported to Child Protective Services."24 Recently abused children, she adds, should be considered for HIV post-exposure prophylaxis.
Adults who have had one STI are prime candidates for a second STI within a year, according to results of a 2419-person analysis of RESPECT-2, a study of HIV prevention counseling in STI clinics in Denver, Long Beach, and Newark.21 Follow-up continued for a year after 1236 women and 1183 men visited the clinic. During 8129 3-month follow-up intervals, 25.8% of women had one or more new STIs, including 9.4% with chlamydia. Among the 1183 men, 14.7% had a new STI, including 9.4% with chlamydia. Two thirds of people with a new STI reported no symptoms. Table 4 summarizes risk factors for a new STI in this study.
In England an 18-month 2002-2003 study of 1971 young women recruited from general practice, family planning clinics, and genitourinary medicine (GUM) clinics found a high chlamydia reinfection rate in all three settings.25 Chlamydia incidence in these 16- to 24-year-old women was higher in GUM clinics than in family planning clinics or general practices (10.6 versus 6.4 versus 4.9 per 100 person-years). But reinfection rates were high in all three settings (21.1 versus 22.3 versus 29.9 per 100 person-years respectively). Finding a new sex partner and failure to treat all partners made reinfection more likely.
An Australian study supports the intuitive assumption that MSM seeking HIV post-exposure prophylaxis will likely benefit from STI screening.26 This 2001-2004 study found that 253 of 298 MSM (85%) agreed to STI testing. While 4.5% had rectal chlamydia, 2.5% had rectal gonorrhea. Only 6 men with an STI (19%) had symptoms at screening.
C trachomatis infects epithelial cells at mucosal surfaces (Figure 2), igniting an inflammatory response that can lead to tissue damage and scarring upon reinfection.27 But little was known about how chlamydia sets off and sustains an inflammatory response until US researchers infected cervical and colonic epithelial cells with C trachomatis and C psittaci.28 Infection prompted secretion of the proinflammatory cytokines IL-6, IL-8, GRO alpha, and GM-CSF. While other invasive bacteria provoke rapid but transient cytokine responses, chlamydia induced a response that began 20 to 24 hours after infection and persisted throughout the chlamydia growth cycle, which lasts 2 to 4 days.
This work also showed that IL-1alpha, which is released during lysis of chlamydia-infected epithelial cells, may amplify the inflammatory response by churning up additional cytokines in uninfected neighboring cells. These investigators believe their findings "suggest a novel concept for chlamydial pathogenesis wherein the acute host response to chlamydia in the genital tract, and at other mucosal surfaces, is primarily initiated and sustained by epithelial cells, the first and main targets of chlamydial infection."28
Like HIV, C trachomatis can jump from one person to another during vaginal or rectal sex.1 But while oral transmission of HIV is inefficient, C trachomatis can exploit the oral route with relative ease,1 a factor that contributes to high chlamydia rates in sexually active people. C trachomatis may also pass from mother to infant during vaginal delivery.
Rectal chlamydia infection can boost the risk of HIV infection in MSM nearly 9 times,29 and chlamydia doubles the risk of HIV shedding in the genital tract,30 upping the odds of HIV transmission from people infected with C trachomatis. Treating chlamydia significantly lowers cervical HIV shedding.31
A retrospective cohort study reported in 2010 by the San Francisco Department of Public Health assessed how the number of rectal infections with C trachomatis or N gonorrhoeae in the past 2 years affects the risk of getting infected with HIV.29 Among 541 initially HIV-negative men studied, 27 (5%) got infected for an estimated annual HIV incidence of 2.25%. Two rectal chlamydia infections or two rectal gonorrhea infections in the past year inflated the risk of HIV seroconversion nearly 9 times (hazard ratio [HR] 8.85, 95% CI 2.57 to 30.4). An early syphilis diagnosis in the past 2 years quadruped the risk (HR 4.04, 95% CI 1.19 to 13.79).
A history of any STI in an HIV-negative woman with an HIV-positive male partner more than doubled the odds that the woman would get infected with HIV.32 This 10-year northern California study involved 360 HIV-positive men and their negative female partners and 82 HIV-positive women and their negative male partners. More than 90% of couples were monogamous. Because this study was reported in mid-1997, follow-up largely occurred before the triple-therapy era. Sixty-eight of 360 initially negative women picked up HIV, compared with only 2 of 82 initially negative men (18.9% versus 2.4%). A history of any STI in a female partner more than doubled the odds of male-to-female HIV transmission (OR 2.6, 95% CI 1.4 to 5.1).
