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1.  Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-Experienced HIV-Infected Children 
Background
Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long term viral suppression have not been adequately defined in children.
Aim
We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy.
Methods
After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to remain on a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post-randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL)
Results
At randomization, the median (IQR) age, CD4+ T-Lymphocyte percentage, weight-for-age and weight-for-height z-scores were 19 (16–24) months, 29 (23–37) %, −0.6(−1.3 to 0.2) and −3.2 (−4.1 to −2.1) respectively. The proportion of children with viral load 51–400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1mg/L vs ≥1mg/L (adjusted hazard ratio 0.62 [95% CI, 0.40–0.94]) and for children with viral loads 51–400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia.
Conclusion
Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1mg/L of lopinavir to ensure sustained viral suppression.
doi:10.1097/INF.0000000000001319
PMCID: PMC5166428  PMID: 27583591
Therapeutic Drug monitoring; Pharmacokinetics; Viremia
2.  Routine Offering of HIV Testing to Hospitalized Pediatric Patients at University Teaching Hospital, Lusaka, Zambia: Acceptability and Feasibility 
Objectives
The difficulties diagnosing infants and children with HIV infection have been cited as barriers to increasing the number of children receiving antiretroviral therapy worldwide.
Design
We implemented routine HIV antibody counseling and testing for pediatric patients hospitalized at the University Teaching Hospital, a national reference center, in Lusaka, Zambia. We also introduced HIV DNA polymerase chain reaction (PCR) testing for early infant diagnosis.
Methods
Caregivers/parents of children admitted to the hospital wards were routinely offered HIV counseling and testing for their children. HIV antibody positive (HIV+) children <18 months of age were tested with PCR for HIV DNA.
Results
From January 1, 2006, to June 30, 2007, among 15,670 children with unknown HIV status, 13,239 (84.5%) received counseling and 11,571 (87.4%) of those counseled were tested. Overall, 3373 (29.2%) of those tested were seropositive. Seropositivity was associated with younger age: 69.6% of those testing HIV antibody positive were <18 months of age. The proportion of counseled children who were tested increased each quarter from 76.0% in January to March 2006 to 88.2% in April to June 2007 (P < 0.001). From April 2006 to June 2007, 1276 PCR tests were done; 806 (63.2%) were positive. The rate of PCR positivity increased with age from 22% in children <6 weeks of age to 61% at 3–6 months and to 85% at 12–18 months (P < 0.001).
Conclusions
Routine counseling and antibody testing of pediatric inpatients can identify large numbers of HIV-seropositive children in high prevalence settings. The high rate of HIV infection in hospitalized infants and young children also underscores the urgent need for early infant diagnostic capacity in high prevalence settings.
PMCID: PMC5117627  PMID: 19504732
Africa; early infant diagnosis; HIV testing; pediatric HIV; provider initiated testing and counseling
3.  Optimizing Antiretroviral Therapy (ART) for Maternal and Child Health (MCH): Rationale and Design of the MCH-ART Study 
Background:
Prevention of mother-to-child transmission of HIV implementation faces significant challenges globally, particularly in the context of universal lifelong antiretroviral therapy (ART) for all HIV-infected pregnant women.
Methods:
We describe the rationale and methods of the Maternal and Child Health-Antiretroviral Therapy (MCH-ART) study, an implementation science project examining strategies for providing HIV care and treatment to HIV-infected women who initiate ART during pregnancy and their HIV-exposed infants.
Results:
MCH-ART is composed of 3 interrelated study designs across the antenatal and postnatal periods. Phase 1 is a cross-sectional evaluation of consecutive HIV-infected pregnant women seeking antenatal care; phase 2 is an observational cohort of all women from phase 1 who are eligible for initiation of ART following local guidelines; and phase 3 is a randomized trial of strategies for delivering ART to breastfeeding women from phase 2 during the postpartum period. During each phase, a set of study measurement visits is carried out separately from antenatal care and ART services; a maximum of 9 visits takes place from the beginning of antenatal care through 12 months postpartum. In parallel, in-depth interviews are used to examine issues of ART adherence and retention qualitatively, and costs and cost-effectiveness of models of care are examined. Separate substudies examine health outcomes in HIV-uninfected women and their HIV-unexposed infants, and the role of the adherence club model for long-term adherence and retention.
Discussion:
Combining observational and experimental components, the MCH-ART study presents a novel approach to understand and optimize ART delivery for MCH.
doi:10.1097/QAI.0000000000001056
PMCID: PMC5113242  PMID: 27355508
HIV; antiretroviral therapy; PMTCT; integration; adherence; retention
4.  Mother Infant Retention for Health (MIR4Health): Study Design, Adaptations, and Challenges With PMTCT Implementation Science Research 
Background:
Effective retention of HIV-infected mothers and their infants is fraught with multiple challenges, resulting in loss across the continuum of prevention of mother-to-child HIV transmission (PMTCT) care and missed opportunities to offer life-saving HIV prevention and treatment.
