Browsing by Author "Davies, Mary-Ann"

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Access to antiretroviral therapy in HIV-infected children aged 0-19 years in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium, 2004-2015: A prospective cohort study.
(2018-May) Desmonde, Sophie; Tanser, Franck; Vreeman, Rachel; Takassi, Elom; Edmonds, Andrew; Lumbiganon, Pagakrong; Pinto, Jorge; Malateste, Karen; McGowan, Catherine; Kariminia, Azar; Yotebieng, Marcel; Dicko, Fatoumata; Yiannoutsos, Constantin ; Mubiana-Mbewe, Mwangelwa; Wools-Kaloustian, Kara; Davies, Mary-Ann; Leroy, Valériane
INTRODUCTION: Access to antiretroviral therapy (ART) is a global priority. However, the attrition across the continuum of care for HIV-infected children between their HIV diagnosis and ART initiation is not well known. We analyzed the time from enrollment into HIV care to ART initiation in HIV-infected children within the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium. METHODS AND FINDINGS: We included 135,479 HIV-1-infected children, aged 0-19 years and ART-naïve at enrollment, between 1 January 2004 and 31 December 2015, in IeDEA cohorts from Central Africa (3 countries; n = 4,948), East Africa (3 countries; n = 22,827), West Africa (7 countries; n = 7,372), Southern Africa (6 countries; n = 93,799), Asia-Pacific (6 countries; n = 4,045), and Latin America (7 countries; n = 2,488). Follow-up in these cohorts is typically every 3-6 months. We described time to ART initiation and missed opportunities (death or loss to follow-up [LTFU]: last clinical visit >6 months) since baseline (the date of HIV diagnosis or, if unavailable, date of enrollment). Cumulative incidence functions (CIFs) for and determinants of ART initiation were computed, with death and LTFU as competing risks. Among the 135,479 children included, 99,404 (73.4%) initiated ART, 1.9% died, 1.4% were transferred out, and 20.4% were lost to follow-up before ART initiation. The 24-month CIF for ART initiation was 68.2% (95% CI: 67.9%-68.4%); it was lower in sub-Saharan Africa-ranging from 49.8% (95% CI: 48.4%-51.2%) in Central Africa to 72.5% (95% CI: 71.5%-73.5%) in West Africa-compared to Latin America (71.0%, 95% CI: 69.1%-72.7%) and the Asia-Pacific (78.3%, 95% CI: 76.9%-79.6%). Adolescents aged 15-19 years and infants <1 year had the lowest cumulative incidence of ART initiation compared to other ages: 62.2% (95% CI: 61.6%-62.8%) and 66.4% (95% CI: 65.7%-67.0%), respectively. Overall, 49.1% were ART-eligible per local guidelines at baseline, of whom 80.6% initiated ART. The following children had lower cumulative incidence of ART initiation: female children (p < 0.01); those aged <1 year, 2-4 years, 5-9 years, and 15-19 years (versus those aged 10-14 years, p < 0.01); those who became eligible during follow-up (versus eligible at enrollment, p < 0.01); and those receiving care in low-income or lower-middle-income countries (p < 0.01). The main limitations of our study include left truncation and survivor bias, caused by deaths of children prior to enrollment, and use of enrollment date as a proxy for missing data on date of HIV diagnosis, which could have led to underestimation of the time between HIV diagnosis and ART initiation. CONCLUSIONS: In this study, 68% of HIV-infected children initiated ART by 24 months. However, there was a substantial risk of LTFU before ART initiation, which may also represent undocumented mortality. In 2015, many obstacles to ART initiation remained, with substantial inequities. More effective and targeted interventions to improve access are needed to reach the target of treating 90% of HIV-infected children with ART.
Authors' Reply: Early Initiation of Antiretroviral Therapy Among Young Children: A Long Way to Go.
(2015-Oct-01) Koller, Manuel; Patel, Kunjal; Chi, Benjamin H.; Wools-Kaloustian, Kara; Dicko, Fatoumata; Chokephaibulkit, Kulkanya; Chimbetete, Cleophas; Hazra, Rohan; Ayaya, Samuel; Leroy, Valeriane; Trong, Huu K.; Egger, Matthias; Davies, Mary-Ann
Brief Report: Assessing the Association Between Changing NRTIs When Initiating Second-Line ART and Treatment Outcomes.