Meta-analysis of 39 studies that weighed the impact of genital tract infections on genital HIV shedding determined that chlamydia nearly doubled the odds, while urethritis or cervicitis from any cause tripled the odds (at the following odds ratios and 95% CIs).30
- Chlamydia infection: OR 1.8, 95% CI 1.1 to 3.1
- Gonorrhea: OR 1.8, 95% CI 1.2 to 2.7
- Vulvovaginal candidiasis: OR 1.8, 95% CI 1.3 to 2.4
- Urethritis: OR 3.1, 95% CI 1.1 to 8.6
- Cervicitis: OR 2.7, 95% CI 1.4 to 5.2
These researchers stressed that "these infections are likely to be particularly important in promoting sexual transmission and mother-to-child intrapartum transmission of HIV-1."30 Another pooled analysis of three studies in women also found that chlamydia nearly doubled the odds of HIV shedding (OR 1.85, 95% CI 1.1 to 3.2, P = 0.02).33
Given findings like these, it is not surprising that treating cervicitis decreases HIV shedding.31 This study involved 36 HIV-positive women treated for cervicitis in Mombasa, Kenya; 16 had N gonorrhoeae, 7 had C trachomatis, and 13 had nonspecific cervicitis. After treatment of cervicitis, cell-free and cell-associated HIV-1 RNA fell from 4.05 to 3.24 log10 copies/swab overall (P = 0.001) and from 4.21 to 3.19 log10 copies/swab in women with chlamydia (P = 0.02). Prevalence of HIV-1 DNA in cells dropped from 67% before treatment to 42% after treatment (OR 2.8, 95% CI 1.3 to 6.0, P = 0.009).
A study of urine-based chlamydia and gonorrhea screening in a New Orleans HIV clinic used a mathematical model to estimate that treating 56 chlamydia infections and 46 gonorrhea infections may have averted 9 HIV infections in sex partners "and saved far more in future medical costs than the cost of the screening."34
CDC chlamydia screening guidelines released in 2002 offer advice on when to screen women but not men in the general population.4 The CDC recommends screening all women up to age 25 and older women with a higher chlamydia risk indicated by multiple sex partners, a history of STIs, or not using condoms consistently or correctly.
Health Resources and Services Administration (HRSA) HIV guidelines from 2011 outline chlamydia and gonorrhea screening guidance for women and men (Table 5).3 For pharyngeal or rectal infection, HRSA recommends a nucleic acid amplification test (NAAT) or culture of an oral swab or a rectal swab. For urethral or cervical infections, HRSA recommends NAAT on a first-catch urine or urethral specimen (in men) or cervical specimen (in women). One STI expert notes that NAATs have a low positive predictive value in populations with low chlamydia prevalence, such as older adults, so "positive test results should be interpreted with caution, and consideration should be given to use of a second testing modality for confirmation of the results."35
Despite guidelines recommending frequent gonorrhea and chlamydia screening in people with HIV, a study of HIV-positive men in the Johns Hopkins University HIV cohort found that fewer than half were getting tested for these STIs.36 Among 1110 men studied in this 1999-2008 analysis, chlamydia and gonorrhea testing rates upon clinic enrollment rose from 4% before 2003 to only 16.5% afterwards. The proportion of men ever tested for these STIs climbed from 34.2% before 2003 to 49.1% afterwards. Yet among 342 men ever tested, 5.2% had a positive result on their first test. A 2004-2010 analysis of HIV-positive men and women in 7 US cities found that syphilis testing rates reached 70% in 2009-2010, while chlamydia and gonorrhea testing rates languished below 40% in those years.37
Almost three quarters of 808 adults visiting a Colorado HIV counseling and testing center (71%) agreed to urine screening for C trachomatis, though only 8 of 560 urine samples processed (1.4%) were positive.38 One third of those who declined urine screening did so because they had no STI symptoms, even though chlamydia infection is often asymptomatic.
Although urine screening is easy, it will probably miss a fair proportion of chlamydia infections, both in men and women. A San Francisco study of 5539 MSM seen at an STI clinic and 895 seen at a gay community health center found the highest chlamydia prevalence in rectal samples (7.9%), followed by urethral (5.2%) and pharyngeal (1.4%) sites.39 More than half of chlamydia infections (53%) were nonurethral, and 85% of rectal infections were asymptomatic.
