We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.
There is limited evidence on the effect of injectable contraception on response to antiretroviral therapy (ART).
Using modified Poisson regression, we assessed data from 418 female Ugandan ART initiators to examine the effect of injectable contraceptive use on a composite virologic failure outcome (defined as failure to achieve virologic suppression, switch to second line therapy, or death within 12 months of ART initiation), and also assessed ART adherence.
About 12% of women reported using injectable contraceptives at ART initiation, and their composite virologic failure rates 12 months later were similar to women not using injectable contraceptives at ART initiation (11% vs. 12%, p=0.99). Multivariable Poisson regression suggested no significant differences in virologic failure by injectable contraceptive use at baseline (PRR: 0.85, p=0.71), but power was limited. Adherence to ART increased with time since ART initiation, but did not appear to differ between injectable contraceptive users and non-users.
Consistent with current WHO guidelines, our results suggest no deleterious effect of injectable contraceptive use on response to ART, but power was limited, injectable contraceptive use patterns over time were inconsistent, and additional evidence is needed.
family planning; hormonal contraception; injectable contraception; HIV; antiretroviral therapy; Uganda
Although voluntary medical male circumcision (VMMC) in Iganga district was launched in 2010 as part of the Uganda national strategy to prevent new HIV infections with a target of having 129,896 eligible males circumcised by 2012, only 35,000 (27%) of the anticipated target had been circumcised by mid 2012. There was paucity of information on why uptake of VMMC was low in this setting where HIV awareness is presumably high. This study sought to understand motivators for uptake of VMMC from the perspective of the clients themselves in order to advocate for feasible approaches to expanding uptake of VMMC in Iganga district and similar settings.
In Iganga district, we conducted seven key informant interviews with staff who work in the VMMC clinics and twenty in-depth interviews with clients who had accepted and undergone VMMC. Ten focus-group discussions including a total of 112 participants were also conducted with clients who had undergone VMMC.
Motivators for uptake of VMMC in the perspective of the circumcised clients and the health care staff included: perceived medical benefit to those circumcised such as protection against acquiring HIV and other sexually transmitted diseases, peer/partner influence, sexual satisfaction and safety and cost to access the service.
Since perceived medical benefit was a motivator for seeking VMMC, it can be used to strengthen campaigns for increasing uptake of VMMC. Peer influence could also be used in advocacy campaigns for VMMC expansion, especially using peers who have already undergone VMMC. There is need to ensure that safety and cost to access the service is affordable especially to rural poor as it was mentioned as a motivator for seeking VMMC.
Motivators; safe male circumcision
Dysglycemia during sepsis is associated with poor outcomes in resource-rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda.
Prospective observational study.
One national and two regional referral hospitals in Uganda.
We enrolled 532 patients with sepsis at three hospitals in Uganda. The analysis included 418 patients from the three sites with inhospital mortality data, a documented admission blood glucose concentration, and evidence of organ dysfunction at admission (systolic blood pressure ≤100 mm Hg, lactate > 4 mmol/L, platelet number <100,000/µL, or altered mental status).
Measurements and Main Results
We evaluated the association between admission point-of-care blood glucose concentration and inhospital mortality. We also assessed the accuracy of altered mental status as a predictor of hypoglycemia. Euglycemia occurred in 33.5% (140 of 418) of patients, whereas 16.3% (68 of 418) of patients were hypoglycemic and 50.2% (210 of 418) were hyperglycemic. Univariate Cox regression analyses comparing inhospital mortality among hypoglycemic (35.3% [24 of 68], hazard ratio 2.0, 95% confidence interval 1.2–3.6, p = .013) and hyperglycemic (29.5% [62 of 210], hazard ratio 1.5, 95% confidence interval 0.96–2.4, p = .08) patients to euglycemic (19.3% [27 of 140]) patients showed statistically significantly higher rates of inhospital mortality for patients with hypoglycemia. Hypoglycemia (adjusted hazard ratio 1.9, 95% confidence interval 1.1–3.3, p = .03) remained significantly and independently associated with inhospital mortality in the multivariate model. The sensitivity and specificity of altered mental status for hypoglycemia were 25% and 86%, respectively.
Hypoglycemia is an independent risk factor for inhospital mortality in patients with severe sepsis and cannot be adequately assessed by clinical examination. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings.
