Carolyn Bolton Moore

Changes in cellular immune activation and memory T-cell subsets in HIV-infected Zambian children receiving HAART.

Background:Increased exposure to a broad array of pathogens in children residing in sub-Saharan Africa may lead to heightened immune activation and increased proportions of memory T cells. Changes in the size of these cellular subsets have implications for restoration of normal immune function after treatment with highly active antiretroviral therapy (HAART) and are not well characterized in young sub-Saharan African children. Methods:CD4+ and CD8+ T-cell subsets were measured by flow cytometry in 157 HIV-infected Zambian children before and at 3-month intervals during HAART for up to 30 months and in 34 control children at a single study visit. Results:Before HAART, HIV-infected children had higher levels of activated and effector memory (EM) CD4+ and CD8+ T cells, and lower levels of naive T cells and CD8+ T cells expressing IL-7R&agr;, compared with control children. The median duration of follow-up was 14.9 months (interquartile range, 6.4–23.2) among 120 HIV-infected children with at least 1 study follow-up visit. Levels of immune activation and EM CD4+ T cells declined within 6 months of HAART, but the percentages of EM CD4+ T cells and effector CD8+ T cells remained elevated through 30 months of HAART. IL-7R&agr;-expressing CD8+ T cells increased with HAART, suggesting expansion of memory capacity. Conclusions:HAART significantly reduced levels of immune activation and EM CD4+ T cells, and promoted reconstitution of naive T cells and IL-7R&agr;-expressing CD8+ T cells. However, persistently high levels of EM CD4+ T cells in HIV-infected children may reflect chronic perturbations in T-cell subset composition.

Antiretroviral therapy restores age-dependent loss of resting memory B cells in young HIV-infected Zambian children.

Background:Antiretroviral therapy (ART) is associated with incomplete restoration of resting memory B (RMB) cell percentages in adults infected with HIV, but the effects on RMB cells in children are less well defined, in part because changes in RMB cell percentages are confounded by the development and maturation of the RMB cell pool. The objective of this study was to assess the effect of age at ART initiation on RMB cell percentages over time in HIV-infected Zambian children. Methods:RMB cell percentages (CD19+CD21+CD27+) were measured by flow cytometry in 146 HIV-infected Zambian children (9–120 months old) at baseline and at 3-month intervals after ART initiation and in 34 control children at a single study visit. Results:RMB cell percentages among untreated HIV-infected children younger than 24 months did not differ from those of control children (P = 0.97). Among HIV-infected children older than 24 months of age, however, each 12-month increase in age at ART initiation was associated with a 1.8% decrease in RMB cell percentage. In contrast, RMB cell percentages in control children up to 48 months increased 4.4% with each 12-month increase in age. After 12 months of ART, children aged 24–60 months had a significant increase in RMB cell percentages that no longer differed from those of control children. Conclusions:Initiation of ART in 2- to 5-year-old HIV-infected children resulted in reconstitution of RMB cell percentages to levels similar to control children and may help restore normal development and maintenance of B-cell immunity.

Pediatric HIV-HBV Coinfection in Lusaka, Zambia: Prevalence and Short-Term Treatment Outcomes.

Hepatitis B virus (HBV) is endemic in Africa, where it may occur as an HIV coinfection. Data remain limited on HIV-HBV epidemiology in Africa, particularly in children. Using programmatic data from pediatric HIV clinics in Lusaka, Zambia during 2011-2014, we analyzed the prevalence of chronic HBV coinfection (defined as a single positive hepatitis B surface antigen [HBsAg] test) and its impact on immune recovery and liver enzyme elevation (LEE) during the first year of antiretroviral therapy. Among 411 children and adolescents, 10.4% (95% confidence interval, 7.6-14.1) had HIV-HBV. Coinfected patients were more likely to have World Health Organization stage 3/4, LEE and CD4 <14% at care entry (all p < 0.05). During treatment, CD4 increases and LEE incidence were similar by HBsAg status. HBsAg positivity decreased (11.8% vs. 6.6%; p = 0.24) following HBV vaccine introduction. These findings support screening pediatric HIV patients in Africa for HBV coinfection. Dedicated cohorts are needed to assess long-term outcomes of coinfection.

Estimated mortality on HIV treatment among active patients and patients lost to follow-up in 4 provinces of Zambia: Findings from a multistage sampling-based survey.

