To assess safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers.
We evaluated the time required for surgery and moderate / severe adverse events (AEs), among circumcisions by trained physicians and clinical officers using sleeve and dorsal slit methods. Univariate and multivariate regression with robust variance was used to assess factors associated with time for surgery (linear regression) and adverse events (logistic regression).
Six physicians and 8 clinical officers conducted 1934 and 3218 MCs, respectively. There were 2471 dorsal slit and 2681 sleeve procedures. The mean duration of surgery was 33 minutes for newly trained providers and decreased to ~20 minutes after ~100 circumcisions. The adjusted mean duration of surgery for dorsal slit was significantly shorter than that for sleeve method (Δ −2.8 minutes, p- <0.001). The duration of surgery was longer for clinical officers than physicians performing the sleeve procedure, but not the dorsal slit procedure. Crude AEs rates were 0.6% for dorsal slit and 1.4% with the sleeve method (p=0.006). However, there were no significant differences after multivariate adjustment. Use of cautery significantly reduced time needed for surgery (Δ − 4.0 minutes, p =0.008), but was associated with higher rates of AEs (adjusted odds ratio 2.13, 95%CI 1.26–3.61, p=0.005).
The dorsal slit resection method of male circumcision is faster and safer than sleeve resection, and can be safely performed by non-physicians. However, use of cautery may be inadvisable in this setting.
Adult male circumcision; HIV; circumcision programs; task shifting; adverse events; safety; Uganda
Medical male circumcision (MC) of HIV-infected men may increase plasma HIV viral load and place female partners at risk of infection. We assessed the effect of MC on plasma HIV viral load in HIV-infected men in Rakai, Uganda.
195 consenting HIV-positive, HAART naïve men aged 12 and above provided blood for plasma HIV viral load testing before surgery and weekly for six weeks and at 2 and 3 months post surgery. Data were also collected on baseline social demographic characteristics and CD4 counts. Change in log10 plasma viral load between baseline and follow-up visits was estimated using paired t tests and multivariate generalized estimating equation (GEE).
Of the 195 men, 129 had a CD4 count ≧350 and 66 had CD4 <350 cells/mm3. Men with CD4 counts <350 had higher baseline mean log10 plasma viral load than those with CD4 counts ≧350 cells/mm3 (4.715 vs 4.217 cps/mL, respectively, p = 0.0005). Compared to baseline, there was no statistically significant increase in post-MC HIV plasma viral loads irrespective of CD4. Multivariate analysis showed that higher baseline log10 plasma viral load was significantly associated with reduction in mean log10 plasma viral load following MC (coef. = −0.134, p<0.001).
We observed no increase in plasma HIV viral load following MC in HIV-infected, HAART naïve men.
An effective HIV vaccine is still elusive. Of the 9 HIV preventive vaccine efficacy trials conducted to-date, only one reported positive results of modest efficacy. More efficacy trials need to be conducted before one or more vaccines are eventually licensed. We assessed the suitability of fishing communities in Uganda for future HIV vaccine efficacy trials.
A community-based cohort study was conducted among a random sample of 2191 participants aged 18–49 years. Data were collected on socio-demographic characteristics, HIV risky behaviors, and willingness to participate in future HIV vaccine trials (WTP). Venous blood was collected for HIV serological testing. Retention/follow rates and HIV incidence rates per 100 person years at-risk (pyar) were estimated. Adjusted prevalence proportion ratios (PPRs) of retention and odds ratios (ORs) of lack of WTP were estimated using log-binomial and logistic regression models respectively.
Overall retention rate was 76.9% (1685/2191), highest (89%) among participants who had spent 5+ years in the community and lowest (54.1%) among those with <1 year stay. Significant predictors of retention included tribe/ethnicity, baseline HIV negative status, and longer than 1 year stay in the community. Overall WTP was 89.1% (1953/2191). Lack of WTP was significantly higher among women than men [adj.OR = 1.51 (95% CI, 1.14- 2.00)] and among participants who had stayed in fishing communities for 10 or more years relative to those with less than one year [adj.OR = 1.78 (95% CI, 1.11 - 2.88)]. Overall HIV incidence rate per 100 pyar was 3.39 (95% CI; 2.55 - 4.49). Participants aged 25–29 years had highest incidence rates (4.61 - 7.67/100 pyar) and high retention rates between 78.5 and 83.1%. In a combined analysis of retention and incidence rates participants aged 30+ years had retention rates ~80% but low incidence rates (2.45 - 3.57 per 100 pyar) while those aged 25–29 years had the highest incidence rates (4.61 - 7.67/100 pyar) and retention rates 78.5 - 83.1%.
