Context Sexually transmitted infections (STIs) are common in female sex workers
(FSWs) and may enhance susceptibility to infection with human immunodeficiency
virus type 1 (HIV-1).
Objective To examine regular antibiotic prophylaxis in FSWs as a strategy for
reducing the incidence of bacterial STIs and HIV-1.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted between
1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs
screened, 466 who were seronegative for HIV-1 infection were enrolled and
randomly assigned to receive azithromycin (n = 230) or placebo (n = 236).
Groups were well matched at baseline for sexual risk taking and STI rates.
Intervention Monthly oral administration of 1 g of azithromycin or identical placebo,
as directly observed therapy. All participants were provided with free condoms,
risk-reduction counseling, and STI case management.
Main Outcome Measures The primary study end point was incidence of HIV-1 infection. Secondary
end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus
ducreyi, as well as bacterial vaginosis. Analysis
of herpes simplex virus type 2 (HSV-2) infection was performed post hoc.
Results Seventy-three percent of participants (n = 341) were followed up for
2 or more years or until they reached an administrative trial end point. Incidence
of HIV-1 did not differ between treatment and placebo groups (4% [19 cases
per 473 person-years of follow-up] vs 3.2% [16 cases per 495 person-years
of follow-up] rate ratio [RR], 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection
was associated with preceding infection with N gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment
group of infection with N gonorrhoeae (RR, 0.46;
95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95%
CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI,
0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%,
and HSV-2 infection at baseline was independently associated with HIV-1 acquisition
(RR, 6.3; 95% CI, 1.5-27.1).
Conclusions Despite an association between bacterial STIs and acquisition of HIV-1
infection, the addition of monthly azithromycin prophylaxis to established
HIV-1 risk reduction strategies substantially reduced the incidence of STIs
but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have
been an important cofactor in acquisition of HIV-1.
Sexually transmitted infections (STIs) are important cofactors in the
human immunodeficiency virus type 1 (HIV-1)/AIDS pandemic. In HIV-infected
individuals, not only may symptomatic and asymptomatic STIs enhance sexual
transmission of HIV-1 by increasing virus shedding from the genital tract,1-3 but at the same time
HIV-1 infection itself increases susceptibility to STIs.4 There
is also considerable evidence that STIs may increase HIV-1 susceptibility
in uninfected individuals,5,6 although
differentiating cause from effect is more difficult in this situation.7
Prevention or control of STIs as a strategy for preventing HIV-1 transmission
has met with mixed success. Improved syndromic management of STIs reduced
HIV-1 incidence in communities in Mwanza, Tanzania,8 but
in Uganda neither a similar strategy nor antibiotic mass-treatment of whole
communities had an impact on HIV-1 incidence.9,10 Factors
contributing to the lack of efficacy in the Uganda trials may have included
the greater effectiveness of continuously available STI treatment services11 and the reduction in spread of HIV-1 during primary
infection due to counseling given at the time of STI therapy.12 Another
important factor may be that the Tanzanian study was performed early in the
epidemic, when community prevalence of HIV-1 was below 5%. The Ugandan studies,
by contrast, were performed later, in communities with much higher prevalences
of HIV-1 (range, 10%-16%).11,13 Curable
STIs may play a lesser role in HIV-1 transmission in the context of a "mature"
epidemic, because most transmission occurs in the context of stable partnerships,
reducing the potential impact of STI prevention and treatment.14 Interventions
based on prevention or control of STIs may therefore be more effective in
communities in the early stages of an epidemic13 or
in subgroups at high risk of STIs.3
Female sex workers (FSWs) constitute an important vulnerable group in
the acquisition and transmission of both HIV-1 infection and STIs15 but may be excluded from household-based community
studies of STI control.16 It has therefore
been suggested that interventions for control of STIs should target these
women specifically.17 Studies in Kenya have
shown that certain FSW cohorts have an annual HIV incidence of 16% to 50%18,19 and a high incidence of cervicitis
due to infection with Neisseria gonorrhoeae and Chlamydia trachomatis.18 This
may be partly attributed to low levels of condom use and poor access to STI
counseling and treatment services.20 We hypothesized
that these high rates of bacterial STI and HIV-1 infection would make FSWs
an ideal population in which to test antibiotic prophylaxis of common genital
tract infections as an HIV-1 prevention strategy. Since the use of prophylactic
antibiotics by FSWs has been associated with increased sexual risk taking,21 we elected to test this intervention in a blinded
fashion.