Background Survival represents the single most important indicator of successful HIV treatment. Routine monitoring fails to capture most deaths. As a result, both regional assessments of the impact of HIV services and identification of hotspots for improvement efforts are limited. We sought to assess true mortality on treatment, characterize the extent under-reporting of mortality in routine health information systems in Zambia, and identify drivers of mortality across sites and over time using a multistage, regionally representative sampling approach. Methods and findings We enumerated all HIV infected adults on antiretroviral therapy (ART) who visited any one of 64 facilities across 4 provinces in Zambia during the 24-month period from 1 August 2013 to 31 July 2015. We identified a probability sample of patients who were lost to follow-up through selecting facilities probability proportional to size and then a simple random sample of lost patients. Outcomes among patients lost to follow-up were incorporated into survival analysis and multivariate regression through probability weights. Of 165,464 individuals (64% female, median age 39 years (IQR 33–46), median CD4 201 cells/mm3 (IQR 111–312), the 2-year cumulative incidence of mortality increased from 1.9% (95% CI 1.7%–2.0%) to a corrected rate of 7.0% (95% CI 5.7%–8.4%) (all ART users) and from 2.1% (95% CI 1.8%–2.4%) to 8.3% (95% CI 6.1%–10.7%) (new ART users). Revised provincial mortality rates ranged from 3–9 times higher than naïve rates for new ART users and were lowest in Lusaka Province (4.6 per 100 person-years) and highest in Western Province (8.7 per 100 person-years) after correction. Corrected mortality rates varied markedly by clinic, with an IQR of 3.5 to 7.5 deaths per 100 person-years and a high of 13.4 deaths per 100 person-years among new ART users, even after adjustment for clinical (e.g., pretherapy CD4) and contextual (e.g., province and clinic size) factors. Mortality rates (all ART users) were highest year 1 after treatment at 4.6/100 person-years (95% CI 3.9–5.5), 2.9/100 person-years (95% CI 2.1–3.9) in year 2, and approximately 1.6% per year through 8 years on treatment. In multivariate analysis, patient-level factors including male sex and pretherapy CD4 levels and WHO stage were associated with higher mortality among new ART users, while male sex and HIV disclosure were associated with mortality among all ART users. In both cases, being late (>14 days late for appointment) or lost (>90 days late for an appointment) was associated with deaths. We were unable to ascertain the vital status of about one-quarter of those lost and selected for tracing and did not adjudicate causes of death. Conclusions HIV treatment in Zambia is not optimally effective. The high and sustained mortality rates and marked under-reporting of mortality at the provincial-level and unexplained heterogeneity between regions and sites suggest opportunities for the use of corrected mortality rates for quality improvement. A regionally representative sampling-based approach can bring gaps and opportunities for programs into clear epidemiological focus for local and global decision makers.

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3-36 months with HIV infection

Objectives: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. Design: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). Methods: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35–180 &mgr;g*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. Results: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 &mgr;g*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. Conclusion: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.

Association between hepatitis B co-infection and elevated liver stiffness among HIV-infected adults in Lusaka, Zambia.

To describe liver disease epidemiology among HIV‐infected individuals in Zambia.

Managing multiple funding streams and agendas to achieve local and global health and research objectives: Lessons from the field

Abstract:Multiple funding sources provide research and program implementation organizations a broader base of funding and facilitate synergy, but also entail challenges that include varying stakeholder expectations, unaligned grant cycles, and highly variable reporting requirements. Strong governance and strategic planning are essential to ensure alignment of goals and agendas. Systems to track budgets and outputs, as well as procurement and human resources are required. A major goal of funders is to transition leadership and operations to local ownership. This article details successful approaches used by the newly independent nongovernmental organization, the Centre for Infectious Disease Research in Zambia.

