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1.  Risk of Drug Resistance Among Persons Acquiring HIV Within a Randomized Clinical Trial of Single- or Dual-Agent Preexposure Prophylaxis 
The Journal of Infectious Diseases  2015;211(8):1211-1218.
Background. Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use.
Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing.
Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment.
Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
doi:10.1093/infdis/jiu677
PMCID: PMC4402339  PMID: 25587020
HIV; pre-exposure prophylaxis; antiretroviral resistance; HIV prevention
2.  Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity in HIV-infected infants is associated with reduced mortality 
Cell host & microbe  2015;17(4):500-506.
SUMMARY
In addition to direct effects on virus infectivity, antibodies mediate antibody-dependent cellular cytotoxicity (ADCC), the killing of an antibody-coated virus-infected cell by cytotoxic effector cells. Although ADCC has been suggested to protect against HIV, the relationship between HIV-specific ADCC antibodies at the time of HIV exposure and infection outcome in humans remains to be assessed. We evaluated the ADCC activity of passively acquired antibodies in infants born to HIV-infected mothers. ADCC levels were higher in uninfected than infected infants, although not significantly. Increase in ADCC antibody activity in infected infants was associated with reduced mortality risk. Infant ADCC positively correlated with the magnitude of IgG1 binding and IgG1 levels were associated with survival in infected infants. Infant IgG3-binding antibodies were not associated with infected infant survival. These data suggest a therapeutic benefit of pre-existing HIV-specific ADCC antibodies and support a role for eliciting ADCC-mediating IgG1 in HIV vaccines.
doi:10.1016/j.chom.2015.03.002
PMCID: PMC4392343  PMID: 25856755
3.  Patient-Delivered Partner Treatment for Chlamydia, Gonorrhea, and Trichomonas Infection Among Pregnant and Postpartum Women in Kenya 
Sexually transmitted diseases  2015;42(11):637-642.
Background
Patient-delivered partner treatment (PDPT) for sexually transmitted infections (STIs) increases rates of partner treatment and decreases reinfection, but has not been evaluated during pregnancy.
Methods
This prospective cohort was nested within a larger study of peripartum HIV acquisition. Participants with microbiologic diagnosis of Chlamydia trachomatis, Neisseria gonorrhoeae, and/or Trichomonas vaginalis were screened for participation. Questionnaires were administered to determine PDPT acceptability and barriers. Women were reassessed at least 30 days to determine partner treatment and reinfection. Women whose partners did or did not receive PDPT were compared.
Results
One hundred twelve (22.2%) women in the parent cohort had a treatable STI; 78 within the PDPT study period, of whom 66 were eligible and 59 (89.3%) accepted PDPT. Fifty-one women had PDPT outcome data, 37 (73%) of whom reported partners treated with PDPT. Fourteen women (27%) refused or did not deliver partner treatment. Median age was 22 years (interquartile range, 20–26 years) and 88% were married. Compared with women who delivered PDPT, those who did not were more likely to have a partner living far away (23% vs. 0%, P = 0.004) and to report current intimate partner violence (14% vs. 0%, P = 0.02). Reported PDPT barriers included fear of partner’s anger/abuse (5%) and accusations of being STI source (5%).
Conclusion
Patient-delivered partner treatment was acceptable and feasible for pregnant/postpartum Kenyan women and may reduce recurrent STIs in pregnancy.
doi:10.1097/OLQ.0000000000000355
PMCID: PMC4758370  PMID: 26462189
5.  Wheeze as an Adverse Event in Pediatric Vaccine and Drug Randomized Controlled Trials: A Systematic Review 
Vaccine  2015;33(41):5333-5341.
Introduction
Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs).
Objective
To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement.
Methods
We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥ 1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement.
Results
Of 1,205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity.
Conclusion
Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
doi:10.1016/j.vaccine.2015.08.060
PMCID: PMC4743983  PMID: 26319071
wheeze; RCT; systematic review; children
6.  Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial 
PLoS Medicine  2016;13(1):e1001934.
Background
Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.
Methods and Findings
Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.
Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52–241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82–2.27, and IRR = 1.43, 95% CI 0.54–3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.
Conclusions
CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.
Trial registration
ClinicalTrials.gov NCT01425073
In a randomized controlled non-inferiority trial, Christina Polyak and colleagues assess whether CTX prophylaxis remains important among HIV+ adults on ART in a malaria-endemic setting.
Editors' Summary
Background
AIDS has killed 39 million people over the past three decades, and 35 million people (mostly living in resource-limited countries) are currently infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells. Because destruction of the immune system leaves HIV-infected individuals susceptible to “opportunistic” infections, early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. In 1996, effective antiretroviral therapy (ART)—drug regimens that stop HIV replicating and allow the immune system to recover its ability to fight infections—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ART was expensive, HIV/AIDS remained fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal access to ART. Now, at least a third of people living with HIV have access to ART, and the global mortality (death) rate from HIV/AIDS is falling.
Why Was This Study Done?
