Mortality Among HIV-Infected Adults on Antiretroviral Therapy in Southern Uganda.

BACKGROUND: Monitoring and evaluation of clinical programs requires assessing patient outcomes. Numerous challenges complicate these efforts, the most insidious of which is loss to follow-up (LTFU). LTFU is a composite outcome, including individuals out of care, undocumented transfers, and unreported deaths. Incorporation of vital status information from routine patient outreach may improve the mortality estimates for those LTFU. SETTINGS: We analyzed routinely collected clinical and patient tracing data for individuals (15 years or older) initiating antiretroviral treatment between January 2014 and December 2018 at 2 public HIV care clinics in greater Rakai, Uganda. METHODS: We derived unadjusted mortality estimates using Kaplan-Meier methods. Estimates, adjusted for unreported deaths, applied weighting through the Frangakis and Rubin method to represent outcomes among LTFU patients who were successfully traced and for whom vital status was ascertained. Confidence intervals were determined through bootstrap methods. RESULTS: Of 1969 patients with median age at antiretroviral treatment initiation of 31 years (interquartile range: 25-38), 1126 (57.2%) were female patients and 808 (41%) were lost. Of the lost patients, 640 patient files (79.2%) were found and reviewed, of which 204 (31.8%) had a tracing attempt. Within the electronic health records of the program, 28 deaths were identified with an estimated unadjusted mortality 1 year after antiretroviral treatment initiation of 2.5% (95% CI: 1.8% to 3.3%). Using chart review and patient tracing data, an additional 24 deaths (total 52) were discovered with an adjusted 1-year mortality of 3.8% (95% CI: 2.6% to 5.0%). CONCLUSIONS: Data from routine outreach efforts by HIV care and treatment programs can be used to support plausible adjustments to estimates of client mortality. Mortality estimates without active ascertainment of vital status of LTFU patients may significantly underestimate program mortality.

Assessing HIV-infected patient retention in a program of differentiated care in sub-Saharan Africa: a G-estimation approach.

Differentiated care delivery aims to simplify care of people living with HIV, reflect their preferences, reduce burdens on the healthcare system, maintain care quality and preserve resources. However, assessing program effectiveness using observational data is difficult due to confounding by indication and randomized trials may be infeasible. Also, benefits can reach patients directly, through enrollment in the program, and indirectly, by increasing quality of and accessibility to care. Low-risk express care (LREC), the program under evaluation, is a nurse-centered model which assigns patients stable on ART to a nurse every two months and a clinician every third visit, reducing annual clinician visits by two thirds. Study population is comprised of 16,832 subjects from 15 clinics in Kenya. We focus on patient retention in care based on whether the LREC program is available at a clinic and whether the patient is enrolled in LREC. We use G-estimation to assess the effect on retention of two "strategies": (i) program availability but no enrollment; (ii) enrollment at an available program; versus no program availability. Compared to no availability, LREC results in a non-significant increase in patient retention, among patients not enrolled in the program (indirect effect), while enrollment in LREC is associated with a significant extension of the time retained in care (direct effect). G-estimation provides an analytical framework useful to the assessment of similar programs using observational data.

The Effect of HIV Treatment Interruption on Subsequent Immunological Response.

Recovery of CD4-positive T lymphocyte count after initiation of antiretroviral therapy (ART) has been thoroughly examined among people with human immunodeficiency virus infection. However, immunological response after restart of ART following care interruption is less well studied. We compared CD4 cell-count trends before disengagement from care and after ART reinitiation. Data were obtained from the East Africa International Epidemiology Databases to Evaluate AIDS (IeDEA) Collaboration (2001-2011; n = 62,534). CD4 cell-count trends before disengagement, during disengagement, and after ART reinitiation were simultaneously estimated through a linear mixed model with 2 subject-specific knots placed at the times of disengagement and treatment reinitiation. We also estimated CD4 trends conditional on the baseline CD4 value. A total of 10,961 patients returned to care after disengagement from care, with the median gap in care being 2.7 (interquartile range, 2.1-5.4) months. Our model showed that CD4 cell-count increases after ART reinitiation were much slower than those before disengagement. Assuming that disengagement from care occurred 12 months after ART initiation and a 3-month treatment gap, CD4 counts measured at 3 years since ART initiation would be lower by 36.5 cells/µL than those obtained under no disengagement. Given that poorer CD4 restoration is associated with increased mortality/morbidity, specific interventions targeted at better retention in care are urgently required.