The study objective was to examine the effect of monthly antibiotic
prophylaxis on the incidence of STIs and HIV-1 infection in a cohort of FSWs.
The study design and methods are summarized below and have been presented
in detail previously.22
Study Population and Design
Self-identified FSWs were recruited from Kibera, an urban slum area
of Nairobi, Kenya. Inclusion criteria for the trial were (1) negative HIV-1
serology results at baseline; (2) current engagement in sex work, ie, reporting
having received money or gifts in exchange for sex over the past month; (3)
age 18 years or older; (4) expected residence in Nairobi for at least 2 years;
and (5) no history of adverse drug reaction to macrolide antibiotics. Although
only HIV-seronegative women were eligible for this trial of HIV-1 prevention,
all FSWs who provided written informed consent for HIV-1 counseling and testing
were provided with medical and counseling services for the duration of the
trial. Approval for the trial was obtained from institutional review boards
at the Kenyatta National Hospital (Nairobi, Kenya) and the University of Manitoba
(Winnipeg, Manitoba).
A total of 466 FSWs seronegative for HIV-1 infection were enrolled.
Recruitment was based on a series of community visits, assisted by an established
network of sex worker peer educators. All study participants were provided
with state-of-the-art HIV prevention services, which included peer and clinic
counseling on reducing high-risk behavior for HIV-1 infection, the provision
of free male condoms, the prompt treatment of any symptomatic STI, and screening
and therapy of asymptomatic STIs every 6 months. Two standardized risk-reduction
counseling sessions of 1 hour were provided to all women at enrollment, with
subsequent peer and clinic-based counseling given upon request. This counseling
followed a previously described model,20 with
the addition of information on the need for consistent condom use with regular
partners or boyfriends.23 To compensate women
for travel expenses and lost revenue, participants were reimbursed a sum of
100 KSh (US $1.65) per study visit, an amount that increased to 150 KSh (US
$2.48) over the course of the study.
The study was designed as a randomized, double-blinded, placebo-controlled
trial. Women were block randomized in groups of 50 to receive 1 g of oral
azithromycin per month or an identical placebo (both provided by Pfizer Canada
Inc, Montreal, Quebec). The study drug was administered as directly observed
therapy, from numbered containers that were packaged, labeled, and shipped
by the Misericordia General Hospital pharmacy (Winnipeg, Manitoba). Clinic
staff assigned study numbers consecutively at enrollment; neither study staff
nor the participants were aware of group assignment. The primary outcome measure
was incidence of HIV-1 infection, and secondary outcome measures were the
rates of bacterial STIs (infection with N gonorrhoeae, C trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi; bacterial vaginosis).
The study drug was administered monthly in the clinic, and a simultaneous
urine specimen was collected and stored at –20°C. After study termination,
all urine specimens were tested for STIs using N gonorrhoeae and C trachomatis polymerase chain reaction
(PCR) assays. A detailed behavioral questionnaire was administered at enrollment
and then every 3 months to collect information on numbers of clients, condom
use (on a semiquantitative scale ranging from 0 [never use] to 5 [always use]),
and types of sexual activity (anal sex, sex during menses). Blood was collected
for HIV-1 enzyme-linked immunosorbent assay every 3 months. All women underwent
a full physical examination and STI diagnostic testing prior to enrollment
and every 6 months thereafter, with cervical swabs obtained for N gonorrhoeae and C trachomatis PCR assays
(Amplicor PCR Diagnostics, Roche Diagnostics, Montreal, Quebec), and for N gonorrhoeae culture. Trichomonas vaginalis culture was performed using the In Pouch TV culture (Biomed Diagnostics,
San Jose, Calif), a Gram stain was performed, and blood was drawn for rapid
plasma reagin testing for syphilis. Bacterial vaginosis was defined as a Nugent
score of 7 to 10,24 and lactobacillus colonization
and candidiasis were defined as the finding of any lactobacilli or yeast,
respectively, on the Gram-stained specimen. Any genital tract infections identified
were treated according to Kenyan national treatment guidelines. Serologic
testing for herpes simplex virus type 2 (HSV-2) was performed on cryopreserved
plasma samples using an HSV-2 IgG enzyme immunoassay (Kalon Biological Ltd,
Aldershot, England).