(2018-Apr-01) Rohr, Julia K.; Ive, Prudence; Horsburgh, Charles R.; Berhanu, Rebecca; Hoffmann, Christopher J.; Wood, Robin; Boulle, Andrew; Giddy, Janet; Prozesky, Hans; Vinikoor, Michael J.; wa Mwanza, Mwanza ; Wandeler, Gilles; Davies, Mary-Ann; Fox, Matthew P.
BACKGROUND: After first-line antiretroviral therapy failure, the importance of change in nucleoside reverse transcriptase inhibitor (NRTI) in second line is uncertain due to the high potency of protease inhibitors used in second line. SETTING: We used clinical data from 6290 adult patients in South Africa and Zambia from the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa cohort. METHODS: We included patients who initiated on standard first-line antiretroviral therapy and had evidence of first-line failure. We used propensity score-adjusted Cox proportional-hazards models to evaluate the impact of change in NRTI on second-line failure compared with remaining on the same NRTI in second line. In South Africa, where viral load monitoring was available, treatment failure was defined as 2 consecutive viral loads >1000 copies/mL. In Zambia, it was defined as 2 consecutive CD4 counts <100 cells/mm. RESULTS: Among patients in South Africa initiated on zidovudine (AZT), the adjusted hazard ratio for second-line virologic failure was 0.25 (95% confidence interval: 0.11 to 0.57) for those switching to tenofovir (TDF) vs. remaining on AZT. Among patients in South Africa initiated on TDF, switching to AZT in second line was associated with reduced second-line failure (adjusted hazard ratio = 0.35 [95% confidence interval: 0.13 to 0.96]). In Zambia, where viral load monitoring was not available, results were less conclusive. CONCLUSIONS: Changing NRTI in second line was associated with better clinical outcomes in South Africa. Additional clinical trial research regarding second-line NRTI choices for patients initiated on TDF or with contraindications to specific NRTIs is needed.
Changes in rapid HIV treatment initiation after national "treat all" policy adoption in 6 sub-Saharan African countries: Regression discontinuity analysis.
(2019-Jun) Tymejczyk, Olga; Brazier, Ellen; Yiannoutsos, Constantin T.; Vinikoor, Michael J.; van Lettow, Monique; Nalugoda, Fred; Urassa, Mark; Sinayobye, Jean D.; Rebeiro, Peter F.; Wools-Kaloustian, Kara; Davies, Mary-Ann; Zaniewski, Elizabeth; Anderegg, Nanina; Liu, Grace; Ford, Nathan; Nash, Denis
BACKGROUND: Most countries have formally adopted the World Health Organization's 2015 recommendation of universal HIV treatment ("treat all"). However, there are few rigorous assessments of the real-world impact of treat all policies on antiretroviral treatment (ART) uptake across different contexts. METHODS AND FINDINGS: We used longitudinal data for 814,603 patients enrolling in HIV care between 1 January 2004 and 10 July 2018 in 6 countries participating in the global International epidemiology Databases to Evaluate AIDS (IeDEA) consortium: Burundi (N = 11,176), Kenya (N = 179,941), Malawi (N = 84,558), Rwanda (N = 17,396), Uganda (N = 96,286), and Zambia (N = 425,246). Using a quasi-experimental regression discontinuity design, we assessed the change in the proportion initiating ART within 30 days of enrollment in HIV care (rapid ART initiation) after country-level adoption of the treat all policy. A modified Poisson model was used to identify factors associated with failure to initiate ART rapidly under treat all. In each of the 6 countries, over 60% of included patients were female, and median age at enrollment ranged from 32 to 36 years. In all countries studied, national adoption of treat all was associated with large increases in rapid ART initiation. Significant increases in rapid ART initiation immediately after treat all policy adoption were observed in Rwanda, from 44.4% to 78.9% of patients (34.5 percentage points [pp], 95% CI 27.2 to 41.7; p < 0.001), Kenya (25.7 pp, 95% CI 21.8 to 29.5; p < 0.001), Burundi (17.7 pp, 95% CI 6.5 to 28.9; p = 0.002), and Malawi (12.5 pp, 95% CI 7.5 to 17.5; p < 0.001), while no immediate increase was observed in Zambia (0.4 pp, 95% CI -2.9 to 3.8; p = 0.804) and Uganda (-4.2 pp, 95% CI -9.0 to 0.7; p = 0.090). The rate of rapid ART initiation accelerated sharply following treat all policy adoption in Malawi, Uganda, and Zambia; slowed in Kenya; and did not change in Rwanda and Burundi. In post hoc analyses restricted to patients enrolling under treat all, young adults (16-24 years) and men were at increased risk of not rapidly initiating ART (compared to older patients and women, respectively). However, rapid ART initiation following enrollment increased for all groups as more time elapsed since treat all policy adoption. Study limitations include incomplete data on potential ART eligibility criteria, such as clinical status, pregnancy, and enrollment CD4 count, which precluded the assessment of rapid ART initiation specifically among patients known to be eligible for ART before treat all. CONCLUSIONS: Our analysis indicates that adoption of treat all policies had a strong effect on increasing rates of rapid ART initiation, and that these increases followed different trajectories across the 6 countries. Young adults and men still require additional attention to further improve rapid ART initiation.
