Longitudinal evaluation of adherence, retention, and transition patterns of adolescents living with HIV in Nigeria.

INTRODUCTION: Adherence to antiretroviral therapy (ART) and retention in treatment programs are required for successful virologic suppression and treatment outcomes. As the number of adolescents living with HIV continues to increase globally, more information about adherence and retention patterns during and through transition from child- to adult-centered care is needed to ensure provision of a high level of care and inform development of targeted interventions to improve patient outcomes in this vulnerable population. In this analysis, we sought to describe long-term trends in adherence, retention, and virologic suppression in adolescents receiving ART at a pediatric HIV clinic in Nigeria through transition to the adult clinic. SETTING: The Jos University Teaching Hospital, United States President's Emergency Plan for AIDS Relief (PEPFAR)-funded HIV clinic in Jos, Plateau State, Nigeria. METHODS: We conducted a retrospective observational longitudinal evaluation of data that had been collected during the course of care in a large pediatric ART program in Nigeria. We used descriptive statistics to define our patient population and quantify retention from ART initiation through adolescence and transition to adult-centered care. Logistic regression was used to evaluate predictors of loss to follow-up. We used medication possession ratio (MPR) to quantify adherence for each year a patient was on ART. To evaluate adherence and virologic suppression, we measured the proportion of patients with ≥95% MPR and the proportion with virologic suppression (viral load ≤400 copies/mL) within each age cohort, and used bivariate analyses to examine any association between MPR and VL suppression for all person-years observed. RESULTS: A total of 476 patients received at least one dose of ART as an adolescent (ages 10-19 years). The proportions of patients lost to follow-up were: 11.9% (71/597) prior to adolescence, 19.1% (31/162) during adolescence, and 13.7% (10/73) during transition to adult-centered care. While over 80% of patients had ≥95% medication adherence in all age groups, their viral load suppression rates through adolescence and post-transition were only 55.6%-64.0%. For patients that successfully transitioned to adult-centered care, we observed 87.7% (50/57) retention at month 12 post-transition, but only 34.6% (9/26) viral load suppression. CONCLUSIONS: Our evaluation found considerable proportions of adolescents lost to follow-up throughout the ART program cascade. We also found discrepancies between the proportions of patients with ≥95% MPR and the proportions with VL suppression, suggesting that true medication adherence in this population may be poor. Significant attention and targeted interventions to improve retention and adherence focused on adolescents are needed in order for global programs to achieve 90-90-90 goals.

Low levels of HIV-1 drug resistance mutations in patients who achieved viral re-suppression without regimen switch: a retrospective study.

BACKGROUND: We identified a HIV-positive cohort in virologic failure (VF) who re-suppressed without drug switch. We characterized their drug resistance mutations (DRM) and adherence profiles to learn how to better manage HIV drug resistance. A retrospective cohort study utilizing clinical data and stored samples. Patients received ART at three Nigerian treatment centres. Plasma samples stored when they were in VF were genotyped. RESULT: Of 126 patients with samples available, 57 were successfully genotyped. From ART initiation, the proportion of patients with adherence ≥90% increased steadily from 54% at first high viral load (VL) to 67% at confirmed VF, and 81% at time of re-suppressed VL. Sixteen (28%) patients had at least one DRM. Forty-six (81%) patients had full susceptibility to the three drugs in their first-line (1 L) regimen. Thirteen (23%) were resistant to at least one antiretroviral drug but three were resistant to drugs not used in Nigeria. Ten patients had resistance to their 1 L drug(s) and six were fully susceptible to the three drugs in the recommended second-line regimen. CONCLUSION: This cohort had little drug resistance mutations. We conclude that if adherence is not assured, patients could exhibit virologic failure without having developed mutations associated with drug resistance.