To prevent opportunistic infections, the World Health Organization (WHO) recommends cotrimoxazole (CTX) prophylaxis for HIV-infected individuals. CTX is a combination of two antimicrobial drugs that is active against a range of bacterial, fungal, and parasitic infections; prophylactic antimicrobials are taken to prevent infection. CTX decreases morbidity (illness) and mortality among HIV-infected individuals primarily by reducing the rates of malaria, pneumonia, diarrhea, and severe bacterial infections. The 2006 WHO guidelines for CTX prophylaxis recommend that, in resource-limited countries, HIV-infected patients whose CD4 count is ≤350 cells/mm3 blood should take CTX and that, in settings with a high prevalence of HIV infection and limited health infrastructure, all HIV-infected adults should take CTX. However, these guidelines were developed before access to ART was scaled-up, and CTX prophylaxis has risks (for example, drug toxicity) as well as benefits. In this unblinded non-inferiority randomized controlled trial, the researchers investigate the effects of CTX discontinuation among ART-treated HIV-infected adults in Kenya. A randomized controlled trial compares the outcomes of individuals randomly assigned to different treatments; in an unblinded trial, everyone involved in the trial knows who is taking which treatment; a non-inferiority trial investigates whether one treatment is not worse than another treatment.
What Did the Researchers Do and Find?
The researchers enrolled 500 HIV-infected adults living in a malaria-endemic region of Kenya (an area where malaria is always present) who had been treated with ART for ≥18 months, who had a CD4 count of >350 cells/mm3, and who were taking CTX. Half the participants continued to take CTX; the remainder stopped taking CTX. After 12 months of follow-up, the combined rate of morbidity (malaria, pneumonia, and diarrhea) and mortality was significantly higher in the CTX discontinuation arm than in the CTX continuation arm (a significant difference is one that is unlikely to have happened by chance). The difference in this primary outcome between the trial arms was driven by malaria morbidity—there were 33 cases of malaria in the CTX discontinuation arm but only one case in the CTX continuation arm. By contrast, the rates of pneumonia and diarrhea did not differ significantly between the trial arms.
What Do These Findings Mean?
Because the difference between the two trial arms in terms of the primary endpoint was greater than the researchers’ predefined non-inferiority limit, these findings suggest that CTX discontinuation is inferior to CTX continuation among ART-treated, immune-reconstituted HIV-infected adults living in a malaria-endemic region. The accuracy of these findings may be affected by the lack of blinding—the clinicians’ care decisions and the patients’ threshold for seeking care may have been influenced by their knowledge of their trial arm assignment. Overall, however, these findings suggest that malaria endemicity should be considered when making decisions about whether to stop CTX after ART-driven immune reconstitution. Indeed, in December 2014, following the release of preliminary data from this trial and the completion of an independent trial on CTX discontinuation, WHO issued supplemental guidelines on CTX prophylaxis. These state that CTX prophylaxis can be discontinued for HIV-infected adults who are clinically stable on ART and have evidence of immune recovery and viral suppression but recommend that CTX prophylaxis be continued regardless of CD4 cell count or HIV/AIDS clinical stage in settings where malaria is endemic and/or severe bacterial infections are common.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001934.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, information on opportunistic infections and on CTX prophylaxis, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV/AIDS in Kenya, on ART, and on opportunistic infections and CTX prophylaxis: Avert also provides personal stories about living with HIV/AIDS
WHO provides information on all aspects of HIV/AIDS, including its 2013 guidelines on using ART to treat HIV infection and its December 2014 supplement to these guidelines, which contains updated recommendations on CTX prophylaxis; a factsheet about CTX prophylaxis is also available
The 2015 World AIDS Day Report provides up-to-date information about the AIDS epidemic, including progress towards universal access to ART
More information about this trial is available
doi:10.1371/journal.pmed.1001934
PMCID: PMC4701407  PMID: 26731191
7.  “If I take my medicine, I will be strong:” Evaluation of a pediatric HIV disclosure intervention in Namibia 
Background
Despite known benefits, only a small proportion of HIV-infected children in sub-Saharan Africa know their status and limited disclosure interventions exist. Namibia's Ministry of Health and Social Services developed and implemented a multi-pronged intervention to support healthcare workers (HCWs) and caregivers in the disclosure process.
Methods
The intervention included a staged disclosure cartoon book, child and caregiver readiness assessment tools, a monitoring form to track progress over visits, and HCW training curriculum. We conducted qualitative interviews with 35 HCWs and 46 caregivers of HIV-positive children at four high volume HIV clinics. Interviews elicited detailed information about intervention uptake and impact. HCWs also participated in a self-efficacy survey.
Results
The intervention improved HCW and caregiver confidence and communication skills in pediatric disclosure. The most valuable intervention component was the disclosure cartoon book, which provided structure, language and guidance for a gradual disclosure process. HCWs reported it greatly reduced caregiver resistance to disclosure. Both caregivers and HCWs reported improved knowledge and ability to support the pediatric patient, improved child understanding of how HIV medications work, increased child hopefulness for their future, and improved child adherence to care and treatment. HCW self-efficacy surveys found that HCWs who received training felt more confident in their ability to engage in the disclosure process
Conclusion
HCWs and caregivers highly endorsed the intervention. Given the urgency to address pediatric HIV disclosure in Africa, and the utility and low cost of the locally-produced disclosure tool, this approach may be useful in other similar settings.
doi:10.1097/QAI.0000000000000387
PMCID: PMC4262649  PMID: 25296096
disclosure; pediatric HIV; HIV education; adherence; program evaluation
8.  Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy 
Background
Infant HIV-1 infection is associated with impaired neurologic and motor development. Antiretroviral therapy (ART) has the potential to improve developmental outcomes but the relative contributions of pre-ART disease status, growth, treatment regimen, and ART response during infancy are unknown.