Clinical and programmatic outcomes of HIV-exposed infants enrolled in care at geographically diverse clinics, 1997-2021: A cohort study.

BACKGROUND: Although 1·3 million women with HIV give birth annually, care and outcomes for HIV-exposed infants remain incompletely understood. We analyzed programmatic and health indicators in a large, multidecade global dataset of linked mother-infant records from clinics and programs associated with the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS AND FINDINGS: HIV-exposed infants were eligible for this retrospective cohort analysis if enrolled at <18 months at 198 clinics in 10 countries across 5 IeDEA regions: East Africa (EA), Central Africa (CA), West Africa (WA), Southern Africa (SA), and the Caribbean, Central, and South America network (CCASAnet). We estimated cumulative incidences of DNA PCR testing, loss to follow-up (LTFU), HIV diagnosis, and death through 24 months of age using proportional subdistribution hazard models accounting for competing risks. Competing risks were transfer, care withdrawal, and confirmation of negative HIV status, along with LTFU and death, when not the outcome of interest. In CA and EA, we quantified associations between maternal/infant characteristics and each outcome. A total of 82,067 infants (47,300 EA, 10,699 CA, 6,503 WA, 15,770 SA, 1,795 CCASAnet) born from 1997 to 2021 were included. Maternal antiretroviral therapy (ART) use during pregnancy ranged from 65·6% (CCASAnet) to 89·5% (EA), with improvements in all regions over time. Twenty-four-month cumulative incidences varied widely across regions, ranging from 12·3% (95% confidence limit [CL], 11·2%,13·5%) in WA to 94·8% (95% CL, 94·6%,95·1%) in EA for DNA PCR testing; 56·2% (95% CL, 55·2%,57·1%) in EA to 98·5% (95% CL, 98·3%,98·7%) in WA for LTFU; 1·9% (95% CL, 1·6%,2·3%) in WA to 10·3% (95% CL, 9·7%,10·9%) in EA for HIV diagnosis; and 0·5% (95% CL, 0·2%,1·0%) in CCASAnet to 4·7% (95% CL, 4·4%,5·0%) in EA for death. Although infant retention did not improve, HIV diagnosis and death decreased over time, and in EA, the cumulative incidence of HIV diagnosis decreased substantially, declining to 2·9% (95% CL, 1·5%,5·4%) in 2020. Maternal ART was associated with decreased infant mortality (subdistribution hazard ratio [sdHR], 0·65; 95% CL, 0·47,0·91 in EA, and sdHR, 0·51; 95% CL, 0·36,0·74 in CA) and HIV diagnosis (sdHR, 0·40; 95% CL, 0·31,0·50 in EA, and sdHR, 0·41; 95% CL, 0·31,0·54 in CA). Study limitations include potential misclassification of outcomes in real-world service delivery data and possible nonrepresentativeness of IeDEA sites and the population of HIV-exposed infants they serve. CONCLUSIONS: While there was marked regional and temporal heterogeneity in clinical and programmatic outcomes, infant LTFU was high across all regions and time periods. Further efforts are needed to keep HIV-exposed infants in care to receive essential services to reduce HIV infection and mortality.

Disparities in Dolutegravir Uptake Affecting Females of Reproductive Age With HIV in Low- and Middle-Income Countries After Initial Concerns About Teratogenicity : An Observational Study.

BACKGROUND: The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. OBJECTIVE: To describe dolutegravir uptake and disparities by sex and age group in LMICs. DESIGN: Observational cohort study. SETTING: 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. PATIENTS: 134 672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. MEASUREMENTS: Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). RESULTS: Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. LIMITATION: Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. CONCLUSION: Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. PRIMARY FUNDING SOURCE: National Institutes of Health.