Africa; hypoglycemia; mortality; outcomes; severe sepsis; Uganda
World Health Organization (WHO) immunological and clinical criteria for monitoring first-line antiretroviral treatment (ART) offer low accuracy for predicting viral failure. Targeting viral load assays to those at high risk has been recommended and a system to do this has been developed in Cambodia. Systems for use in Sub-Saharan African populations were evaluated.
A new Ugandan based scoring system for targeting viral load assays was developed from data of the first 4 years of a Ugandan cohort (N=559) receiving first-line ART. The accuracy of this, the Cambodian based system and the WHO criteria to predict viral failure, through targeting viral load assays, was compared in a separate population of 496 Ugandans.
The new Ugandan scoring system included CD4 count, mean cell volume, adherence, and HIV associated clinical events as predictors of viral failure. In the validation population, the Ugandan system undertook viral load assays in 61 (12.3%) cases offering 20.5% sensitivity and 100% positive predictive value (PPV) to predict viral failure. The Cambodian system undertook viral load assays in 33 (6.7%) cases producing 23.1% sensitivity and 90.0% PPV. WHO criteria recommended viral load assays in 72 (14.5%) cases offering 30.8% sensitivity and 100% PPV.
Locally developed algorithms based on clinical and immunological criteria may offer little additional accuracy over WHO criteria for targeting viral load assays. Where possible, confirming viral load before switching therapy is recommended. Scoring systems are more flexible than WHO criteria in allowing ART providers to choose the proportion of the population that undergo targeted viral load testing.
Antiretroviral therapy; HIV; resource-constrained settings; treatment failure; Uganda; viral load
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
In Iganga, Uganda, 45% of women who tested HIV-positive during antenatal care between 2007 and 2010 were lost to follow-up (LTFU). We explored reasons for LTFU during prevention of mother-to-child transmission (PMTCT) from a client perspective in eastern Uganda, where antiretroviral therapy (ART) awareness is presumably high.
Seven key informant interviews and 20 in-depth interviews, including both clients who had been retained under PMTCT care and those LTFU during PMTCT were held. Ten focus-group discussions involving a total of 112 participants were also conducted with caretakers/ relatives of the PMTCT clients. Content analysis was performed to identify recurrent themes.
Our findings indicate that LTFU during PMTCT in eastern Uganda was due to sex inequality, high transport costs to access the services, inadequate posttest counseling, lack of HIV status disclosure, and the isolated/exposed location of the ART clinic, which robs the clients of their privacy.
There is a need for approaches that empower women with social capital, knowledge, and skills to influence health-seeking practices. There is also a need to train low-ranking staff and take PMTCT services closer to the clients at the lower-level units to make them affordable and accessible to rural clients. Posttest counseling should be improved to enable PMTCT clients to appreciate the importance of PMTCT services through increasing the number of staff in antenatal care to match the client numbers for improved quality. The counseling should emphasize HIV status disclosure to partners and encourage partner escort for antenatal care visits for further counseling. The exposed and isolated ART clinic should be integrated with the other regular outpatient services to reduce the labeling stigma.
mother-to-child transmission; HIV; Uganda; sex inequality
Viral load monitoring (VLM) to identify individuals failing antiretroviral therapy (ART) is not widely available in resource-limited settings. We compared the genotypic resistance patterns between clients with VLM versus immunological monitoring (IM).
Between 2004–2008, 559 ART naïve clients were enrolled in a prospective cohort, initiated on ART, and monitored with viral load (VL) and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36–40 months (corresponding to the follow-up time of the VLM group) at the same clinic and monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Samples from VLM clients at 12, 24 and 36 months and IM clients at 36–40 months with VL > 2000 copies/ml underwent genotypic drug resistance testing.
Baseline characteristics were similar. Virologic failure (VL > 400 copies/ml) at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and in the IM group 10% at 36–40 months. Samples from 39 VLM and 70 IM clients were genotyped. 23/39 (59%) clients in the VLM group (at 12, 24 or 36 months) compared to 63/70 (90%) in the IM group, (P < 0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. 19/39 (49%) of VLM clients had an M184V mutation compared to 61/70 (87%) in the IM group (P < 0.0001). Only 2/39 (5%) of VLM clients developed thymidine analogue mutations compared to 34/70 (49%) of IM clients (P < 0.0001).