Methods
Kenyan ART-naive infants <5 months old initiated ART and had monthly assessment of age of full neck control, unsupported walking, and monosyllabic speech during 24 months of follow-up. Pre- and post-ART correlates of age at milestone attainment were evaluated using t-tests or multivariate linear regression.
Results
Among 99 infants, pre-ART correlates of later milestone attainment included: underweight and stunted (neck control, walking and speech, all P-values <0.05), missed prevention of mother-to-child transmission (P=0.04) (neck control), previous hospitalization, WHO Stage III/IV, low CD4 count, and wasting (speech and walking, all P-values <0.05), and low maternal CD4 (speech, P=0.04). Infants initiated ART at a median of 14 days following enrollment. Infants receiving nevirapine- vs lopinavir/ritonavir-based ART attained later speech (18.1 vs. 15.5 months, P=0.003). Adjusting for pre-ART level, lower 6-month gain in CD4% was associated with later walking (0.18 months earlier per unit increase in CD4%; P=0.004) and speech (0.12 months earlier per unit increase in CD4%; P=0.05), and lower 6-month gains in weight-for-age (P=0.009), height-for-age (P=0.03), and weight-for-height (P=0.02) were associated with later walking.
Conclusion
In HIV-infected infants, compromised pre-ART immune and growth status, poor post-ART immune and growth responses, and use of nevirapine- vs. lopinavir/ritonavir-based ART were each associated with later milestone attainment. The long-term consequences of these delays are unknown.
doi:10.1097/INF.0000000000000526
PMCID: PMC4336221  PMID: 25144793
Sub-Saharan Africa; infant; antiretroviral therapy; HIV-1; neurocognitive; neurodevelopment
9.  Genital infections and syndromic diagnosis among HIV-infected women in HIV care programs in Kenya 
Background
Control of genital infections remains challenging in most regions. Despite advocacy by the World Health Organization (WHO) for syndromic case management, there are limited data on the syndromic approach, especially in HIV care settings. This study compared the syndromic approach against laboratory diagnosis among women in HIV care in Kenya.
Methods
A mobile team visited 39 large HIV care programs in Kenya and enrolled participants using population-proportionate sampling. Participants provided behavioral and clinical data with genital and blood specimens for lab testing.
Results
Among 1,063 women, 68.4% had been on antiretroviral therapy >1 year; 58.9% were using cotrimoxazole prophylaxis; 51 % had CD4+T-lymphocytes < 350 cells/mL. Most women (63.1%) reported at least one genital symptom. Clinical signs were found in 63% of women; and 30.8% had an etiological diagnosis. Bacterial vaginosis (17.4%), vaginal candidiasis (10.6%) and trichomoniasis (10.5%) were the most common diagnoses. Using laboratory diagnoses as gold standard, sensitivity and positive predictive value of the syndromic diagnosis for vaginal discharge were 47.6% and 52.7%, respectively, indicating a substantial amount of overtreatment. A systematic physical examination increased by 9.3% the positive predictive value for genital ulcer disease.
Conclusions
Women attending HIV care programs in Kenya have high rates of vaginal infections. Syndromic diagnosis was a poor predictor of those infections.
doi:10.1177/0956462415568982
PMCID: PMC4511718  PMID: 25614522
Genital infections; syndromic management; vaginal discharge; Kenya
10.  Maternal Tenofovir Disoproxil Fumarate Use in Pregnancy and Growth Outcomes among HIV-Exposed Uninfected Infants in Kenya 
Background. Tenofovir disoproxil fumarate (TDF) is commonly used in antiretroviral treatment (ART) and preexposure prophylaxis regimens. We evaluated the relationship of prenatal TDF use and growth outcomes among Kenyan HIV-exposed uninfected (HEU) infants. Materials and Methods. We included PCR-confirmed HEU infants enrolled in a cross-sectional survey of mother-infant pairs conducted between July and December 2013 in Kenya. Maternal ART regimen during pregnancy was determined by self-report and clinic records. Six-week and 9-month z-scores for weight-for-age (WAZ), weight-for-length (WLZ), length-for-age (LAZ), and head circumference-for-age (HCAZ) were compared among HEU infants with and without TDF exposure using t-tests and multivariate linear regression models. Results. Among 277 mothers who received ART during pregnancy, 63% initiated ART before pregnancy, of which 89 (32%) used TDF. No differences in birth weight (3.0 kg versus 3.1 kg, p = 0.21) or gestational age (38 weeks versus 38 weeks, p = 0.16) were detected between TDF-exposed and TDF-unexposed infants. At 6 weeks, unadjusted mean WAZ was lower among TDF-exposed infants (−0.8 versus −0.4, p = 0.03), with a trend towards association in adjusted analyses (p = 0.06). There were no associations between prenatal TDF use and WLZ, LAZ, and HCAZ in 6-week or 9-month infant cohorts. Conclusion. Maternal TDF use did not adversely affect infant growth compared to other regimens.
doi:10.1155/2015/276851
PMCID: PMC4707364  PMID: 26823647
11.  Environmental Transmission of Typhoid Fever in an Urban Slum 
PLoS Neglected Tropical Diseases  2015;9(12):e0004212.