Administration of the study medication within 2 weeks of the scheduled
monthly clinic visit was defined as "on time" and after this point was defined
as a "late" dose. An STI was defined as symptomatic if cervical-vaginal discharge
or acute abdominal pain were associated with a simultaneous positive cervical
PCR and/or cervical culture result, or with a positive urine PCR result within
a month of symptoms.
Sample Size and Statistical Analyses
Based on previous studies of sex worker cohorts in Kenya, we estimated
that the annual HIV-1 incidence would be 15%.18,19 In
the Mwanza trial, improved management of bacterial STIs in a population with
relatively low rates of STIs reduced incidence of HIV-1 infection by 40%.8 We hypothesized that bacterial STIs would be more
frequent in sex workers and therefore would be responsible for a greater population-attributable
fraction of HIV-1 infections. Therefore, we estimated that prevention of bacterial
STIs would reduce HIV-1 incidence in a cohort of FSWs by 50%. With a β
error of .20, a 2-sided α error of .05, a 2-year follow-up period, and
an anticipated loss to follow-up of 30% at most, 170 women were required per
study group.
Incidence of HIV-1 infection and STI was calculated as number per 100
person-years. Poisson regression was used to calculate rate ratios (RRs) and
95% confidence intervals (CIs) for comparison of STI incidence rates between
study groups. Time to HIV-1 seroconversion was analyzed using Kaplan-Meier
survival analysis and Cox regression with time-dependent variables. Seroconversion
occurring between enrollment and the first 3-monthly follow-up visit was assumed
to be due to HIV-1 infection acquired prior to enrollment and was not recorded
as a study end point. An STI was defined as incident when the preceding test
for that STI had been negative, and as incident syphilis when an RPR titer
increased from less than 1:8 to 1:8 or greater. Statistical analysis was performed
using SPSS 11 (SPSS Inc, Chicago, Ill); P<.05
was used to determine statistical significance. Analysis was based on intention
to treat, with all outcomes analyzed in relation to the original randomization
assignment (azithromycin or placebo). Statistical analysis included all data
available from all participants, in either group, up to the time of loss to
follow-up or discontinuation of treatment, for whatever reason.
Study Enrollment and Baseline Characteristics of Participants
Recruitment began in May 1998, and after 2 years the data and safety
monitoring board recommended that both enrollment and participant follow-up
be extended due to a lower than expected incidence of HIV-1 infection. Recruitment
therefore continued until the end of January 2002; blinded follow-up continued
until the end of July 2002.
The trial profile is shown in Figure
1. A total of 890 self-identified FSWs underwent HIV-1 counseling
and testing and were screened and treated (if necessary) for prevalent genital
tract infections: 251 (28.2%) were seropositive for HIV-1, and 173 (19.4%)
were seronegative but declined enrollment. The remaining 466 women were randomized
to receive monthly azithromycin (n = 230) or placebo (n = 236). Baseline characteristics,
including risk-taking behavior for HIV-1 and prevalence of genital tract infections,
were similar in the 2 groups. However, women seropositive for HIV-1 reported
a younger age at first sex, used condoms less frequently, were more likely
to drink alcohol every day, and were more likely to have bacterial vaginosis
or T vaginalis infection. Compared with seronegative
FSWs enrolled in the study, those who were seronegative and declined enrollment
or who were not eligible for enrollment had lower numbers of sexual partners
and a lower prevalence of C trachomatis infection
and a higher prevalence of infection with N gonorrhoeae and T vaginalis (Table 1). Female sex workers randomly allocated to treatment and
placebo groups were generally well matched (Table 1).