There is high HIV incidence, retention and WTP among fishing communities around L. Victoria, Uganda which make these communities appropriate for future HIV prevention efficacy studies including vaccine trials.
HIV-1 incidence; Retention; Willingness to participate; Fishing communities; Uganda
Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort.
Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination.
Results. We showed that YF-17D–induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D–neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination.
Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity.
Trial registration. Registration is not required for observational studies.
Funding. This study was funded by Canada’s Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.
High HIV-1 incidence rates were reported among persons in fisherfolk communities (FFC) in Uganda who were selected for high risk behaviour. We assessed the incidence of HIV-1 and associated risk factors in a general population FFC to determine population-wide HIV rates.
A community-based cohort study was conducted among a random sample of 2191 participants aged 18–49 years. At baseline and 12 months post-baseline, data were collected on socio-demographic characteristics and risky behaviors (including number of partners, new partners, condom use, use of alcohol and illicit drug use). Venous blood was collected for HIV serological testing. HIV incidence was calculated per 100 person years at-risk (pyar) and adjusted incidence rate ratios (Adj.IRR) were estimated by multivariable Poisson regression.
Overall follow up at 12 months was 76.9% (1685/2191) and was significantly higher among HIV uninfected persons and those with at least 1 year duration of stay in community. Overall HIV-1 incidence was 3.39/100 pyar (95% CI: 2.55–4.49). Among the 25–29 years who drank alcohol, HIV incidence was 7.67/100pyar (95% CI;4.62–12.7) while it was 5.67/100pyar (95% CI;3.14–10.2) for 18–24 year olds who drank alcohol. The risk of HIV infection was higher among 25–29 years (adj.IRR = 3.36; 95% CI: 1.48–7.65) and 18–24 years (adj.IRR = 2.65; 95% CI: 1.05–6.70) relative to 30+ years. Compared to non-drinkers, HIV incidence increased by frequency of alcohol drinking - occasional drinkers (adj.IRR = 3.18; 95% CI: 1.18–8.57) and regular drinkers (adj.IRR = 4.93; 95% CI: 1.91–12.8).
HIV-1 incidence in general fisherfolk population along L.Victoria, Uganda, is high and is mainly associated with young age and alcohol drinking. HIV prevention and control strategies are urgently needed in this population.
Dihydroartemisinin-piperaquine administered at monthly intervals, but not that dosed once a school term, is a remarkably effective measure for the prevention of incidence of malaria, prevalence of parasitemia, and prevalence of anemia in schoolchildren living in a high-transmission setting.
Background. Intermittent preventive treatment (IPT) in schoolchildren offers a promising option for malaria control. However, the optimal drug and dosing regimens for IPT remain to be determined.
Methods. We conducted a randomized, double-blind, placebo-controlled trial in 740 schoolchildren aged 6–14 years living in a setting of high malaria transmission in Uganda. Enrolled children were randomized to dihydroartemisinin-piperaquine (DP) given once a month (IPTm), DP given once a school term (4 treatments over 12 months, IPTst), or placebo and followed for 12 months. The primary outcome was the incidence of malaria over 12 months. Secondary outcomes included parasite prevalence and anemia over 12 months. Analyses were conducted on an intention-to-treat basis.
Results. In the placebo arm, the incidence of malaria was 0.34 episodes per person-year and the prevalence of parasitemia and anemia was 38% and 20%, respectively. IPTm reduced the incidence of malaria by 96% (95% confidence interval [CI], 88%–99%, P < .0001), the prevalence of asymptomatic parasitemia by 94% (95% CI, 92%–96%, P < .0001), and the prevalence of anemia by 40% (95% CI, 19%–56%, P < .0001). IPTst had no significant effect on the incidence of symptomatic malaria or the prevalence of anemia, but reduced the prevalence of asymptomatic parasitemia by 54% (95% CI, 47%–60%, P < .0001).
Conclusions. Monthly IPT with DP offered remarkable protection against clinical malaria, parasitemia, and anemia in schoolchildren living in a high-malaria-transmission setting.
Clinical Trials Registration. NCT01231880.
malaria; intermittent preventive treatment; schoolchildren
Little is known about HIV infection and the related vulnerabilities of young people living in resource-scarce, post-emergency transit camps that are now home to thousands of Internally Displaced Persons (IDPs) following two decades of war in northern Uganda. The objective of this analysis was to assess the prevalence and correlates of HIV infection among young people living in post-conflict transition in Gulu District, northern Uganda.