Methods:
The Mother Infant Retention for Health study is an individual-randomized study evaluating the effectiveness of active patient follow-up compared with standard of care on the combined outcome of attrition of HIV-infected women and their infants at 6 months postpartum. Lay counselors administered the active patient follow-up package of interventions, including individualized health education, use of flip charts during clinic visits, and at home, phone and short message service appointment reminders, active phone and physical tracking of patients immediately after missed clinic visits, and individualized retention and adherence support.
Results:
Use of study visits to indicate participant progression along the PMTCT cascade highlights the nature of loss among women and infants in PMTCT care because of issues such as pregnancy complications, infant deaths, and transfer out. Delay in implementation of Option B+, unanticipated slow enrollment, a health-care worker strike, rapid HIV test kit shortages, and changes in national PMTCT guidelines necessitated several modifications to the protocol design and implementation to ensure successful completion of the study.
Conclusions:
Flexibility when operationalizing an implementation science study is critical in the context of the shifting landscape in a noncontrolled “real-world” setting.
Trial Registration:
Clinicaltrials.gov NCT01962220.
doi:10.1097/QAI.0000000000001060
PMCID: PMC5113246  PMID: 27355501
PMTCT; HIV; attrition; pregnant women; implementation research
5.  Decentralization of HIV Care and Treatment Services in Central Province, Kenya 
Background
Since 2006, the government of Kenya began decentralizing HIV care from secondary health facilities (SHF) to an expanded network, including primary health facilities (PHF). We evaluated the impact of this strategy on enrollment, care, and outcomes among adult patients in Central Province, Kenya, from 2006 to 2010.
Methods
We analyzed electronic patient-level data for 26,690 patients at 15 SHF and 22 PHF. Enrollment, patient, and facility characteristics and patterns in CD4+ testing, World Health Organization staging, and antiretroviral treatment (ART) initiation were compared between SHF and PHF. Survival analysis was used to estimate cumulative death and loss to follow-up (LTF) rates in PHF and SHF. Multivariate competing risks regression and Cox proportional hazards models were constructed to identify correlates of LTF and death.
Results
Enrollment in PHF increased mainly between 2007 and 2009, representing 5% and 25% of all new enrollments, respectively. CD4+ test provision and World Health Organization staging, time to ART initiation, and CD4+ count at ART initiation were for the most part similar between PHF and SHF. In multivariate analyses, pre-ART patients enrolled in PHF had a lower risk of LTF than those enrolled in SHF (SHR = 0.77, 95% confidence interval: 0.61 to 0.96). No differences in risk of death among pre-ART patients or in LTF or death among ART patients were observed.
Conclusions
Enrollment at PHF increased substantially during the period; death rates were comparable between PHF and SHF, whereas LTF among pre-ART patients was lower at PHF. This suggests that decentralization can be a successful strategy for expanding HIV care.
doi:10.1097/QAI.0000000000000264
PMCID: PMC5108298  PMID: 24977728
Kenya; decentralization; antiretroviral therapy; pre-ART; retention; operations research
6.  Characteristics and outcomes of HIV-infected youth and young adolescents enrolled in HIV care in Kenya 
AIDS (London, England)  2014;28(18):2729-2738.
Background
The number of youth and adolescents (10–24 years) with HIV infection has increased substantially presenting unique challenges to effective health service delivery.
Methods
We examined routinely collected patient-level data for antiretroviral treatment (ART)-naive HIV-infected patients, aged 10–24 years, enrolled in care during 2006–2011 at 109 ICAP-supported health facilities in three provinces in Kenya. Loss to follow-up (LTF) was defined as having no clinic visit for 12 months prior to ART initiation (pre-ART) and 6 months for ART patients. Competing risk and Kaplan–Meier estimators were used to calculate LTF and death rates. Sub-distributional and Cox proportional-hazards models were used to identify potential predictors of death and LTF.
Results
Overall 22 832 patients were enrolled in care at 10–24 years of age, 69.5% were aged 20–24 years, and 82% were female. Median CD4+ cell count was 332 cells/μl (interquartile range 153–561); 70.8% were WHO stage I/II. Young adolescents (10–14 years) had more advanced WHO stage and lower median CD4+ cell count compared to youth (15–24 years) at enrollment (284 vs. 340 cells/μl; P <0.0001). Cumulative incidence of LTF and death at 24 months for pre-ART patients was 46.1% [95% confidence interval (CI) 45.4–46.8%) and 2.1% (95% CI 1.9–2.3%), respectively. For those on ART, 32.2% (95% CI 31.1–33.3%) were LTF and 3.9% (95% CI 1.7–2.3%) died within 24 months. LTF among pre-ART and ART patients was twice as high among youth compared to young adolescents.
Conclusion
LTF of young people with HIV in this Kenyan cohort was high and notably greater among youth compared to young adolescents. Novel strategies targeting these populations are urgently needed to improve retention.
doi:10.1097/QAD.0000000000000473
PMCID: PMC5098333  PMID: 25493599
adolescents; antiretroviral therapy; Kenya; retention
7.  Retention of HIV-infected children on antiretroviral treatment in HIV care and treatment programs in Kenya, Mozambique, Rwanda and Tanzania 
Background
Retention of children in HIV care is essential for prevention of disease progression and mortality.