Background
Enteric fever due to Salmonella Typhi (typhoid fever) occurs in urban areas with poor sanitation. While direct fecal-oral transmission is thought to be the predominant mode of transmission, recent evidence suggests that indirect environmental transmission may also contribute to disease spread.
Methods
Data from a population-based infectious disease surveillance system (28,000 individuals followed biweekly) were used to map the spatial pattern of typhoid fever in Kibera, an urban informal settlement in Nairobi Kenya, between 2010–2011. Spatial modeling was used to test whether variations in topography and accumulation of surface water explain the geographic patterns of risk.
Results
Among children less than ten years of age, risk of typhoid fever was geographically heterogeneous across the study area (p = 0.016) and was positively associated with lower elevation, OR = 1.87, 95% CI (1.36–2.57), p <0.001. In contrast, the risk of typhoid fever did not vary geographically or with elevation among individuals less than 6b ten years of age.
Conclusions
Our results provide evidence of indirect, environmental transmission of typhoid fever among children, a group with high exposure to fecal pathogens in the environment. Spatially targeting sanitation interventions may decrease enteric fever transmission.
Author Summary
Typhoid fever, a serious bloodstream infection caused by the bacterium Salmonella Typhi, is commonly associated with direct, person-to-person transmission as a result of improper hygiene and unsafe food/water handling practices. Recent evidence, however, suggests that individuals may be indirectly exposed to typhoid through contact with fecal contamination in their immediate environment. In this study we investigated the role of environmental sources in the transmission of typhoid fever across an urban slum in Kenya by mapping the occurrence of cases in both children and adults. We tested the hypothesis that cases (relative to non-cases) cluster in low elevation areas as a result of the downstream flow and accumulation of fecal waste. We found that cases of typhoid fever among children tended to be concentrated in the downstream area. In adolescents and adults, on the other hand, there was little evidence of a geographic pattern in the risk of typhoid fever. These results provide evidence that environmental transmission of typhoid fever contributes to the risk of disease in children but not adults and adolescents, an observation most likely attributed to the fact that children are more likely to be exposed to fecal contamination through outside play. Interventions to improve local sanitation may therefore provide particular benefit to children who are at most risk of exposure to and acquisition of typhoid fever from environmental sources.
doi:10.1371/journal.pntd.0004212
PMCID: PMC4669139  PMID: 26633656
12.  Shame, Guilt, and Stress: Community Perceptions of Barriers to Engaging in Prevention of Mother to Child Transmission (PMTCT) Programs in Western Kenya 
AIDS Patient Care and STDs  2014;28(12):643-651.
Abstract
While global scale-up of prevention of mother-to-child transmission of HIV (PMTCT) services has been expansive, only half of HIV-infected pregnant women receive antiretroviral regimens for PMTCT in sub-Saharan Africa. To evaluate social factors influencing uptake of PMTCT in rural Kenya, we conducted a community-based, cross-sectional survey of mothers residing in the KEMRI/CDC Health and Demographic Surveillance System (HDSS) area. Factors included referrals and acceptability, HIV-related stigma, observed discrimination, and knowledge of violence. Chi-squared tests and multivariate regression analyses were used to detect stigma domains associated with uptake of PMTCT services. Most HIV-positive women (89%) reported blame or judgment of people with HIV, and 46% reported they would feel shame if they were associated with someone with HIV. In multivariate analyses, shame was significantly associated with decreased likelihood of maternal HIV testing (Prevalence Ratio 0.91, 95% Confidence Interval 0.84–0.99), a complete course of maternal antiretrovirals (ARVs) (PR 0.73, 95% CI 0.55–0.97), and infant HIV testing (PR 0.86, 95% CI 0.75–0.99). Community perceptions of why women may be unwilling to take ARVs included stigma, guilt, lack of knowledge, denial, stress, and despair or futility. Interventions that seek to decrease maternal depression and internalization of stigma may facilitate uptake of PMTCT.
doi:10.1089/apc.2014.0171
PMCID: PMC4250952  PMID: 25361205
13.  Oligonucleotide Ligation Assay Detects HIV Drug Resistance Associated with Virologic Failure among Antiretroviral-Naïve Adults in Kenya 
Background
Transmitted drug resistance (TDR) is increasing in some areas of Africa. Detection of TDR may predict virologic failure of first-line non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). We evaluated the utility of a relatively inexpensive oligonucleotide ligation assay (OLA) to detect clinically relevant TDR at time of ART initiation.