Viral Load Status Before Switching to Dolutegravir-Containing Antiretroviral Therapy and Associations With Human Immunodeficiency Virus Treatment Outcomes in Sub-Saharan Africa.

BACKGROUND: Dolutegravir is being rolled out globally as part of preferred antiretroviral therapy (ART) regimens, including among treatment-experienced patients. The role of viral load (VL) testing before switching patients already on ART to a dolutegravir-containing regimen is less clear in real-world settings. METHODS: We included patients from the International epidemiology Databases to Evaluate AIDS consortium who switched from a nevirapine- or efavirenz-containing regimen to one with dolutegravir. We used multivariable cause-specific hazards regression to estimate the association of the most recent VL test in the 12 months before switching with subsequent outcomes. RESULTS: We included 36 393 patients at 37 sites in 5 countries (Democratic Republic of the Congo, Kenya, Rwanda, Tanzania, Uganda) who switched to dolutegravir from July 2017 through February 2020, with a median follow-up of approximately 11 months. Compared with those who switched with a VL <200 copies/mL, patients without a recent VL test or with a preswitch VL ≥1000 copies/mL had significantly increased hazards of an incident VL ≥1000 copies/mL (adjusted hazard ratio [aHR], 2.89; 95% confidence interval [CI], 1.99-4.19 and aHR, 6.60; 95% CI, 4.36-9.99, respectively) and pulmonary tuberculosis or a World Health Organization clinical stage 4 event (aHR, 4.78; 95% CI, 2.77-8.24 and aHR, 13.97; 95% CI, 6.62-29.50, respectively). CONCLUSIONS: A VL test before switching to dolutegravir may help identify patients who need additional clinical monitoring and/or adherence support. Further surveillance of patients who switched to dolutegravir with an unknown or unsuppressed VL is needed.

Outcomes of retained and disengaged pregnant women living with HIV in Uganda.

INTRODUCTION: Loss-to-follow-up among women living with HIV (WLWHIV) may lead to unfavorable outcomes for both mother and exposed infant. This study traced WLWHIV disengaged from care and their infants and compared their outcomes with those retained in care. METHODS: The study included WLWHIV who initiated ART during pregnancy at six public clinics in Uganda. A woman was defined as disengaged (DW) if she had not attended her 6-week post-partum visit by 10 weeks after her estimated date of delivery. DW were matched with retained women (RW) by age and duration on ART. Nurse counselors traced all selected DW via telephone and community visits to assess vital status, infant HIV sero-status and maternal HIV viral load through blood draws. RESULTS: Between July 2017 and July 2018, 734 women (359 DW and 375 RW) were identified for the study. Tracing was attempted on 349 DW and 160 (44.6%) were successfully located and enrolled in the study. They were matched with 162 RW. Among DW, 52 (32.5%) transferred to another health facility. Very few DW, 39.0% were HIV virally suppressed (<1000 copies/ml) compared to RW 89.5%, P<0.001). Among 138 babies born to DW, 4.3% tested positive for HIV compared to 1.4% among babies born to RW (P = 0.163). CONCLUSION: Pregnant and breastfeeding WLWHIV who disengage from care are difficult to find in urban environments. Many have detectable viral loads, leading to the potential for an increased risk of MTCT. Efforts to reduce disengagement from care are critical for the successful elimination of MTCT in resource-limited settings.

Decreasing incidence of pregnancy among HIV-positive adolescents in a large HIV treatment program in western Kenya between 2005 and 2017: a retrospective cohort study.

