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Background: Co-infection with herpes simplex virus type 2 (HSV-2) has been associated with increased HIV-1 RNA levels and immune activation, two predictors of HIV-1 progression. The impact of HSV-2 on clinical outcomes among HIV-1 infected pregnant women is unclear. Methods: HIV-1 infected pregnant women in Nairobi were enrolled antenatally and HSV-2 serology was obtained. HIV-1 RNA and CD4 count were serially measured for 12-24 months postpartum. Survival analysis using endpoints of death, opportunistic infection (OI), and CD4<200 cells μL, and linear mixed models estimating rate of change of HIV-1 RNA and CD4, were used to determine associations between HSV-2 serostatus and HIV-1 progression. Results: Among 296 women, 254 (86%) were HSV-2-seropositive. Only 30 (10%) women had prior or current genital ulcer disease (GUD); median baseline CD4 count was 422 cells μL. Adjusting for baseline CD4, women with GUD were significantly more likely to have incident OIs (adjusted hazard ratio (aHR) 2.79, 95% CI: 1.33-5.85), and there was a trend for association between HSV-2-seropositivity and incident OIs (aHR 3.83, 95% CI: 0.93-15.83). Rate of change in CD4 count and HIV-1 RNA did not differ by HSV-2 status or GUD, despite a trend toward higher baseline HIV-1 RNA in HSV-2-seropositive women (4.73 log10 copies/ml vs. 4.47 log10 copies/ml, P = 0.07). Conclusions: HSV-2 was highly prevalent and pregnant HIV-1 infected women with GUD were significantly more likely to have incident OIs than women without GUD, suggesting that clinically evident HSV-2 is a more important predictor of HIV-1 disease progression than asymptomatic HSV-2. © 2011 Roxby et al.
HIV-1-seropositive pregnant women in Nairobi, Kenya were recruited from Nairobi City Council clinics and enrolled into a prospective cohort study of immunological markers, morbidity and infant feeding practices, as described previously [3]. The first 216 women, enrolled between 1999 and 2002, were followed for 12 months; the remaining 319 women, enrolled between 2002 and 2005, were followed for 24 months. Written informed consent was obtained from all study subjects in the cohort. Human experimentation guidelines from the US Department of Health and Human Services were followed. Ethical approvals were obtained from the institutional review board of the University of Washington and the ethics review committee of Kenyatta National Hospital (KNH) and the Kenya Medical Research Institute (KEMRI). Women were followed during pregnancy and postpartum with regular physical exams, and plasma samples were taken at postpartum months 1, 3, 6, 9, and 12, and then quarterly for those followed during the second postpartum year. At enrollment, a pelvic exam was done and the presence of any ulcer was recorded. Women were classified as having genital ulcer disease (GUD) if they had either reported having a history of an ulcer prior to enrollment or had an ulcer observed during the exam at enrollment. All women were screened for syphilis, the other main cause of GUD in this population, with baseline rapid plasma reagin (RPR) testing, and treated if positive. The following opportunistic infections (OIs) were recorded: incident pulmonary or extrapulmonary tuberculosis, herpes zoster, Pneumocystis jirovecii pneumonia (PCP), Kaposi's sarcoma (KS), meningitis or encephalitis. These diagnoses were made in study clinic or were abstracted from records of hospitalized participants. Women were provided zidovudine (ZDV) prophylaxis according to standard prevention of mother-to-child transmission (PMTCT) protocols in Kenya at that time, which included short courses of ZDV beginning at 34–36 weeks gestation through delivery. Women with CD4 counts≤200 cells/µl received co-trimoxazole prophylaxis per Kenyan guidelines during the study period and were referred for highly-active antiretroviral therapy (HAART), although access to HAART in Kenya remained limited until 2003. Consistent with clinical practice in Kenya at the time, acyclovir was not used for treatment of GUD, but some women received it for severe herpes zoster. Cryopreserved plasma samples from the date of study enrollment were identified from women in the cohort. HSV-2 antibody was detected using HSV-2 enzyme-linked immunosorbency assays (ELISA) (HerpeSelect, Focus Diagnostics, Cypress, CA, USA), performed at University of Washington in 2007 (first 175 specimens) and University of Nairobi in 2009 (remaining 124 specimens). A cutoff index value ≥3.5 was used to determine a positive result. In Seattle, positive and equivocal results were repeated with Western blot testing and participants were considered positive if Western blot testing was positive. In Nairobi, Western blot testing was not done but samples with indeterminate results were re-tested; if a result remained indeterminate, the participant was excluded from analysis. CD4 count was measured in Nairobi with a FACScan flow cytometer (BD Biosciences, San Jose, CA USA), with semiannual proficiency testing performed. Plasma HIV-1 RNA levels were quantified at the Fred Hutchinson Cancer Research Center in Seattle using a transcription-mediated amplification assay (Gen-Probe, San Diego, CA USA), which has been validated to quantify prevalent HIV-1 subtypes in Kenya [21]. Maternal plasma was tested for syphilis at enrollment using the rapid plasma reagin (RPR) (Becton Dickinson, Cockeysville, MD) and confirmed using the Treponema pallidum hemagglutination assay (Randox Laboratories Ltd, Ardmore, Crumlin, UK). To determine baseline correlates of HSV-2-seropositivity in the cohort, univariate analyses were performed using Chi-squared, Fisher's exact test, and Student t-tests. Maternal HIV-1 disease progression was defined using three separate endpoints: death, CD4≤200 cells/µl, and first OI. Participants were censored after the first occurrence of an event. The following combined outcomes were also evaluated: 1) death or CD4≤200 cells/µl, 2) death or OI, and 3) death, CD4≤200 cells/µl or OI. Cumulative incidence was estimated using the Kaplan-Meier curves. Associations between disease progression and baseline risk factors were assessed using Cox proportional hazards regression, adjusted for baseline CD4 count. Data were also censored if any of the following occurred: death, start of HAART, or second pregnancy. To estimate rates of change of postpartum CD4 count and HIV-1 RNA levels, linear mixed effects models with random slopes were constructed. HIV-1 RNA levels and CD4 counts during pregnancy were excluded from linear mixed effects models. A locally weighted scatterplot smoother was applied to scatterplots of CD4 and plasma HIV-1 RNA level. Stata Version 10.0 (College Station, Texas USA) software was used for statistical analysis.
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