Prosper Okonkwo

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.

Intimate Partner Violence among Women of Childbearing Age in a Primary Health Care Centre in Nigeria

This study assessed the prevalence and characteristics of intimate partner violence among women of childbearing age in a primary health centre. With interviewer-administered questionnaire, information on partner violence was elicited from three hundred women of childbearing age selected by systematic sampling in a primary health care (PHC) centre. Over 40% had experienced violence within the last 12 months. Type of marriage and partners education had effect on violence. Perceived reasons for violence were economic demand (56.1%), reproductive issues (42.5%), alcohol and drugs (61.2%). Forty eight per cent reported to family members. Only 1% reported to the Police. Intimate partner violence is a prevalent public health problem in eastern Nigeria. Health workers and social organisations should recognise the problem and offer necessary support, and women should be empowered to navigate through the problem.

Time-Dependent Predictors of Loss to Follow-up in a Large HIV Treatment Cohort in Nigeria

Evaluation of time-dependent predictors of loss to follow-up in a large HIV treatment program revealed that early adherence patterns, in addition to CD4 count and viral load, predicted loss to follow-up and should be used as measures in devising targeted interventions to increase program retention.

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 1st- and 2nd-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3rd-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.

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.

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.

Identifying and prioritizing implementation barriers, gaps, and strategies through the Nigeria implementation science alliance: Getting to zero in the prevention of mother-to-child transmission of HIV

Background:In 2013, Nigeria accounted for 15% of the 1.3 million pregnant women living with HIV in sub-Saharan Africa and 26% of new infections among children worldwide. Despite this, less than 20% of pregnant women in Nigeria received an HIV test during pregnancy, and only 23% of HIV-infected pregnant women received appropriate intervention following HIV diagnosis. This article reports findings from 2 structured group exercises conducted at the first Nigeria Implementation Science Alliance Conference to identify (1) barriers and research gaps related to prevention of mother-to-child transmission (PMTCT) and (2) potential strategies and interventions that could address PMTCT challenges. Methods:Two 1-hour structured group exercises were conducted with 10 groups of 14–15 individuals (n = 145), who were asked to brainstorm barriers and strategies and to rank their top 3 in each category. Data analysis eliminated duplicate responses and categorized each of the priorities along the HIV care continuum: HIV diagnosis, linkage to care, or retention in care. Results:Participating stakeholders identified 20 unique barriers and research gaps related to PMTCT across the HIV continuum. Twenty-five unique interventions and implementation strategies were identified. Similar to the barriers and research gaps, these interventions and strategies were distributed across the HIV care continuum. Conclusions:The barriers and strategies identified in this study represent important pathways to progress addressing MTCT. The deliberate involvement of state and federal policy makers, program implementers, and researchers helps ensure that they are relevant and actionable.

Clinical Utility of Pharmacy-Based Adherence Measurement in Predicting Virologic Outcomes in an Adult HIV-Infected Cohort in Jos, North Central Nigeria

Objectives: We examined the association between adherence to drug-refill visits and virologic outcomes in a cohort of HIV-infected adults on combination antiretroviral therapy (cART) in North Central Nigeria. Methods: Retrospectively, 588 HIV-infected, cART-naive adults (aged ≥15 years), initiated on first-line ART between 2009 and 2010 at the Jos University Teaching Hospital, were evaluated. Association between adherence to drug-refill visits, virologic (viral load > 1000 copies/mL), and immunologic failure was assessed using multivariable logistic regression. Results: After a median of 12 months on cART, 16% (n = 94) and 10% (n = 59) of patients had virologic and immunologic failures, respectively. In the final multivariable model, suboptimal adherence to drug-refill visits was a significant predictor of both virologic (adjusted odds ratio [AOR] 1.6; 95% confidence interval [CI]:1.2–2.3) and immunologic (AOR 1.92; 95% CI:1.06–3.49) failures. Conclusion: Adherence to drug refill is a useful predictor of successful virologic control and could be utilized for routine monitoring of adherence to cART in our clinical setting.

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

While tenofovir-containing antiretroviral therapy is generally considered superior to zidovudine, our analysis demonstrates a higher rate of virologic failure when tenofovir, as compared with zidovudine, was combined with nevirapine-based first-line antiretroviral therapy in a Nigerian human immunodeficiency virus treatment program.

Incidence and predictors of adverse drug events in an African cohort of HIV-infected adults treated with efavirenz

INTRODUCTION Adverse drug reactions associated with efavirenz (EFV) therapy are poorly described beyond the first year of treatment. We aimed to describe the incidence and predictors of EFV-related adverse drug reactions (ADRs) in a cohort of adult Nigerian HIV-infected patients on antiretroviral therapy (ART). METHODS This retrospective cohort study utilized clinical data of HIV-1 infected adults (aged ≥15 years), commenced on efavirenz containing-regimen between January 2004 and December 2011. The time-dependent occurrence of clinical adverse events as defined by the World Health Organization was analyzed by Cox regression analysis. RESULTS A total of 2920 patients with baseline median (IQR) age of 39 (33-46) years, largely made up of men (78%) were included in the study. During 8834 person-years of follow up, 358 adverse drug events were reported; the incidence rate was 40.3 ADRs per 1000 person-years of treatment. Lipodystrophy and neuropsychiatric disorders were the most common ADRs with incidences of 63 and 30 per 1000 patients respectively. About one-third of the neuropsychiatric adverse events were within 12 months of commencement of ART. The risk of neuropsychiatric ADRs was independently predicted for women [adjusted hazard ratio (aHR) 9.05; 95% CI: 5.18-15.82], those aged <40 years (aHR 2.59; 95% CI: 1.50-4.45), advanced HIV disease (WHO stage 3 or 4) [aHR 2.26; 95% CI: 1.37-3.72], and zidovudine [aHR 2.21; 95% CI: 1.27-3.83] or stavudine [aHR 4.22; 95% CI: 1.99-8.92] containing regimen compared to tenofovir. CONCLUSION Neuropsychiatric adverse drug events associated with efavirenz-based ART had both early and late onset in our clinical cohort of patients on chronic EFV therapy. Continuous neuropsychiatric assessment for improved detection and management of neuropsychiatric ADRs is recommended in resource-limited settings where the use of efavirenz-based regimens has been scaled up.