A study of people attending an STI clinic or one of three HIV clinics focused on those who reported anal intercourse or women with a high risk of chlamydia or gonorrhea.40 More than 80% of chlamydia infections would have been missed if rectal samples had not been tested. Culture of rectal swabs had chlamydia sensitivities ranging from 36.1% to 45.7%, while sensitivities of two NAATs were 91.4% to 95.8% for PCR and 100% for transcription-mediated amplification (TMA). Specificities of the two NAATs were also high.
People reluctant to get tested for chlamydia at an STI clinic or their provider's office may try an Internet site offering STI testing. But a 2010 survey of such sites found them highly unreliable.41 These researchers identified 27 US or international sites offering STI self-collection kits and services for chlamydia, gonorrhea, syphilis, and other STIs. Only two sites completed a mailed or e-mailed survey about these services. Six sites appeared to be invalid because mail or e-mail to them was returned undelivered. Only 5 of 7 sites that provided test kits returned results. Two sites that were sent urine samples never responded. Two kits yielded false-negative results, while two kits yielded correct positive results.
Behavioral interventions have proved successful in curbing the risk of chlamydia infection, as has a partner-delivered azithromycin program. But steady condom use is the surest way to prevent spreading or acquiring chlamydia. Both the CDC1 and the Health Resources and Services Administrations (HRSA)3 stress the reliability of condoms: "Male latex condoms, when used consistently and correctly," HRSA HIV guidelines say, "are highly effective in preventing sexual transmission of HIV and many other STIs, including syphilis, chlamydia, gonorrhea, and Trichomoniasis."3
Inconsistent condom use upped the odds of chlamydia infection by 50% in an Australian study of 3805 MSM (Table 4).20 In the same study, women whose partners did not wear condoms consistently also had 50% higher odds of picking of chlamydia. CDC investigators examined the impact of consistent condom use in people enrolling in a trial of sex-counseling interventions at five publicly funded US STI clinics from 1993 through 1997.42 Among 429 participants with known exposure to chlamydia or gonorrhea, consistent condom use sliced the odds of prevalent infection with one of those STIs by almost 60% (adjusted OR 0.42, 95% CI 0.18 to 0.99). Among 4314 participants with unknown exposure to chlamydia or gonorrhea, consistent condom use trimmed those odds by almost 20% (adjusted OR 0.82, 95% CI 0.66 to 1.01).
Some of the same CDC investigators conducted a systematic review of chlamydia and gonorrhea risk in 45 studies of condom use.43 All studies assessed male condom use and were published from 1966 through 2004. Most studies had methodologic limitations, such as failing to distinguish between consistent and inconsistent condom use. Despite these limitations, which probably resulted in underestimates of condom effectiveness, in the overall analysis condoms did lower chlamydia and gonorrhea rates in both men and women.
Asking women with chlamydia to hand-deliver antibiotics to their sex partners may lower the reinfection risk in those women. A randomized trial conducted by the CDC involved 1787 women from 14 to 34 years old with uncomplicated genital C trachomatis infection diagnosed in 5 US cities.44 The investigators randomized women to deliver a dose of azithromycin (a "partner pack") to each of their sex partners or to refer their sex partners for treatment.
Four months later, urine ligase chain reaction or polymerase chain reaction indicated a lower risk of chlamydia reinfection in women who took azithromycin to their partners (87 of 728, 12%) than in women who referred partners for treatment (106 of 726, 15%). Although that difference fell short of statistical significance (OR 0.80, 95% CI 0.62 to 1.05, P = 0.102), the CDC team suggested that patient-delivered treatment "may be an appropriate option for some patients" with uncomplicated chlamydia.
A randomized trial of expedited partner notification and treatment versus standard notification, described in the next section, found lower rates of persistent or recurrent chlamydia or gonorrhea in index patients. Two accelerated partner notification and treatment models tested in the UK, also described in the next section, documented higher chlamydia and gonorrhea treatment rates among partners benefiting from these approaches than among partners who received standard notification.
