The impact of early monitored management on survival in hospitalized adult Ugandan patients with severe sepsis: a prospective intervention study*.

UNLABELLED: In sub-Saharan Africa, sepsis is an important cause of mortality. Optimal sepsis management including fluid resuscitation, early antibiotic administration, and patient monitoring is limited by lack of supplies and skilled health workers. OBJECTIVE: To evaluate whether early, monitored sepsis management provided by a study medical officer can improve survival among patients with severe sepsis admitted to two public hospitals in Uganda. DESIGN, SETTING, AND PATIENTS: A prospective before and after study of an intervention cohort (n = 426) with severe sepsis receiving early, monitored sepsis management compared to an observation cohort (n = 245) of similarly ill patients with severe sepsis receiving standard management after admission to the medical wards of two Ugandan hospitals. INTERVENTION: Early sepsis management provided by a dedicated study medical officer comprising fluid resuscitation, early antibiotics, and regular monitoring in the first 6 hrs of hospitalization. MEASUREMENTS: Kaplan-Meier survival and unadjusted and adjusted Cox proportional hazards analysis were used to compare the effect of early, monitored sepsis management on 30-day mortality between the intervention cohort (enrolled May 2008 to May 2009) and observation cohort (enrolled July 2006 to November 2006). RESULTS: The majority (86%) of patients in both cohorts were human immuno-deficiency virus-infected. Median fluid volume provided in the first 6 hrs of hospitalization was higher in intervention than observation cohort patients (3000 mL vs. 500 mL, p < .001) and a greater proportion of intervention cohort patients received antibacterial therapy in <1 hr (67% vs. 30.4%, p < .001). Mortality at 30 days was significantly lower in the intervention cohort compared to the observation cohort (33.0% vs. 45.7%, log-rank p = .005). After adjustment for potential confounders, the hazard of 30-day mortality was 26% less in the intervention cohort compared to the observation cohort (adjusted hazards ratio 0.74, 95% confidence interval 0.55-0.98). Mortality among the 13% of intervention patients who developed signs of respiratory distress was associated with baseline illness severity rather than fluid volume administered. CONCLUSION: Early, monitored management of severely septic patients in Uganda improves survival and is feasible and safe even in a busy public referral hospital.

Circumcision of HIV-infected men: effects on high-risk human papillomavirus infections in a randomized trial in Rakai, Uganda.

UNLABELLED: In Rakai, Uganda, human immunodeficiency virus (HIV)-positive men were randomized to undergo either immediate circumcision (intervention arm) or delayed circumcision (control arm). Penile swab samples were assayed for high-risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and at 24 months (intervention arm, 103 subjects; control arm, 107 subjects). Rate ratios (RRs) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was found in 57 (55.3%) of 103 subjects in the intervention arm and in 77 (71.7%) of 107 subjects in the control arm (RR, 0.77; 95% confidence interval [CI], 0.62-0.97). Multiple HR-HPV infections were found in 19 (22.4%) of 85 subjects in the intervention arm and in 45 (42.5%) of 106 subjects in the control arm (RR, 0.53; 95% CI, 0.33-0.83). New HR-HPV genotypes were acquired by 34 (42.0%) of 81 subjects in the intervention arm and by 53 (57.0%) 85 subjects in the control arm (RR, 0.74; 95% CI, 0.54-1.01; P = .06). Multiple new HR-HPV genotypes were acquired by 8 (9.9%) of 81 subjects in the intervention arm and by 23 (24.7%) of 93 subjects in the control arm (RR, 0.40; 95% CI, 0.19-0.84; P = .01). Circumcision did not affect the acquisition of single HR-HPV infections (RR, 1.00; 95% CI 0.65-1.53) or clearance of HR-HPV infections (RR, 1.09; 95% CI 0.94-1.27). Circumcision of HIV-positive men reduced the prevalence and incidence of multiple HR-HPV infections. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00124878 .

Male circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda.