Routine VL monitoring reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda.
HIV-1; Antiretroviral therapy; Drug resistance
Systematic disparities in rates of HIV incidence by socioeconomic status were assessed among men attending three sexually transmitted disease (STD) clinics in Pune, India, to identify key policy-intervention points to increase health equity. Measures of socioeconomic status included level of education, family income, and occupation. From 1993 to 2000, 2,260 HIV-uninfected men who consented to participate in the study were followed on a quarterly basis. Proportional hazards regression analysis of incident HIV infection identified a statistically significant interaction between level of education and genital ulcer disease. Compared to the lowest-risk men without genital ulcer disease who completed high school, the relative risk (RR) for acquisition of HIV was 7.02 (p<0.001) for illiterate men with genital ulcer disease, 3.62 (p<0.001) for men with some education and genital ulcer disease, and 3.02 (p<0.001) for men who completed high school and had genital ulcer disease. For men with no genital ulcer disease and those with no education RR was 1.09 (p=0.84), and for men with primary/middle school it was 1.70 (p=0.03). The study provides evidence that by enhancing access to treatment and interventions that include counselling, education, and provision of condoms for prevention of STDs, especially genital ulcer disease, among disadvantaged men, the disparity in rates of HIV incidence could be lessened considerably. Nevertheless, given the same level of knowledge on AIDS, the same level of risk behaviour, and the same level of biological co-factors, the most disadvantaged men still have higher rates of HIV incidence.
Health equity; HIV; Acquired immunodeficiency syndrome; Sexually transmitted infections; Sexually transmitted diseases; Socioeconomic status; Prospective studies; India
Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa.
500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIV-uninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScan®) to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariable logistic regression.
19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3–3.5, p = 0.002), herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9–8.7, p<0.001), and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2–9.2, p = 0.017) were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0–5.0, p = 0.044) and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7–14.7, p = 0.004) were associated with increased liver fibrosis.
Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda.
The global human immunodeficiency virus (HIV) pandemic reached staggering proportions over the past 2 decades, particularly in areas of sub-Saharan Africa and other developing countries. Tremendous increases in donor resources over the past decade have allowed for a rapid scale-up of antiretroviral treatment and greater access to basic care and prevention programs in countries worst affected by HIV infection and AIDS. These programs have had a tremendous impact on the lives of millions of individuals and have also created optimism and hope where previously there was despair. Major challenges remain in combating the current HIV pandemic with regard to access to treatment; efficiency, quality, and sustainability of current programs; and the scale-up of evidence-based, effective prevention strategies. The global health community and political leaders will need to overcome these challenges if a long-term effective response to the HIV pandemic is to be achieved.
Antiretroviral therapy programs in Africa are currently providing treatment for almost two million people. The long-term success of large scale antiretroviral therapy programs in sub-Saharan Africa remains uncertain because of the limited information currently available on rates of virologic failure and selection for drug-resistant variants in the different HIV subtypes. This article provides a comprehensive review of the published literature on the prevalence of primary and secondary HIV drug resistance with different subtypes and in various settings across sub-Saharan Africa.
Antiretroviral therapy; ART; Resistance; Africa; Subtypes; Phenotypic; Genotypic
To determine the extent of viral resistance over time among non-clade B HIV-1 infected patients in Uganda maintained on first line highly active antiretroviral therapy (HAART) following virologic failure.
Genotyping was performed on sixteen patients with virologic failure who were enrolled in an open label randomized clinical trial of short-cycle treatment interruption.
All patients receiving efavirenz containing HAART had at least 1 efavirenz resistance mutation develop during follow-up. The majority 13/15 (86%) developed lamivudine resistance during follow-up but no thymidine analogue mutations (TAMS) developed during a median duration of virologic failure of 325.5 days.