In 2010, a cross-sectional demographic and behavioural survey was conducted in two of Gulu District’s sub-counties with 384 purposively selected transit camp residents aged 15 to 29 years. Biological specimens were collected for rapid HIV testing in the field and confirmatory laboratory testing. Multivariable logistic regression identified independent determinants of HIV infection.
HIV prevalence was alarmingly high at 12.8% (95% CI: 9.6%, 16.5%). The strongest determinant of HIV infection among young people was a non-consensual sexual debut (adjusted odds ratio [AOR], 9.88; 95% CI: 1.70–18.06). Residing in Awach sub-county (AOR, 2.93; 95% CI: 1.28–6.68), experiencing STI symptoms in the previous 12 months (AOR, 2.36; 95% CI: 1.43–6.17), and practicing dry sex (AOR, 2.31; 95% CI: 1.04–5.13) were other key determinants of HIV infection.
Study findings contribute to filling an important gap in epidemiological evidence and are useful for planning public health interventions in northern Uganda that effectively target young people in post-conflict transition and support them in the resettlement process. Findings serve to recommend reaching beyond traditional prevention programming in a way more effectively beneficial to young people in post-conflict settings by developing population-specific responses sensitive to local contexts and sufficient to address the underlying causes of the complex risk factors influencing the spread of HIV.
Rheumatic heart disease (RHD), the only long term consequence of acute rheumatic fever, remains a leading cause of morbidity and mortality among young adults in Uganda. An inherited susceptibility to acute rheumatic fever centers around the major histocompatibility class II human leucocyte antigens. However, there is paucity of data from sub-Saharan Africa. This study compares the frequency of HLA class II DR alleles between RHD cases and normal controls in Uganda.
One hundred ninety-nine participants including 96 established RHD cases aged 5–60 years and 103 age and sex matched normal controls were recruited for participation. DNA was manually extracted from buffy coat samples and HLA analysis was performed. HLA-DR allelic frequency comparison between cases and controls were estimated using conditional logistic regression with 95% confidence intervals. P -values were corrected for multiple hypothesis testing.
199 participants (103 female, 51.8%) completed the study. The mean (SD) age in years for cases and controls were 29.6 (10.2) and 29(18), respectively. After conditional logistic regression and multiple hypothesis testing, HLA-DR1was associated with a decreased risk of RHD (OR = 0.42, CI 0.21-085, P = 0.01, Corrected P value (PC) = 0.09,) while HLA-DR11 was associated with increased risk of RHD (OR = 3.31, CI 1.57-6.97, P = <0.001, Pc < 0.001). No other significant associations were found.
In this first study of HLA genetic susceptibility to RHD in Uganda, HLA- DR1 was more common in normal controls while HLA- DR11 was more common among RHD cases suggesting a disease susceptibility association. In future studies, high resolution HLA analysis and genome wide studies should be carried out to confirm this pattern.
Rheumatic heart disease; HLA-DR1; HLA-DRB11; MHC- major histocompatibility complex
We have previously shown that in successful pregnancies increased arginase activity is a mechanism that contributes to the suppression of the maternal immune system. We identified the main type of arginase-expressing cells as a population of activated low-density granulocytes (LDGs) in peripheral blood mononuclear cells and in term placentae. In the present study, we analyzed the phenotype of LDGs and compared it to the phenotype of normal density granulocytes (NDGs) in maternal peripheral blood, placental biopsies and cord blood. Our data reveal that only LDGs but no NDGs could be detected in placental biopsies. Phenotypically, NDGs and LDGs from both maternal and cord blood expressed different levels of maturation, activation and degranulation markers. NDGs from the maternal and cord blood were phenotypically similar, while maternal, cord and placental LDGs showed different expression levels of CD66b. LDGs present in cord blood expressed higher levels of arginase compared to maternal and placental LDGs. In summary, our results show that in maternal and cord blood, two phenotypically different populations of neutrophils can be identified, whereas in term placentae, only activated neutrophils are present.
HIV epidemics are sustained and propagated by new cases of infection which result from transmission from infected persons to uninfected susceptible individuals. People living with HIV (PLHIV) play a critical role in prevention if they adopt safer sexual behaviors. This study estimated the prevalence of and factors associated with safer sexual behaviors among PLHIV seeking care from civil society organizations (CSOs).