Three behavioral intervention studies found that these strategies cut the risk of chlamydia infection in adults and adolescents. "Intervention" is a term laden with visions of multi-month counseling conducted by specially trained (and richly paid) staff, but the Safe in the City approach involves only a video with STI prevention messages seen in the waiting room before appointments.45 This study involved 38,635 people who came to publicly funded STI clinics in three US cities between December 2003 and August 2005. Participants were randomized to the usual waiting-room environment or to watch a 23-minute video showing couples overcoming barriers to safer-sex behaviors. After an average 14.8 months of follow-up, the risk of incident lab-confirmed chlamydia, gonorrhea, Trichomoniasis, syphilis, or HIV was about 10% lower in the intervention group, a significant difference (HR 0.91, 95% CI 0.84 to 0.99). To access and preview this video, go to www.safeinthecity.org.
The WiLLOW Program involves four 4-hour sessions for women delivered over 4 consecutive weeks and emphasizing gender pride, maintaining current and identifying new network members, enhancing HIV transmission knowledge, improving communication and condom use skills, and developing healthy relationships (for details go to www.cdc.gov/hiv/topics/research/prs/resources/factsheets/WILLOW.htm#ref1). A trial reported in 2004 randomized 366 HIV-positive women in Alabama and Georgia to the WiLLOW Program or to no intervention.46 Through 12 months of follow-up, incidence of chlamydia or gonorrhea was about 80% lower in the WiLLOW group (OR 0.19, P = 0.006). Women who completed WiLLOW also reported significantly fewer episodes of unprotected vaginal intercourse and were significantly less likely to report never using condoms. The CDC ranks WiLLOW as one of its "best-evidence" interventions to prevent infection with HIV and other STIs.
A culturally tailored STI/HIV intervention for African-American girls and young women involves two 4-hour group sessions and 4 telephone contacts during a 1-year period.47 A trial randomized 715 youngsters seeking sexual health services to receive the intervention or standard care. Participants completed a computer-assisted self-interview and gave self-collected vaginal specimens for STI testing. Girls and women randomized to the interview had a 35% lower risk of a new chlamydia infection (risk ratio [RR] 0.65, 95% CI 0.42 to 0.98, P = 0.04) and a 75% lower risk of recurrent chlamydia (RR 0.25, 95% CI 0.08 to 0.83, P = 0.02). Participants in the intervention group also reported a higher proportion of condom-protected sex acts in the previous 60 days and a higher rate of condom use at last intercourse.
STI screening itself may temper risk-taking behavior, according to results of a study in 636 sexually active African-American teens in two US cities with high STI prevalence.48 Among adolescents screened for chlamydia, gonorrhea, and Trichomoniasis, the 6.6% with positive tests received treatment and counseling, while those with negative results received no further intervention. Among the 85% of study participants who completed 3- and 6-month follow-up visits, teens with a positive STI result lowered their number of vaginal and oral sex partners and the number of unprotected sex acts. STI-negative adolescents made no changes in numbers of partners or unprotected sex acts. STI testing at the 6-month point determined that 4.3% of initially STI-negative youngsters had a positive test.
Work is under way to develop a T-cell vaccine against chlamydia infection.49 Researchers at the British Columbia Centre for Disease Control and the University of British Columbia formulated a vaccine with three chlamydia T-cell antigens that generated protection against infection in mice. These investigators cautioned that "an ongoing challenge for chlamydia vaccine research remains the discovery of strategies that maximize the protective effects of immune T cells while simultaneously preventing such cells from causing immune-mediated tissue damage."
Recent research details the benefits of prompt notification and treatment of chlamydia patients' partners, and the CDC provides extensive advice on partner notification for chlamydia, HIV, and other STIs.50 Yet chlamydia partner notification rates in the United States were abysmal when last evaluated.51 In 1998 researchers asked US health departments in areas with the highest reported rates of chlamydia, syphilis, gonorrhea, and HIV to indicate how many people with these infections were interviewed for partner notification. Only 26,487 of 228,210 chlamydia patients (12%) were asked to provide partner contact information, below the rates for gonorrhea (17%), HIV (52%), or syphilis (77%). Twenty-seven of 60 responding health departments (45%) provided no routine partner notification services to chlamydia patients.
Given this lackluster health-department performance, clinicians might be expected to take up the slack. But that wasn't happening the last time the CDC checked. A random survey of 7300 providers reported in 2002 found that 80% of respondents told chlamydia patients to notify their partners rather than doing so themselves.52 And only 20% of providers followed up with patients to see if partners had been referred for treatment.