Methods
Retrospective cohort of children (0 to <15 years) initiating antiretroviral treatment (ART) at health facilities in Kenya, Mozambique, Rwanda and Tanzania, January 2005–June 2011. Retention was defined as the proportion of children known to be alive and attending care at their initiation facility; lost to follow-up (LTF) was defined as no clinic visit for > 6 months. Cumulative incidence of ascertained survival and retention after ART initiation was estimated through 24 months using Kaplan-Meier methods. Factors associated with LTF and death were assessed using Cox proportional hazard modeling.
Results
17,712 children initiated ART at 192 facilities: median age was 4.6 years (IQR: 1.9–8.3), median CD4 was 15% (IQR: 10–20) for children < 5 years and 265 cells/uL (IQR: 111–461) for children ≥ 5 years. At 12 and 24 months, 80% and 72% of children were retained with 16% and 22% LTF and 5% and 7% known deaths respectively. Retention ranged from 71–95% and 62–93% at 12 and 24 months across countries, and was lowest for children < 1 year (51% at 24 months). LTF and death were highest in children < 1 year of age and children with advanced disease.
Conclusion
Retention was lowest in young children and differed across country programs. Young children and those with advanced disease are at highest risk for LTF and death. Further evaluation of patient- and program-level factors is needed to improve health outcomes.
doi:10.1097/QAI.0b013e318278bcb0
PMCID: PMC5094048  PMID: 23111575
HIV; retention; pediatric; antiretrovirals
8.  Use of a Comprehensive HIV Care Cascade for Evaluating HIV Program Performance: Findings From 4 Sub-Saharan African Countries 
Background
The traditional HIV treatment cascade has been noted to have limitations. A proposed comprehensive HIV care cascade that uses cohort methodology offers additional information as it accounts for all patients. Using data from 4 countries, we compare patient outcomes using both approaches.
Methods
Data from 390,603 HIV-infected adults (>15 years) enrolled at 217 facilities in Kenya, Mozambique, Rwanda, and Tanzania from 2005 to 2011 were included. Outcomes of all patients at 3, 6, and 12 months after enrollment were categorized as optimal, suboptimal, or poor. Optimal outcomes included retention in care, antiretroviral therapy (ART) initiation, and documented transfer. Suboptimal outcomes included retention in care without ART initiation among eligible patients or those without eligibility data. Poor outcomes included loss to follow-up and death.
Results
The comprehensive HIV care cascade demonstrated that at 3, 6 and 12 months, 58%, 51%, and 49% of patients had optimal outcomes; 22%, 12%, and 7% had suboptimal outcomes, and 20%, 37% and 44% had poor outcomes. Of all patients enrolled in care, 56% were retained in care at 12 months after enrollment. In comparison, the traditional HIV treatment cascade found 89% of patients enrolled in HIV care were assessed for ART eligibility, of whom 48% were determined to be ART-eligible with 70% initiating ART, and 78% of those initiated on ART retained at 12 months.
Conclusions
The comprehensive HIV care cascade follows outcomes of all patients, including pre-ART patients, who enroll in HIV care over time and uses quality of care parameters for categorizing outcomes. The comprehensive HIV care cascade provides complementary information to that of the traditional HIV treatment cascade and is a valuable tool for monitoring HIV program performance.
doi:10.1097/QAI.0000000000000745
PMCID: PMC5094356  PMID: 26375466
HIV; retention; antiretroviral; HIV care cascade
9.  Mother and Child Both Matter: Re-conceptualizing the PMTCT Care Continuum 
Current opinion in HIV and AIDS  2015;10(6):403-410.
Purpose of review
To propose a prevention of mother-to-child transmission (PMTCT) care continuum that defines the programmatic steps necessary to provide HIV care to the HIV-infected pregnant woman and her infant during the risk period for HIV transmission.
Recent findings
There are several complexities of PMTCT care that should be considered in the care continuum including the evolution in the population of women entering PMTCT care, various models of PMTCT service delivery and patterns of PMTCT care, and the critical step of transfer of women’s HIV care from PMTCT programs to adult HIV clinics.
Summary
We propose a re-conceptualized PMTCT care continuum that accounts for the complexities of PMTCT care. We also propose a combined outcome for pregnant women and their infants across an interlinked PMTCT continuum to measure both maternal and child health outcomes.
doi:10.1097/COH.0000000000000199
PMCID: PMC4707659  PMID: 26352391
HIV; PMTCT (prevention of mother-to-child transmission); vertical transmission
10.  Time to Initiation of Antiretroviral Therapy Among Patients Who Are ART Eligible in Rwanda: Improvement Over Time 
Background
Delayed initiation of antiretroviral therapy (ART) in eligible patients is a concern in resource-limited countries.
