The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased ...antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition.
To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda.
Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted OR = 0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, P = 0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, P = 0.0002 and 0.013).
This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In sub-Saharan Africa, the predominant mode of transmission of human immunodeficiency virus type 1 (HIV-1) is through heterosexual contact, and the rate of transmission by this means is increasing ...throughout Asia and in many industrialized countries.
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A wide variety of behavioral and biologic risk factors are associated with the risk of transmission, including the frequency
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and types
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of sexual contact, the use or nonuse of condoms,
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immunologic status,
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and the presence or absence of the acquired immunodeficiency syndrome (AIDS),
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circumcision (in men),
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and sexually transmitted diseases.
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Other potential factors include plasma HIV-1 RNA levels, . . .
The probability of HIV-1 transmission per coital act in representative African populations is unknown. We aimed to calculate this probability overall, and to estimate how it is affected by various ...factors thought to influence infectivity.
174 monogamous couples, in which one partner was HIV-1 positive, were retrospectively identified from a population cohort in Rakai, Uganda. Frequency of intercourse and reliability of reporting within couples was assessed prospectively. HIV-1 seroconversion was determined in the uninfected partners, and HIV-1 viral load was measured in the infected partners. Adjusted rate ratios of transmission per coital act were estimated by Poisson regression. Probabilities of transmission per act were estimated by log-log binomial regression for quartiles of age and HIV-1 viral load, and for symptoms or diagnoses of sexually transmitted diseases (STDs) in the HIV-1-infected partners.
The mean frequency of intercourse was 8·9 per month, which declined with age and HIV-1 viral load. Members of couples reported similar frequencies of intercourse. The overall unadjusted probability of HIV-1 transmission per coital act was 0·0011 (95% CI 0·0008–0·0015). Transmission probabilities increased from 0·0001 per act at viral loads of less than 1700 copies/mL to 0·0023 per act at 38 500 copies/mL or more (p=0·002), and were 0·0041 with genital ulceration versus 0·0011 without (p=0·02). Transmission probabilities per act did not differ significantly by HIV-1 subtypes A and D, sex, STDs, or symptoms of discharge or dysuria in the HIV-1-positive partner.
Higher viral load and genital ulceration are the main determinants of HIV-1 transmission per coital act in this Ugandan population.
OBJECTIVE:To assess the validity of self-reported antiretroviral therapy use (ART) using population-based cohort data.
METHODS:Self-reported ART use and nonuse was compared with a validated ...laboratory assay in 557 HIV-positive participants in the Rakai Community Cohort Study surveyed between September and December 2011 in Rakai, Uganda. The study population included participants from seven communities, including one fishing community with high HIV prevalence (∼41%). ART use was assayed using liquid chromatography–tandem mass spectrometry, which detects 20 antiretroviral drugs. HIV viral load measurements were also obtained. Individuals with at least two antiretroviral drugs detected were considered to be using ART.
RESULTS:One hundred and fifty-three (27%) participants self-reported ART use of whom 148 (97%) had at least two antiretroviral drugs detected. There were at least two antiretroviral drugs detected in 11% (n = 44/404) of individuals with no self-reported ART use. Overall, the specificity of self-reported ART use was 99% (95% CI 97–100%) and the sensitivity was 77% (70–83%). Positive and negative predictive values were 97% (95% CI 93–99%) and 89% (95% CI 86–92%), respectively. Nondisclosure of ART use was significantly more common in younger persons (<30 years) and among those in trading occupations.
CONCLUSION:Self-reported ART use has high specificity and moderate sensitivity providing reasonable, but conservative estimates of population-based ART use. There is more under-reporting of ART use among younger persons and traders suggesting a need for more research on barriers to self-reporting of ART use in these sub-groups.
Summary 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 μL 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.
OBJECTIVE:To determine the prevalence, risk factors, and functional impairment associated with peripheral neuropathy in a prospective cohort of adults in rural Uganda.
METHODS:Eight hundred ...participants (400 HIV− and 400 antiretroviral-naive HIV+) in the Rakai Community Cohort Study underwent detailed neurologic evaluations including assessment of neuropathy symptoms, functional measures (Patient Assessment of Own Functioning Inventory and Karnofsky Performance Status scores), and neurologic evaluation by a trained medical officer. Neuropathy was defined as ≥1 subjective symptom and ≥1 sign of neuropathy on examination. Neuropathy risk factors were assessed using log binomial regression.
