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1.  Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis 
AIDS Research and Human Retroviruses  2013;29(7):1026-1030.
Abstract
A high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement ≥9.3 kPa (cases=133) and normal controls (n=133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR=1.19, p=0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR=1.54, p<0.001); however, the opposite was observed in HIV-negative individuals (adjMOR=0.57, p=0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease.
doi:10.1089/aid.2013.0004
PMCID: PMC3685686  PMID: 23548102
2.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
Objectives
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
Methods
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
Results
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
Conclusions
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
doi:10.1136/sextrans-2013-051230
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
3.  Cost analyses of peer health worker and mHealth support interventions for improving AIDS care in Rakai, Uganda 
AIDS care  2012;25(5):652-656.
A cost analysis study calculates resources needed to deliver an intervention and can provide useful information on affordability for service providers and policy makers. We conducted cost analyses of both a peer health worker (PHW) and a mHealth (mobile phone) support intervention. Excluding supervisory staffing costs, total yearly costs for the PHW intervention was $8,475, resulting in a yearly cost per patient of $8.74, per virologic failure averted cost of $189, and per patient lost to follow-up averted cost of $1025. Including supervisory staffing costs increased total yearly costs to $14,991. Yearly costs of the mHealth intervention were an additional $1046, resulting in a yearly cost per patient of $2.35. In a threshold analysis, the PHW intervention was found to be cost saving if it was able to avert 1.50 patients per year from switching to second-line antiretroviral therapy. Other AIDS care programs may find these intervention costs affordable.
doi:10.1080/09540121.2012.722600
PMCID: PMC3773472  PMID: 22971113
cost analysis; mHealth; community health workers; Uganda; antiretroviral treatment
4.  HIV-1 envelope replication and α4β7 utilization among newly infected subjects and their corresponding heterosexual partners 
Retrovirology  2013;10:162.
Background
Previous studies suggest that active selection limits the number of HIV-1 variants acquired by a newly infected individual from the diverse variants circulating in the transmitting partner. We compared HIV-1 envelopes from 9 newly infected subjects and their linked transmitting partner to explore potential mechanisms for selection.
Results
Recipient virus envelopes had significant genotypic differences compared to those present in the transmitting partner. Recombinant viruses incorporating pools of recipient and transmitter envelopes showed no significant difference in their sensitivity to receptor and fusion inhibitors, suggesting they had relatively similar entry capacity in the presence of low CD4 and CCR5 levels. Aggregate results in primary cells from up to 4 different blood or skin donors showed that viruses with envelopes from the transmitting partner as compared to recipient envelopes replicated more efficiently in CD4+ T cells, monocyte derived dendritic cell (MDDC) – CD4+ T cell co-cultures, Langerhans cells (LCs) – CD4+ T cell co-cultures and CD4+ T cells expressing high levels of the gut homing receptor, α4β7, and demonstrated greater binding to α4β7 high / CD8+ T cells. These transmitter versus recipient envelope virus phenotypic differences, however, were not always consistent among the primary cells from all the different blood or skin donation volunteers.
Conclusion
Although genotypically unique variants are present in newly infected individuals compared to the diverse swarm circulating in the chronically infected transmitting partner, replication in potential early target cells and receptor utilization either do not completely dictate this genetic selection, or these potential transmission phenotypes are lost very soon after HIV-1 acquisition.
doi:10.1186/1742-4690-10-162
PMCID: PMC3883469  PMID: 24369910
HIV-1; Envelope; Transmission; Receptor; Replication; Alpha4 beta7; Dendritic cells; Langerhans cells; Selection
5.  High Prevalence of Malaria Parasitemia and Anemia among Hospitalized Children in Rakai, Uganda 
PLoS ONE  2013;8(12):e82455.
Background
There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda.
Methods
Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities.
Results
2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18–4.24) and seizures (aPRR 1.12; CI 1.09–1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91–0.93), HIV infected children (aPRR 0.60 CI 0.52–0.71), and children with diarrhea (aPRR 0.76; CI 0.65–0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%.