Methods
We analyzed data on HIV-positive patients ≥15 years enrolled at 41 ICAP-supported health care facilities in Rwanda, 2005–2010, to determine time to ART initiation among patients eligible at enrollment compared with those ineligible or of indeterminate eligibility who become eligible during follow-up. ART eligibility was based on CD4+ cell count (CD4+) and WHO staging; patients lacking CD4+ and WHO stage were considered indeterminate. Cumulative incidence of reaching ART eligibility and to ART initiation after eligibility was generated using competing risk estimators.
Results
A total of 31,033 ART-naive adults were enrolled; 64.2% were female. At enrollment, 10,158 (32.7%) patients were ART eligible, 13,372 (43.1%) were ineligible for ART, and 7503 (24.2%) patients were indeterminate. Among patients retained in care pre-ART eligibility, 17.9% [95% confidence interval (CI): 17.2 to 18.6] of ineligible and 22.8% (95% CI: 21.7 to 23.8) of indeterminate patients at enrollment reached ART eligibility within 12 months. Cumulative incidence of ART initiation within 3 months for patients eligible at enrollment was 77.2% (95% CI: 76.4 to 78.0) compared with 67.9% (95% CI: 66.4 to 69.3) for ineligible and 63.8% (95% CI: 61.9 to 65.8) for patients with indeterminate eligibility at enrollment (P < 0.05). Over the study period, there was more rapid ART initiation for patients who became ART eligible.
Conclusions
We found higher rates of ART initiation within 3 months among patients who were ART eligible at enrollment compared with those who reached eligibility during follow-up. From 2006 to 2011, earlier initiation of ART after eligibility was observed likely reflecting improved program quality.
doi:10.1097/QAI.0000000000000432
PMCID: PMC5074335  PMID: 25415291
antiretroviral therapy; Rwanda; eligibility for treatment; CD4 cell count
11.  Self-Reported Side Effects and Adherence to Antiretroviral Therapy in HIV-Infected Pregnant Women under Option B+: A Prospective Study 
PLoS ONE  2016;11(10):e0163079.
Background
Antiretroviral therapy (ART) regimens containing efavirenz (EFV) are recommended as part of universal ART for pregnant and breastfeeding women. EFV may have appreciable side effects (SE), and ART adherence in pregnancy is a major concern, but little is known about ART SE and associations with adherence in pregnancy.
Methods
We investigated the distribution of patient-reported SE (based on Division of AIDS categories) and the association of SE with missed ART doses in a cohort of 517 women starting EFV+3TC/FTC+TDF during pregnancy. In analysis, SE were considered in terms of their overall frequency, by systems category, and by latent classes.
Results
Overall 97% of women reported experiencing at least one SE after ART initiation, with 48% experiencing more than five SE. Gastrointestinal, central nervous system, systemic and skin SE were reported by 81%, 85%, 79% and 31% of women, respectively, with considerable overlap across groups. At least one missed dose was reported by 32% of women. In multivariable models, ART non-adherence was associated with systemic SE compared to other systems categories, and measures of the overall burden of SE experienced were most strongly associated with missed ART doses.
Conclusion
These data demonstrate very high levels of SE in pregnant women initiating EFV-based ART and a strong association between SE burden and ART adherence. ART regimens with reduced SE profiles may enhance adherence, and as countries expand universal ART for all adult patients, counseling must include preparation for ART SE.
doi:10.1371/journal.pone.0163079
PMCID: PMC5070813  PMID: 27760126
12.  High Retention Among HIV-infected Children in Rwanda During Scale-up and Decentralization of HIV Care and Treatment Programs, 2004 to 2010 
Background
Efforts to scale-up HIV treatment in high burden countries have resulted in wider access to care, improved survival and decreased morbidity for HIV-infected children. The country of Rwanda has made significant achievements in expanding coverage of pediatric HIV services.
Methods
We describe the extent of and factors associated with mortality and lost to follow-up (LTF) in children (<15 years) enrolled in HIV care at 39 ICAP-supported facilities across Rwanda from 2004 to 2010 by antiretroviral treatment (ART) status. We estimated the 1-year cumulative incidence of death and LTF among all children enrolled in care (pre-ART) and children on ART. Survival analysis was used to evaluate factors associated with death and LTF in both groups.
Results
Between January 2004 and June 2010, 3244 children with a median age of 5.7 years (interquartile range 2.8–9.6) enrolled in HIV care. One-year cumulative incidence for death and LTF among pre-ART children was 4% (95% confidence interval [CI]: 3–5%) and 5% (95% CI: 4–6%), respectively. Overall, 2035 (63%) children initiated ART, median age 6.3 years (interquartile range 3.3–10.4): 1-year Kaplan–Meier estimates of death and LTF were 3% (95% CI: 3–4%) and 1% (95% CI: 1–2%), respectively. Factors associated with an increased hazard for death among pre-ART children included being <18 months old versus ≥5 years (adjusted sub hazard ratio [aSHR] = 4.4, 95% CI: 2.9–6.8) and World Health Organization stage IV versus I (aSHR = 4.1, 95% CI: 2.0–8.4), whereas children entering care through prevention of mother-to-child transmission had lower hazard than those from voluntary counseling and testing (aSHR = 0.50, 95% CI: 0.25–1.0). Markers of advanced disease, including severe immunosuppression (aSHR = 0.25, 95% CI: 0.12–0.54), and enrollment in care in rural versus urban clinics (aSHR = 0.71, 95% CI: 0.53–0.97) were protective against LTF. For children on ART, factors associated with hazard of death included younger age (adjusted hazard ratio [aHR] <18 months versus ≥5 years = 2.1, 95% CI: 1.3–3.6), severe malnutrition versus not malnourished (aHR = 3.2, 95% CI: 1.3–8.1), advanced World Health Organization stage (aHR IV versus I = 9.8, 95% CI: 3.5–27.4) and severe immunodeficiency versus no evidence (aHR = 2.3, 95% CI: 1.7–3.3). No associations were observed with LTF among children on ART.