The role of point-of-care viral load monitoring in achieving the target of 90% suppression in HIV-infected patients in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: The Joint United Nations Programme on HIV/AIDS 90-90-90 goal envisions 90% of all people receiving antiretroviral therapy to be virally suppressed by 2020. Implied in that goal is that viral load be quantified for all patients receiving treatment, which is a challenging undertaking given the complexity and high cost of standard-of-care viral load testing methods. Recently developed point-of-care viral load testing devices offer new promise to improve access to viral load testing by bringing the test closer to the patient and also returning results faster, often same-day. While manufactures have evaluated point-of-care assays using reference panels, empiric data examining the impact of the new technology against standard-of-care monitoring in low- and middle-income settings are lacking. Our goal in this trial is to compare a point-of-care to standard-of-care viral load test on impact on various clinical outcomes as well to assess the acceptability and feasibility of using the assay in a resource-limited setting. METHODS: Using a two-arm randomized control trial design, we will enroll 794 patients from two different HIV treatment sites in Nigeria. Patients will be randomized 1:1 for point-of-care or standard-of-care viral load monitoring (397 patients per arm). Following initiation of treatment, viral load will be monitored at patients' 6- and 12-month follow-up visits using either point-of-care or standard-of-care testing methods, based on trial assignment. The monitoring schedule will follow national treatment guidelines. The primary outcome measure in this trial is proportion of patients with viral suppression at month 12 post-initiation of treatment. The secondary outcome measures encompass acceptability, feasibility, and virologic impact variables. DISCUSSION: This clinical trial will provide information on the impact of using point-of-care versus standard-of-care viral load testing on patient clinical outcomes; the study will also supply data on the acceptability and feasibility of point-of-care viral load monitoring in a resource-limited setting. If this method of testing is acceptable and feasible, and also superior to standard of care, the results of the trial and the information gathered will inform future scaled implementation and further optimization of the clinic-laboratory network that is critical for monitoring achievement of the 90-90-90 goals. TRIAL REGISTRATION: US National Institutes of Health Clinical Trials.gov: NCT03533868 . Date of Registration: 23 May 2018. Protocol Version: 10. Protocol Date: 30 March 2018.

Retention in Differentiated Care: Multiple Measures Analysis for a Decentralized HIV Care and Treatment Program in North Central Nigeria.

OBJECTIVE: Differentiated care refers collectively to flexible service models designed to meet the differing needs of HIV-infected persons in resource-scarce settings. Decentralization is one such service model. Retention is a key indicator for monitoring the success of HIV treatment and care programs. We used multiple measures to compare retention in a cohort of patients receiving HIV care at "hub" (central) and "spoke" (decentralized) sites in a large public HIV treatment program in north central Nigeria. METHODS: This retrospective cohort study utilized longitudinal program data representing central and decentralized levels of care in the Plateau State Decentralization Initiative, north central Nigeria. We examined retention with patient- level (retention at fixed times, loss-to-follow-up [LTFU]) and visit-level (gaps-in-care, visit constancy) measures. Regression models with generalized estimating equations (GEE) were used to estimate the effect of decentralization on visit-level measures. Patient-level measures were examined using survival methods with Cox regression models, controlling for baseline variables. RESULTS: Of 15,650 patients, 43% were enrolled at the hub. Median time in care was 3.1 years. Hub patients were less likely to be LTFU (adjusted hazard ratio (AHR)=0.91, 95% CI: 0.85-0.97), compared to spoke patients. Visit constancy was lower at the hub (-4.5%, 95% CI: -3.5, -5.5), where gaps in care were also more likely to occur (adjusted odds ratio=1.95, 95% CI: 1.83-2.08). CONCLUSION: Decentralized sites demonstrated better retention outcomes using visit-level measures, while the hub achieved better retention outcomes using patient-level measures. Retention estimates produced by incorporating multiple measures showed substantial variation, confirming the influence of measurement strategies on the results of retention research. Future studies of retention in HIV care in sub-Saharan Africa will be well-served by including multiple measures.

Implication of First-Line Antiretroviral Therapy Choice on Second-Line Options.

BACKGROUND: Although there are a number of studies comparing the currently recommended preferred and alternative first-line (1L) antiretroviral therapy (ART) regimens on clinical outcomes, there are limited data examining the impact of 1L regimen choice and duration of virologic failure (VF) on accumulation of drug resistance mutations (DRM). The patterns of DRM from patients failing zidovudine (AZT)-containing versus tenofovir (TDF)-containing ART were assessed to evaluate the predicted susceptibility to second-line (2L) nucleoside reverse-transcriptase inhibitor (NRTI) backbone options in the context of an ongoing programmatic setting that uses viral load (VL) monitoring. METHODS: Paired samples from Nigerian ART patients who experienced VF and switched to 2L ART were retrospectively identified. For each sample, the human immunodeficiency virus (HIV)-1 polymerase gene was sequenced at 2 time points, and DRM was analyzed using Stanford University's HIVdb program. RESULTS: Sequences were generated for 191 patients. At time of 2L switch, 28.2% of patients on AZT-containing regimens developed resistance to TDF, whereas only 6.8% of patients on TDF-containing 1L had mutations compromising susceptibility to AZT. In a stratified evaluation, patients with 0-6 months between tested VL samples had no difference in proportion compromised to 2L, whereas those with >6 months between samples had a statistically significant difference in proportion with compromised 2L NRTI. In multivariate analyses, patients on 1L AZT had 9.90 times higher odds of having a compromised 2L NRTI option than patients on 1L TDF. CONCLUSIONS: In the context of constrained resources, where VL monitoring is limited, we present further evidence to support use of TDF as the preferred 1L NRTI because it allows for preservation of the recommended 2L NRTI option.