Methods
Pre-ART plasmas from ART-naive Kenyans initiating an NNRTI-based fixed-dose combination ART in a randomized adherence trial conducted in 2006 were retrospectively analyzed by OLA for mutations conferring resistance to NNRTI (K103N, Y181C, and G190A) and lamivudine (M184V). Post-ART plasmas were analyzed for virologic failure (≥1,000 copies/mL) at 6 month intervals over 18-month follow-up. Pre-ART plasmas of those with virologic failure were evaluated for drug resistance by consensus and 454-pyrosequencing.
Results
Among 386 participants, TDR was detected by OLA in 3.89% [95% Confidence Interval (CI), 2.19-6.33], and was associated with a 10-fold higher rate of virologic failure [Hazard Ratio (HR), 10.39; 95% CI, 3.23-32.41; p<0.001) compared to those without TDR. OLA detected 24 TDR mutations (K103N, n=13; Y181C, n=5; G190A, n=3; M184V, n=3) in 15 subjects (NNRTI, n=15; 3TC, n=3). Among 51 participants who developed virologic failure, consensus sequencing did not detect additional TDR mutations conferring high-level resistance, and pyrosequencing only detected additional mutations at frequencies <2%. Mutant frequencies <2% at ART initiation were significantly less likely to be found at the time of virologic failure compared to frequencies ≥2% (22% vs. 63%; p<0.001).
Conclusions
Detection of TDR by a point mutation assay may prevent use of sub-optimal ART.
doi:10.1097/QAI.0000000000000312
PMCID: PMC4197120  PMID: 25140907
transmitted drug resistance; oligonucleotide ligation assay; HIV; Kenya; antiretroviral therapy
14.  Single-Agent Tenofovir versus Combination Emtricitabine/Tenofovir for Pre-Exposure Prophylaxis against HIV-1 Acquisition: A Randomized Trial 
The Lancet. Infectious diseases  2014;14(11):1055-1064.
SUMMARY
Background
Antiretroviral pre-exposure prophylaxis (PrEP), using daily oral tenofovir disoproxil fumarate (TDF) or TDF in combination with emtricitabine (FTC/TDF), has been demonstrated to be efficacious for HIV-1 prevention. While the use of multiple antiretroviral agents is essential for effective HIV-1 treatment, multiple agents may not be required for effective prophylaxis. The relative efficacy of single-agent TDF versus combination FTC/TDF PrEP has not been directly assessed.
Methods
We conducted a randomized, double-blind, placebo-controlled three-arm trial of daily oral TDF and FTC/TDF PrEP among HIV-1 uninfected members of heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial’s placebo arm was discontinued due to demonstration of PrEP efficacy, and the results of each active PrEP agent compared to placebo were reported (TDF 67%, FTC/TDF 75%). Thereafter, the active arms were continued, and participants initially randomized to placebo were offered re-randomization to TDF or FTC/TDF PrEP.
Findings
4410 couples received TDF or FTC/TDF PrEP and were followed for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 were among those assigned TDF (incidence 0.71 per 100 person-years) and 21 were among those assigned FTC/TDF (incidence 0.48 per 100 person-years); for comparison, HIV-1 incidence in the placebo arm prior to its discontinuation was 2.00 per 100 person-years. HIV-1 prevention efficacy for FTC/TDF compared to TDF alone was not statistically significantly different: HR 0.67, 95% 0.39–1.17, p=0.16. Detection of tenofovir in plasma samples, compared to no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the TDF arm and 93% for the FTC/TDF arm (both p<0.0001).
Interpretation
These results do not rule out the potential for a modest difference in HIV-1 protection for TDF compared to FTC/TDF, but they demonstrate that once-daily oral TDF or FTC/TDF both provide high protection against HIV-1 acquisition among heterosexual men and women.
doi:10.1016/S1473-3099(14)70937-5
PMCID: PMC4252589  PMID: 25300863
pre-exposure prophylaxis; HIV-1 prevention; randomized clinical trial; Africa
15.  Rapid Antiretroviral Therapy Initiation for Women in an HIV-1 Prevention Clinical Trial Experiencing Primary HIV-1 Infection during Pregnancy or Breastfeeding 
PLoS ONE  2015;10(10):e0140773.
During an HIV-1 prevention clinical trial in East Africa, we observed 16 cases of primary HIV-1 infection in women coincident with pregnancy or breastfeeding. Nine of eleven pregnant women initiated rapid combination antiretroviral therapy (ART), despite having CD4 counts exceeding national criteria for ART initiation; breastfeeding women initiated ART or replacement feeding. Rapid ART initiation during primary HIV-1 infection during pregnancy and breastfeeding is feasible in this setting.
doi:10.1371/journal.pone.0140773
PMCID: PMC4607156  PMID: 26469986
16.  FCGR2A and FCGR3A Genotypes in Human Immunodeficiency Virus Mother-to-Child Transmission 
Open Forum Infectious Diseases  2015;2(4):ofv149.
Host FcγR polymorphisms may influence HIV infection and disease progression. Here, we examine FCGR2A and FCGR3A genotypes in HIV mother-to-child transmission. Infant genotypes did not impact infection or progression, but the maternal FCGR3A genotype may influence early breastfeeding transmission risk.