Follow-up of Study Participants
Women were encouraged to remain in the trial for at least 2 years. Since
trial follow-up was extended beyond this time, after 2 years participants
were free to choose to continue in their randomization group or to exit the
trial and continue to attend the clinic as needed for medical reasons. Study
staff and participants remained double-blinded throughout the study. Duration
of follow-up was similar in the 2 groups (treatment group: median, 801 days;
range, 0-1607 days; placebo group: median, 764 days; range, 0-1524 days) (P = .70). Overall, 341 (73.1%) participants (169 in the
treatment group and 172 in the placebo group) were followed up for 2 or more
years or until they reached an administrative end point (defined as seroconversion
[n = 35], death [n = 3], severe adverse event requiring discontinuation [n
= 5], followed up for 2 years or until trial termination [n = 298]). One hundred
twenty-five participants stopped the trial prematurely (treatment group, n
= 61; placebo group, n = 64) for the following reasons: bad health precluded
attendance (treatment, n = 1; placebo, n = 0); moved away (treatment, n =
21; placebo, n = 27); stopped sex work (treatment, n = 5; placebo, n = 5);
lost interest (treatment, n = 34; placebo, n = 32). Of the 125 women who discontinued
early, 75 (60%) attended at least one 3-month clinic visit for repeat HIV-1
serologic testing, and no follow-up serology results were available for the
remaining 50 participants (10.7% [treatment: 25/230 {10.9%}; placebo: 25/236
{10.6%}]). There were 17 pregnant women at enrollment. After excluding them,
we have reported pregnancy data on 430 women in the follow-up period, 210
in the treatment group and 220 in the placebo group. The pregnancy rate was
30.0% (63/210) in the treatment group and 30.9% (68/220) in the placebo group
(P = .84). There were a total of 9966 scheduled drug
administration follow-up visits, and attendance was classified as on time
(ie, within 2 weeks of scheduled date) for 9149 visits (91.8%). At only 5
visits was drug not administered by directly observed therapy (3 in treatment
group, 2 in the placebo group).
Effect of Azithromycin on HIV-1 Incidence
There were a total of 35 incident HIV-1 infections during the study
period, 19 (per 473 person-years of follow-up) (4%) in the treatment group
and 16 (per 495 person-years of follow-up) (3.2%) in the placebo group. There
was no difference between study groups in the risk of HIV-1 infection (RR,
1.2; 95% CI, 0.6-2.5; P = .50) by Kaplan-Meier analysis
(Figure 2). The HIV-1 incidence
was 4.0 per 100 person-years in the treatment group and 3.2 per 100 person-years
in the placebo group.
Effect of Azithromycin on Incidence and Prevalence of Bacterial STIs
There was a significant reduction in the incidence of STIs in the treatment
group (Table 2), including laboratory-confirmed
infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). Most of these
STIs (73.2% of N gonorrhoeae, 83.7% of C trachomatis, and 81.0% of T vaginalis infections)
were asymptomatic. Azithromycin also reduced the incidence of symptomatic
infection with N gonorrhoeae (RR, 0.24; 95% CI, 0.08-0.71)
and C trachomatis (RR, 0.15; 95% CI, 0.04-0.68) but
not with T vaginalis (RR, 0.66; 95% CI, 0.31-1.40)
(P = .30). No difference was observed in the incidence
of bacterial vaginosis (RR, 0.91; 95% CI, 0.77-1.10) or syphilis (RR, 1.02;
95% CI, 0.54-1.95), or in the prevalence of colonization by candida (RR, 1.16;
95% CI, 0.87-1.56) or lactobacillus species (RR, 1.04; 95% CI, 0.92-1.17).
Ulcerative STIs were very uncommon in both study groups, with only 12 incident
cases of genital ulcer disease recorded during the study (4 in the treatment
group, 8 in the placebo group). All genital ulcers were culture-negative for H ducreyi and were clinically compatible with recurrent
HSV-2 infection.
The duration of laboratory-confirmed STIs was examined in both groups
using results of monthly N gonorrhoeae and C trachomatis urine PCR assays. The duration of N gonorrhoeae infections, reported as consecutive monthly visits presenting
with infection, was shorter in the azithromycin group than in the placebo
group (mean monthly visits, 1.05 [SD, 0.22] vs 1.38 [SD, 0.78], respectively; P = .04), as was the duration of C trachomatis infections (mean monthly visits, 1.11 [SD, 0.42] vs 1.84 [SD, 1.26]; P = .001). Using urine PCR, we examined the incidence of N gonorrhoeae or C trachomatis infection
among women more than 2 weeks late for their monthly drug administration visits.