RESULTS:Fifty-three percent of participants were men, with a mean (SD) age of 35 (8) years. Neuropathy was present in 13% of the cohort and was more common in HIV+ vs HIV− participants (19% vs 7%, p < 0.001). Older age (relative risk RR 1.04, 95% confidence interval CI 1.02–1.06), female sex (RR 1.49, 95% CI 1.04–2.15), HIV infection (RR 2.82, 95% CI 1.86–4.28), tobacco use (RR 1.59, 95% CI 1.02–2.48), and prior neurotoxic medication use (RR 2.08, 95% CI 1.07–4.05) were significant predictors of neuropathy in the overall cohort. Only older age was associated with neuropathy risk in the HIV+ (RR 1.03, 95% CI 1.01–1.05) and HIV− (RR 1.06, 95% CI 1.02–1.10) cohorts. Neuropathy was associated with impaired functional status on multiple measures across all participant groups.
CONCLUSIONS:Peripheral neuropathy is relatively common and associated with impaired functional status among adults in rural Uganda. Older age, female sex, and HIV infection significantly increase the risk of neuropathy. Neuropathy may be an underrecognized but important condition in rural Uganda and warrants further study.
Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is crucial for an effective and targeted HIV response. We assessed community-level ...variations in HIV prevalence, risk factors, and treatment and prevention service uptake in Rakai, Uganda.
The Rakai Community Cohort Study (RCCS) is an open, population-based cohort of people aged 15-49 years in 40 communities. Participants are HIV tested and interviewed to obtain sociodemographic, behavioural, and health information. RCCS data from Aug 10, 2011, to May 30, 2013, were used to classify communities as agrarian (n=27), trading (n=9), or lakeside fishing sites (n=4). We mapped HIV prevalence with Bayesian methods, and characterised variability across and within community classifications. We also assessed differences in HIV risk factors and uptake of antiretroviral therapy and male circumcision between community types.
17 119 individuals were included, 9215 (54%) of whom were female. 9931 participants resided in agrarian, 3318 in trading, and 3870 in fishing communities. Median HIV prevalence was higher in fishing communities (42%, range 38-43) than in trading (17%, 11-21) and agrarian communities (14%, 9-26). Antiretroviral therapy use was significantly lower in both men and women in fishing communities than in trading (age-adjusted prevalence risk ratio in men 0·64, 95% CI 0·44-0·97; women 0·53, 0·42-0·66) and agrarian communities (men 0·55, 0·42-0·72; women 0·65, 0·54-0·79), as was circumcision coverage among men (vs trading 0·48, 0·42-0·55; vs agrarian 0·64, 0·56-0·72). Self-reported risk behaviours were significantly higher in men than in women and in fishing communities than in other community types.
Substantial heterogeneity in HIV prevalence, risk factors, and service uptake in Rakai, Uganda, emphasises the need for local surveillance and the design of targeted HIV responses. High HIV burden, risk behaviours, and low use of combination HIV prevention in fishing communities make these populations a priority for intervention.
National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, and the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research.
Bacterial vaginosis (BV) is a common vaginal bacterial imbalance associated with risk for HIV and poor gynecologic and obstetric outcomes. Male circumcision reduces BV-associated bacteria on the ...penis and decreases BV in female partners, but the link between penile microbiota and female partner BV is not well understood. We tested the hypothesis that having a female partner with BV increases BV-associated bacteria in uncircumcised men. We characterized penile microbiota composition and density (i.e., the quantity of bacteria per swab) by broad-coverage 16S rRNA gene-based sequencing and quantitative PCR (qPCR) in 165 uncircumcised men from Rakai, Uganda. Associations between penile community state types (CSTs) and female partner's Nugent score were assessed. We found seven distinct penile CSTs of increasing density (CST1 to 7). CST1 to 3 and CST4 to 7 were the two major CST groups. CST4 to 7 had higher prevalence and abundance of BV-associated bacteria, such as Mobiluncus and Dialister, than CST1 to 3. Men with CST4 to 7 were significantly more likely to have a female partner with a high Nugent score (P = 0.03). Men with two or more extramarital partners were significantly more likely to have CST4 to 7 than men with only marital partners (CST4 to 7 prevalence ratio, 1.84; 95% confidence interval CI, 1.16 to 2.92). Female partner Nugent BV is significantly associated with penile microbiota. Our data support the exchange of BV-associated bacteria through intercourse, which may explain BV recurrence and persistence.
Bacterial vaginosis (BV) is sexually associated but not considered a sexually transmitted disease. Our findings suggest that the uncircumcised penis is an important niche for BV-associated genital anaerobes. In addition, we found a link between extramarital sexual relationships and BV-associated bacteria in men, which parallels earlier findings of the association between sexual activity and BV in women. This suggests the sexual transmissibility of BV-associated bacteria. Reducing bacterial exchange by barrier methods and managing carriage of BV-associated bacteria in men may decrease BV persistence and recurrence in women.