Conclusions
The results demonstrate very high retention among children enrolled in HIV care in Rwanda. Younger children continue to be particularly vulnerable, underscoring the urgent need for early identification, rapid treatment initiation and long-term retention in care.
doi:10.1097/INF.0b013e31828c2744
PMCID: PMC5066568  PMID: 23407098
Rwanda; HIV; retention; pediatric; antiretrovirals
13.  Disclosing in utero HIV/ARV exposure to the HIV-exposed uninfected adolescent: is it necessary? 
Introduction
The tremendous success of antiretroviral therapy has resulted in a diminishing population of perinatally HIV-infected children on the one hand and a mounting number of HIV-exposed uninfected (HEU) children on the other. As the oldest of these HEU children are reaching adolescence, questions have emerged surrounding the implications of HEU status disclosure to these adolescents. This article outlines the arguments for and against disclosure of a child's HEU status.
Discussion
Disclosure of a child's HEU status, by definition, requires disclosure of maternal HIV status. It is necessary to weigh the benefits and harms which could occur with disclosure in each of the following domains: psychosocial impact, long-term physical health of the HEU individual and the public health impact. Does disclosure improve or worsen the psychological health of the HEU individual and extended family unit? Do present data on the long-term safety of in utero HIV/ARV exposure reveal potential health risks which merit disclosure to the HEU adolescent? What research and public health programmes or systems need to be in place to afford monitoring of HEU individuals and which, if any, of these require disclosure?
Conclusions
At present, it is not clear that there is sufficient evidence on whether long-term adverse effects are associated with in utero HIV/ARV exposures, making it difficult to mandate universal disclosure. However, as more countries adopt electronic medical record systems, the HEU status of an individual should be an important piece of the health record which follows the infant not only through childhood and adolescence but also adulthood. Clinicians and researchers should continue to approach the dialogue around mother–child disclosure with sensitivity and a cogent consideration of the evolving risks and benefits as new information becomes available while also working to maintain documentation of an individual's perinatal HIV/ARV exposures as a vital part of his/her medical records. As more long-term adult safety data on in utero HIV/ARV exposures become available these decisions may become clearer, but at this time, they remain complex and multi-faceted.
doi:10.7448/IAS.19.1.21099
PMCID: PMC5065689  PMID: 27741954
HIV exposure; disclosure; in utero; antiretrovirals
14.  The use of dried blood spot specimens for HIV-1 drug resistance genotyping in young children initiating antiretroviral therapy 
Paired plasma and dried blood spots (DBS) from 232 South African HIV-infected children initiating antiretroviral therapy (ART) were genotyped for drug resistance mutations, most of who had prior exposure to ART for prevention-of-mother-to-child-transmission. Non-nucleoside reverse transcriptase inhibitor mutations were most commonly detected in both specimen types, particularly Y181C/I and K103N/S. Resistance interpretation concordance was achieved in 97% of pairs with 7 children having mutations detected in DBS only. These results validate the preferential use of DBS specimens for HIVDR genotyping in this patient group.
doi:10.1016/j.jviromet.2015.07.005
PMCID: PMC4561412  PMID: 26192603
HIV drug resistance genotyping; dried blood spots; children
15.  The impact of Option B+ on the infant PMTCT cascade in Lilongwe, Malawi 
This observational study compared uptake of infant PMTCT services pre/post implementation of Option B+ in Lilongwe, Malawi. There were 845 (pre) and 998 (post) births. Post-B+ infants had longer median pre-delivery maternal ART (62 [38, 94]pre- vs. 95days [IQR61, 131]post-; p<0.0001), and improved PCR testing (82.0% vs. 86.5%; p=0.01) at younger median age (7.6weeks[6.6, 10.9] vs. 6.9[6.4, 8.1]; p <0.0001). Proportion testing PCR positive decreased (4.6% vs. 2.6%; p=0.03). Proportion of HIV-infected infants starting ART (75% vs. 77.3%) and age at initiation (19.7weeks[15.4, 31.1 vs. 16[IQR13.3, 17.9]) remained unchanged. These findings suggest modest improvements in infant care with Option B+.
doi:10.1097/QAI.0000000000000692
PMCID: PMC4537054  PMID: 26322670
16.  Paediatric HIV: Progress on Prevention, Treatment and Cure 
Current pediatrics reports  2015;3(3):219-229.