Incident STIs were more common at visits classified as late than at those
classified as on time. The association between late visits and an STI was
strongest for women randomized to receive azithromycin (24.4% of STIs; odds
ratio, 3.6; 95% CI, 1.8-7.5), but an association was also observed in the
placebo group (12.4% of STIs; odds ratio, 1.9; 95% CI, 1.1-3.4). Therefore,
although the association of STIs with late clinic attendance might have reflected
a loss of azithromycin protection in the treatment group, behavioral factors
were also involved.
Determinants of Incident HIV-1 Infection
Enrollment was associated with major increases in use of condoms (the
proportion using condoms with all clients increased from <20% to >50% within
1 month) and decreases in numbers of clients (from >16/wk to <6/wk within
6 months), as previously reported.25 There
were no differences between treatment and placebo groups in reduced high-risk
behavior during follow-up. At the last recorded follow-up visit, the mean
number of weekly clients was 3.0 (SD, 4.4) vs 3.5 (SD, 5.4) (P = .30), and condom use with all clients was reported by 48% (105/219)
vs 50% (113/225) (P = .60) of sex workers in the
treatment and placebo groups, respectively. Self-reported client numbers and
condom use were combined into an estimated number of weekly unprotected sex
contacts to examine behavioral associations of HIV-1 seroconversion using
Cox regression with time-dependent covariables. There was a significant association
between HIV-1 seroconversion and the estimated mean number of weekly unprotected
sex contacts during the year of seroconversion (per-partner RR, 1.19; 95%
CI, 1.03-1.35).
Strategies for controlling bacterial STIs to prevent HIV-1 acquisition
assume an association between incident STIs and HIV-1 infection. We therefore
examined the association between acute HIV-1 seroconversion and the presence
of a genital tract infection over the preceding 3 months. There was an association
between HIV-1 seroconversion and infection with either N gonorrhoeae (RR, 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9) during this time. No association was found
between seroconversion and a preceding T vaginalis infection
(RR, 0.7; 95% CI, 0.2-5.0), vaginal candidiasis (RR, 0.7; 95% CI, 0.1-5.1),
or bacterial vaginosis (RR, 1.2; 95% CI, 0.2-3.3). The association between
seroconversion and a recent urine PCR assay result positive for either N gonorrhoeae or C trachomatis (overall
RR, 4.5; 95% CI, 2.0-10.1) was strongest in the azithromycin group (RR, 9.3;
95% CI, 2.9-29.7), with a similar trend in the placebo group (RR, 2.9; 95%
CI, 0.8-9.2).
Since STIs and HIV-1 infection may be correlated due to measured or
unmeasured behavioral and/or biological factors that enhance risk of acquisition
of both infections, the association between bacterial STIs and subsequent
HIV-1 seroconversion could be due to confounding by common risk factors. To
adjust for this, the Cox analysis was rerun to examine the association of
incident HIV-1 infection with an STI diagnosed in the preceding 3 months,
with the addition of extra covariables: (1) the sum of all urine specimens
testing positive for gonorrheal or chlamydial infection prior to the time
of seroconversion, and (2) the number of estimated weekly unprotected sex
contacts. This adjustment did not substantially alter the association between
incident HIV-1 infection and recent STIs, suggesting that seroconversion was
specifically associated with a recent STI rather than with a higher overall
STI prevalence and was not due to confounding by behavior.
Prevalent HSV-2 Infection and HIV-1
Analysis of HSV-2 infection was not a predefined primary or secondary
study end point, since our major aim was to examine the impact of bacterial
STIs and their treatment/prevention on incidence of HIV-1 infection. Analysis
of HSV-2 infection was performed post hoc using cryopreserved plasma samples
for 95.1% of FSWs (443/466), including all 35 women who acquired HIV-1 during
the study. The baseline prevalence of HSV-2 infection in the cohort was 72.7%
(322/443) and did not differ between the treatment and placebo groups (74.9%
vs 70.6%, P = .30) (Table 1). The association between prevalent HSV-2 infection and
subsequent HIV-1 acquisition was then examined in a multivariable model that
included the covariables of study group, HSV-2 serostatus at baseline, age,
and estimated number of weekly unprotected sexual contacts. Among the 322
women with HSV-2 infection, 33 acquired HIV-1 infection; 2 women acquired
HIV-1 infection among the 121 without HSV-2 infection. Prevalent HSV-2 infection
was significantly associated with subsequent HIV-1 infection (RR, 5.8; 95%
CI, 1.4-24.0) in univariate analysis, and this association was strengthened
slightly in multivariable analysis using Cox regression with fixed covariates
(RR, 6.3; 95% CI, 1.5-27.1). As only 2 HIV-1 seroconversions occurred among
women who were HSV-2 seronegative at baseline, it was not possible to examine
the association between incident HSV-2 infection and HIV-1 seroconversion.
Study Deaths and Potential Adverse Effects of Study Drug
There were 3 deaths during the study, 1 in the treatment group and 2
in the placebo group. All deaths were due to trauma, and the study drug was
not believed to have contributed to any death. Five women withdrew from the
study due to adverse events, all related to severe epigastric pain; 2 of these
required hospitalization. Of these severe adverse events, 3 occurred in the
treatment group and 2 in the placebo group. Forty additional women (47 visits)
had adverse events believed to be possibly or probably related to the study
drug (22 in the treatment group, 18 in the placebo group), including epigastric
pain, vomiting, hyperacidity, and diarrhea. All resolved with symptomatic
treatment. Overall, there was no significant difference in rates of death
or adverse events between the treatment and placebo groups.
This study randomly allocated 466 HIV-1–seronegative FSWs to receive
either monthly azithromycin for bacterial STI prophylaxis, or an identical
placebo. No effect on HIV-1 incidence was demonstrated, despite substantial
reductions in the treatment group of the incidence of bacterial STIs. The
study was powered to demonstrate a 50% reduction in HIV-1 incidence over 2
years, based on a 15% annual incidence of HIV-1, with 170 women per group
and 30% loss to follow-up. There was a lower than expected incidence of HIV-1
infection in the study cohort, so both the sample size and duration of follow-up
were increased while maintaining study blinding. Despite these measures, 35
primary outcomes (incident HIV-1 infections) were observed compared with the
54 expected in our power calculations, and the 95% CI for the effect of azithromycin
ranged from a 40% reduction in risk of HIV-1 infection to a 150% increase
in risk. Thus, although minor reductions in incidence of HIV-1 infection cannot
be ruled out, our results do allow us to definitively rule out the hypothesized
50% protective effect as well as the 40% reduction in HIV-1 incidence observed
in the Mwanza trial.8
Incident HIV-1 infection was strongly associated with infection with
both N gonorrhoeae and C trachomatis over the preceding 3 months, confirming the association between HIV-1
and a prior STI. However, the observed failure of monthly antibiotic prophylaxis
to protect against HIV-1 acquisition was not due to a failure to prevent bacterial
STIs. Bacterial STIs were common, with incidence rates in the placebo group
of PCR-confirmed infection by N gonorrhoeae and C trachomatis of 13 per 100 person-years and 15 per 100
person-years, respectively. Azithromycin administration was associated with
substantial decreases in both the incidence and period prevalence of these
STIs as well as of infection with T vaginalis.
There are several plausible explanations for these seemingly contradictory
findings. First, the high level of care provided to all study participants
may have reduced our power to detect a treatment effect. Symptomatic genital
infections were promptly treated in both study groups, and asymptomatic STIs
were screened and treated every 6 months. This baseline level of care was
well above the standard of care for this region, and this may have reduced
the fraction of seroconversions potentially attributable to STIs. In addition,
we observed a substantial increase in reported condom use after peer- and
clinic-based counseling and a decrease in reported client numbers.25 These changes were each associated with reduced STI
rates, suggesting that they were real rather than the result of reporting
bias. Therefore, although providing STI prevention services that are above
the prevailing standard of care clearly provides an important benefit to study
participants, future clinical trials will need to consider the potential impact
of such interventions on study end point rates and statistical power. That
said, both the baseline prevalence and the reduction in incidence of N gonorrhoeae and C trachomatis infection
in this cohort were substantial, making it unlikely that the trial missed
a significant intervention effect on this basis. However, these STI preventive
services may explain the low rates of ulcerative STIs observed in the cohort.
Participant follow-up can also be problematic in highly mobile groups such
as FSWs, but in this study we exceeded our predefined criteria for successful
follow-up, which compared favorably with another recent large trial in a multicenter
cohort of African FSWs.26
An alternative explanation for the failure to demonstrate a reduced
HIV-1 incidence, despite dramatic reductions in STI rates, is that other causal
pathways may account for the observed association between STIs and seroconversion.
Such pathways could include increased viral shedding in male clients infected
with HIV-1 and coinfected with STIs, a high prevalence of STIs among HIV-1–positive
men, and enhanced host susceptibility to additional STIs after acute HIV-1
infection. If HIV-1–infected men are commonly coinfected with STIs,
and these infections enhance HIV-1 shedding, then the acquisition of an STI
by a FSW would be a surrogate marker for high-level HIV-1 exposure, and treatment
of the woman's STI would not reduce her risk of HIV-1 infection. Although
these pathways will all result in the acquisition of an STI either coincident
with or after HIV-1 infection, the STI may still be diagnosed first. This
potential "diagnostic bias" is due to 2 factors. First, serologic testing
for HIV-1 was performed every 3 months in this trial, while STIs were screened
monthly in urine, which could bias to earlier diagnosis of STIs. In addition,
there is a window between HIV-1 infection and seroconversion, so that an STI
acquired coincident with or after HIV-1 may be diagnosed first. If this explains
the association found between STIs and incident HIV-1 infection, then the
major effect of STIs in facilitating HIV-1 transmission could be increased
HIV-1 infectivity in a sex partner who is co-infected with both HIV-1 and
an STI, so that reduction of STIs in HIV-1–infected individuals would
be an important strategy for preventing sexual transmission. The feasibility
of such an approach has recently been demonstrated in a South African mining
community, where FSW presumptive treatment with monthly azithromycin reduced
STI incidence in FSWs and STI prevalence in the miners themselves.27
A final explanation for the lack of effect of STI reduction on HIV-1
incidence is that control of bacterial STIs in this setting is simply not
an effective means of preventing HIV-1 infection. There is no doubt that STI
prevention is a laudable outcome in and of itself, since untreated bacterial
STIs may be associated with severe health outcomes such as ectopic pregnancy,
sterility, and chronic pelvic pain.28 However,
recent community-based trials examining prevention of bacterial STIs as a
means to prevent HIV-1 have given conflicting results.8-10 The
rationale underlying the current study was that an FSW population, in which
both STIs and HIV-1 are very prevalent, would be an ideal one in which to
address this issue. Although several other possible reasons for the negative
trial outcome exist, as outlined above, a lack of efficacy of the strategy
must be considered as a possible explanation.
To investigate a possible role of HSV-2 infection on HIV-1 acquisition,
we performed a post hoc analysis of HSV-2 prevalence at enrollment and of
subsequent HIV-1 incidence. As expected, HSV-2 infection was very common in
this FSW cohort, with 73% of women infected at baseline. Prevalent HSV-2 infection
was strongly associated with subsequent acquisition of HIV-1 in multivariable
analysis, with 33 HIV-1 infections in the 322 HSV-2–infected FSWs (10.2%),
and just 2 infections in the 121 HSV-2–uninfected women (1.7%; neither
of these 2 cases had acquired incident HSV-2 infection prior to HIV-1 infection).
It should be emphasized that our study was not designed to study the role
of prevalent or incident HSV-2 infection in HIV-1 acquisition but was focused
on prevention of bacterial STIs. We cannot prove that the association is causal;
for example, unexamined biological factors may have increased participants'
susceptibility to both HSV-2 and HIV-1. Nonetheless, the findings confirm
the association between HSV-2 infection and HIV-1 acquisition29-31 and
provide a strong rationale for current trials of HSV-2 suppression as an HIV-1
prevention strategy in Africa.
Unexpectedly, azithromycin was associated with a significant reduction
in the incidence of genital infection with T vaginalis.
There were no reported differences between study groups in risk-taking behavior,
suggesting that the observed difference may have been due to an active effect
of the antibiotic. Azithromycin has demonstrated activity against other protozoa,32 including Plasmodium, Cryptosporidium,
Leishmania, and Toxoplasma, and so it is perhaps
not surprising to find a degree of activity against Trichomonas. However, whether this activity will be sufficient to treat established Trichomonas infection is an issue that will need to be
addressed in future studies.
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