Understanding preferences for HIV care and treatment in Zambia: Evidence from a discrete choice experiment among patients who have been lost to follow-up

Background In public health HIV treatment programs in Africa, long-term retention remains a challenge. A number of improvement strategies exist (e.g., bring services closer to home, reduce visit frequency, expand hours of clinic operation, improve provider attitude), but implementers lack data about which to prioritize when resource constraints preclude implementing all. We used a discrete choice experiment (DCE) to quantify preferences for a number of potential clinic improvements to enhance retention. Methods and findings We sought a random sample of HIV patients who were lost to follow-up (defined as >90 days late for their last scheduled appointment) from treatment facilities in Lusaka Province, Zambia. Among those contacted, we asked patients to choose between 2 hypothetical clinics in which the following 5 attributes of those facilities were varied: waiting time at the clinic (1, 3, or 5 hours), distance from residence to clinic (5, 10, or 20 km), ART supply given at each refill (1, 3, or 5 months), hours of operation (morning only, morning and afternoon, or morning and Saturday), and staff attitude (“rude” or “nice”). We used mixed-effects logistic regression to estimate relative utility (i.e., preference) for each attribute level. We calculated how much additional waiting time or travel distance patients were willing to accept in order to obtain other desired features of care. Between December 9, 2015 and May 31, 2016, we offered the survey to 385 patients, and 280 participated (average age 35; 60% female). Patients exhibited a strong preference for nice as opposed to rude providers (relative utility of 2.66; 95% CI 1.9–3.42; p < 0.001). In a standard willingness to wait or willingness to travel analysis, patients were willing to wait 19 hours more or travel 45 km farther to see nice rather than rude providers. An alternative analysis, in which trade-offs were constrained to values actually posed to patients in the experiment, suggested that patients were willing to accept a facility located 10 km from home (as opposed to 5) that required 5 hours of waiting per visit (as opposed to 1 hour) and that dispensed 3 months of medications (instead of 5) in order to access nice (as opposed to rude) providers. This study was limited by the fact that attributes included in the experiment may not have captured additional important determinants of preference. Conclusions In this study, patients were willing to expend considerable time and effort as well as accept substantial inconvenience in order to access providers with a nice attitude. In addition to service delivery redesign (e.g., differentiated service delivery models), current improvement strategies should also prioritize improving provider attitude and promoting patient centeredness—an area of limited policy attention to date.

Quality of Care and Service Expansion for HIV Care and Treatment

The last two decades have seen exceptional development of antiretroviral treatment programs throughout the world. Over 14 million persons are accessing antiretroviral treatment (ART) treatment as of early 2015, and life expectancy has risen markedly in the most-affected populations. However, large patient numbers threaten to overwhelm already over-burdened health care systems and retention in care remains suboptimal. Developing innovative strategies to alleviate these burdens and retain patients in care remains a challenge. Furthermore, despite this expansion, large populations of HIV-infected persons remain undiagnosed and are unwilling or unable to access care and treatment programs. Marginalized and high-risk populations are particularly in danger of remaining outside of care and are also disproportionately affected by HIV. To reverse the trend and “fast track” our way out of the epidemic, ambitious treatment targets are required, and a concerted effort has to be made to engage these populations into care, initiate ART, and attain viral suppression.

Application of a Multistate Model to Evaluate Visit Burden and Patient Stability to Improve Sustainability of Human Immunodeficiency Virus Treatment in Zambia

Background Differentiated service delivery (DSD) for human immunodeficiency virus (HIV)-infected persons who are clinically stable on antiretroviral therapy (ART) has been embraced as a solution to decrease access barriers and improve quality of care. However, successful DSD implementation is dependent on understanding the prevalence, incidence, and durability of clinical stability. Methods We evaluated visit data in a cohort of HIV-infected adults who made at least 1 visit between 1 March 2013 and 28 February 2015 at 56 clinics in Zambia. We described visit frequency and appointment intervals using conventional stability criteria and used a mixed-effects linear regression model to identify predictors of appointment interval. We developed a multistate model to characterize patient stability over time and calculated incidence rates for transition between states. Results Overall, 167819 patients made 3418018 post-ART initiation visits between 2004 and 2015. Fifty-four percent of visits were pharmacy refill-only visits, and 24% occurred among patients on ART for >6 months and whose current CD4 was >500 cells/mm3. Median appointment interval at clinician visits was 59 days, and time on ART and current CD4 were not strong predictors of appointment interval. Cumulative incidence of clinical stability was 66.2% at 2 years after enrollment, but transition to instability (31 events per 100 person-years) and lapses in care (41 events per100 person-years) were common. Conclusions Current facility-based care was characterized by high visit burden due to pharmacy refills and among treatment-experienced patients. Differentiated service delivery models targeted toward stable patients need to be adaptive given that clinical stability was highly transient and lapses in care were common.