Purpose of review
This review provides an update on current developments with prevention, treatment and cure strategies in the field of pediatric HIV.
Recent findings/Summary
There has been tremendous progress in the prevention and treatment of pediatric HIV infection. With new strategies for prevention of mother-to-child transmission, we are growing ever closer towards elimination of pediatric HIV, though challenges with retention of pregnant woman and their HIV-exposed infants remain. Ongoing vigilance regarding the potential hazards of in utero ART exposure to infants continues with no significant alarms yet identified. Though cure has not been achieved, evidence of the impact of early treatment on reducing HIV-1 reservoir size with subsequent prolonged remission has enlivened efforts to rapidly identify and treat HIV-infected newborns. There is an increasing array of treatment options for pediatric patients and reassuring evidence regarding long-term complications of ART. Unfortunately, despite evidence suggesting the benefit of early treatment, timely identification and treatment of children remains a challenge. Better strategies for effective case-finding and engagement in care are urgently needed in addition to an improved understanding of how to retain HIV-positive children and adolescents on treatment. However, further emboldened by recent international commitments and robust global support, the future is hopeful.
doi:10.1007/s40124-015-0087-7
PMCID: PMC4687896  PMID: 26709366
Pediatric HIV; PMTCT; review
17.  Evolution of antiretroviral therapy services for HIV-infected pregnant women in Cape Town, South Africa 
Journal of acquired immune deficiency syndromes (1999)  2015;10.1097/QAI.0000000000000584.
Background
Approaches to antiretroviral therapy (ART) in HIV-infected pregnant women have changed considerably in recent years, but there are few comparative data on the implementation of different models of service delivery.
Methods
Using routine clinic records we examined ART initiation in pregnant women attending a large antenatal care (ANC) facility between January 2010 and December 2013 in Cape Town, South Africa. Over this time six different service delivery models were implemented sequentially to provide ART in pregnancy, including the integration of ART into ANC, use of point-of-care CD4 cell count testing, and universal ART initiation for all HIV-infected pregnant women.
Results
During the study period 19,432 women sought ANC, levels of HIV testing were high (98%) and 30% of pregnant women tested HIV-positive. Integration of ART into ANC was associated with significant increases in the proportion of eligible women initiating treatment before delivery compared to referral to a separate ART clinic (p<0.001). When CD4 cell counts were used to determine ART eligibility, point-of-care testing was associated with decreased delays to ART initiation compared to laboratory-based testing (p<0.001). The strategy of universal ART led to the highest levels of ART initiation (with 92% of women starting before delivery) and the shortest delays, with 82% of women starting ART on the day of the first ANC visit.
Conclusion
Developments in service delivery models, most notably service integration and universal ART for pregnant women, have improved antenatal ART initiation dramatically in this setting. Further research is needed into how strategies for antenatal ART initiation impact maternal and child health over the long-term.
doi:10.1097/QAI.0000000000000584
PMCID: PMC4550573  PMID: 25723138
antiretroviral therapy; mother-to-child transmission; pregnancy; antenatal care; service integration; point-of-care CD4; South Africa
18.  Intimate partner violence experienced by HIV-infected pregnant women in South Africa: a cross-sectional study 
BMJ Open  2016;6(8):e011999.
Objectives
Intimate partner violence (IPV) during pregnancy may be common in settings where HIV is prevalent but there are few data on IPV in populations of HIV-infected pregnant women in Southern Africa. We examined the prevalence and correlates of IPV among HIV-infected pregnant women.
Setting
A primary care antenatal clinic in Cape Town, South Africa.
Participants
623 consecutive HIV-infected pregnant women initiating lifelong antiretroviral therapy.
Measures
IPV, depression, substance use and psychological distress were assessed using the 13-item WHO Violence Against Women questionnaire, the Edinburgh Postnatal Depression Scale (EPDS), Alcohol and Drug Use Disorders Identification Tests (AUDIT/DUDIT) and the Kessler 10 (K-10) scale, respectively.
Results
The median age in the sample was 28 years, 97% of women reported being in a relationship, and 70% of women reported not discussing and/or agreeing on pregnancy intentions before conception. 21% of women (n=132) reported experiencing ≥1 act of IPV in the past 12 months, including emotional (15%), physical (15%) and sexual violence (2%). Of those reporting any IPV (n=132), 48% reported experiencing 2 or more types. Emotional and physical violence was most prevalent among women aged 18–24 years, while sexual violence was most commonly reported among women aged 25–29 years. Reported IPV was less likely among married women, and women who experienced IPV were more likely to score above threshold for substance use, depression and psychological distress. In addition, women who reported not discussing and/or not agreeing on pregnancy intentions with their partner prior to conception were significantly more likely to experience violence.
Conclusions
HIV-infected pregnant women in the study reported experiencing multiple forms of IPV. While the impact of IPV on maternal and child health outcomes in the context of HIV infection requires further research attention, IPV screening and support services should be considered within the package of routine care for HIV-infected pregnant women.