BACKGROUND: The objective of this study was to estimate the prevalence, incidence and risk factors for pregnancy among HIV-positive adolescents in a large HIV treatment program in western Kenya. METHODS: The Academic Model Providing Access to Healthcare (AMPATH) program is a partnership between Moi University, Moi Teaching and Referral Hospital and a consortium of 11 North American academic institutions. AMPATH currently provides care to 85,000 HIV-positive individuals in western Kenya. Included in this analysis were adolescents aged 10-19 enrolled in AMPATH between January 2005 and February 2017. Socio-demographic, behavioural, and clinical data at baseline and time-updated antiretroviral treatment (ART) data were extracted from the electronic medical records and summarized using descriptive statistics. Follow up time was defined as time of inclusion in the cohort until the date of first pregnancy or age 20, loss to follow up, death, or administrative censoring. Adolescent pregnancy rates and associated risk factors were determined. RESULTS: There were 8565 adolescents eligible for analysis. Median age at enrolment in HIV care was 14.0 years. Only 17.7% had electricity at home and 14.4% had piped water, both indicators of a high level of poverty. 12.9% (1104) were pregnant at study inclusion. Of those not pregnant at enrolment, 5.6% (448) became pregnant at least once during follow-up. Another 1.0% (78) were pregnant at inclusion and became pregnant again during follow-up. The overall pregnancy incidence rate was 21.9 per 1000 woman years or 55.8 pregnancies per 1000 women. Between 2005 and 2017, pregnancy rates have decreased. Adolescents who became pregnant in follow-up were more likely to be older, to be married or living with a partner and to have at least one child already and less likely to be using family planning. CONCLUSIONS: A considerable number of these HIV-positive adolescents presented at enrolment into HIV care as pregnant and many became pregnant as adolescents during follow-up. Pregnancy rates remain high but have decreased from 2005 to 2017. Adolescent-focused sexual and reproductive health and ante/postnatal care programs may have the potential to improve maternal and neonatal outcomes as well as further decrease pregnancy rates in this high-risk group.

Lower rates of ART initiation and decreased retention among ART-naïve patients who consume alcohol enrolling in HIV care and treatment programs in Kenya and Uganda.

OBJECTIVES: Almost 13 million people are estimated to be on antiretroviral therapy in Eastern and Southern Africa, and their disease course and program effectiveness could be significantly affected by the concurrent use of alcohol. Screening for alcohol use may be important to assess the prevalence of alcohol consumption and its impact on patient and programmatic outcomes. METHODS: As part of this observational study, data on patient characteristics and alcohol consumption were collected on a cohort of 765 adult patients enrolling in HIV care in East Africa. Alcohol consumption was assessed with the AUDIT questionnaire at enrollment. Subjects were classified as consuming any alcohol (AUDIT score >0), hazardous drinkers (AUDIT score ≥8) and hyper drinkers (AUDIT score ≥16). The effects of alcohol consumption on retention in care, death and delays in antiretroviral therapy (ART) initiation were assessed through competing risk (Fine & Gray) models. RESULTS: Of all study participants, 41.6% consumed alcohol, 26.7% were classified as hazardous drinkers, and 16.0% as hyper drinkers. Depending on alcohol consumption classification, men were 3-4 times more likely to consume alcohol compared to women. Hazardous drinkers (median age 32.8 years) and hyper drinkers (32.7 years) were slightly older compared to non-hazardous drinkers (30.7 years) and non-hyper drinkers (30.8 years), (p-values = 0.014 and 0.053 respectively). Median CD4 at enrollment was 330 cells/µl and 16% were classified World Health Organization (WHO) stage 3 or 4. There was no association between alcohol consumption and CD4 count or WHO stage at enrollment. Alcohol consumption was associated with significantly lower probability of ART initiation (adjusted sub-distribution hazard ratio aSHR = 0.77 between alcohol consumers versus non-consumers; p-value = 0.008), and higher patient non-retention in care (aSHR = 1.77, p-value = 0.023). DISCUSSION: Alcohol consumption is associated with significant delays in ART initiation and reduced retention in care for patients enrolling in HIV care and treatment programs in East Africa. Consequently, interventions that target alcohol consumption may have a significant impact on the HIV care cascade.

Implementation of "Treat-all" at adult HIV care and treatment sites in the Global IeDEA Consortium: results from the Site Assessment Survey.