In a cross sectional study PLHIV were interviewed about their sexual practices, use of alcohol, HIV status of their regular sexual partners, desire for more children and about their socio-demographic characteristics. We calculated the proportion of PLHIV who abstained and consistently used condoms in the previous twelve months. Independent associations between safer sex and other variables were estimated using adjusted prevalence ratios (aPR) and their 95% confidence intervals (CI).
Of the 939 PLHIV, 54% (508) were either abstaining or using condoms consistently and 291 (31%) desired more children. The prevalence of consistent condom use among the sexually active was 41.3% (300/731). Consistent condom use was higher among PLHIV who: didn't use alcohol (aPR 1.30, CI 1.03–1.63); were educated about re-infection with a new strain of HIV (aPR 1.84, CI 1.08–3.12) and had regular sexual partner who was HIV negative (aPR 1.29, CI 1.05–1.57). Prevalence of abstinence was 22.2% (208/939). Abstinence increased with age from 9.4% among PLHIV <25 years to 40.5% among those >50 years. Abstinence was extremely low (2.5%) among PLHIV who were married.
Effective interventions that reduce alcohol consumption among PLHIV are needed to avert HIV transmission, prevent acquisition of new HIV strains and STIs. In addition, strategies are needed to address needs of PLHIV who desire more children.
In sub-Saharan Africa, a large proportion of HIV positive patients on antiretroviral therapy (ART) are lost to follow-up, some of whom are dead. The objective of this study was to validate methods used to correct mortality estimates for loss-to-follow-up using a cohort with complete death ascertainment.
Routinely collected data from HIV patients initiating first line antiretroviral therapy (ART) at the Infectious Diseases Institute (IDI) (Routine Cohort) was used. Three methods to estimate mortality after initiation were: 1) standard Kaplan-Meier estimation (uncorrected method) that uses passively observed data; 2) double-sampling methods by Frangakis and Rubin (F&R) where deaths obtained from patient tracing studies are given a higher weight than those passively ascertained; 3) Nomogram proposed by Egger et al. Corrected mortality estimates in the Routine Cohort, were compared with the estimates from the IDI research observational cohort (Research Cohort), which was used as the “gold-standard”.
We included 5,633 patients from the Routine Cohort and 559 from the Research Cohort. Uncorrected mortality estimates (95% confidence interval ) in the Routine Cohort at 1, 2 and 3 years were 5.5% (4.9%–6.3%), 6.6% (5.9%–7.5%) and 7.4% (6.5%–8.5%), respectively. The F&R corrected estimates at 1, 2 and 3 years were 11.2% (5.8%–21.2%), 15.8% (9.9%–24.8%) and 18.5% (12.3% –27.2%) respectively. The estimates obtained from the Research Cohort were 15.6% (12.8%–18.9%), 17.5% (14.6%–21.0%) and 19.0% (15.3%–21.9%) at 1, 2 and 3 years respectively. Using the nomogram method in the Routine Cohort, the corrected programme-level mortality estimate in year 1 was 11.9% (8.0%–15.7%).
Mortality adjustments provided by the F&R and nomogram methods are adequate and should be employed to correct mortality for loss-to-follow-up in large HIV care centres in Sub-Saharan Africa.
Background. A genetic bottleneck is known to exist for human immunodeficiency virus (HIV) at the point of sexual transmission. However, the nature of this bottleneck and its effect on viral diversity over time is unclear.
Methods. Interhost and intrahost HIV diversity was analyzed in a stable population in Rakai, Uganda, from 1994 to 2002. HIV-1 envelope sequences from both individuals in initially HIV-discordant relationships in which transmission occurred later were examined using Sanger sequencing of bulk polymerase chain reaction (PCR) products (for 22 couples), clonal analysis (for 3), and next-generation deep sequencing (for 9).
Results. Intrahost viral diversity was significantly higher than changes in interhost diversity (P < .01). The majority of HIV-1–discordant couples examined via bulk PCR (16 of 22 couples), clonal analysis (3 of 3), and next-generation deep sequencing (6 of 9) demonstrated that the viral populations present in the newly infected recipient were more closely related to the donor partner's HIV-1 variants found earlier during infection as compared to those circulating near the estimated time of transmission (P = .03).
Conclusions. These findings suggest that sexual transmission constrains viral diversity at the population level, partially because of the preferential transmission of ancestral as opposed to contemporary strains circulating in the transmitting partner. Future successful vaccine strategies may need to target these transmitted ancestral strains.