Trial registration number
NCT01933477.
doi:10.1136/bmjopen-2016-011999
PMCID: PMC5013465  PMID: 27531735
PUBLIC HEALTH
19.  Genetic Changes in HIV-1 Gag-Protease Associated with Protease Inhibitor-Based Therapy Failure in Pediatric Patients 
Abstract
Studies have shown a low frequency of HIV-1 protease drug resistance mutations in patients failing protease inhibitor (PI)-based therapy. Recent studies have identified mutations in Gag as an alternate pathway for PI drug resistance in subtype B viruses. We therefore genotyped the Gag and protease genes from 20 HIV-1 subtype C-infected pediatric patients failing a PI-based regimen. Major protease resistance mutations (M46I, I54V, and V82A) were identified in eight (40%) patients, as well as Gag cleavage site (CS) mutations (at codons 373, 374, 378, 428, 431, 449, 451, and 453) in nine (45%) patients. Four of these Gag CS mutations occurred in the absence of major protease mutations at PI failure. In addition, amino acid changes were noted at Gag non-CS with some predicted to be under HLA/KIR immune-mediated pressure and/or drug selection pressure. Changes in Gag during PI failure therefore warrant further investigation of the Gag gene and its role in PI failure in HIV-1 subtype C infection.
doi:10.1089/aid.2014.0349
PMCID: PMC4533029  PMID: 25919760
20.  PEPFAR Scale-up of Pediatric HIV Services: Innovations, Achievements, and Challenges 
HIV/AIDS has had a profound impact on children around the world since the start of the epidemic. There are currently 3.4 million children under the age of 15 years living with HIV globally, and more than 450,000 children currently receiving lifesaving antiretroviral treatment. This article describes efforts supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) to expand access to treatment for children living with HIV in high-burden countries. The article also highlights a series of case studies that illustrate the impact that the PEPFAR initiative has had on the pediatric HIV epidemic. Through its support of host governments and partner organizations, the PEPFAR initiative has expanded HIV testing and treatment for pregnant women to reduce vertical transmission of HIV, increased access to early infant diagnosis for HIV-exposed infants, improved training and resources for clinicians who provide pediatric care and antiretroviral treatment, and, through public–private partnerships with pharmaceutical manufacturers, helped increase the number of medications available for the treatment of HIV-infected children in resource-limited settings.
doi:10.1097/QAI.0b013e31825cf4f5
PMCID: PMC4941954  PMID: 22797731
PEPFAR; pediatric; treatment; HIV
21.  Enhancing Lay Counselor Capacity to Improve Patient Outcomes with Multimedia Technology 
AIDS and behavior  2015;19(0 2):163-176.
Multimedia technologies offer powerful tools to increase capacity of health workers to deliver standardized, effective, and engaging antiretroviral medication adherence counseling. Masivukeni is an innovative multimedia-based, computer-driven, lay counselor-delivered intervention designed to help people living with HIV in resource-limited settings achieve optimal adherence. This pilot study examined medication adherence and key psychosocial outcomes among 55 non-adherent South African HIV+ patients, on ART for at least 6 months, who were randomized to receive either Masivukeni or standard of care (SOC) counseling for ART non-adherence. At baseline, there were no significant differences between the SOC and Masivukeni groups on any outcome variables. At post-intervention (approximately 5–6 weeks after baseline), clinic-based pill count adherence data available for 20 participants (10 per intervention arm) showed a 10% improvement for Masivukeni participants and a decrease of 8% for SOC participants. Masivukeni participants reported significantly more positive attitudes towards disclosure and medication social support, less social rejection, and better clinic-patient relationships than did SOC participants. Masivukeni shows promise to promote optimal adherence and provides preliminary evidence that multimedia, computer-based technology can help lay counselors offer better adherence counseling than standard approaches.
doi:10.1007/s10461-014-0988-4
PMCID: PMC4537057  PMID: 25566763
HIV; ART adherence; Technology; Multimedia; Task-Shifting; Intervention
22.  The impact of Option B+ on the antenatal PMTCT cascade in Lilongwe, Malawi 
Objective
In 2011, Malawi implemented Option B+ (B+), lifelong antiretroviral therapy (ART) for pregnant and breast-feeding women. We aimed to describe changes in service uptake and outcomes along the antenatal PMTCT cascade post B+ implementation.
Design
Pre/post study using routinely collected program data from two large Lilongwe-based health centers.
Methods
We compared testing of HIV-infected pregnant women at antenatal care, enrollment into PMTCT services, receipt of ART and six-month ART outcomes pre- (Oct 2009–Mar 2011) and post- (Oct 2011–Mar 2013) B+.