Characterizing the double-sided cascade of care for adolescents living with HIV transitioning to adulthood across Southern Africa.
(2020-Jan) Tsondai, Priscilla R.; Sohn, Annette H.; Phiri, Sam; Sikombe, Kombatende; Sawry, Shobna ; Chimbetete, Cleophas; Fatti, Geoffrey; Hobbins, Michael A.; Technau, Karl-Günter ; Rabie, Helena; Bernheimer, Jonathan; Fox, Matthew P.; Judd, Ali; Collins, Intira J.; Davies, Mary-Ann
INTRODUCTION: As adolescents and young people living with HIV (AYLH) age, they face a "transition cascade," a series of steps associated with transitions in their care as they become responsible for their own healthcare. In high-income countries, this usually includes transfer from predominantly paediatric/adolescent to adult clinics. In sub-Saharan Africa, paediatric HIV care is mostly provided in decentralized, non-specialist primary care clinics, where "transition" may not necessarily include transfer of care but entails becoming more autonomous for one's HIV care. Using different age thresholds as proxies for when "transition" to autonomy might occur, we evaluated pre- and post-transition outcomes among AYLH. METHODS: We included AYLH aged <16 years at enrolment, receiving antiretroviral therapy (ART) within International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) sites (2004 to 2017) with no history of transferring care. Using the ages of 16, 18, 20 and 22 years as proxies for "transition to autonomy," we compared the outcomes: no gap in care (≥2 clinic visits) and viral suppression (HIV-RNA <400 copies/mL) in the 12 months before and after each age threshold. Using log-binomial regression, we examined factors associated with no gap in care (retention) in the 12 months post-transition. RESULTS: A total of 5516 AYLH from 16 sites were included at "transition" age 16 (transition-16y), 3864 at 18 (transition-18y), 1463 at 20 (transition-20y) and 440 at 22 years (transition-22y). At transition-18y, in the 12 months pre- and post-transition, 83% versus 74% of AYLH had no gap in care (difference 9.3 (95% confidence interval (CI) 7.8 to 10.9)); while 65% versus 62% were virally suppressed (difference 2.7 (-1.0 to 6.5%)). The strongest predictor of being retained post-transition was having no gap in the preceding year, across all transition age thresholds (transition-16y: adjusted risk ratio (aRR) 1.72; 95% CI (1.60 to 1.86); transition-18y: aRR 1.76 (1.61 to 1.92); transition-20y: aRR 1.75 (1.53 to 2.01); transition-22y: aRR 1.47; (1.21 to 1.78)). CONCLUSIONS: AYLH with gaps in care need targeted support to prevent non-retention as they take on greater responsibility for their healthcare. Interventions to increase virologic suppression rates are necessary for all AYLH ageing to adulthood.
Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: A comparative analysis between a multi-country tracing study and linkage to a health information exchange.
(2024-Aug) Nyakato, Patience; Schomaker, Michael ; Boulle, Andrew ; Euvrard, Jonathan; Wood, Robin ; Eley, Brian; Prozesky, Hans; Christ, Benedikt; Anderegg, Nanina; Ayakaka, Irene; Rafael, Idiovino ; Kunzekwenyika, Cordelia; Moore, Carolyn B.; Lettow, Monique van ; Chimbetete, Cleophas ; Mbewe, Safari; Ballif, Marie; Egger, Matthias; Yiannoutsos, Constantin T.; Cornell, Morna; Davies, Mary-Ann
OBJECTIVES: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. METHODS: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correcting mortality estimates for all children, adolescents and young adults with HIV. RESULTS: We found substantial variations of mortality estimates among children, adolescents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI(asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. CONCLUSIONS: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out-of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.