Thousands of former child soldiers who were abducted during the prolonged conflict in northern Uganda have returned to their home communities. Programmes that facilitate their successful reintegration continue to face a number of challenges. Although there is increasing knowledge of the dynamics of HIV infection during conflict, far less is known about its prevalence and implications for population health in the post-conflict period. This study investigated the effects of abduction on the prevalence of HIV and HIV-risk behaviours among young people in Gulu District, northern Uganda. An understanding of abduction experiences and HIV-risk behaviours is vital to both the development of effective reintegration programming for former child soldiers and the design of appropriate HIV prevention interventions for all young people.
In 2010, we conducted a cross-sectional study of 2 sub-counties in Gulu District. A demographic and behavioural survey was interview-administered to a purposively selected sample of 384 transit camp residents aged 15–29. Biological specimens were collected for HIV rapid testing in the field and confirmatory laboratory testing. Descriptive statistics were used to describe characteristics of abduction. Additionally, a gender-stratified bivariate analysis compared abductees’ and non-abductees’ HIV risk profiles.
Of the 384 participants, 107 (28%) were former child soldiers (61% were young men and 39% were young women). The median age of participants was 20 and median age at abduction was 13. HIV prevalence was similar among former abductees and non-abductees (12% vs. 13%; p = 0.824), with no differences observed by gender. With respect to differences in HIV vulnerability, our bivariate analysis identified greater risky sexual behaviours in the past year for former abductees than non-abductees, but there were no differences between the two groups’ survival/livelihood activities and food insufficiency experiences, both overall and by gender. The analysis further revealed that young northern Ugandans in general are in desperate need of education, skills development, and support for victims of sexual violence.
This study persuasively demonstrates that all young people in northern Ugandan have been similarly affected by HIV infection during war and displacement. Post-conflict programme planners must therefore abandon rudimentary targeting practices based on abductees as a high-profile category. Instead, they must develop evidence-based HIV interventions that are commensurate with young people’s specific needs. As such programmes will be less stigmatizing, more oriented to self-selection, and more inclusive, they will effectively reach the most vulnerable young people in northern Uganda.
Child soldiers; HIV/AIDS; Post-conflict programming; Young people; Northern Uganda
HIV epidemics in sub-Saharan Africa are generalized, but high-risk subgroups exist within these epidemics. A recent study among fisher-folk communities (FFC) in Uganda showed high HIV prevalence (28.8%) and incidence (4.9/100 person-years). However, those findings may not reflect population-wide HIV rates in FFC since the study population was selected for high-risk behaviour.
Between September 2011 and March 2013, we conducted a community-based cohort study to determine the population representative HIV rates and willingness to participate (WTP) in hypothetical vaccine trials among FFC, Uganda. At baseline (September 2011–January 2012), a household enumeration census was done in eight fishing communities (one lakeshore and seven islands), after which a random sample of 2200 participants aged 18–49 years was selected from 5360 individuals. Interviewer-administered questionnaire data were collected on HIV risk behaviours and WTP, and venous blood was collected for HIV testing using rapid HIV tests with enzyme-linked immunosorbent assay (EIA) confirmation. Adjusted prevalence proportion ratios (adj.PPRs) of HIV prevalence were determined using log-binomial regression models.
Overall baseline HIV prevalence was 26.7% and was higher in women than men (32.6% vs. 20.8%, p<0.0001). Prevalence was lower among fishermen (22.4%) than housewives (32.1%), farmers (33.1%) and bar/lodge/restaurant workers (37%). The adj.PPR of HIV was higher among women than men (adj.PPR =1.50, 95%; 1.20, 1.87) and participants aged 30–39 years (adj.PPR=1.40, 95%; 1.10, 1.79) and 40–49 years (adj.PPR=1.41, 95%; 1.04, 1.92) compared to those aged 18–24 years. Other factors associated with HIV prevalence included low education, previous marriage, polygamous marriage, alcohol and marijuana use before sex. WTP in hypothetical vaccine trials was 89.3% and was higher in men than women (91.2% vs. 87.3%, p=0.004) and among island communities compared to lakeshore ones (90.4% vs. 85.8%, p=0.004).
The HIV prevalence in the general fisher-folk population in Uganda is similar to that observed in the “high-risk” fisher folk. FFC have very high levels of willingness to participate in future HIV vaccine trials.