Genotypic resistance to both efavirenz and lamivudine developed early during the course of treatment after virologic failure. TAMs did not emerge early despite moderate exposure time to thymidine analogs during virologic failure.
human immunodeficiency virus (HIV); antiretroviral drug resistance; virologic failure
Herpes simplex virus type 2 (HSV-2) infection is one of the most commonly sexually transmitted infections worldwide. While glycoprotein G-2 ELISA based assays are commonly used for the serologic detection of HSV-2 infections, they have low specificity in developing countries. Euroline Western blot (WB) is a commercially available assay that is easy to perform; however, little is known about its performance characteristics. This study evaluated Euroline WB for the detection of HSV-2 antibodies compared to University of Washington Western blot in three geographically different regions, Baltimore, Maryland, Rakai, Uganda, and Kunming, China. Among the 135 American men attending an STD clinic in Baltimore, Maryland, 72% (n=97) were HSV-2 positive by Euroline WB. The Euroline WB had a sensitivity of 97.8% and a specificity of 81.8%. Among the 273 commercial sex workers in Kunming, 62.3% were HSV-2 positive by Euroline WB. The Euroline WB had a sensitivity of 96.9% and a specificity of 89.1%. Among the 437 Ugandans in Rakai, 67.3% were HSV-2 positive by Euroline WB. The Euroline WB had a sensitivity of 98.7% and a specificity of 65.4%. The Euroline WB has a consistently high sensitivity, but specificity varied significantly among the different locations.
HIV and hepatitis B virus (HBV) co-infection poses important public health considerations in resource-limited settings. Demographic data and sera from adult participants of the Rakai Health Sciences Program Cohort in Southwestern Uganda were examined to determine HBV seroprevalence patterns in this area of high HIV endemicity prior to the introduction of antiretroviral therapy. Commercially available EIAs were used to detect prevalent HBV infection (positive for HBV core antibody [anti-HBc] and/or positive HBV surface antigen [HBsAg]), and chronic infection (positive for HBsAg). Of 438 participants, 181 (41%) had prevalent HBV infection while 21 (5%) were infected chronically. Fourteen percent of participants were infected with HIV. Fifty three percent showed evidence of prevalent HBV infection compared to 40% among participants infected with HIV (p=0.067). Seven percent of participants infected with HIV were HBsAg positive compared to 4% among participants not infected with HIV (p=0.403). The prevalence of prevalent HBV infection was 55% in adults aged >50 years old, and 11% in persons under 20 years. In multivariable analysis, older age, HIV status and serologic syphilis were significantly associated with prevalent HBV infection. Transfusion status and receipt of injections were not significantly associated with HBV infection. Contrary to expectations that HBV exposure in Uganda occurred chiefly during childhood, prevalent HBV infection was found to increase with age and was associated sexually transmitted diseases (HIV and syphilis.) Therefore vaccination against HBV, particularly susceptible adults with HIV or at risk of HIV/STDs should be a priority.
Hepatitis B virus HBV; HIV; Sexual transmission; Uganda; Africa
To evaluate the impact of antiretroviral therapy (ART) on HIV-1 transmission rates among HIV-1 discordant couples in Rakai, Uganda.
Observational cohort study.
HIV-1 discordant couples were retrospectively identified between 2004 and 2009. Study participants underwent annual screening for HIV-1 and were interviewed to evaluate risk behaviors. Participants were offered voluntary counseling and testing and provided with risk reduction counseling. Free ART was offered to participants with a CD4 cell count of 250 cells/μl or less or WHO stage IV disease. HIV-1 incidence and sexual risk behaviors were compared before and after the HIV-1-positive index partners started ART.
Two hundred and fifty HIV-1 discordant couples were followed between 2004 and 2009 and 32 HIV-1-positive partners initiated ART. Forty-two HIV-1 transmissions occurred over 459.4 person-years prior to ART initiation, incidence 9.2/100 person-years [95% confidence interval (CI) 6.59–12.36]. In 32 couples in which the HIV-1 index partners started ART, no HIV-1 transmissions occurred during 53.6 person-years. The 95% CI for the incidence rate difference was −11.91 to −6.38 (P=0.0097). Couples reported more consistent condom use during ART use, but there was no significant difference in the number of sexual partners or other risk behaviors. Viral load was markedly reduced in persons on ART.