Summary Background Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male ...circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men. Methods In two parallel but independent randomised controlled trials of male circumcision, we enrolled HIV-negative men and their female partners between 2003 and 2006, in Rakai, Uganda. With a computer-generated random number sequence in blocks of 20, men were assigned to undergo circumcision immediately (intervention) or after 24 months (control). HIV-uninfected female partners (648 of men from the intervention group, and 597 of men in the control group) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 months, and 24 months. Vaginal swabs were tested for high-risk HPV by Roche HPV Linear Array. Female HPV infection was a secondary endpoint of the trials, assessed as the prevalence of high-risk HPV infection 24 months after intervention and the incidence of new infections during the trial. Analysis was by intention-to-treat. An as-treated analysis was also done to account for study-group crossovers. The trials were registered, numbers NCT00425984 and NCT00124878. Findings During the trial, 18 men in the control group underwent circumcision elsewhere, and 31 in the intervention group did not undergo circumcision. At 24-month follow-up, data were available for 544 women in the intervention group and 488 in the control group; 151 (27·8%) women in the intervention group and 189 (38·7%) in the control group had high-risk HPV infection (prevalence risk ratio=0·72, 95% CI 0·60–0·85, p=0·001). During the trial, incidence of high-risk HPV infection in women was lower in the intervention group than in the control group (20·7 infections vs 26·9 infections per 100 person-years; incidence rate ratio=0·77, 0·63–0·93, p=0·008). Interpretation Our findings indicate that male circumcision should now be accepted as an efficacious intervention for reducing the prevalence and incidence of HPV infections in female partners. However, protection is only partial; the promotion of safe sex practices is also important. Funding The Bill & Melinda Gates Foundation, National Institutes of Health, and Fogarty International Center.
Effective implementation strategies are needed to increase engagement in HIV services in hyperendemic settings. We conducted a pragmatic cluster-randomized trial in a high-risk, highly mobile fishing ...community (HIV prevalence: approximately 38%) in Rakai, Uganda, to assess the impact of a community health worker-delivered, theory-based (situated Information, Motivation, and Behavior Skills), motivational interviewing-informed, and mobile phone application-supported counseling strategy called "Health Scouts" to promote engagement in HIV treatment and prevention services.
The study community was divided into 40 contiguous, randomly allocated clusters (20 intervention clusters, n = 1,054 participants at baseline; 20 control clusters, n = 1,094 participants at baseline). From September 2015 to December 2018, the Health Scouts were deployed in intervention clusters. Community-wide, cross-sectional surveys of consenting 15 to 49-year-old residents were conducted at approximately 15 months (mid-study) and at approximately 39 months (end-study) assessing the primary programmatic outcomes of self-reported linkage to HIV care, antiretroviral therapy (ART) use, and male circumcision, and the primary biologic outcome of HIV viral suppression (<400 copies/mL). Secondary outcomes included HIV testing coverage, HIV incidence, and consistent condom use. The primary intent-to-treat analysis used log-linear binomial regression with generalized estimating equation to estimate prevalence risk ratios (PRR) in the intervention versus control arm. A total of 2,533 (45% female, mean age: 31 years) and 1,903 (46% female; mean age 32 years) residents completed the mid-study and end-study surveys, respectively. At mid-study, there were no differences in outcomes between arms. At end-study, self-reported receipt of the Health Scouts intervention was 38% in the intervention arm and 23% in the control arm, suggesting moderate intervention uptake in the intervention arm and substantial contamination in the control arm. At end-study, intention-to-treat analysis found higher HIV care coverage (PRR: 1.06, 95% CI: 1.01 to 1.10, p = 0.011) and ART coverage (PRR: 1.05, 95% CI: 1.01 to 1.10, p = 0.028) among HIV-positive participants in the intervention compared with the control arm. Male circumcision coverage among all men (PRR: 1.05, 95% CI: 0.96 to 1.14, p = 0.31) and HIV viral suppression among HIV-positive participants (PRR: 1.04, 95% CI: 0.98 to 1.12, p = 0.20) were higher in the intervention arm, but differences were not statistically significant. No differences were seen in secondary outcomes. Study limitations include reliance on self-report for programmatic outcomes and substantial contamination which may have diluted estimates of effect.
A novel community health worker intervention improved HIV care and ART coverage in an HIV hyperendemic setting but did not clearly improve male circumcision coverage or HIV viral suppression. This community-based, implementation strategy may be a useful component in some settings for HIV epidemic control.
ClinicalTrials.gov NCT02556957.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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