HIV-1; willingness to participate in HIV vaccine trials; fishing communities; Uganda
Asymptomatic parasitemia is common among schoolchildren living in areas of high malaria transmission, yet little is known about its effect on cognitive function in these settings. To investigate associations between asymptomatic parasitemia, anemia, and cognition among primary schoolchildren living in a high malaria transmission setting, we studied 740 children enrolled in a clinical trial in Tororo, Uganda. Parasitemia, measured by thick blood smears, was present in 30% of the children. Infected children had lower test scores for abstract reasoning (adjusted mean difference [AMD] −0.6, 95% confidence interval [CI] −1.01 to −0.21) and sustained attention (AMD −1.6 95% CI −2.40 to −0.81) compared with uninfected children. There was also evidence for a dose–response relationship between parasite density and scores for sustained attention. No associations were observed between anemia and either test of cognition. Schoolchildren in high transmission settings may experience cognitive benefits, from interventions aimed at reducing the prevalence of asymptomatic parasitemia.
Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda
In a single site trial, 440 HIV-1, HSV-2 dually infected consenting adults with CD4+ T-cell counts 300-400 cells/μL and not on antiretroviral therapy were randomized 1:1 to receive either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Intent-to-treat analysis used Cox proportional hazards (CPH) models, adjusting for baseline log10 viral load (VL), CD4 cell count, gender and age to assess the risk of disease progression. The impact of suppressive HSV-2 treatment by baseline VL was also investigated in a CPH model. This trial is registered with clinicaltrials.gov, number NCT00405821.
Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (Adj HR 0.75, 95% CI 0.58-0.99; p=0.040). In a sub-analysis stratified by baseline VL quintile, participants with a baseline VL >= 50,000 copies/ml experienced a 38% reduction in HIV disease progression in the treatment compared to placebo arm (Adj HR 0.62, 95% CI 0.43-0.96;p=0.03).
Acyclovir reduced the rate of disease progression by 25%, with the greatest impact occurring among individuals with high baseline VL. Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals with viral loads >= 50,000 copies/ml prior to antiretroviral treatment.
HIV-1; herpes simplex virus; acyclovir; disease progression
CCR5 is the primary coreceptor for HIV entry. Early after infection, the HIV viral population diversifies rapidly into a quasispecies. It is not known whether the initial efficiency of the viral quasispecies to utilize CCR5 is associated with HIV disease progression or if it changes in an infected individual over time. The CCR5 and CXCR4 utilization efficiencies (R5-UE and X4-UE) of the HIV quasispecies were examined using a pseudovirus, single-round infection assay for samples obtained from known seroconverters from Rakai district, Uganda (n=88). Initial and longitudinal R5-UE values were examined to assess the association of R5-UE with HIV disease progression using multivariate Cox proportional hazard models. Longitudinal samples were analyzed for 35 seroconverters who had samples available from multiple time points. There was no association between initial or longitudinal changes in R5-UE and the hazard of HIV disease progression (p=0.225 and p=0.942, respectively). In addition, R5-UE increased significantly over time after HIV seroconversion (p<0.001), regardless of HIV subtype or the emergence of CXCR4-tropic virus. These data demonstrate that the R5-UE of the viral quasispecies early in HIV infection is not associated with disease progression, and that R5-UE levels increase in HIV-infected individuals over time.
Large datasets for investigating vaginal flora change at frequent, repeated intervals are limited and graphical methods for exploring such data are inadequate. We report 2-year weekly vaginal flora changes based on Gram stain using lasagna plots.
Weekly vaginal flora patterns were evaluated among 211 sexually experienced women with 18 months or more of follow-up in Rakai, Uganda. Vaginal flora swabs were self-collected weekly and categorized by Nugent Gram stain criteria (0–3, normal; 4–6, intermediate; 7–10, BV). Vaginal flora patterns were analyzed as the percentage of weekly observations with BV (longitudinal prevalence) and illustrated by lasagna plots. Characteristics of women were compared across tertiles of longitudinal prevalence of BV.
Ninety-five percent of women had at least 1 episode of BV over 2 years with one-third of women spending over half (52–100%) of their time with BV. Vaginal pH > 4.5 increased with increasing tertiles of longitudinal prevalence of BV (p < 0.001). Weekly fluctuation in vaginal flora states, as measured by a change in flora states from the prior to current visit, was highest in the middle (41.9%) compared to the lower (30.1%) and upper tertiles (27.8%, p < 0.001). HIV status and reported vaginal symptoms did not differ significantly across BV tertiles.
Women exhibited different patterns of vaginal flora changes over time, which could not be described by baseline behaviors. Lasagna plots aided in describing the natural history of BV within and across women and may be applied to future BV natural history studies.