Conclusion
There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population.
doi:10.1371/journal.pone.0082455
PMCID: PMC3866122  PMID: 24358185
6.  Antiretroviral Drug Susceptibility Among HIV-Infected Adults Failing Antiretroviral Therapy in Rakai, Uganda 
AIDS Research and Human Retroviruses  2012;28(12):1739-1744.
Abstract
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.
doi:10.1089/aid.2011.0352
PMCID: PMC3505045  PMID: 22443282
7.  Effect of injectable contraceptive use on response to antiretroviral therapy among women in Rakai, Uganda 
Contraception  2012;86(6):725-730.
Background
There is limited evidence on the effect of injectable contraception on response to antiretroviral therapy (ART).
Design
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.
Results
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.
Conclusions
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.
doi:10.1016/j.contraception.2012.05.001
PMCID: PMC3449005  PMID: 22717186
family planning; hormonal contraception; injectable contraception; HIV; antiretroviral therapy; Uganda
9.  Perceived medical benefit, peer/partner influence and safety and cost to access the service: client motivators for voluntary seeking of medical male circumcision in Iganga District Eastern Uganda, a qualitative study 
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.11604/pamj.2013.15.117.2540
PMCID: PMC3830467  PMID: 24255723
Motivators; safe male circumcision
10.  Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis 
Critical care medicine  2011;39(10):2271-2276.
Objective
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.
Design
Prospective observational study.
Setting
One national and two regional referral hospitals in Uganda.
Patients
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).
Interventions
None.
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.
Conclusion
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.
doi:10.1097/CCM.0b013e3182227bd2
PMCID: PMC3730257  PMID: 21666451
Africa; hypoglycemia; mortality; outcomes; severe sepsis; Uganda
11.  Development and validation of systems for rational use of viral load testing in adults receiving first-line antiretroviral treatment in sub-Saharan Africa 
AIDS (London, England)  2011;25(13):1627-1635.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAD.0b013e328349a414
PMCID: PMC3725464  PMID: 21673555
Antiretroviral therapy; HIV; resource-constrained settings; treatment failure; Uganda; viral load
12.  Daily acyclovir to prevent disease progression among HIV-1/HSV-2 co-infected individuals: a randomized, double-blinded placebo controlled trial in Rakai, Uganda 
The Lancet infectious diseases  2012;12(6):441-448.
Background
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
Methods
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.
Findings
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).
Interpretation
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.
doi:10.1016/S1473-3099(12)70037-3
PMCID: PMC3420068  PMID: 22433279
HIV-1; herpes simplex virus; acyclovir; disease progression
13.  Sex inequality, high transport costs, and exposed clinic location: reasons for loss to follow-up of clients under prevention of mother-to-child HIV transmission in eastern Uganda – a qualitative study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.2147/PPA.S19327
PMCID: PMC3669003  PMID: 23737663
mother-to-child transmission; HIV; Uganda; sex inequality
14.  Setting the Stage: Current State of Affairs and Major Challenges 
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.
doi:10.1086/651476
PMCID: PMC2937353  PMID: 20397959
15.  Virologic versus immunologic monitoring and the rate of accumulated genotypic resistance to first-line antiretroviral drugs in Uganda 
BMC Infectious Diseases  2012;12:381.
Background
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).
Methods
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.
Results
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).
Conclusions
Routine VL monitoring reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda.
doi:10.1186/1471-2334-12-381
PMCID: PMC3548731  PMID: 23270482
HIV-1; Antiretroviral therapy; Drug resistance
16.  Evolution of drug resistance after virologic failure of a first highly active antiretroviral therapy regimen in Uganda 
Antiviral therapy  2009;14(2):293-297.
Objective
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.
Methods
Genotyping was performed on sixteen patients with virologic failure who were enrolled in an open label randomized clinical trial of short-cycle treatment interruption.
Results
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.
Conclusions
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.
PMCID: PMC2749943  PMID: 19430104
human immunodeficiency virus (HIV); antiretroviral drug resistance; virologic failure
17.  Incident HIV Infection among Men Attending STD Clinics in Pune, India: Pathways to Disparity and Interventions to Enhance Equity 
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.