METHODS: Uncircumcised human immunodeficiency virus (HIV)-negative men aged 15-49 years were randomized to immediate circumcision (intervention arm, 441 subjects) or delayed circumcision (control arm, 399 subjects). Human papillomavirus (HPV) was detected by Roche HPV Linear Array at enrollment, and at 6, 12, and 24 months. Incident high-risk HPV (HR-HPV) was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RRs) and 95% confidence intervals (CIs) of HR-HPV acquisition were estimated by Poisson multiple regression. RESULTS: Enrollment characteristics were comparable between study groups. HR-HPV incidence was 19.7 cases per 100 person-years (PYs) in the intervention arm (70 cases per 355.8 PYs) and 29.4 cases per 100 PYs (125 cases per 424.8 PYs) in the control arm (RR, 0.67; 95% CI, 0.51-0.89; P = .006). The incidence of multiple HR-HPV infections was 6.7 cases per 100 PYs in the intervention arm and 14.8 cases per 100 PYs in the control arm (RR, 0.45; 95% CI, 0.28-0.73), but there was no significant effect on single infections (RR, 0.89; 95% CI, 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of preexisting HR-HPV infections was 215.8 cases per 100 PYs (205 cases per 95 PYs) in the intervention arm and 159.1 cases per 100 PYs (255 cases per 160.25 PYs) in the control arm (adjusted RR, 1.39; 95% CI, 1.17-1.64). CONCLUSIONS: Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00425984 .

Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial.

BACKGROUND: Observational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. We assessed whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners. METHODS: 922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 years with CD4-cell counts 350 cells per microL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878. FINDINGS: The trial was stopped early because of futility. 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0.36). Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7-33.4) in the intervention group and 13.4% (6.7-25.8) in the control group (adjusted hazard ratio 1.49, 95% CI 0.62-3.57; p=0.368). INTERPRETATION: Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention. FUNDING: Bill & Melinda Gates Foundation with additional laboratory and training support from the National Institutes of Health and the Fogarty International Center.

Effects of genital ulcer disease and herpes simplex virus type 2 on the efficacy of male circumcision for HIV prevention: Analyses from the Rakai trials.

BACKGROUND: Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC. METHODS AND FINDINGS: HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43-0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51-0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30-0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (chi(2)p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15-0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19-1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49-1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0-38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI -1.2 to 77.1). CONCLUSIONS: Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.

T-cell enumeration from dried blood spots by quantifying rearranged T-cell receptor-beta genes.

Significant hurdles remain to large-scale implementation of medical interventions in the developing world due to the lack of a modern diagnostic infrastructure. This is especially pertinent to the international roll-out of antiretroviral drugs to treat HIV, which ideally includes a CD4 T-cell count to determine eligibility. We designed a novel technique to estimate mature T-cell numbers by calculating the amount of rearranged T-cell receptor beta genes from dried blood spots of HIV-infected individuals in the United States and Uganda. It was observed that the rearranged T-cell receptor beta count correlated well with total lymphocyte counts from both study populations (Baltimore R=0.602, Uganda R=0.497; p<0.001) and the ability for this measurement to determine antiretroviral initiation was similar to total lymphocyte counts, which can be used to determine eligibility in HIV+children. This technique as well as other dried blood spot based technologies could increase the diagnostic and monitoring capabilities in resource-limited settings.

Incident HIV and herpes simplex virus type 2 infection among men in Rakai, Uganda.