Effect of baseline renal function on tenofovir-containing antiretroviral therapy outcomes in Zambia.
(2014-May) Mulenga, Lloyd; Musonda, Patrick; Mwango, Albert; Vinikoor, Michael J.; Davies, Mary-Ann; Mweemba, Aggrey; Calmy, Alexandra; Stringer, Jeffrey S.; Keiser, Olivia; Chi, Benjamin H.; Wandeler, Gilles
BACKGROUND: Although tenofovir disoproxil fumarate (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. METHODS: We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (estimated glomerular filtration rate [eGFR], 60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) according to the chronic kidney disease-epidemiology (CKD-EPI) formula. Differences in eGFR during ART were analyzed using linear mixed-effect models. The odds of developing moderate or severe eGFR decrease and mortality were assessed using logistic and competing risk regression, respectively. RESULTS: We included 62 230 adults, of which 38 716 (62.2%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF than in the non-TDF group (1.9% vs 4.0%). Among patients with no or mild renal dysfunction, those receiving TDF were more likely to develop moderate (adjusted odds ratio, 3.11; 95% confidence interval, 2.52-3.87) or severe (2.43; 1.80-3.28) eGFR decrease, although the incidence in such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen, and mortality rates were similar in both treatment groups. CONCLUSIONS: TDF use did not attenuate renal function recovery or increase the mortality rate in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.
Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries.
(2015-Jan-01) Koller, Manuel; Patel, Kunjal; Chi, Benjamin H.; Wools-Kaloustian, Kara; Dicko, Fatoumata; Chokephaibulkit, Kulkanya; Chimbetete, Cleophas; Avila, Dorita; Hazra, Rohan; Ayaya, Samual ; Leroy, Valeriane; Truong, Huu K.; Egger, Matthias; Davies, Mary-Ann
BACKGROUND: The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries. METHODS: We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year. RESULTS: A total of 34,706 children from 9 low-income, 6 lower middle-income, 4 upper middle-income countries, and 1 high-income country (United States) were included; 20,624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle-income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation. CONCLUSIONS: Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority.
Impact of Antiretroviral Therapy on Liver Fibrosis Among Human Immunodeficiency Virus-Infected Adults With and Without HBV Coinfection in Zambia.
(2017-May-15) Vinikoor, Michael J.; Sinkala, Edford; Chilengi, Roma; Mulenga, Lloyd B.; Chi, Benjamin H.; Zyambo, Zude; Hoffmann, Christopher J.; Saag, Michael S.; Davies, Mary-Ann; Egger, Matthias ; Wandeler, Gilles
BACKGROUND: We investigated changes in hepatic fibrosis, based on transient elastography (TE), among human immunodeficiency virus (HIV)-infected patients with and without hepatitis B virus (HBV) coinfection on antiretroviral therapy (ART) in Zambia. METHODS: Patients' liver stiffness measurements (LSM; kiloPascals [kPa]) at ART initiation were categorized as no or minimal fibrosis (equivalent to Metavir F0-F1), significant fibrosis (F2-F3), and cirrhosis (F4). TE was repeated following 1 year of ART. Stratified by HBV coinfection status (hepatitis B surface antigen positive at baseline), we described LSM change and the proportion with an increase/decrease in fibrosis category. Using multivariable logistic regression, we assessed correlates of significant fibrosis/cirrhosis at 1 year on ART. RESULTS: Among 463 patients analyzed (61 with HBV coinfection), median age was 35 years, 53.7% were women, and median baseline CD4+ count was 240 cells/mm3. Nearly all (97.6%) patients received tenofovir disoproxil fumarate-containing ART, in line with nationally recommended first-line treatment. The median LSM change was -0.70 kPa (95% confidence interval, -3.0 to +1.7) and was similar with and without HBV coinfection. Significant fibrosis/cirrhosis decreased in frequency from 14.0% to 6.7% (P < .001). Increased age, male sex, and HBV coinfection predicted significant fibrosis/cirrhosis at 1 year (all P < .05). CONCLUSION: The percentage of HIV-infected Zambian adults with elevated liver stiffness suggestive of significant fibrosis/cirrhosis decreased following ART initiation-regardless of HBV status. This suggests that HIV infection plays a role in liver inflammation. HBV-coinfected patients were more likely to have significant fibrosis/cirrhosis at 1 year on ART. CLINICAL TRIALS REGISTRATION: NCT02060162.