INTRODUCTION: Since 2015, the World Health Organization (WHO) has recommended that all people living with HIV (PLHIV) initiate antiretroviral treatment (ART), irrespective of CD4+ count or clinical stage. National adoption of universal treatment has accelerated since WHO's 2015 "Treat All" recommendation; however, little is known about the translation of this guidance into practice. This study aimed to assess the status of Treat All implementation across regions, countries, and levels of the health care delivery system. METHODS: Between June and December 2017, 201/221 (91%) adult HIV treatment sites that participate in the global IeDEA research consortium completed a survey on capacity and practices related to HIV care. Located in 41 countries across seven geographic regions, sites provided information on the status and timing of site-level introduction of Treat All, as well as site-level practices related to ART initiation. RESULTS: Almost all sites (93%) reported that they had begun implementing Treat All, and there were no statistically significant differences in site-level Treat All introduction by health facility type, urban/rural location, sector (public/private) or country income level. The median time between national policy adoption and site-level introduction was one month. In countries where Treat All was not yet adopted in national guidelines, 69% of sites reported initiating all patients on ART, regardless of clinical criteria, and these sites had been implementing Treat All for a median period of seven months at the time of the survey. The majority of sites (77%) reported typically initiating patients on ART within 14 days of confirming diagnosis, with 60% to 62% of sites implementing Treat All in East, Southern and West Africa reporting same-day ART initiation for most patients. CONCLUSIONS: By mid- to late-2017, the Treat All strategy was the standard of care at almost all IeDEA sites, including rural, primary-level health facilities in low-resource settings. While further assessments of site-level capacity to provide high-quality HIV care under Treat All and to support sustained viral suppression after ART initiation are needed, the widespread introduction of Treat All at the service delivery level is a critical step towards global targets for ending the HIV epidemic as a public health threat.

Adolescent pregnancy at antiretroviral therapy (ART) initiation: a critical barrier to retention on ART.

INTRODUCTION: Adolescence and pregnancy are potential risk factors for loss to follow-up (LTFU) while on antiretroviral therapy (ART). We compared adolescent and adult LTFU after ART initiation to quantify the impact of age, pregnancy, and site-level factors on LTFU. METHODS: We used routine clinical data for patients initiating ART as young adolescents (YA; 10 to 14 years), older adolescents (OA; 15 to 19 years) and adults (≥20 years) from 2000 to 2014 at 52 health facilities affiliated with the International epidemiology Databases to Evaluate AIDS (IeDEA) East Africa collaboration. We estimated cumulative incidence (95% confidence interval, CI) of LTFU (no clinic visit for ≥6 months after ART initiation) and identified patient and site-level correlates of LTFU, using multivariable Cox proportional hazards models for all patients as well as individual age groups. RESULTS: A total of 138,387 patients initiated ART, including 2496 YA, 2955 OA and 132,936 adults. Of these, 55%, 78% and 66%, respectively, were female and 0.7% of YA, 22.3% of OA and 8.3% of adults were pregnant at ART initiation. Cumulative incidence of LTFU at five years was 26.6% (24.6 to 28.6) among YA, 44.1% (41.8 to 46.3) among OA and 29.3% (29.1 to 29.6) among adults. Overall, compared to adults, the adjusted hazard ratio, aHR, (95% CI) of LTFU for OA was 1.54 (1.41 to 1.68) and 0.77 (0.69 to 0.86) for YA. Compared to males, pregnant females had higher hazard of LTFU, aHR 1.20 (1.14 to 1.27), and nonpregnant women had lower hazard aHR 0.90 (0.88 to 0.93). LTFU hazard among the OA was primarily driven by both pregnant and nonpregnant females, aHR 2.42 (1.98 to 2.95) and 1.51 (1.27 to 1.80), respectively, compared to men. The LTFU hazard ratio varied by IeDEA program. Site-level factors associated with overall lower LTFU hazard included receiving care in tertiary versus primary-care clinics aHR 0.61 (0.56 to 0.67), integrated adult and adolescent services and food ration provision aHR 0.93 (0.89 to 0.97) versus nonintegrated clinics with food ration provision, having patient support groups aHR 0.77 (0.66 to 0.90) and group adherence counselling aHR 0.61 (0.57 to 0.67). CONCLUSIONS: Older adolescents experienced higher risk of LTFU compared to YA and adults. Interventions to prevent LTFU among older adolescents are critically needed, particularly for female and/or pregnant adolescents.

Trends Over Time for Adolescents Enrolling in HIV Care in Kenya, Tanzania, and Uganda From 2001-2014.

BACKGROUND: The data needed to understand the characteristics and outcomes, over time, of adolescents enrolling in HIV care in East Africa are limited. SETTING: Six HIV care programs in Kenya, Tanzania, and Uganda. METHODS: This retrospective cohort study included individuals enrolling in HIV care as younger adolescents (10-14 years) and older adolescents (15-19 years) from 2001-2014. Descriptive statistics were used to compare groups at enrollment and antiretroviral therapy (ART) initiation over time. The proportion of adolescents was compared with the total number of individuals aged 10 years and older enrolling over time. Competing-risk analysis was used to estimate 12-month attrition after enrollment/pre-ART initiation; post-ART attrition was estimated by Kaplan-Meier method. RESULTS: A total of 6344 adolescents enrolled between 2001 and 2014. The proportion of adolescents enrolling among all individuals increased from 2.5% (2001-2004) to 3.9% (2013-2014, P < 0.0001). At enrollment, median CD4 counts in 2001-2004 compared with 2013-2014 increased for younger (188 vs. 379 cells/mm, P < 0.0001) and older (225 vs. 427 cells/mm, P < 0.0001) adolescents. At ART initiation, CD4 counts increased for younger (140 vs. 233 cells/mm, P < 0.0001) and older (64 vs. 323 cells/mm, P < 0.0001) adolescents. Twelve-month attrition also increased for all adolescents both after enrollment/pre-ART initiation (4.7% vs. 12.0%, P < 0.001) and post-ART initiation (18.7% vs. 31.2%, P < 0.001). CONCLUSIONS: Expanding HIV services and ART coverage was likely associated with earlier adolescent enrollment and ART initiation but also with higher attrition rates before and after ART initiation. Interventions are needed to promote retention in care among adolescents.

Time to First-Line ART Failure and Time to Second-Line ART Switch in the IeDEA Pediatric Cohort.

BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second-line. METHODS: Children initiating their first ART regimen between 2 and 14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis. Outcomes of interest were: first-line ART failure (clinical, immunologic, or virologic), change to second-line, and attrition (death or loss to program ). Cumulative incidence was computed for first-line failure and second-line initiation, with attrition as a competing event. RESULTS: In 27,031 children, median age at ART initiation was 6.7 years. Median baseline CD4% for children ≤5 years of age was 13.2% and CD4 count for those >5 years was 258 cells per microliter. Almost all (94.4%) initiated a nonnucleoside reverse transcriptase inhibitor; 5.3% a protease inhibitor, and 0.3% a triple nucleoside reverse transcriptase inhibitor-based regimen. At 1 year, 7.7% had failed and 14.4% had experienced attrition; by 5 years, the cumulative incidence was 25.9% and 29.4%, respectively. At 1 year after ART failure, 13.7% had transitioned to second-line and 11.2% had experienced attrition; by 5 years, the cumulative incidence was 31.6% and 25.9%, respectively. CONCLUSIONS: High rates of first-line failure and attrition were identified in children within 5 years after ART initiation. Of children meeting failure criteria, only one-third were transitioned to second-line ART within 5 years.

Adherence to antiretroviral therapy in a clinical cohort of HIV-infected children in East Africa.

OBJECTIVE: To describe antiretroviral therapy (ART) adherence and associated factors for a large HIV-infected pediatric cohort followed by sites of the East Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) consortium. METHODS: This study utilized prospectively collected clinical data from HIV-infected children less than 13 years of age who initiated ART within 4 clinical care programs (with 26 clinical sites) in Kenya, Uganda, and Tanzania and were followed for up to 6 years. Programs used one of 3 adherence measures, including 7-day quantitative recall, 7-day categorical recall, and clinician pill assessments. We fit a hierarchical, three-level, logistic-regression model to examine adherence, with observations nested within patient, and patients within the 26 sites providing pediatric HIV data to this analysis. RESULTS: In East Africa, 3,304 children, 52.0% male, were enrolled in care and were subsequently observed for a median of 92 weeks (inter-quartile range [IQR] 50.3-145.0 weeks). Median age at ART initiation was 5.5 years ([IQR] 3.0-8.5 years). "Good" adherence, as reported by each clinic's measures, was extremely high, remaining on average above 90% throughout all years of follow-up. Longer time on ART was associated with higher adherence (adjusted Odds Ratio-aOR-per log-transformed week on ART: 1.095, 95% Confidence Interval-CI-[1.052-1.150].) Patients enrolled in higher-volume programs exhibited higher rates of clinician-assessed adherence (aOR per log-500 patients: 1.174, 95% CI [1.108-1.245]). Significant site-level variability in reported adherence was observed (0.28), with even higher variability among patients (0.71). In a sub-analysis, being an orphan at the start of ART was strongly associated with lower ART adherence rates (aOR: 0.919, 95% CI [0.864-0.976]). CONCLUSIONS: Self-reported adherence remained high over a median of 1.8 years in HIV care, but varied according to patient-level and site-level factors. Consistent adherence monitoring with validated measures and attention to vulnerable groups is recommended.

Increased prevalence of pregnancy and comparative risk of program attrition among individuals starting HIV treatment in East Africa.

BACKGROUND: The World Health Organization now recommends initiating all pregnant women on life-long antiretroviral therapy (ART), yet there is limited information about the characteristics and program outcomes of pregnant women already on ART in Africa. Our hypothesis was that pregnant women comprised an increasing proportion of those starting ART, and that sub-groups of these women were at higher risk for program attrition. METHODS AND FINDINGS: We used the International Epidemiology Databases to Evaluate AIDS- East Africa (IeDEA-EA) to conduct a retrospective cohort study including HIV care and treatment programs in Kenya, Uganda, and Tanzania. The cohort consecutively included HIV-infected individuals 13 years or older starting ART 2004-2014. We examined trends over time in the proportion pregnant, their characteristics and program attrition rates compared to others initiating and already receiving ART. 156,474 HIV-infected individuals (67.0% women) started ART. The proportion of individuals starting ART who were pregnant women rose from 5.3% in 2004 to 12.2% in 2014. Mean CD4 cell counts at ART initiation, weighted for annual program size, increased from 2004 to 2014, led by non-pregnant women (annual increase 20 cells/mm3) and men (17 cells/mm3 annually), with lower rates of change in pregnant women (10 cells/mm3 per year) (p<0.0001). There was no significant difference in the cumulative incidence of program attrition at 6 months among pregnant women starting ART and non-pregnant women. However, healthy pregnant women starting ART (WHO stage 1/2) had a higher rate of attrition rate (9.6%), compared with healthy non-pregnant women (6.5%); in contrast among women with WHO stage 3/4 disease, pregnant women had lower attrition (8.4%) than non-pregnant women (14.4%). Among women who initiated ART when healthy and remained in care for six months, subsequent six-month attrition was slightly higher among pregnant women at ART start (3.5%) compared to those who were not pregnant (2.4%), (absolute difference 1.1%, 95% CI 0.7%-1.5%). CONCLUSIONS: Pregnant women comprise an increasing proportion of those initiating ART in Africa, and pregnant women starting ART while healthy are at higher risk for program attrition than non-pregnant women. As ART programs further expand access to healthier pregnant women, further studies are needed to better understand the drivers of loss among this high risk group of women to optimize retention.

Diagnostic and Prognostic Value of JC Virus DNA in Plasma in Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (John Cunningham; JCV) that affects patients with impaired immune systems. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is uncertain. Methods: We retrospectively analyzed plasma samples from PML patients that were drawn close to disease onset and from controls without PML. In PML patients, we compared plasma JCV-DNA detection and levels to clinical and laboratory parameters, and patient survival. Results: JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, human immunodeficiency virus [HIV] negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive), respectively. Among 16 PML patients with undetectable CSF JCV-DNA, 4 (25%) had detectable plasma JCV-DNA. Plasma JCV-DNA levels were independently associated with CSF levels (P < .0001) and previous corticosteroid treatment (P = .012). Higher plasma JCV-DNA levels were associated with disease progression in HIV-negative patients (P = .005); in HIV-positive patients, there was an increased risk of progression only in those treated with combination antiretroviral therapy (cART; P < .0001). Conclusions: Testing JCV-DNA in plasma might complement PML diagnosis, especially when CSF is unavailable or JCV-DNA not detectable in CSF. In addition, JCV-DNA plasma levels could be useful as a marker of disease progression in both HIV-negative and cART-treated, HIV-positive PML patients.

A state transition framework for patient-level modeling of engagement and retention in HIV care using longitudinal cohort data.

The human immunodeficiency virus (HIV) care cascade is a conceptual model used to outline the benchmarks that reflects effectiveness of HIV care in the whole HIV care continuum. The models can be used to identify barriers contributing to poor outcomes along each benchmark in the cascade such as disengagement from care or death. Recently, the HIV care cascade has been widely applied to monitor progress towards HIV prevention and care goals in an attempt to develop strategies to improve health outcomes along the care continuum. Yet, there are challenges in quantifying successes and gaps in HIV care using the cascade models that are partly due to the lack of analytic approaches. The availability of large cohort data presents an opportunity to develop a coherent statistical framework for analysis of the HIV care cascade. Motivated by data from the Academic Model Providing Access to Healthcare, which has provided HIV care to nearly 200,000 individuals in Western Kenya since 2001, we developed a state transition framework that can characterize patient-level movements through the multiple stages of the HIV care cascade. We describe how to transform large observational data into an analyzable format. We then illustrate the state transition framework via multistate modeling to quantify dynamics in retention aspects of care. The proposed modeling approach identifies the transition probabilities of moving through each stage in the care cascade. In addition, this approach allows regression-based estimation to characterize effects of (time-varying) predictors of within and between state transitions such as retention, disengagement, re-entry into care, transfer-out, and mortality. Copyright © 2017 John Wiley & Sons, Ltd.

Observational Study of the Effect of Patient Outreach on Return to Care: The Earlier the Better.

BACKGROUND: The burden of HIV remains heaviest in resource-limited settings, where problems of losses to care, silent transfers, gaps in care, and incomplete mortality ascertainment have been recognized. METHODS: Patients in care at Academic Model Providing Access to Healthcare (AMPATH) clinics from 2001-2011 were included in this retrospective observational study. Patients missing an appointment were traced by trained staff; those found alive were counseled to return to care (RTC). Relative hazards of RTC were estimated among those having a true gap: missing a clinic appointment and confirmed as neither dead nor receiving care elsewhere. Sample-based multiple imputation accounted for missing vital status. RESULTS: Among 34,522 patients lost to clinic, 15,331 (44.4%) had a true gap per outreach, 2754 (8.0%) were deceased, and 837 (2.4%) had documented transfers. Of 15,600 (45.2%) remaining without active ascertainment, 8762 (56.2%) with later RTC were assumed to have a true gap. Adjusted cause-specific hazard ratios (aHRs) showed early outreach (a ≤8-day window, defined by grid-search approach) had twice the hazard for RTC vs. those without (aHR = 2.06; P < 0.001). HRs for RTC were lower the later the outreach effort after disengagement (aHR = 0.86 per unit increase in time; P < 0.001). Older age, female sex (vs. male), antiretroviral therapy use (vs. none), and HIV status disclosure (vs. none) were also associated with greater likelihood of RTC, and higher enrollment CD4 count with lower likelihood of RTC. CONCLUSION: Patient outreach efforts have a positive impact on patient RTC, regardless of when undertaken, but particularly soon after the patient misses an appointment.