Sputum culture is the gold standard for diagnosis of pulmonary tuberculosis (PTB). Although mostly used for research, culture is recommended by the World Health Organization for TB diagnosis among HIV infected smear negative PTB suspects. Even then, the number of sputum samples required remains unspecified. Here, we determined the Incremental Yield (IY) and number of samples required to diagnose an additional PTB case upon second and third serial sputum culture.
This was a cross sectional study done between January and March 2011. Serial sputum samples were provided by participants within two days and cultured using Lowenstein Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) methods. A PTB case was defined as a positive culture on either one or both methods. The IY from the second and third serial cultures was determined and the reciprocal of the product of the fractions of IY provided the number of samples required for an additional PTB case. Of the 170 smear negative PTB suspects, 62 (36.5%) met the case definition. The IY of the second sample culture was 12.7%, 23.6% and 12.6% and for the third sample culture was 6.8%, 7.5% and 7.3% with LJ, MGIT and LJ or MGIT, respectively. The number of samples required for an additional PTB case and 95% CI upon the second sample culture were 29.9 (16.6, 156.5), 11.3 (7.6, 21.9) and 20.8 (12.5, 62.7); while for the third sample culture were 55.6 (26.4, 500.4), 35.7 (19.0, 313.8) and 36.1 (19.1, 330.9) by LJ, MGIT and LJ or MGIT respectively.
Among HIV infected smear negative PTB suspects in Kampala, 93% of PTB cases are diagnosed upon the second serial sputum culture. The number of cultures needed to diagnose an additional PTB case, ranges from 11–30 and 35–56 by the second and third sputum samples, respectively.
To describe changes in vaginal microbiota and pH over time among never sexually active adolescents at different menarcheal stages.
A cohort of 49 sexually inexperienced Ugandan adolescents provided weekly self-collected vaginal swabs and behavioral/health information for up to two years. Menarcheal stage was classified as: not experiencing menarche during follow-up (premenarcheal, n=9), achieving menarche during follow-up (perimenarcheal, n=20), and being postmenarcheal (n=20) at enrollment. Vaginal microbiota were characterized as morphotypes of large Gram-positive rods, small Gram-negative or variable rods, and curved Gram-negative rods based on Nugent Gram-stain criteria. Baseline measures were compared using nonparametric tests. Mean changes (β) in morphotypes and pH over time were estimated using longitudinal mixed-effects models.
The baseline median (IQR: interquartile range) Nugent score was 8 (7-8) in premenarcheal, 4.5 (1-8) in perimenarcheal, and 1 (0-3) in postmenarcheal girls (p=0.001). For each respective menarcheal stage, the median counts of (IQR) Gram-positive rods were 0 (0-0), 10 (0-30), and 30 (18-30) (p=0.002) and Gram-negative or variable rods were 30 (30-30), 16 (0.5-30), and 0.5 (0-2.5) (p=0.002) at enrollment. Counts of Gram-positive rods increased (β = 0.259, 95% CI: 0.156, 0.362) and Gram-negative or variable rods decreased (β = -0.201, 95% CI:-0.298,-0.103) significantly over time in premenarcheal girls, but not in other groups. Vaginal pH declined significantly in peri- and postmenarcheal girls only.
Vaginal microbiota composition varied by menarcheal stage at enrollment. Over time, significant changes in vaginal morphotypes occurred in premenarcheal girls, suggesting this may be an important period of transition.
vaginal microbiota; pH; menarche; lactobacilli; bacterial vaginosis; Gram-stain; Nugent score
High viral load (VL) setpoint is a marker for rapid HIV progression, but few studies have examined whether use of hormonal contraception (HC) prior to HIV seroconversion affects VL setpoint.
We determined VL setpoints in 285 HIV seroconverters using blood samples collected six months or more after estimated HIV seroconversion but before disease progression to CD4≤250 or WHO Stage 3 or 4. We used multivariate linear regression to estimate the effect of HC use prior to HIV seroconversion on VL setpoint, and multivariate Cox regression to estimate the hazards ratio of death associated with VL setpoint.
Of 285 women, 42 (15%) reported using HC prior to HIV seroconversion. Mean VL setpoint was 4.49 (SD 0.79) log10 copies/mL among women who used HC prior to HIV seroconversion and 4.47 (SD 0.86) among non-HC users (p=0.88). In multivariate analysis, HC prior to HIV seroconversion was not associated with VL setpoint (+0.11 log10 copies /mL; p=0.47). Higher socioeconomic status was associated with lower VL setpoint (-0.43 log10 copies/mL; p=0.04). VL setpoints above the median were associated with faster time to death (adjHR: 2.54, 95% CI: 1.30-4.98, p-value <0.01).