PMCID: PMC3516674  PMID: 14717571
Health equity; HIV; Acquired immunodeficiency syndrome; Sexually transmitted infections; Sexually transmitted diseases; Socioeconomic status; Prospective studies; India
18.  Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda 
PLoS ONE  2012;7(11):e41737.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0041737
PMCID: PMC3507824  PMID: 23209545
19.  The Challenge of HIV-1 Antiretroviral Resistance in Africa in the Era of HAART 
AIDS reviews  2009;11(2):59-70.
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.
PMCID: PMC3412282  PMID: 19529746
Antiretroviral therapy; ART; Resistance; Africa; Subtypes; Phenotypic; Genotypic
20.  Performance of Euroline Western Blot Assay in the Detection of Herpes Simplex Virus type 2 Antibody in Uganda, China, and the United States 
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.
doi:10.1258/ijsa.2009.009327
PMCID: PMC3262047  PMID: 21680672
21.  Hepatitis B virus and sexual behavior in Rakai, Uganda 
Journal of Medical Virology  2011;83(5):796-800.
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.
doi:10.1002/jmv.22051
PMCID: PMC3262046  PMID: 21412787
Hepatitis B virus HBV; HIV; Sexual transmission; Uganda; Africa
22.  HIV-1 transmission among HIV-1 discordant couples before and after the introduction of antiretroviral therapy 
AIDS (London, England)  2011;25(4):473-477.
Objective
To evaluate the impact of antiretroviral therapy (ART) on HIV-1 transmission rates among HIV-1 discordant couples in Rakai, Uganda.
Design
Observational cohort study.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/QAD.0b013e3283437c2b
PMCID: PMC3261071  PMID: 21160416
antiretroviral; discordant couples; HIV transmission; HIV-1
23.  A Quality Management Approach to Implementing Point-of-Care Technologies for HIV Diagnosis and Monitoring in Sub-Saharan Africa 
Journal of Tropical Medicine  2012;2012:651927.
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.
doi:10.1155/2012/651927
PMCID: PMC3263631  PMID: 22287974
24.  Indices to Measure Risk of HIV Acquisition in Rakai, Uganda 
PLoS ONE  2014;9(4):e92015.
Introduction
Targeting most-at-risk individuals with HIV preventive interventions is cost-effective. We developed gender-specific indices to measure risk of HIV among sexually active individuals in Rakai, Uganda.
Methods
We used multivariable Cox proportional hazards models to estimate time-to-HIV infection associated with candidate predictors. Reduced models were determined using backward selection procedures with Akaike's information criterion (AIC) as the stopping rule. Model discrimination was determined using Harrell's concordance index (c index). Model calibration was determined graphically. Nomograms were used to present the final prediction models.
Results
We used samples of 7,497 women and 5,783 men. 342 new infections occurred among females (incidence 1.11/100 person years,) and 225 among the males (incidence 1.00/100 person years). The final model for men included age, education, circumcision status, number of sexual partners, genital ulcer disease symptoms, alcohol use before sex, partner in high risk employment, community type, being unaware of a partner's HIV status and community HIV prevalence. The Model's optimism-corrected c index was 69.1 percent (95% CI = 0.66, 0.73). The final women's model included age, marital status, education, number of sex partners, new sex partner, alcohol consumption by self or partner before sex, concurrent sexual partners, being employed in a high-risk occupation, having genital ulcer disease symptoms, community HIV prevalence, and perceiving oneself or partner to be exposed to HIV. The models optimism-corrected c index was 0.67 (95% CI = 0.64, 0.70). Both models were well calibrated.
Conclusion
These indices were discriminative and well calibrated. This provides proof-of-concept that population-based HIV risk indices can be developed. Further research to validate these indices for other populations is needed.
doi:10.1371/journal.pone.0092015
PMCID: PMC3976261  PMID: 24704778
25.  High Prevalence of Liver Fibrosis Associated with HIV Infection: A Cross-Sectional Study in Rural Rakai, Uganda 
Antiviral therapy  2011;16(3):405-411.
Background
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.
Methods
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.
Findings
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).
Interpretation
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.
doi:10.3851/IMP1783
PMCID: PMC3142695  PMID: 21555823
HIV; fibrosis; hepatitis co-infection; liver; Uganda

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