Background. Fc-mediated effector functions have been suggested to influence human immunodeficiency virus (HIV) acquisition and disease progression. Analyzing the role of host Fc gamma receptor (FcγR) polymorphisms on HIV outcome in mother-to-child transmission (MTCT) will increase our understanding of how host genetics may alter immune responses in prevention, therapy, and disease. This study analyzed the impact of FCGR2A and FCGR3A genotypes on MTCT in a cohort in which Fc-mediated antibody functions are predictive of infant HIV outcome.
Methods. Human immunodeficiency virus-positive mothers and their infants from a historical MTCT cohort were genotyped for FCGR2A and FCGR3A. We assessed the impact of these genotypes on transmission and acquisition of HIV and disease progression using χ2 tests, survival analyses, and logistic regression.
Results. Among 379 mother-infant pairs, infant FCGR2A and FCGR3A genotypes were not associated with infant HIV infection or disease progression. Maternal FCGR2A was not associated with transmission, but there was a trend between maternal FCGR3A genotype and transmission (P = .07). When dichotomizing mothers into FCGR3A homozygotes and heterozygotes, heterozygotes had a 64.5% higher risk of transmission compared with homozygotes (P = .02). This risk was most evident in the early breastfeeding window, but a trend was only observed when restricting analyses to breastfeeding mothers (hazards ratio, 1.64; P = .064).
Conclusions. Infant FCGR2A and FCGR3A genotypes were not associated with HIV infection or disease progression, and, thus, host FcγR genotype may not significantly impact vaccination or therapeutic regimens that depend on Fc-mediated antibody functions. Maternal FCGR3A genotype may influence early breastfeeding transmission risk, but more studies should be conducted to clarify this association and its mechanism.
doi:10.1093/ofid/ofv149
PMCID: PMC4653957  PMID: 26613093
Fc gamma receptors (FcγR); FCGR2A; FCGR3A; HIV; mother-to-child transmission (MTCT)
17.  Using Health Provider Insights to Inform Pediatric HIV Disclosure: A Qualitative Study and Practice Framework from Kenya 
AIDS Patient Care and STDs  2014;28(10):555-564.
Abstract
Optimal pediatric HIV disclosure impacts illness and developmental experiences while improving access to timely treatment. However, disclosure rates in high HIV prevalence countries remain low and there are limited data on best practices. We conducted a qualitative study of disclosure practices and interviewed healthcare providers from five pediatric HIV clinics in Kenya. We identified themes central to disclosure practices, rationale for approaches, barriers to implementing disclosure, and creative strategies to overcome challenges. We used these insights to develop a practice-based framework for disclosure that is sensitive to practical challenges. Overall, providers had limited training but extensive experience in disclosure, endorsed individualized disclosure practices, invested substantial time on disclosure despite clinical burden, and noted adverse outcomes associated with unplanned or abrupt disclosure. Providers advocated for an approach to disclosure that is child-centered but respects caregiver fears and values. Caregiver support was provided to enable caregivers to be the person who ultimately disclosed HIV status to children. Unplanned or abrupt disclosure to children was reported to have severe and persistent adverse impact and was a stimulus to accelerate disclosure in scenarios when providers believed children may be suspecting their diagnosis. Based on these expert insights, the framework we developed incorporates concurrent evaluation of child and caregiver readiness, identifies cues to prompt disclosure discussions, includes caregiver education and support, and utilizes a gradual approach of unveiling HIV diagnosis to the child.
doi:10.1089/apc.2014.0040
PMCID: PMC4183914  PMID: 25216105
18.  Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility 
Science translational medicine  2015;7(297):297ra115.
Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy.
doi:10.1126/scitranslmed.aac5722
PMCID: PMC4547537  PMID: 26203083
19.  Estimating PMTCT's Impact on Heterosexual HIV Transmission: A Mathematical Modeling Analysis 
PLoS ONE  2015;10(8):e0134271.
Introduction
Prevention of mother-to-child HIV transmission (PMTCT) strategies include combined short-course antiretrovirals during pregnancy (Option A), triple-drug antiretroviral treament (ART) during pregnancy and breastfeeding (Option B), or lifelong ART (Option B+). The WHO also recommends ART for HIV treatment and prevention of sexual transmission of HIV. The impact of PMTCT strategies on prevention of sexual HIV transmission of HIV is not known. We estimated the population-level impact of PMTCT interventions on heterosexual HIV transmission in southwestern Uganda and KwaZulu-Natal, South Africa, two regions with different HIV prevalence and fertility rates.
Materials and Methods
We constructed and validated dynamic, stochastic, network-based HIV transmission models for each region. PMTCT Options A, B, and B+ were simulated over ten years under three scenarios: 1) current ART and PMTCT coverage, 2) current ART and high PMTCT coverage, and 3) high ART and PMTCT coverage. We compared adult HIV incidence after ten years of each intervention to Option A (and current ART) at current coverage.