HIV-1 transmission may be reduced among HIV-1 discordant couples after initiation of ART due to reductions in HIV-1 viral load and increased consistent condom use.
antiretroviral; discordant couples; HIV transmission; HIV-1
Technology advances in rapid diagnosis and clinical monitoring of human immunodeficiency virus (HIV) infection have been made in recent years, greatly benefiting those at risk of HIV infection, those needing care and treatment, and those on antiretroviral (ART) therapy in sub-Saharan Africa. However, resource-limited, geographically remote, and harsh climate regions lack uniform access to these technologies. HIV rapid diagnostic tests (RDTs) and monitoring tools, such as those for CD4 counts, as well as tests for coinfections, are being developed and have great promise in these settings to aid in patient care. Here we explore the advances in point-of-care (POC) technology in the era where portable devices are bringing the laboratory to the patient. Quality management approaches will be imperative for the successful implementation of POC testing in endemic settings to improve patient care.
The promise of combination HIV prevention—the application of multiple HIV prevention interventions to maximize population-level impact—has never been greater. However, to succeed in achieving significant reductions in HIV incidence, an additional concept needs to be considered—combination implementation. Combination implementation for HIV prevention is defined here as the pragmatic, localized application of evidence-based strategies to realize high sustained uptake and quality of HIV prevention interventions. This review explores diverse implementation strategies including HIV testing and counseling models, task shifting, linkage to and retention in care, antiretroviral therapy support, behavior change, demand creation, and structural interventions and discusses how they could be used in the provision of HIV prevention interventions such as medical male circumcision and treatment as prevention. Only through careful consideration of how to implement and operationalize HIV prevention interventions will the HIV community be able to move from clinical trial evidence to population-level impact.
Liver disease is a leading cause of mortality among HIV-infected persons in the US and Europe; however, data regarding effects of HIV and anti-retroviral therapy (ART) on liver disease in Africa remains sparse.
500 HIV-infected participants in an HIV care program in Rakai, Uganda were frequency-matched by age, gender and site to 500 HIV-uninfected participants in a population cohort. All participants underwent transient elastography (FibroScan®) to quantify liver stiffness measurements (LSM) and identify participants with significant liver fibrosis, defined as LSM ≥9.3 kPa (≈ Metavir F ≥2). 962 (96 %) of participants had valid LSM data. Risk factors for liver fibrosis were identified by estimating adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariate regression.
The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (p =0.008). In multivariate analysis, HIV infection was associated with a 50% increase in liver fibrosis (adjPRR 1.5, 95%CI 1.1–2.1; p=0.010). Fibrosis was also associated with male gender (adjPRR 1.4, 95% CI 1.0–1.9; p=0.045), herbal medicine use (adjPRR 2.0, 95%CI 1.2–3.3; p=0.005), heavy alcohol consumption (adjPRR 2.3, 95% CI 1.3–3.9; 0.005), occupational fishing (adjPRR 2.5, 1.2–5.3; p=0.019), and chronic HBV infection (adjPRR 1.7, 95% CI 1.0–3.1; p=0.058). Among HIV-infected participants, ART appeared to reduce fibrosis risk (adjPRR 0.6, 95% CI 0.4–1.0; p=0.030).
The burden of liver fibrosis among rural Ugandans is high, particularly among persons with HIV infection. These data suggest that liver disease may represent a significant cause of HIV-related morbidity and mortality in Africa; clarifying the etiology of liver disease in this population is a research priority.
HIV; fibrosis; hepatitis co-infection; liver; Uganda
Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. We used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 38% of sporadic BL (sBL) cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting constitutive B cell receptor signaling. These findings suggest opportunities to improve therapy for patients with BL.
Randomized trials show that medical male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in men. We assessed the efficacy of MC to reduce HR-HPV in female partners.
HIV-negative men were randomized to immediate MC (intervention) or MC delayed for 24 months (control). HIV-uninfected female partners of married men (648 intervention and 597 control arm) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 and 24 months. Female HPV infection was a secondary trial end point. Vaginal swabs were evaluated for HR-HPV by Roche HPV Linear Array. An intention-to-treat analysis estimated prevalence risk and incident rate ratios (PRR and IRR) and 95% confidence intervals (95%CI) of HR-HPV by Poisson multiple regression. In women with pre-existing HR-HPV, we estimated the risk ratio (RR) of cleared infection (i.e., loss of detection). The trials were registered with ClinicalTrials.gov, NCT00425984 and NCT00124878.)