The CDC says all sex partners of people with chlamydia should be contacted and tested,1 and the Health Resources and Services Administration (HRSA) says partners should be treated empirically if they had sex with the index patient within 60 days since that person's symptoms began.3 If a person diagnosed with chlamydia cannot remember sex partners within the past 60 days, the most recent sex partners before that should be contacted and treated. The CDC urges people diagnosed with chlamydia to avoid sex with partners who are not examined and treated.1
HRSA underscores the potential value of antibiotic "partner packs" delivered by the index patient to partners who may be unlikely to come to the clinic for evaluation.3 This approach, described in the preceding section, may result in a lower reinfection rate among index patients.44 A British trial of a similar but more comprehensive partner-treatment approach is described below. HRSA notes that most recurrent chlamydia infections occur in people whose sex partners are not treated.3 Anyone treated for chlamydia should be retested about 3 months later, regardless of whether they believe their sex partners got treated.1
In 2008 the CDC released comprehensive guidelines on partner notification and treatment for people diagnosed with HIV, chlamydia, and other STIs, including a flowchart detailing the steps in contacting, notifying, treating, and monitoring partners (Figure 3).50 Among other things, these guidelines cover (1) counseling index patients about reducing their risk for acquiring or transmitting infection to others and referring them for additional prevention services, if needed, (2) notifying partners of their exposure, (3) counseling partners about reducing their risk for acquiring HIV infection and other STIs and referring them for additional prevention services, if needed, (4) offering partners STI/HIV testing, and (5) treating partners or linking them to medical care and treatment. The CDC also suggests which patients diagnosed with chlamydia fall into a high-priority group for partner notification, and which partners should be considered high-priority:50
High-priority index patients for partner services, regardless of the STI:
- Pregnant women and male index patients with pregnant partners
- Index patients suspected of or known to be engaging in behaviors that substantially increase risk of transmission to multiple partners (for example, those with multiple sex partners or drug-injection partners)
- Persons coinfected with HIV and one or more other STIs
- Persons with recurrent STIs
High-priority index patients for partner services for chlamydia, syphilis, and gonorrhea:
- Persons with clinical signs or symptoms suggesting infection
- Infected persons from high STI prevalence areas
Partners with the highest priority for notification, regardless of the STI:
- Female partners who are known or likely to be pregnant
- Partners suspected of or known to be engaging in behaviors that substantially increase the risk for transmission to multiple other persons
- Partners with whom the index patient reports having had unprotected anal or vaginal sex
To determine whether faster notification and treatment of chlamydia and gonorrhea patients' partners would lower rates of persistent or recurrent infection in the index case, researchers planned a randomized trial of expedited treatment (patients offered medication to give to sex partners or offered contact of partners by staff who gave partners medication without a clinic exam) or standard referral (patients asked to refer partners for treatment and offered assistance in finding partners).53 Patients included women and heterosexual men, but not MSM.
Three to 9 weeks after index patients got treated for chlamydia or gonorrhea, persistent or recurrent infection could be detected in 92 of 929 people (10%) assigned to expedited partner treatment and in 121 of 931 (13%) assigned to standard partner referral.53 Relative risk of persistent or recurrent gonorrhea or chlamydia infection was about 25% lower in the expedited group (RR 0.76, 95% CI 0.59 to 0.98). When the researchers assessed the impact of expedited partner treatment on the two STIs separately, the persistent or recurrent infection rate was significantly lower for gonorrhea (3% versus 11%, P = 0.01), but that difference fell short of statistical significance for chlamydia (11% versus 13%, P = 0.17). These researchers noted three potential disadvantages to treating partners without evaluating them:
- "Some partners may have allergic reactions or other drug-related adverse effects.
- "Partners treated without a clinical evaluation may have concurrent STIs identifiable only if they seek medical care.
- "An opportunity may be lost to counsel sex partners to refer their other partners for evaluation and treatment."53
On the basis of these findings, the investigators argued that "the inadequacies of current approaches to partner notification and the persistence of unacceptably high levels of morbidity from sexually transmitted infections in the United States should motivate both clinicians and public health authorities to incorporate patient-delivered partner therapy and other approaches to expedited care of partners into clinical and public health policies."53
British researchers conducted a preliminary, nonrandomized comparison of two accelerated partner therapy (APT) models and routine partner notification for partners of people with a lab diagnosis of C trachomatis and/or N gonorrhoeae or nongonococcal urethritis (men only).54 The study involved 226 adults enrolled in a sexual health clinic or a genitourinary medicine clinic. The researchers did not specify how many were women, heterosexual men, or MSM.