Use of HC prior to HIV seroconversion was not associated with elevated VL setpoint.
hormonal contraception; viral load setpoint; HIV progression; Uganda
HIV-1 subtype D (HIV-1D) progresses to disease faster and has lower transmissibility than subtype A (HIV-1A). We examined whether these differences could lead to a population level change in the distribution of these subtypes over time. HIV-1 viral RNA was extracted from stored serum samples from HIV-positive subjects participating in a population-based cohort study in Rakai, Uganda in 1994 and 2002. Portions of the viral proteins gag and gp41 were sequenced and subtyped. HIV-1 subtype assignments were generated for 773 subjects in 1994 and 812 subjects in 2002. The change in subtype distribution of the population as a whole as well as quartile age groups were examined for significant changes using a linear model. There was a significant decrease in the proportion of subjects infected with HIV-1D from 70.2% to 62.4% and a significant increase in subjects infected with HIV-1A from 16.7% to 23.3% over the 8-year period (p = 0.005). The most marked changes in proportion of HIV-1D and A were seen in the younger individuals (<25 and 25–30 years; p < 0.05). The percentages of subjects infected with HIV-1C and recombinant subtypes did not change significantly. Over this 8-year period, the overall viral population in this region evolved toward the less virulent HIV-1A strain, most likely as a consequence of the faster disease progression and lower transmissibility of HIV-1D.
Disclosure of HIV seropositive results among HIV-discordant couples in sub-Saharan Africa is generally low. We describe a facilitated couple counselling approach to enhance disclosure among HIV-discordant couples.
Using unique identifiers, 293 HIV-discordant couples were identified through retrospective linkage of married or cohabiting consenting adults individually enrolled into a cohort study and into two randomized trials of male circumcision in Rakai, Uganda. HIV discordant couples and a random sample of HIV-infected concordant and HIV-negative concordant couples (to mask HIV status) were invited to sensitization meetings to discuss the benefits of disclosure and couple counselling. HIV-infected partners were subsequently contacted to encourage HIV disclosure to their HIV uninfected partners. If the index positive partner agreed, the counsellor facilitated the disclosure of HIV results, and provided ongoing support. The proportion of disclosure was determined.
81% of HIV-positive partners in discordant relationships disclosed their status to their HIV-uninfected partners in the presence of the counsellor. The rates of disclosure were 81.3% in male HIV-positive and 80.2% in female HIV-positive discordant couples. Disclosure did not vary by age, education or occupation.
In summary, disclosure of HIV-positive results in discordant couples using facilitated couple counselling approach is high, but requires a stepwise process of sensitization and agreement by the infected partner.
HIV disclosure; Facilitated couple counselling; Discordant couples
Male circumcision reduces HIV acquisition in men. We assessed whether foreskin surface area was associated with HIV acquisition prior to circumcision.
In two randomized trials of male circumcision, the surface area of the foreskin was measured after surgery using standardized procedures. Nine hundred and sixty-five initially HIV-negative men were enrolled in a community cohort who subsequently enrolled in the male circumcision trials, provided 3920.8 person-years of observation prior to circumcision. We estimated HIV incidence per 100 person-years prior to circumcision, associated with foreskin surface area categorized into quartiles.
Mean foreskin surface area was significantly higher among men who acquired HIV (43.3 cm2, standard error 2.1) compared with men who remained uninfected (36.8 cm2, standard error 0.5, P = 0.01). HIV incidence was 0.80/100 person-years (8/994.9 person-years) for men with foreskin surface areas in the lowest quartile ( ≤26.3 cm2), 0.92/100 person-years (9/975.3 person-years) with foreskin areas in the second quartile (26.4–35.0 cm2), 0.90/100 person-years (8/888.5 person-years) with foreskin area in the third quartile (35.2–45.5 cm2) and 2.48/100 person-years (23/926.8 person-years) in men with foreskin surfaces areas in the highest quartile (>45.6 cm2). Compared with men with foreskin surface areas in the lowest quartile, the adjusted incidence rate ratio of HIV acquisition was 2.37 (95% confidence interval 1.05–5.31) in men with the largest quartile of foreskin surface area.
The risk of male HIV acquisition is increased among men with larger foreskin surface areas.
foreskin surface area; HIV acquisition; HIV target cells; male circumcision