Female characteristics and HPV prevalence were similar between arms at enrollment. Two year retention rates were 84.7% (549/648) in intervention arm and 84.1% (502/597) in control arm spouses. Year 2 female HR-HPV prevalence was 27.8% (151/544) in the intervention and 38.7% (189/488) in the control arm (PRR=0.72, 95%CI 0.60–0.85, p=0.001). HR-HPV incidence was 20.7/100py in the intervention arm and 26.9/100py in the control arm wives (IRR=0.77, 95%CI 0.63-0.93, p=0.008). HR-HPV incidence was lower in intervention than control arm wives for 13 of 14 (92.9%) HR-HPV genotypes and in most demographic/behavioral subgroups. Genotype specific HR-HPV clearance was higher in the wives of men in the intervention arm (66.2%, 376/568) than the control arm (59.2%, 339/573, RR=1.12, 95%CI 1.02-1.22).
MC reduces the prevalence and incidence and increases clearance of HR-HPV infections in female partners.
Bill & Melinda Gates Foundation with additional laboratory and training support from National Institutes of Health and Fogarty International Center.
Male circumcision; transmission; female partners; human papillomavirus (HPV); cervical cancer; HIV; Uganda; sexually transmitted infections
In Rakai, Uganda, HIV+ men were randomized to immediate (intervention) or delayed circumcision (controls). Penile swabs were assayed for high risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and 24 months (intervention n=103, control n=107). Rate ratios (RR) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was intervention 55.3% and control 71.7% (RR=0.77, 95%CI 0.62–0.97). Multiple HR-HPV infections were intervention 22.4% and controls 42.5% (RR=0.53, 95%CI 0.33–0.83). New HR-HPV genotypes were acquired by 42.0% of intervention and 57.0% of control arm men (RR=0.74, 95%CI 0.54–1.01, p=0.06). Multiple new HR-HPV genotypes were acquired by 9.9% intervention and 24.7% control arm men (RR = 0.40, 95%CI 0.19–0.84, p = 0.01). 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 (RR=1.09, 95%CI 0.94–1.27). Circumcision of HIV+ men reduced the prevalence and incidence of multiple HR-HPV infections.
Uncircumcised HIV-negative men aged 15-49 years were randomized to immediate circumcision (n=441) or delayed circumcision (n=399). HPV was detected by Roche HPV Linear Array at enrollment, 6, 12 and 24 months. Incident 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 (RR) and 95% confidence intervals (95%CI) of HR-HPV acquisition were estimated by Poisson multiple regression
Enrollment characteristics were comparable between groups. HR-HPV incidence was 19.7/100 py in the intervention (70/355.8 py) and 29.4/100 py (125/424.8 py) in the control arm (RR=0.67, 95%CI 0.51-0.89, p = 0.006.) The incidence of multiple HR-HPV infections was 6.7/100 py in the intervention and 14.8/100 py in 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 pre-existing HR-HPV infections was 215.8/100py (205/95 py) in intervention and 159.1/100py (255/160.25 py) in control arm men (adjRR=1.39, 95%CI 1.17-1.64).
Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men.
The trial was registered with ClinicalTrials.gov numbers NCT00425984
Background. Use of antiretroviral therapy (ART) may be associated with higher pregnancy rates.
Methods. The prevalence and incidence of pregnancy was assessed in 712 HIV+ pre-ART women of reproductive age (WRA) (15–45) and 244 HIV+ WRA initiating ART. Prevalence rate ratios (PRR), incidence rate ratios (IRR), and 95% confidence interval (CI) were assessed.
Results. The incidence of pregnancy was 13.1/100 py among women in pre-ART care compared to 24.6/100 py among women on ART (IRR = 0.54; 95% CI 0.37, 0.81, p < 0.0017). The prevalence of pregnancy at ART initiation was 12.0% with CD4 counts 100–250 compared with 3.2% with CD4 <100 (PRR = 3.24, CI 1.51–6.93), and the incidence of pregnancy while on ART was highest in women with a good immunologic response. Desire for more children was a very important factor in fertility.
Conclusion. ART was associated with increased pregnancy rates in HIV+ women, particularly those with higher CD4 counts and good immunologic response to therapy, suggesting a need to strengthen reproductive health services for both women and their partners that could address their fertility decisions/intentions particularly after ART initiation.