Results
At current coverage, Options B and B+ reduced heterosexual HIV incidence by about 5% and 15%, respectively, in both countries. With current ART and high PMTCT coverage, Option B+ reduced HIV incidence by 35% in Uganda and 19% in South Africa, while Option B had smaller, but meaningful, reductions. The greatest reductions in HIV incidence were achieved with high ART and PMTCT coverage. In this scenario, all PMTCT strategies yielded similar results.
Discussion
Implementation of Options B/B+ reduces adult HIV incidence, with greater effect (relative to Option A at current levels) in Uganda than South Africa. These results are likely driven by Uganda’s higher fertility rates.
doi:10.1371/journal.pone.0134271
PMCID: PMC4532442  PMID: 26262889
20.  Water Filter Provision and Home-Based Filter Reinforcement Reduce Diarrhea in Kenyan HIV-Infected Adults and Their Household Members 
Among human immunodeficiency virus (HIV) -infected adults and children in Africa, diarrheal disease remains a major cause of morbidity and mortality. We evaluated the effectiveness of provision and home-based reinforcement of a point-of-use water filtration device to reduce diarrhea among 361 HIV-infected adults in western Kenya by comparing prevalence of self-reported diarrhea before and after these interventions. After provision of the filter, 8.7% of participants reported diarrhea compared with 17.2% in the 3 months before filter provision (odds ratio [OR] = 0.39, 95% confidence interval [95% CI] = 0.23–0.66, P < 0.001). The association was similar among 231 participants who were already taking daily cotrimoxazole prophylaxis before being given a filter (OR = 0.47, 95% CI = 0.25–0.88, P = 0.019). Educational reinforcement was also associated with a modest reduction in self-reported diarrhea (OR = 0.50, 95% CI = 0.20–0.99, P = 0.047). Provision and reinforcement of water filters may confer significant benefit in reducing diarrhea among HIV-infected persons, even when cotrimoxazole prophylaxis is already being used.
doi:10.4269/ajtmh.13-0552
PMCID: PMC4125248  PMID: 24842881
21.  Expanding Clinical Medical Training Opportunities at the University of Nairobi: Adapting a Regional Medical Education Model from the WWAMI Program at the University of Washington 
A major medical education need in Sub-Saharan Africa includes expanding clinical training opportunities to develop health professionals. Medical education expansion is a complicated process that requires significant investment of financial and human resources, but it can also provide opportunities for innovative approaches and partnerships. In 2010, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) launched the Medical Education Partnership Initiative to invest in medical education and health system strengthening in Africa. Building on a 30-year collaborative clinical and research training partnership, the University of Nairobi in Kenya developed a pilot regional medical education program modeled on the WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) medical education program at the University of Washington in the United States. The University of Nairobi adapted key elements of the WWAMI model to expand clinical training opportunities without requiring major capital construction of new buildings or campuses. The pilot program provides short-term clinical training opportunities for undergraduate students and recruits and trains clinical faculty at 14 decentralized training sites. The adaptation of a model from the Northwestern United States to address medical education needs in Kenya is a successful transfer of knowledge and practices that can be scaled up and replicated across Sub-Saharan Africa.
doi:10.1097/ACM.0000000000000350
PMCID: PMC4183931  PMID: 25072575
22.  Home-based HIV testing for men preferred over clinic-based testing by pregnant women and their male partners, a nested cross-sectional study 
BMC Infectious Diseases  2015;15:298.
Background
Male partner HIV testing and counseling (HTC) is associated with enhanced uptake of prevention of mother-to-child HIV transmission (PMTCT), yet male HTC during pregnancy remains low. Identifying settings preferred by pregnant women and their male partners may improve male involvement in PMTCT.
Methods
Participants in a randomized clinical trial (NCT01620073) to improve male partner HTC were interviewed to determine whether the preferred male partner HTC setting was the home, antenatal care (ANC) clinic or VCT center. In this nested cross sectional study, responses were evaluated at baseline and after 6 weeks. Differences between the two time points were compared using McNemar’s test and correlates of preference were determined using logistic regression.
Results
Among 300 pregnant female participants, 54 % preferred home over ANC clinic testing (34.0 %) or VCT center (12.0 %). Among 188 male partners, 68 % preferred home-based HTC to antenatal clinic (19 %) or VCT (13 %). Men who desired more children and women who had less than secondary education or daily income < $2 USD were more likely to prefer home-based over other settings (p < 0.05 for all comparisons). At 6 weeks, the majority of male (81 %) and female (65 %) participants recommended home over alternative HTC venues. Adjusting for whether or not the partner was tested during follow-up did not significantly alter preferences.
Conclusions
Pregnant women and their male partners preferred home-based compared to clinic or VCT-center based male partner HTC. Home-based HTC during pregnancy appears acceptable and may improve male testing and involvement in PMTCT.
doi:10.1186/s12879-015-1053-2
PMCID: PMC4520092  PMID: 26223540
Male; Partner; Couple; HIV testing; Pregnancy; Antenatal settings; Home-based
23.  Pregnancy Incidence and Outcomes among Women Receiving Pre-Exposure Prophylaxis for HIV Prevention: A Randomized Clinical Trial 
JAMA  2014;312(4):362-371.