Impact of Universal Antiretroviral Treatment Eligibility on Rapid Treatment Initiation Among Young Adolescents with Human Immunodeficiency Virus in Sub-Saharan Africa.
(2020-Aug-04) Tymejczyk, Olga; Brazier, Ellen; Wools-Kaloustian, Kara; Davies, Mary-Ann; Dilorenzo, Madeline ; Edmonds, Andrews; Vreeman, Rachel; Bolton-Moore, Carolyn; Twizere, Christella; Okoko, Nicollate; Phiri, Sam; Nakigozi, Gertrude; Lelo, Patricia; von Groote, Per; Sohn, Annette H.; Nash, Denis
BACKGROUND: Young adolescents with perinatally acquired human immunodeficiency virus (HIV) are at risk for poor care outcomes. We examined whether universal antiretroviral treatment (ART) eligibility policies (Treat All) improved rapid ART initiation after care enrollment among 10-14-year-olds in 7 sub-Saharan African countries. METHODS: Regression discontinuity analysis and data for 6912 patients aged 10-14-years were used to estimate changes in rapid ART initiation (within 30 days of care enrollment) after adoption of Treat All policies in 2 groups of countries: Uganda and Zambia (policy adopted in 2013) and Burundi, Democratic Republic of the Congo, Kenya, Malawi, and Rwanda (policy adopted in 2016). RESULTS: There were immediate increases in rapid ART initiation among young adolescents after national adoption of Treat All. Increases were greater in countries adopting the policy in 2016 than in those adopting it in 2013: 23.4 percentage points (pp) (95% confidence interval, 13.9-32.8) versus 11.2pp (2.5-19.9). However, the rate of increase in rapid ART initiation among 10-14-year-olds rose appreciably in countries with earlier treatment expansions, from 1.5pp per year before Treat All to 7.7pp per year afterward. CONCLUSIONS: Universal ART eligibility has increased rapid treatment initiation among young adolescents enrolling in HIV care. Further research should assess their retention in care and viral suppression under Treat All.
Medication Side Effects and Retention in HIV Treatment: A Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia.
(2018-Sep-01) Brennan, Alana T.; Bor, Jacob; Davies, Mary-Ann; Wandeler, Gilles; Prozesky, Hans; Fatti, Geoffrey; Wood, Robin; Stinson, Kathryn; Tanser, Frank; Bärnighausen, Till; Boulle, Andrew; Sikazwe, Izukanji; Zanolini, Arianna; Fox, Matthew P.
Tenofovir is less toxic than other nucleoside reverse-transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of human immunodeficiency virus (HIV)-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir for first-line ART. We applied regression discontinuity in a prospective cohort study of 52,294 HIV-infected adults initiating first-line ART within 12 months (±12 months) of each guideline change. We compared outcomes in patients presenting just before and after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24 months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentages of patients initiating tenofovir in South Africa (risk difference (RD) = 81 percentage points, 95% confidence interval (CI): 73, 89) and Zambia (RD = 42 percentage points, 95% CI: 38, 45). With the guideline change, the percentage of single-drug substitutions decreased substantially in South Africa (RD = -15 percentage points, 95% CI: -18, -12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD = -1.8% (95% CI: -3.5, -0.1); complier relative risk = 0.74) but not in South Africa (RD = -0.9% (95% CI: -5.9, 4.1); complier relative risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts.
Monitoring and switching of first-line antiretroviral therapy in adult treatment cohorts in sub-Saharan Africa: collaborative analysis.
