Graham SM, Masese L, Gitau R, et al. Increased risk of genital ulcer disease in women during the first month after initiating antiretroviral therapy. J Acquir Immune Defic Syndr 2009 Dec;52(5):600-3.
Genital ulcer disease (GUD) increases the risk of HIV transmission. Among HIV-infected persons, decreasing CD4 cell counts increases the risk of GUD.(1) Immune reconstitution with initiation of antiretroviral therapy (ART) has been associated with recurrence of GUD. As such, ART initiation may be associated with increased risk of HIV transmission, particularly among those with herpes simplex virus type 2 (HSV-2), which is the most frequent cause of GUD worldwide.(1, 2, 3) The timing and frequency of GUD following ART initiation is not known. Knowledge of these factors could be used as part of risk-reduction counseling.
To measure the timing and frequency of and risk factors for GUD after initiation of ART
HIV-1-infected women enrolled in the cohort who initiated ART according to World Health Organization (WHO) and Kenya national guidelines
Trends in GUD prevalence and risk factors for GUD
Female participants in an ongoing cohort who were eligible for ART were started on stavudine or zidovudine with lamivudine and nevirapine. Women were interviewed at baseline and at monthly follow-up visits. Women received a standard physical examination that included an examination of the genitals using a speculum and were serologically tested for syphilis at baseline and every three months thereafter. Cultures for chancroid were obtained when genital ulcers were not typical of HSV-2. Genital ulcer disease was ascertained by interview, physical examination, or both before and after ART initiation. The prevalence of GUD was calculated for each time point. Logistic regression was used to measure the independent predictors of GUD, which included the month following the start of treatment, CD4 cell count at baseline, WHO disease stage, and history of GUD prior to baseline.
From March 8, 2004 through January 18, 2008, 134 women enrolled in the study and initiated ART. Participants attended a median of seven visits (interquartile range 6-7) through six months of observation. The median CD4 count at baseline was 127 cells/mm3. Eighty-two (61.2%) women had a history of GUD before starting ART and GUD was reported or observed in 54 women (40.3%) at 85 visits. Genital ulcer disease was identified by examination alone in 32 (37.6%) ulcers, by report alone in 38 (44.7%), and by both methods in 15 (17.6%). Genital ulcer disease by examination was associated with GUD by history (P=0.001). Syphilis was diagnosed at five visits, of which four included the diagnosis of GUD at examination. There were 18 atypical ulcers cultured for chancroid and all were negative.
The prevalence of GUD at baseline was 9.7% and this increased to 16.7 at the first monthly visit and then decreased to 6.4% by six months. Detection of GUD was significantly greater among women with a history of GUD (13.9% vs. 3.9%, P<0.001). The risk of GUD from baseline to the first monthly visit was increased relative to baseline (odd ratio [OR] 1.9, 95% confidence interval [CI]: 1.0-3.6) but not thereafter after controlling for CD4 count, clinical stage of disease, and history of GUD. The other independent predictors of GUD were CD4 count <100 cells/mm3 at baseline (OR 1.8, 95% CI: 1.0-3.4) and a history of GUD (OR 3.8, 95% CI: 1.9-7.7). When the analysis was restricted to GUD detected only by examination, similar trends were found, although with the smaller sample this did not reach statistical significance. The other predictors remained significant.
The first month following initiation of ART was associated with an increased risk of GUD, as were a low baseline CD4 count and history of GUD.
This was a nicely conducted cohort study. The outcome of interest was appropriately measured. A particular strength of the study is the sub-analysis restricted to GUD identified by examination alone, and the follow-up time was adequate for assessing the outcome (GUD shortly after initiation of ART). Another strength of the study was its evaluation of the timing of GUD relative to ART initiation and baseline CD4 count. The study did not compare an "exposed" to "unexposed" group, which limits the factors by which to evaluate the quality of a cohort study. Information concerning the representativeness of the cohort was not available.
The findings from this study support the hypothesis of an increased risk of GUD during the period when immune reconstitution inflammatory syndrome occurs. It is assumed that with the high prevalence of HSV-2, the GUD reported and identified is most likely due to this virus. This result is supported by the negative chancroid cultures and few positive syphilis serology tests. Given the high prevalence of HSV-2 in Africa and among HIV-infected women, the data from this study support offering HIV-infected women who have evidence of GUD (either from examination or self-report) HSV-2 suppressive therapy during ART initiation. Although the evidence to date has not shown that HSV-2 suppression decreases HIV transmission(4, 5), it is likely to decrease recurrences and promote ulcer healing. There are ongoing clinical trials assessing the efficacy of long-term HSV suppression on reducing HIV transmission. The results of these studies may affect programmes of suppressive treatment during ART initiation. In addition, programmes using counseling to reduce sexual transmission of HIV may consider including the findings from this study.
- Pickering JM, Whitworth JA, Hughes P, et al. Aetiology of sexually transmitted infections and response to syndromic treatment in southwest Uganda. Sex Transm Infect 2005;81:488-93.
- Gomes CMM, Giraldo PC, Gomes FM, et al. Genital ulcers in women: clinical, microbiologic and histopathologic characteristics. Braz J Infect Dis 2007;11:254-60.
- Paz-Bailey G, Rahman M, Chen C, et al. Changes in the etiology of sexually transmitted diseases in Botswana between 1993 and 2002: implications for the clinical management of genital ulcer disease. Clin Infect Dis 2005;41:1304-12.
- Celum C, Wald A, Hughes J, et al. Effect of acyclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomized, double-blind, placebo-controlled trial. Lancet 2008;371:2109-19.
- Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008;358:1560-71.