Importance
Antiretroviral pre-exposure prophylaxis (PrEP), using tenofovir disoproxil fumarate and combination tenofovir disoproxil fumarate / emtricitabine, is efficacious for prevention of HIV acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined.
Objective
To assess pregnancy incidence and outcomes among women using PrEP during the periconception period.
Design
Randomized trial among 1785 HIV serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda.
Intervention
Daily oral tenofovir disoproxil fumarate (TDF) (n=598), combination tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) (n=566), or placebo (n=621) through July 2011, when PrEP demonstrated efficacy for HIV prevention; thereafter, participants continued receiving active PrEP, without placebo. Pregnancy testing occurred monthly and study medication was discontinued upon pregnancy detection.
Main Outcomes
Pregnancy incidence, birth outcomes (pregnancy loss, preterm birth, congenital anomalies), infant growth.
Results
A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference 1.9, 95% confidence interval [CI] −1.1–4.9, p=0.22 versus placebo), and 8.8 among those assigned TDF-FTC (incidence difference −1.3, 95% CI −4.1–1.5, p=0.39 versus placebo). Prior to discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies), was 42.5% for women receiving TDF-FTC compared with 32.3% for those receiving placebo (difference for TDF-FTC versus placebo 10.2%, 95% CI −5.3–25.7, p=0.16) and was 27.7% for those receiving TDF alone (difference versus placebo −4.6%, 95% CI −18.1–8.9, p=0.46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for TDF-FTC and 36.7% for TDF alone (difference 0.8%, 95% CI −16.8–18.5, p=0.92). Preterm birth and congenital anomalies did not differ significantly for those who received PrEP versus placebo. Infants born to women randomized to PrEP had growth throughout the first year of life not statistically different than placebo and with point estimates that did not suggest growth restriction.
Conclusions and Relevance
Among HIV serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination TDF-FTC compared to placebo at the time of conception. Given that PrEP was discontinued when pregnancy was detected and that confidence intervals for the birth outcomes were wide, definitive statements about safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV uninfected women receiving PrEP who are considering becoming pregnant. (ClinicalTrials.gov number, NCT00557245)
doi:10.1001/jama.2014.8735
PMCID: PMC4362516  PMID: 25038355
pre-exposure prophylaxis; HIV; pregnancy
24.  A Lifecycle Approach to HIV Prevention in African Women and Children 
Current HIV/AIDS reports  2014;11(2):119-127.
Effective biomedical and structural HIV prevention approaches are being implemented throughout sub-Saharan Africa. A “lifecycle approach” to HIV prevention recognizes the interconnectedness of the health of women, children and adolescents, and prioritizes interventions that have benefits across these populations. We review new biomedical prevention strategies for women, adolescents and children, structural prevention approaches, and new modalities for eliminating infant HIV infection, and discuss the implications of a lifecycle approach for the success of these methods. Some examples of the lifecycle approach include evaluating education and HIV prevention strategies among adolescent girls not only for their role in reducing risk of HIV infection and early pregnancy, but also to promote healthy adolescents who will have healthier future children. Similarly, early childhood interventions such as exclusive breastfeeding not only prevent HIV, but also contribute to better child and adolescent health outcomes.. The most ambitious biomedical infant HIV prevention effort, Option B+, also represents a lifecycle approach by leveraging the prevention benefits of optimal HIV treatment for mothers; maternal survival benefits from Option B+ may have ultimately more health impact on children than the prevention of infant HIV in isolation. The potential for synergistic and additive benefits of lifecycle interventions should be considered when scaling up HIV prevention efforts in sub-Saharan Africa.
doi:10.1007/s11904-014-0203-2
PMCID: PMC4077944  PMID: 24659344
HIV prevention; maternal health; child health; adolescent health; millennium development goals; PMTCT; mother-to-child transmission of HIV; global epidemic; HIV
25.  Toll-like Receptor Polymorphism Associations With HIV-1 Outcomes Among Sub-Saharan Africans 
The Journal of Infectious Diseases  2013;209(10):1623-1627.
Objective. We evaluated Toll-like receptors (TLRs) single nucleotide polymorphisms (SNPs) for associations with HIV-1 acquisition, set-point and disease progression in African couples.
Methods. Seven candidate and 116 haplotype-tagging SNPs (tagSNPs) were genotyped in 504 HIV-1 infected cases, and 343 seronegative controls.
Results. TLR9 1635A/G was associated with reduced HIV-1 acquisition among HIV-seronegative controls with high but not low HIV-1 exposure (odds ratio [OR] = 0.7; P = .03 and OR = 0.9, P = .5, respectively). TLR7 rs179012 and TLR2 597C/T reduced set-point; the latter modified by time since HIV-1 acquisition. TLR8 1A/G reduced disease progression.
Conclusions. TLR SNPs impact HIV-1 outcomes with epidemiologic factors modifying these relationships.
doi:10.1093/infdis/jit807
PMCID: PMC3997584  PMID: 24325963
Acute Infection; Genetics; Heterosexual HIV-1 transmission; Progression; Risk Factors; Viral load; Toll-like Receptors; HIV-1 set-point; HIV-1 acquisition

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