(2015-Jul) Haas, Andreas D.; Keiser, Olivia; Balestre, Eric; Brown, Steve; Bissagnene, Emmanuel; Chimbetete, Cleophas; Dabis, François; Davies, Mary-Ann; Hoffmann, Christopher J.; Oyaro, Patrick; Parkes-Ratanshi, Rosalind; Reynolds, Steven J.; Sikazwe, Izukanji; Wools-Kaloustian, Kara; Zannou, Marcel D.; Wandeler, Gilles; Egger, Matthias
BACKGROUND: HIV-1 viral load testing is recommended to monitor antiretroviral therapy (ART) but is not universally available. The aim of our study was to assess monitoring of first-line ART and switching to second-line ART in sub-Saharan Africa. METHODS: We did a collaborative analysis of cohort studies from 16 countries in east Africa, southern Africa, and west Africa that participate in the international epidemiological database to evaluate AIDS (IeDEA). We included adults infected with HIV-1 who started combination ART between January, 2004, and January, 2013. We defined switching of ART as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to one including a protease inhibitor, with adjustment of one or more nucleoside reverse-transcriptase inhibitors (NRTIs). Virological and immunological failures were defined according to WHO criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% CIs comparing routine viral load monitoring, targeted viral load monitoring, CD4 monitoring, and clinical monitoring, adjusting for programme and individual characteristics. FINDINGS: Of 297,825 eligible patients, 10,352 (3%) switched to second-line ART during 782 ,412 person-years of follow-up. Compared with CD4 monitoring, hazard ratios for switching were 3·15 (95% CI 2·92-3·40) for routine viral load monitoring, 1·21 (1·13-1·30) for targeted viral load monitoring, and 0·49 (0·43-0·56) for clinical monitoring. Of 6450 patients with confirmed virological failure, 58·0% (95% CI 56·5-59·6) switched by 2 years, and of 15,892 patients with confirmed immunological failure, 19·3% (18·5-20·0) switched by 2 years. Of 10,352 patients who switched, evidence of treatment failure based on one CD4 count or viral load measurement ranged from 86 (32%) of 268 patients with clinical monitoring to 3754 (84%) of 4452 with targeted viral load monitoring. Median CD4 counts at switching were 215 cells per μL (IQR 117-335) with routine viral load monitoring, but were lower with other types of monitoring (range 114-133 cells per μL). INTERPRETATION: Overall, few patients switched to second-line ART and switching happened late in the absence of routine viral load monitoring. Switching was more common and happened earlier after initiation of ART with targeted or routine viral load testing. FUNDING: National Institute of Allergy and Infectious Diseases, Swiss National Science Foundation.
Outcomes of Infants Starting Antiretroviral Therapy in Southern Africa, 2004-2012.
(2015-Aug-15) Porter, Mireille; Davies, Mary-Ann; Mapani, Muntanga K.; Rabie, Helena; Phiri, Sam; Nuttall, James; Fairlie, Lee; Technau, Karl-Günter ; Stinson, Kathryn; Wood, Robin; Wellington, Maureen; Haas, Andreas D.; Giddy, Janet; Tanser, Frank; Eley, Brian
BACKGROUND: There are limited published data on the outcomes of infants starting antiretroviral therapy (ART) in routine care in Southern Africa. This study aimed to examine the baseline characteristics and outcomes of infants initiating ART. METHODS: We analyzed prospectively collected cohort data from routine ART initiation in infants from 11 cohorts contributing to the International Epidemiologic Database to Evaluate AIDS in Southern Africa. We included ART-naive HIV-infected infants aged <12 months initiating ≥3 antiretroviral drugs between 2004 and 2012. Kaplan-Meier estimates were calculated for mortality, loss to follow-up (LTFU), transfer out, and virological suppression. We used Cox proportional hazard models stratified by cohort to determine baseline characteristics associated with outcomes mortality and virological suppression. RESULTS: The median (interquartile range) age at ART initiation of 4945 infants was 5.9 months (3.7-8.7) with follow-up of 11.2 months (2.8-20.0). At ART initiation, 77% had WHO clinical stage 3 or 4 disease and 87% were severely immunosuppressed. Three-year mortality probability was 16% and LTFU 29%. Severe immunosuppression, WHO stage 3 or 4, anemia, being severely underweight, and initiation of treatment before 2010 were associated with higher mortality. At 12 months after ART initiation, 17% of infants were severely immunosuppressed and the probability of attaining virological suppression was 56%. CONCLUSIONS: Most infants initiating ART in Southern Africa had severe disease with high probability of LTFU and mortality on ART. Although the majority of infants remaining in care showed immune recovery and virological suppression, these responses were suboptimal.
Retention and mortality on antiretroviral therapy in sub-Saharan Africa: collaborative analyses of HIV treatment programmes.
(2018-Feb) Haas, Andreas D.; Zaniewski, Elizabeth; Anderegg, Nanina; Ford, Nathan; Fox, Matthew P.; Vinikoor, Michael J.; Dabis, François; Nash, Denis; Sinayobye, Jean D.; Niyongabo, Thêodore; Tanon, Aristophane; Poda, Armel; Adedimeji, Adebola A.; Edmonds, Andrew; Davies, Mary-Ann; Egger, