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.

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.

Tuberculosis Treatment Outcomes Among HIV/TB-Coinfected Children in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Network.

INTRODUCTION: Management of tuberculosis (TB) is challenging in HIV/TB-coinfected children. The World Health Organization recommends nucleic acid amplification tests for TB diagnosis, a 4-drug regimen including ethambutol during intensive phase (IP) of treatment, and initiation of antiretroviral therapy (ART) within 8 weeks of TB diagnosis. We investigated TB treatment outcomes by diagnostic modality, IP regimen, and ART status. METHODS: We conducted a retrospective cohort study among HIV/TB-coinfected children enrolled at the International Epidemiology Databases to Evaluate AIDS treatment sites from 2012 to 2014. We modeled TB outcome using multivariable logistic regression including diagnostic modality, IP regimen, and ART status. RESULTS: Among the 386 HIV-infected children diagnosed with TB, 20% had microbiologic confirmation of TB, and 20% had unfavorable TB outcomes. During IP, 78% were treated with a 4-drug regimen. Thirty-one percent were receiving ART at the time of TB diagnosis, and 32% were started on ART within 8 weeks of TB diagnosis. Incidence of ART initiation within 8 weeks of TB diagnosis was higher for those with favorable TB outcomes (64%) compared with those with unfavorable outcomes (40%) (P = 0.04). Neither diagnostic modality (odds ratio 1.77; 95% confidence interval: 0.86 to 3.65) nor IP regimen (odds ratio 0.88; 95% confidence interval: 0.43 to 1.80) was associated with TB outcome. DISCUSSION: In this multinational study of HIV/TB-coinfected children, many were not managed as per World Health Organization guidelines. Children with favorable TB outcomes initiated ART sooner than children with unfavorable outcomes. These findings highlight the importance of early ART for children with HIV/TB coinfection, and reinforce the need for implementation research to improve pediatric TB management.

Frequency and impact of suboptimal immune recovery on first-line antiretroviral therapy within the International Epidemiologic Databases to Evaluate AIDS in East Africa.

OBJECTIVE: To describe patterns of suboptimal immune recovery (SO-IR) and associated HIV-related-illnesses during the first 5 years following first-line antiretroviral therapy (ART) initiation across seven ART sites in East Africa. DESIGN: Retrospective analysis of data from seven ART clinical sites (three Uganda, two Kenya and two Tanzania). METHODS: SO-IR was described by proportions of ART-treated adults with CD4 cell counts less than 200, less than 350 and less than 500 cells/µl. Kaplan-Meier survival analysis techniques were used to assess predictors of SO-IR, and incident rates of HIV-related illnesses at CD4 cell counts less than 200, 200-350, 351-499, and >500 cells/µl, respectively. RESULTS: Overall 80 843 adults initiated non-nucleoside reverse transcriptase inhibitor-based first-line ART; 65% were women and median CD4 cell count was 126 [interquartile range (IQR), 52-202] cells/µl. Cumulative probability of SO-IR <200 cells/µl, <350 cells/µl and <500 cells/µl, after 5 years, was 11, 38 and 63%, respectively. Incidence of HIV-related illnesses was higher among those with CD4 cell counts less than 200 and 200-350 cells/µl, than those who achieved CD4 counts above these thresholds. The most common events, at CD4 < 200 cells/µl, were pulmonary tuberculosis [incident rate 15.98 (15.47-16.51)/100 person-years at risk (PYAR), oral candidiasis [incident rate 12.5 (12.03-12.94)] and herpes zoster [incident rate 6.30 (5.99-6.64)] events/100 PYAR. With attainment of a CD4 cell count level 200-350 cells/µl, there was a substantial reduction in events/100 PYAR - by 91% to 1.45 (1.29-1.63) for TB, by 94% to 0.75 (0.64-0.89) for oral candidiasis, by 84% to 0.99 (0.86-1.14) for Herpes Zoster, and by 78% to 1.22 (1.07-1.39) for chronic diarrhea. The incidence of all events decreased further with CD4 counts above these thresholds. CONCLUSION: Around 40% of adults initiated on ART have suboptimal immune recovery with CD4 counts <350 cells/µl after five years. Such patients will require closer monitoring for both HIV-related and non-HIV-related clinical events.

Implementation and Operational Research: Declining Tuberculosis Incidence Among People Receiving HIV Care and Treatment Services in East Africa, 2007-2012.

BACKGROUND: Antiretroviral therapy (ART) reduces the risk of Tuberculosis (TB) among people living with HIV (PLWH). With ART scale-up in sub-Saharan Africa over the past decade, incidence of TB among PLWH engaged in HIV care is predicted to decline. METHODS: We conducted a retrospective analysis of routine clinical data from 168,330 PLWH receiving care at 35 facilities in Kenya, Tanzania, and Uganda during 2003-2012, participating in the East African region of the International Epidemiologic Databases to Evaluate AIDS. Temporal trends in facility-based annual TB incidence rates (per 100,000 person years) among PLWH and country-specific standardized TB incidence ratios using annual population-level TB incidence data from the World Health Organization were computed between 2007 and 2012. We examined patient-level and facility-level factors associated with incident TB using multivariable Cox models. RESULTS: Overall, TB incidence rates among PLWH in care declined 5-fold between 2007 and 2012 from 5960 to 985 per 100,000 person years [P = 0.0003] (Kenya: 7552 to 1115 [P = 0.0007]; Tanzania: 7153 to 635 [P = 0.0025]; Uganda: 3204 to 242 [P = 0.018]). Standardized TB incidence ratios significantly decreased in the 3 countries, indicating a narrowing gap between incidence rates among PLWH and the general population. We observed lower hazards of incident TB among PLWH on ART and/or isoniazid preventive therapy and receiving care in facilities offering TB treatment onsite. CONCLUSIONS: Annual TB incidence rates among PLWH significantly declined during ART scale-up but remained higher than the general population. Increasing access to ART and isoniazid preventive therapy and co-location of HIV and TB treatment may further reduce TB incidence among PLWH.

Incidence of World Health Organization stage 3 and 4 events, tuberculosis and mortality in untreated, HIV-infected children enrolling in care before 1 year of age: an IeDEA (International Epidemiologic Databases To Evaluate AIDS) East Africa regional analysis.

BACKGROUND: Few studies have reported CD4%- and age-stratified rates of World Health Organization Stage 3 (WHO3) events, World Health Organization Stage 4 (WHO4) events, tuberculosis (TB) and mortality in HIV-infected infants before initiation of antiretroviral therapy. METHODS: HIV-infected children enrolled before 1 year of age in the International Epidemiologic Databases to Evaluate AIDS East Africa region (October 1, 2002, to November, 2008) were included. We estimated incidence rates of earliest clinical event (WHO3, WHO4 and TB), before antiretroviral therapy initiation per local guidelines, stratified by current age (< or ≥6 months) and current CD4% (<15%, 15-24%, ≥25%). CD4%-stratified mortality rates were estimated separately for children who did not experience a clinical event ("background" mortality) and for children who experienced an event, including "acute" mortality (≤30 days post event) and "later" mortality (>30 days post event). RESULTS: Among 847 children (median enrollment age: 4.8 months; median pre-antiretroviral therapy follow up: 10.8 months; 603 (71%) with ≥1 CD4% recorded), event rates were comparable for those aged <6 and ≥6 months. Current CD4% was associated with risk of WHO4 events for children <6 months of age and with all evaluated events for children ≥6 months old (P < 0.05). "Background" mortality was 3.7-8.4/100 person-years (PY). "Acute" mortality (≤30 days post event) was 33.8/100 PY (after TB) and 41.1/100 PY (after WHO3 or WHO4). "Later" mortality (>30 days post event) ranged by CD4% from 4.7 to 29.1/100 PY. CONCLUSIONS: In treatment-naïve, HIV-infected infants, WHO3, WHO4 and TB events were common before and after 6 months of age and led to substantial increases in mortality. Early infant HIV diagnosis and treatment are critically important, regardless of CD4%.

Evaluating a scalable model for implementing electronic health records in resource-limited settings.

Current models for implementing electronic health records (EHRs) in resource-limited settings may not be scalable because they fail to address human-resource and cost constraints. This paper describes an implementation model which relies on shared responsibility between local sites and an external three-pronged support infrastructure consisting of: (1) a national technical expertise center, (2) an implementer's community, and (3) a developer's community. This model was used to implement an open-source EHR in three Ugandan HIV-clinics. Pre-post time-motion study at one site revealed that Primary Care Providers spent a third less time in direct and indirect care of patients (p<0.001) and 40% more time on personal activities (p=0.09) after EHRs implementation. Time spent by previously enrolled patients with non-clinician staff fell by half (p=0.004) and with pharmacy by 63% (p<0.001). Surveyed providers were highly satisfied with the EHRs and its support infrastructure. This model offers a viable approach for broadly implementing EHRs in resource-limited settings.