The two accelerated partner therapy models involved (1) a hotline that sex partners called for a phone consultation with a qualified provider or (2) a pharmacy that sex partners visited for consultation. In both models partners picked up or received from the index patient an "APT pack" including (1) 1 g of azithromycin or 400 mg of cefixime, (2) relevant drug information sheets, (3) a urine NAAT sample collection kit for C trachomatis and N gonorrhoeae and appropriate packaging for mailing samples back to the study lab, (4) condoms, and (5) full details of the study. Partners in the comparison group had to attend the clinic for evaluation and treatment. Both APT options also featured an "assertive invitation" to the partner to get fast-track HIV and syphilis tests at a local sexual health clinic.
While 42 of 117 of contactable partners (36%) reached by routine partner notification got treated, 80 of 135 partners (59%) reached by the hotline and 29 of 44 (66%) who visited a pharmacy were treated (P = 0.003 and P = 0.001 compared with routine partner notification). From 40% to 60% of partners in the accelerated partner therapy groups returned urine samples for STI testing, but almost none followed up for HIV or syphilis testing. The investigators hope to test these approaches in a cluster-randomized trial.
A stochastic simulation model estimated the impact of chlamydia screening coverage and partner notification on positivity in the United States.55 The model described pair formation and dissolution in an age-structured heterosexual population of highly sexually active people. These researchers figured the impact of a chlamydia screening program reaching 20%, 35%, 50%, and 65% of women 15 to 24 years old, male partner notification rates of 20%, 40%, and 55%, screening rates of 20% and 35% in 15- to 24-year-old men, and female partner notification rates of 25% and 40%. The model estimated a 23% reduction in chlamydia positivity by increasing screening 3-fold or partner notification 2-fold.
- A single 1-g oral dose of azithromycin
- A 100-mg oral dose of doxycycline twice daily for 7 days
- Erythromycin base 500 mg orally four times a day for 7 days
- Erythromycin ethylsuccinate 800 mg by mouth four times a day for 7 days
- Ofloxacin 300 mg by mouth twice daily for 7 days
- Levofloxacin 500 mg by mouth once daily for 7 days
For pregnant women, the CDC and HRSA recommend a single 1-g oral dose of azithromycin or 500 mg of amoxicillin by mouth three times a day for 7 days.3,56 CDC guidelines also spell out advice on treating chlamydia in infants and children.56
HRSA guidelines suggest providers advise patients to take medications with food if they feel nauseated and to call immediately if they experience vomiting or cannot take their medications.3 Treated individuals should abstain from sex for 7 days after single-dose azithromycin or until a 7-day course is completed.
Except for pregnant women, infants, and children, the CDC does not recommend repeat testing 3 to 4 weeks after therapy "unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected."56 (Results of work described below suggest a test for cure may be advisable in people with asymptomatic rectal chlamydia.57) If chlamydia symptoms persist after treatment, HRSA recommends evaluating patients for possible reinfection, treatment failure, or a different cause of symptoms.3 If the provider suspects treatment failure, HRSA recommends culture and antimicrobial sensitivity testing.
The CDC recommends rescreening all men and women treated for C trachomatis 3 months after they finish therapy, "regardless of whether they believe that their sex partners were treated."56 If a person cannot be retested 3 months after treatment, the CDC advises retesting whenever that person has a follow-up visit in the 12 months after finishing therapy.
Does single-dose azithromycin work consistently for people with asymptomatic rectal gonorrhea, a common presentation in MSM? A case series at an Edinburgh genitourinary medicine clinic suggests no.57 Edinburgh investigators reviewed all 101 cases of rectal chlamydia diagnosed from June 2005 to June 2006. After excluding symptomatic cases, they counted 9 failures of single-dose azithromycin in 68 people for a failure rate of 13%. The researchers believe this result "suggests that single-dose azithromycin may be a less than effective treatment in asymptomatic rectal C trachomatis infection" and that "the potential treatment failure rate with this regimen emphasizes the need for a test of cure at the appropriate interval following treatment to ensure clearance of infection."57
In a 37-study systematic review of STIs acquired by people already infected with HIV, taking combination antiretroviral therapy did not affect STI incidence. 2 On the basis of this finding, the investigators cautioned that "STI co-infections could undermine efforts to use HIV treatments for prevention by increasing genital secretion infectiousness."2
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- Annan NT, Sullivan AK, Nori A, et al. Rectal chlamydia -- a reservoir of undiagnosed infection in men who have sex with men. Sex Transm Infect. 2009;85:176-179.
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