Results
A total of 13,926 (pre) and 14,532 (post) women presented to antenatal care. Post-B+ a smaller proportion were HIV tested (99.3% vs. 87.7% post-; p<0.0001). There were 1654 (pre) and 1535 (post) HIV-infected women identified, with a larger proportion already known to be HIV-infected (18.1% vs. 41.2% post-; p<0.001) and on ART post-B+ (18.7% vs. 30.2% post-; p<0.001). A significantly greater proportion enrolled into the PMTCT program (68.3% vs. 92.6% post-; p<0.001) and was retained through delivery post-B+ (51.1% vs. 65% post-; p<0.0001). Amongst those not on ART at enrollment there was no change in the proportion newly initiating ART/ARVs (79% vs. 81.9% post-; p=0.11); although median days to initiation of ART decreased (48d [19,130] vs. 0d [0,15.5] post-; p<0.001). Amongst those newly initiating ART, a smaller proportion was alive on ART six-months post-initiation (89.3% vs. 78.8% post-; p=0.0004).
Conclusion
While several improvements in PMTCT program performance were noted with implementation of B+, challenges remain at several critical steps along the cascade requiring innovative solutions to ensure an AIDS-free generation.
doi:10.1097/QAI.0000000000000517
PMCID: PMC4359035  PMID: 25585302
HIV; PMTCT; Option B+ (B+); retention; Malawi; Africa
23.  Family, Community, and Health System Considerations for Reducing the Burden of Pediatric Sickle Cell Disease in Uganda Through Newborn Screening 
Global Pediatric Health  2016;3:2333794X16637767.
Sickle cell disease (SCD) is associated with high mortality for children under 5 years of age in sub-Saharan Africa. Newborn sickle screening program and enhanced capacity for SCD treatment are under development to reduce disease burden in Uganda and elsewhere in the region. Based on an international stakeholder meeting and a family-directed conference on SCD in Kampala in 2015, and interviews with parents, multinational experts, and other key informants, we describe health care, community, and family perspectives in support of these initiatives. Key stakeholder meetings, discussions, and interviews were held to understand perspectives of public health and multinational leadership, patients and families, as well as national progress, resource needs, medical and social barriers to program success, and resources leveraged from HIV/AIDS. Partnering with program leadership, professionals, patients and families, multinational stakeholders, and leveraging resources from existing programs are needed for building successful programs in Uganda and elsewhere in sub-Saharan Africa.
doi:10.1177/2333794X16637767
PMCID: PMC4905129  PMID: 27336011
sickle cell disease; newborn; screening; Uganda; family; community
24.  Why Did I Stop? Barriers and Facilitators to Uptake and Adherence to ART in Option B+ HIV Care in Lilongwe, Malawi 
PLoS ONE  2016;11(2):e0149527.
Causes for loss-to-follow-up, including early refusals of and stopping antiretroviral therapy (ART), in Malawi’s Option B+ program are poorly understood. This study examines the main barriers and facilitators to uptake and adherence to ART under Option B+. In depth interviews were conducted with HIV-infected women who were pregnant or postpartum in Lilongwe, Malawi (N = 65). Study participants included women who refused ART initiation (N = 10), initiated ART and then stopped (N = 26), and those who initiated ART and remained on treatment (N = 29). The barriers to ART initiation were varied and included concerns about partner support, feeling healthy, and needing time to think. The main reasons for stopping ART included side effects and lack of partner support. A substantial number of women started ART after initially refusing or stopping ART. There were several facilitators for re-starting ART, including encouragement from community health workers, side effects subsiding, decline in health, change in partner, and fear of future sickness. Amongst those who remained on ART, desire to prevent transmission and improve health were the most influential facilitators. Reasons for refusing and stopping ART were varied. ART-related side effects and feeling healthy were common barriers to ART initiation and adherence. Providing consistent pre-ART counseling, early support for patients experiencing side effects, and targeted efforts to bring women who stop treatment back into care may improve long term health outcomes.
doi:10.1371/journal.pone.0149527
PMCID: PMC4762691  PMID: 26901563
25.  Sexual Health Knowledge in a Sample of Perinatally HIV-infected and Perinatally-exposed Uninfected Youth 
This study describes sexual health knowledge in perinatally HIV-infected (PHIV+) and perinatally-exposed uninfected (PHIV-) ethnic-minority youth, ages 9–16 years, residing in NYC (n=316). Data on youth sexual health knowledge (e.g., pregnancy, STDs, birth control) and caregiver-adolescent communication about sexual health were examined. Participants in both groups answered only 35% of the sexual health knowledge questions correctly (mean=6.6/19). Higher scores were found among youth who reported more communication about sex with caregivers (vs. those who did not report talking about sex with caregivers; 8.54 vs. 5.84, p<.001) and among PHIV+ youth who were aware of their status (vs. PHIV+ youth who were not; 7.27 vs. 4.70, p<.001). Age was positively correlated with sexual health knowledge (beta=.489, p<.001). Both PHIV+ and PHIV− youth had poor sexual health knowledge, suggesting a need for sexual health education for both groups. Data suggest that interventions focused on caregiver-child risk communication may be important for prevention.
doi:10.1080/15381501.2014.912177
PMCID: PMC4743908  PMID: 26855617
STD knowledge; perinatal infection; adolescents; HIV

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