Vaginal Cytomegalovirus Shedding Before and After Initiation of Antiretroviral Therapy in Rakai, Uganda.

Vaginal shedding of cytomegalovirus (CMV) DNA was determined longitudinally among 96 women coinfected with human immunodeficiency virus (HIV), herpes simplex virus 2, and CMV starting antiretroviral therapy (ART) during a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Vaginal CMV was detected in 75 of 96 women (78.0%) and 379 of 1080 individual visits (35.1%). ART status, higher HIV RNA viral load before ART initiation, and younger age were significantly associated with increased frequency of CMV shedding (P < .01). Compared to pre-ART, CMV shedding peaked from month 2 to month 4 after ART initiation, suggesting possible immune reconstitution inflammatory syndrome. Further studies need to determine the clinical significance of asymptomatic CMV shedding.

Decreased monocyte activation with daily acyclovir use in HIV-1/HSV-2 coinfected women.

OBJECTIVES: Several clinical trials have demonstrated that daily treatment of HIV-infected individuals with the antiherpes drug acyclovir slightly decreases HIV-1 viral load and slows disease progression. This study examines if this slowing in clinical progression is a direct cause of the decrease in viral load or an indirect effect of lower immune activation due to lower levels of herpetic reactivation. METHODS: Women who participated in a randomised clinical trial of daily acyclovir use (n=301) were monitored every 6 months for changes in immune activation. Soluble CD14 (sCD14), a marker for monocyte activation, and C-reactive protein (CRP), a marker for general immune activation, were measured by ELISA. RESULTS: Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multivariant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels. CONCLUSIONS: These data suggest that decreased monocyte activation may play a minor role in the ability of daily acyclovir use to slow HIV disease progression. CLINICAL TRIAL REGISTRATION NUMBER: NCT00405821.

Hypertension, cardiovascular risk factors and antihypertensive medication utilisation among HIV-infected individuals in Rakai, Uganda.

OBJECTIVES: To assess the prevalence of hypertension, elevated blood pressure and cardiovascular risk factors among HIV-positive individuals in rural Rakai District, Uganda. METHODS: We assessed 426 HIV-positive individuals in Rakai, Uganda from 2007 to 2010. Prevalence of hypertension and elevated blood pressure assessed by clinical measurement was compared to clinician-recorded hypertension in case report forms. Multiple logistic regression and z-tests were used to examine the association of hypertension and elevated blood pressure with age, sex, body mass index (BMI), CD4 cell count and antiretroviral treatment (ART) use. For individuals on antihypertensives, medication utilisation was reviewed. RESULTS: The prevalence of hypertension (two elevated blood pressure readings at different time points) was 8.0% (95% CI: 5.4-10.6%), and that of elevated blood pressure (one elevated blood pressure reading) was 26.3% (95% CI: 22.1-30.5%). Age ≥50 years and higher BMI were positively associated with elevated blood pressure. ART use, time on ART and CD4 cell count were not associated with hypertension. Eighty-three percent of subjects diagnosed with hypertension were on antihypertensive medications, most commonly beta-blockers and calcium channel blockers. CONCLUSIONS: Hypertension is common among HIV-positive individuals in rural Uganda.

Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy.

BACKGROUND: The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated. METHODS: GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding. RESULTS: Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04-3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35-1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48-4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04-.41). CONCLUSIONS: The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation.

Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment.

Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus-infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF-α (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation.

The acceptability and safety of the Shang Ring for adult male circumcision in Rakai, Uganda.

OBJECTIVES: Medical male circumcision (MMC) is recommended for HIV prevention in men. We assessed the acceptability and safety of the Shang Ring device compared with those of the dorsal slit method. METHODS: HIV-negative, uncircumcised men aged 18 years or older who requested free MMC services in rural Rakai, Uganda, were informed about the Shang Ring and dorsal slit procedures and offered a free choice of procedure. Men were followed at 7 days postoperatively to assess adverse events related to surgery and to remove the Shang Ring. Wound healing was assessed at 4 weeks postoperatively. RESULTS: Six hundred twenty-one men were enrolled, of whom 508 (81.8%) chose the Shang Ring and 113 the dorsal slit. The Shang Ring was provided to 504 men, among whom there were 4 failures of Ring placement (0.8%) that required surgical hemostasis and wound closure. Five hundred men received the Shang Ring and postoperative surgery-related moderate adverse events were 1.0%, compared with 0.8% among dorsal slit recipients. Complete wound healing at 4 weeks was 84% with the Ring and 100% with the dorsal slit (P < 0001). Resumption of intercourse before 4 weeks was 7.0% with the Ring and 15.0% with the dorsal slit (P = 0.01.) The mean time for surgery was 6.1 minutes with the Ring and 17.7 minutes with the dorsal slit. The mean time for Ring removal was 2.2 minutes. CONCLUSIONS: The Shang Ring is highly acceptable and safe in this setting, and could improve the efficiency of MMC services. However, back-up surgical services are needed in cases of Ring placement failures.

Frequent detection of HPV before and after initiation of antiretroviral therapy among HIV/HSV-2 co-infected women in Uganda.

OBJECTIVES: Most data on HPV and antiretroviral therapy (ART) come from high-resource countries with infrequent sampling for HPV pre- and post-ART initiation. Therefore, we examined the frequency of cervical HPV DNA detection among HIV/HSV-2 co-infected women followed monthly for 6 months both before and after initiation of ART in Rakai, Uganda. METHODS: Linear Array was used to detect 37 HPV genotypes in self-collected cervicovaginal swabs from 96 women who initiated ART. Random-effects log-binomial regression was used to compare the prevalence of HPV detection in the pre- and post-ART periods and determine other potential risk factors, including CD4 counts and HIV viral load. RESULTS: Nearly all women had detectable HPV in the 6 months preceding ART initiation (92%) and the cumulative prevalence remained high following initiation of therapy (90%). We found no effect of ART on monthly HPV DNA detection (prevalence ratio: 1.0; 95% confidence interval: 0.96, 1.08), regardless of immune reconstitution or HIV viral suppression. Older age and higher pre-ART CD4 counts were associated with a significantly lower risk of HPV DNA detection. CONCLUSIONS: ART did not impact HPV detection within 6 months of therapy initiation, highlighting the importance of continued and consistent screening, even after ART-initiation and immune reconstitution.

Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial.

BACKGROUND: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. METHODS: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per µL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per µL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. FINDINGS: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50,000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50,000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. INTERPRETATION: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50,000 copies per mL or more before initiation of antiretroviral treatment. FUNDING: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).