OBJECTIVE: Herpes simplex virus type 2 (HSV-2) infection is associated with an increased risk for acquiring HIV, but little is known about the temporal sequence of these infections. DESIGN: : Six thousand three hundred ninety-six men were evaluated for serologic HSV-2 and HIV infections and behaviors during a male circumcision trial in Rakai, Uganda. METHODS: HIV and HSV-2 status were determined using enzyme-linked immunosorbent assays and confirmed by HIV-1 and HSV-2 western blots. A Poisson multivariable model was used to estimate adjusted incidence rate ratios of HIV acquisition associated with HSV-2 and other covariates. RESULTS: HIV incidence was 1.09/100 person-years and acquisition was associated with incident HSV-2 infection [adjusted incidence rate ratio (adjIRR) 5.28, 95% confidence interval (CI) 2.79-9.98], chronic HSV-2 infection (adjIRR 2.78, 95% CI 1.64-5.68), genital ulcer disease, urethral discharge, genital washing after intercourse, being unmarried, and being uncircumcised. Sixteen men acquired both HIV and HSV-2 during the trial: four acquired HIV first, three acquired HSV-2 first, and nine acquired both infections in the same follow-up interval. CONCLUSION: The findings suggest that unsafe sex places men at risk of both HIV and HSV-2 infections, and it is unclear whether HSV-2 acquisition is a cofactor for HIV infection or a marker of correlated sexual exposures. This reinforces the need for promotion of safe sex as the primary method of prevention of both viruses.

Factors associated with the prevalence and incidence of herpes simplex virus type 2 infection among men in Rakai, Uganda.

Little is known about risk factors for incident herpes simplex virus type 2 (HSV-2) infection among men in Africa. In a trial in Rakai, Uganda, 6396 men aged 15-49 years were evaluated for serological evidence of HSV-2, human immunodeficiency virus (HIV), and syphilis infections at enrollment and at 6, 12, and 24 months. The prevalence of HSV-2 infection was 33.76%, and the incidence was 4.90 cases per 100 person-years. HSV-2 incidence increased with alcohol use with sexual intercourse (adjusted incidence rate ratio [adjIRR], 1.92 [95% confidence interval {CI}, 1.46-2.53]), decreased with consistent condom use (adjIRR, 0.56 [95% CI, 0.36-0.89]) and male circumcision (adjIRR, 0.70 [95% CI, 0.55-0.91]), and was not significantly affected by enrollment HIV status. Education on modifiable behavioral changes may reduce the acquisition of HSV-2. (ClinicalTrials.gov identifiers: NCT00425984 and NCT00124878 .).

Frequency of long-term nonprogressors in HIV-1 seroconverters From Rakai Uganda.

OBJECTIVE: Studies on long-term nonprogressors (LTNP) have been conducted in the USA and Europe. This study examined the frequency of LTNPs and HIV controllers among 637 HIV-1 seroconverters in rural Uganda. DESIGN AND METHODS: LTNPs were defined as being infected for more than 7 years with a CD4 T-cell count above 600 cells per microliter, and HIV controllers as having undetectable viral loads on 3 separate occasions without antiretroviral treatment. HIV-1 viral load and subtype distribution between LTNP and non-LTNP populations were determined. RESULTS: Of the HIV seroconverters, 9.1% (58/637) were LTNPs and 1.4% (9/637) were HIV controllers. LTNPs had a significantly lower viral load at set point than non-LTNP participants (P < 0.001). The Kaplan-Meier joint probability of surviving to 7 years with a CD4 count >600 was 19.2%. Individuals who survived 7 years had a significantly higher frequency of HIV-1 subtype A (P < 0.05), but seroconverters infected with HIV-1A did not have a significantly higher probability of becoming an LTNP. CONCLUSIONS: The frequency of LTNPs appears to be relatively high in Uganda and it may be important to take this into account when designing studies of viral pathogenesis and performing HIV vaccine trials in sub-Saharan Africa.

CD4 stabilization tubes provide improved accuracy of absolute CD4 T-cell counts compared to standard k3 EDTA tubes in human immunodeficiency virus immunologic monitoring in resource-poor settings.

CD4 stabilization tubes have the ability to ensure internal quality control in the human immunodeficiency virus (HIV) monitoring laboratory by maintaining accurate absolute CD4 T-cell counts for up to 6 days. Here, we assessed this technology for its use in an HIV clinical monitoring laboratory in a resource-poor setting in rural Uganda.