Drug resistance patterns following pharmacy stock shortage in Nigerian Antiretroviral Treatment Program.

BACKGROUND: For patients on antiretroviral therapy (ART), treatment interruptions can impact patient outcomes and result in the accumulation of drug resistance mutations leading to virologic failure. There are minimal published data on the impact of an ART stock shortage on development of drug resistance mutations (DRMs). In this report, we evaluate data from patients enrolled in the Government of Nigeria National ART Program that were receiving treatment at the time of a national drug shortage in late 2003. METHODS: We conducted a cross-sectional evaluation of samples collected between December 2004 and August 2005 from ART patients in virologic failure that either had a treatment interruption or did not during the late 2003 drug shortage period at the Jos University Teaching Hospital (JUTH). Plasma virus was genotyped, sequence data were edited and analyzed, and mutation profiles were categorized to evaluate predicted drug susceptibility. Data were analyzed to examine factors associated with development of resistance mutations. A genotypic sensitivity score to the alternate recommended regimen was computed to assess drug susceptibility if regimens were changed. RESULTS: A total of 56 patients were included in this evaluation (28 interrupted, 28 uninterrupted). Patients in the interrupted group had more DRMs than those in the uninterrupted group (p < 0.001); interrupted patients were more likely than uninterrupted patients to have one or more TAM-2 mutations (57.1% interrupted vs. 21.3% uninterrupted; p = 0.04). There was a statistically significant difference in resistance to both d4T (53.7% interrupted vs. 17.9 uninterrupted; p = 0.011) and AZT (64.3% interrupted vs. 25.0% uninterrupted; p = 0.003) by drug interruption status. Examining genotypic sensitivity scores, we found that 67.9% of the interrupted patients, as compared to 25.0% of the uninterrupted patients, did not have full susceptibility to one drug in the regimen to which guidelines recommended they be switched (p = 0.001). DISCUSSION: In this small observational study, we found evidence of a difference in resistance profiles and ART susceptibility between those that were stocked-out of drug versus those that were not. We believe that these data are relevant for many other low- and middle-income countries (LMIC) that also experienced similar ART shortages as they rapidly scaled up their national programs.

Prevalence and predictors of severe menopause symptoms among HIV-positive and -negative Nigerian women.

We compared the prevalence of menopause symptoms between women living with HIV to their HIV-negative peers and determined predictors of severe menopause symptoms in Jos, Nigeria. This descriptive cross-sectional study included 714 women aged 40-80 years. We compared prevalence and severity of menopause symptoms using the menopause rating scale (MRS). Logistic regression analysis was used to determine the predictors of severe symptoms. Six-hundred and seven (85.0%) were HIV-positive, with a mean duration of infection of 5.6 ± 2.7 years. The mean age of the cohort was 46 ± 5 years. The most prevalent menopause symptoms were hot flushes (67.2%), joint and muscle discomfort (66.2%), physical/mental exhaustion (65.3%), heart discomfort (60.4%), and anxiety (56.4%). The median MRS score was higher for HIV-positive compared to HIV-negative women (p = 0.01). Factors associated with severe menopause symptoms included HIV-positive status (aOR: 3.01, 95% CI: 1.20-7.54) and history of cigarette smoking (aOR: 4.18, 95% CI: 1.31-13.26). Being married (aOR: 0.49, 95% CI: 0.32-0.77), premenopausal (aOR: 0.60, 95% CI: 0.39-0.94), and self-reporting good quality of life (aOR: 0.62. 95% CI: 0.39-0.98) were protective against severe menopause symptoms. We found HIV infection, cigarette smoking, quality of life, and stage of the menopause transition to be associated with severe menopause symptoms. As HIV-positive populations are aging, additional attention should be given to the reproductive health of these women.

Sexual dysfunction and its determinants among women infected with HIV.

OBJECTIVE: To describe the prevalence of female sexual dysfunction (FSD) and its determinants among women with HIV infection enrolled for care and treatment in an ambulatory care setting. METHODS: A questionnaire-based cross-sectional survey was conducted among women attending the HIV clinic of Jos University Teaching Hospital, Nigeria, between March 2013 and February 2014. The self-administered Female Sexual Function Index (FSFI) was used to assess FSD; a score of less than 26.55 indicated FSD. Pearson coefficient was used to assess interdomain correlation, and multiple linear regression was used to identify factors associated with FSD. RESULTS: Among 370 participants, 330 (89.2%, 95% confidence interval [CI] 85.6%-92.2%) had FSD. The overall median FSFI score was 19.2 (interquartile range [IQR] 6.4-23.9). The arousal domain had the lowest subscore (median 2.7, IQR 0.0-3.6). The highest interdomain correlations were between lubrication and orgasm (r=0.87), arousal and lubrication (r=0.84), and arousal and orgasm (r=0.81) domains. Satisfactory health (ß=3.34, 95% CI 1.16-5.52) and history of alcohol use (ß=2.38, 95% CI 0.28-4.47) were independently associated with FSD. CONCLUSION: FSD was prevalent among women with HIV infection. Care providers need to routinely address FSD as part of a comprehensive care package in the study setting.

Treatment Outcomes Among Older Human Immunodeficiency Virus-Infected Adults in Nigeria.

BACKGROUND: Older age at initiation of combination antiretroviral therapy (cART) has been associated with poorer clinical outcomes. Our objectives were to compare outcomes between older and younger patients in our clinical cohort in Jos, Nigeria. METHODS: This retrospective cohort study evaluated patients enrolled on cART at the Jos University Teaching Hospital, Nigeria between 2004 and 2012. We compared baseline and treatment differences between older (≥50 years) and younger (15-49 years) patients. Kaplan-Meier analysis and Cox proportional hazard models estimated survival and loss to follow-up (LTFU) and determined factors associated with these outcomes at 24 months. RESULTS: Of 8352 patients, 643 (7.7%) were aged ≥50 years. The median change in CD4 count from baseline was 151 vs 132 (P = .0005) at 12 months and 185 vs 151 cells/mm3 (P = .03) at 24 months for younger and older patients, respectively. A total of 68.9% vs 71.6% (P = .13) and 69.6% vs 74.8% (P = .005) of younger and older patients achieved viral suppression at 12 and 24 months, with similar incidence of mortality and LTFU. In adjusted hazard models, factors associated with increased risk of mortality were male sex, World Health Organization (WHO) stage III/IV, and having a gap in care, whereas being fully suppressed was protective. The risk of being LTFU was lower for older patients, those fully suppressed virologically and with adherence rates >95%. Male sex, lack of education, WHO stage III/IV, body mass index <18.5 kg/m2, and having a gap in care independently predicted LTFU. CONCLUSIONS: Older patients achieved better viral suppression, and older age was not associated with increased mortality or LTFU in this study.

Long-Term Outcomes on Antiretroviral Therapy in a Large Scale-Up Program in Nigeria.

BACKGROUND: While there has been a rapid global scale-up of antiretroviral therapy programs over the past decade, there are limited data on long-term outcomes from large cohorts in resource-constrained settings. Our objective in this evaluation was to measure multiple outcomes during first-line antiretroviral therapy in a large treatment program in Nigeria. METHODS: We conducted a retrospective multi-site program evaluation of adult patients (age ≥15 years) initiating antiretroviral therapy between June 2004 and February 2012 in Nigeria. The baseline characteristics of patients were described and longitudinal analyses using primary endpoints of immunologic recovery, virologic rebound, treatment failure and long-term adherence patterns were conducted. RESULTS: Of 70,002 patients, 65.2% were female and median age was 35 (IQR: 29-41) years; 54.7% were started on a zidovudine-containing and 40% on a tenofovir-containing first-line regimen. Median CD4+ cell counts for the cohort started at 149 cells/mm3 (IQR: 78-220) and increased over duration of ART. Of the 70,002 patients, 1.8% were reported as having died, 30.1% were lost to follow-up, and 0.1% withdrew from treatment. Overall, of those patients retained and with viral load data, 85.4% achieved viral suppression, with 69.3% achieving suppression by month 6. Of 30,792 patients evaluated for virologic failure, 24.4% met criteria for failure and of 45,130 evaluated for immunologic failure, 34.0% met criteria for immunologic failure, with immunologic criteria poorly predicting virologic failure. In adjusted analyses, older age, ART regimen, lower CD4+ cell count, higher viral load, and inadequate adherence were all predictors of virologic failure. Predictors of immunologic failure differed slightly, with age no longer predictive, but female sex as protective; additionally, higher baseline CD4+ cell count was also predictive of failure. Evaluation of long-term adherence patterns revealed that the majority of patients retained through 84 months maintained ≥95% adherence. CONCLUSION: While improved access to HIV care and treatment remains a challenge in Nigeria, our study shows that a high quality of care was achieved as evidenced by strong long-term clinical, immunologic and virologic outcomes.

Superior Effectiveness of Zidovudine Compared With Tenofovir When Combined With Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort.

BACKGROUND: Despite sparse efficacy data, tenofovir-emtricitabine or tenofovir-lamivudine plus nevirapine is used in many resource-constrained settings. METHODS: This retrospective cohort study included patients initiating nevirapine-based antiretroviral therapy (ART) with either tenofovir-emtricitabine or lamivudine (tenofovir group) or zidovudine-lamivudine (zidovudine group). Clinical, virologic, and immunologic evaluations were performed at baseline and every 6 months. Virologic failure was defined as 2 consecutive human immunodeficiency virus (HIV)-RNA values >1000 copies/mL. Patients were included from ART initiation until time of failure, regimen switch, discontinuation, or last HIV-RNA measurement. Cox proportional hazards regression was used to model factors influencing time to failure. Bias due to dependent censoring was investigated via inverse probability weighted pooled logistic regression. RESULTS: A total of 5547 patients were evaluated; 1484 (26.8%) were in the tenofovir group and 4063 (73.2%) were in the zidovudine group. In the adjusted model, tenofovir regimen (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.21-1.79) and higher baseline log10 HIV-RNA (HR, 1.15; 95% CI, 1.03-1.28) were associated with virologic failure. Higher baseline log10 CD4+ cell count (HR, 0.50; 95% CI, .40-.63) and increasing age (HR, 0.98; 95% CI, .97-.99) decreased the risk of virologic failure. Inverse probability weighting results were consistent with the primary analysis. CONCLUSIONS: Compared with zidovudine-lamivudine, the use of tenofovir-lamivudine or emtricitabine in combination with nevirapine was a strong predictor of virologic failure in our cohort, which was not explained by other risk factors or criteria for regimen selection.

Mother-to-Child Transmission Outcomes of HIV-Exposed Infants Followed Up in Jos North-Central Nigeria.

OBJECTIVE: Since 2010, Nigeria has adopted World Health Organization (WHO) 'Option B' which requires administration of triple antiretroviral prophylaxis or treatment (ART) to all HIVinfected pregnant women. We studied the transmission outcomes of HIV-exposed children up to 18 months of age. DESIGN: This was a retrospective, observational study of HIV-infected pregnant women and their exposed infants who accessed prevention of mother to child transmission (PMTCT) services at Jos University Teaching Hospital, Jos, North-central Nigeria. METHODS: HIV-infected women were enrolled during antenatal care or at labor/delivery between January 1, 2010 and December 31, 2012. Antiretroviral (ARV) prophylaxis/therapy was provided according to the 2010 Nigerian PMTCT guidelines (adapted WHO 2010 guidelines); Infant HIV diagnosis was performed at 6 weeks and at 6 months. HIV antibody diagnosis was used for exposed children at 18 months. RESULTS: A total of 996 HIV-exposed children were followed up. Of those children, 140 (14.1%) were lost to follow up by 18 months of age. Twelve children (1.4%) died (all HIV negative) before 18 months of age and six infants (0.7%) were confirmed to be HIV-infected (4 by the age of 6 months and 2 thereafter) and were referred for treatment. A total of 838 (84.1%) children tested HIV negative at 18 months and were discharged. Mother-to-child transmission (MTCT) of HIV by 18 months was lower among women on ART before pregnancy compared to those women who started ART/Triple ARV prophylaxis during pregnancy/delivery. (0.4%; 3/700 vs 2.0%; 3/150 P=0.05). Home delivery was associated with higher transmission than facility delivery (p=0.03). Mode of delivery or method of infant feeding had no significant impact on vertical transmission by 18 months. CONCLUSION: In North-central Nigeria where HIV is prevalent, ART started before pregnancy is enormously effective in preventing mother-to-child transmission. Adoption of WHO 'Option B+' deserves serious consideration in such settings.

Patterns of Adherence and Loss to Follow-Up in Pediatric Patients on ART in Nigeria.

INTRODUCTION: High levels of adherence to antiretroviral therapy (ART) and retention in treatment programs are required for successful virologic suppression and treatment outcomes. While there have been numerous studies focusing on adherence and loss to follow-up (LTFU) in adults, studies in children and young adolescents are limited. For this study, we examined patterns of adherence and LTFU in HIV-infected pediatric patients receiving ART in PEPFAR-funded sites in Nigeria. METHODS: We conducted a retrospective observational study utilizing data that had been collected during the course of care in a large pediatric ART program in Nigeria. RESULTS: A total of 3,513 children ages 0-14.9 years enrolled at 31 different sites between June 2005 and March 2011 were included in the study. Of the enrolled patients, 1,987 (56%) were LTFU by the end of the study period. LTFU was highest in those ages<2 years and those≥13 years (versus aged 2-12.9 years). Year of ART initiation was a strong predictor of LTFU across all age groups. For those patients retained to 12 months, less than half showed optimal adherence (≥95%). While there were no differences in adherence rates at month 12 by age group, those aged 10 years and older did have declining adherence starting at 18 months. DISCUSSION: Adherence is critical for optimal ART patient outcomes. We found both low adherence and high LTFU rates in our study cohort. Additional studies focused on barriers to adherence and development of age-specific intervention programs are critical to improving overall pediatric outcomes.

Loss to Follow-Up within the Prevention of Mother-to-Child Transmission Care Cascade in a Large ART Program in Nigeria.

BACKGROUND: The 2013 WHO guidelines incorporated simplified and more effective antiretroviral regimens for the purposes of preventing mother-to-child transmission of HIV. With ideal implementation of these recommendations, perinatal HIV transmission could be reduced to less than 2%. However, loss to follow-up (LTFU) has the potential to erode the success of programs and a number of studies report high rates of LTFU within the prevention of mother-to-child transmission (PMTCT) care cascade. We evaluated the timing and magnitude of LTFU in a large programmatic PMTCT cohort in Nigeria in order to focus future efforts to reduce loss in this high burden setting. METHODS: From 2004-2014, the APIN/Harvard PEPFAR program supported antenatal HIV screening for nearly one million pregnant women and provided PMTCT care to over 30,000 women. The care cascade for women enrolling in the PMTCT program includes antenatal, delivery, and infant follow-up services through 12-18 months of life. In this retrospective cohort analysis, we examined data collected between 2004-2014 from 31 clinical sites in Nigeria and assessed the numbers of mothers and infants enrolled and LTFU at various points along the care cascade. RESULTS: Among 31,504 women (median age 30, IQR: 27-34) entering PMTCT care during the antenatal period, 20,679 (66%) completed the entire cascade of services including antenatal, delivery, and at least one infant follow-up visit. The median gestational age at presentation for antenatal care services was 23 weeks (IQR: 17-29). The median infant age at last follow-up visit was 12 months (IQR: 5-18). The greatest loss in the PMTCT care cascade occurred prior to delivery care (21%), with a further 16% lost prior to first infant visit. Of the 38,223 women who entered at any point along the PMTCT cascade, an HIV DNA PCR was available for 20,202 (53%) of their infants. Among infants for whom DNA PCR results were available, the rate of HIV transmission for infants whose mothers received any antenatal and/or delivery care was 2.8% versus 20.0% if their mother received none. CONCLUSION: In this large cohort analysis, the proportion of women LTFU in the PMTCT care cascade was lower than that reported in previous cohort analyses. Nevertheless, this proportion remains unacceptably high and inhibits the program from maximally achieving the goals of PMTCT care. We also provide the largest analysis to date on rates of perinatal HIV transmission, with low rates among women receiving NNRTI- or PI-based regimens, approaching that reported in clinical trials. However, among mothers who received any antenatal care, infant outcomes were unknown for 48%, and women presented later in pregnancy than that recommended by current guidelines. Implementation research to evaluate ways to improve integration of services, particularly transitions from antenatal to delivery and pediatric care, are critically needed to reduce LTFU within PMTCT programs and achieve the ultimate goal of eliminating pediatric HIV infection.

Building laboratory capacity to support HIV care in Nigeria: Harvard/APIN PEPFAR, 2004-2012.

INTRODUCTION: From 2004-2012, the Harvard/AIDS Prevention Initiative in Nigeria, funded through the US President's Emergency Plan for AIDS Relief programme, scaled up HIV care and treatment services in Nigeria. We describe the methodologies and collaborative processes developed to improve laboratory capacity significantly in a resource-limited setting. These methods were implemented at 35 clinic and laboratory locations. METHODS: Systems were established and modified to optimise numerous laboratory processes. These included strategies for clinic selection and management, equipment and reagent procurement, supply chains, laboratory renovations, equipment maintenance, electronic data management, quality development programmes and trainings. RESULTS: Over the eight-year programme, laboratories supported 160 000 patients receiving HIV care in Nigeria, delivering over 2.5 million test results, including regular viral load quantitation. External quality assurance systems were established for CD4+ cell count enumeration, blood chemistries and viral load monitoring. Laboratory equipment platforms were improved and standardised and use of point-of-care analysers was expanded. Laboratory training workshops supported laboratories toward increasing staff skills and improving overall quality. Participation in a World Health Organisation-led African laboratory quality improvement system resulted in significant gains in quality measures at five laboratories. CONCLUSIONS: Targeted implementation of laboratory development processes, during simultaneous scale-up of HIV treatment programmes in a resource-limited setting, can elicit meaningful gains in laboratory quality and capacity. Systems to improve the physical laboratory environment, develop laboratory staff, create improvements to reduce costs and increase quality are available for future health and laboratory strengthening programmes. We hope that the strategies employed may inform and encourage the development of other laboratories in resource-limited settings.

Enhancement of health research capacity in Nigeria through north-south and in-country partnerships.

Research productivity in Sub-Saharan Africa has the potential to affect teaching, student quality, faculty career development, and translational country-relevant research as it has in developed countries. Nigeria is the most populous country in Africa, with an academic infrastructure that includes 129 universities and 45 medical schools; however, despite the size, the country has unacceptably poor health status indicators. To further develop the research infrastructure in Nigeria, faculty and research career development topics were identified within the six Nigerian universities of the nine institutions of the Medical Education Partnership Initiative in Nigeria (MEPIN) consortium. The consortium identified a training model that incorporated multi-institutional "train-the-trainers" programs at the University of Ibadan, followed by replication at the other MEPIN universities. More than 140 in-country trainers subsequently presented nine courses to more than 1,600 faculty, graduate students, and resident doctors throughout the consortium during the program's first three years (2011-2013). This model has fostered a new era of collaboration among the major Nigerian research universities, which now have increased capacity for collaborative research initiatives and improved research output. These changes, in turn, have the potential to improve the nation's health outcomes.

Predictors of Mortality in a Clinic Cohort of HIV-1 Infected Children Initiated on Antiretroviral Therapy in Jos, Nigeria.

BACKGROUND: Mortality among human immunodeficiency virus-1 (HIV-1) infected children initiated on antiretroviral therapy (ART) though on a decline still remains high in resource-limited countries (RLC). Identifying baseline factors that predict mortality could allow their possible modification in order to improve pediatric HIV care and reduce mortality. METHODS: We conducted a retrospective cohort study analyzing data on 691 children, aged 2 months-15 years, diagnosed with HIV-1 infection and initiated on ART between July 2005 and March 2013 at the pediatric HIV clinic of Jos University Teaching Hospital. Lost to follow-up children were excluded from the analyses. A multivariate Cox proportional hazards model was fitted to identify predictors of mortality. RESULTS: Median follow-up time for the 691 children initiated on ART was 4.4 years (interquartile range (IQR), 1.8-5.9) and at the end of 2752 person-years of follow-up, 32 (4.6%) had died and 659 (95.4%) survived. The mortality rate was 1.0 per 100 child-years of follow-up period. The median age of those who died was about two times lower than that of survivors [1.7 years (IQR, 0.6-3.6) versus 3.9 years (IQR, 3.9-10.3), p<0.001]. On unadjusted Cox regression, the risk of dying was about three and half times more in children <5 years of age compared to those >5 years (p=0.02) Multivariate modeling identified age as the main predictor of death with mortality decreasing by 24% for every 1 year increase in age (Adjusted Hazard Ratio (AHR)=0.76 [0.62-0.94], p=0.013. CONCLUSION: The lower mortality rate for our study suggests that even in RLC, mortality rates could be reduced given a good standard of care. Early initiation of ART in younger children with close monitoring during follow-up could further reduce mortality.

Accumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in Nigeria.

BACKGROUND: To date, antiretroviral therapy (ART) guidelines and programs in resource-limited settings (RLS) have focused on 1(st)- and 2(nd)-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3(rd)-line (3 L) ART is needed. We aimed to examine the impact of maintaining patients on failing 2 L ART on the accumulation of protease (PR) mutations. METHODS AND FINDINGS: From 2004-2011, the Harvard/APIN PEPFAR Program provided ART to >100,000 people in Nigeria. Genotypic resistance testing was performed on a subset of patients experiencing 2 L failure, defined as 2 consecutive viral loads (VL)>1000 copies/mL after ≥6 months on 2 L. Of 6714 patients who received protease inhibitor (PI)-based ART, 673 (10.0%) met virologic failure criteria. Genotypes were performed on 61 samples. Patients on non-suppressive 2 L therapy for <12 months prior to genotyping had a median of 2 (IQR: 0-5) International AIDS Society (IAS) PR mutations compared with 5 (IQR: 0-6) among patients failing for >24 months. Patients developed a median of 0.6 (IQR: 0-1.4) IAS PR mutations per 6 months on failing 2 L therapy. In 38% of failing patients no PR mutations were present. For patients failing >24 months, high- or intermediate-level resistance to lopinavir and atazanavir was present in 63%, with 5% to darunavir. CONCLUSIONS: This is the first report assessing the impact of duration of non-suppressive 2 L therapy on the accumulation of PR resistance in a RLS. This information provides insight into the resistance cost of failing to switch non-suppressive 2 L regimens and highlights the issue of 3 L access.

Declining rate of infection with maternal human immunodeficiency virus at delivery units in north-central Nigeria.

HIV testing during labour and delivery provides a critical opportunity for administering appropriate interventions to prevent mother-to-child-transmission (PMTCT). We studied current HIV rates and infection trend among women tested during delivery following scale-up of PMTCT and antiretroviral therapy (ART) programs in Jos, north central Nigeria. Between March 2010 and January 2012, provider-initiated HIV testing and counselling was offered in early labour. Women were recruited from a government tertiary health centre, a faith-based hospital, and a private health centre. Those who previously tested HIV negative during antenatal care (ANC) and those who presented at the labour ward with unknown HIV status were tested. A total of 944 subjects (727 re-tested for HIV infection and 217 with unknown HIV status) were enrolled and tested during labour. The HIV incidence and sero-conversion rates during pregnancy among women who repeated HIV testing at delivery was 1.7 per 100 person-years of observation (pyo) and 0.6% (4/727), respectively, while the rate among those who tested for the first time in labour was 1.8% (4/217). Women who accessed ANC were older and had achieved a higher educational status than those who did not access ANC. A 3- to 5-fold decline in HIV incidence and prevalence rates was detected among women tested at delivery when compared to data from a report in 2004. It is not certain whether the decline in maternal HIV infection is due to the major state-wide scale-up of PMTCT and HIV treatment programs. A broader and purposefully designed evaluation study would be required to verify observed occurrence.

Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings.

BACKGROUND: Viral load (VL) quantification is considered essential for determining antiretroviral treatment (ART) success in resource-rich countries. However, it is not widely available in resource-limited settings where the burden of human immunodeficiency virus infection is greatest. In the absence of VL monitoring, switches to second-line ART are based on World Health Organization (WHO) clinical or immunologic failure criteria. METHODS: We assessed the performance of CD4 cell criteria to predict virologic outcomes in a large ART program in Nigeria. Laboratory monitoring consists of CD4 cell count and VL at baseline, then every 6 months. Failure was defined as 2 consecutive VLs >1000 copies/mL after at least 6 months of ART. Virologic outcomes were compared with the 3 WHO-defined immunologic failure criteria. RESULTS: A total of 9690 patients were included in the analysis (median follow-up, 33.2 months). A total of 1225 patients experienced failure by both immunologic and virologic criteria, 872 by virologic criteria only, and 1897 by immunologic criteria only. The sensitivity of CD4 cell criteria to detect viral failure was 58%, specificity was 75%, and the positive-predictive value was 39%. For patients with both virologic and immunologic failure, VL criteria identified failure significantly earlier than CD4 cell criteria (median, 10.4 vs 15.6 months; P < .0001). CONCLUSIONS: Because of the low sensitivity of immunologic criteria, a substantial number of failures are missed, potentially resulting in accumulation of resistance mutations. In addition, specificity and predictive values are low, which may result in large numbers of unnecessary ART switches. Monitoring solely by immunologic criteria may result in increased costs because of excess switches to more expensive ART and development of drug-resistant virus.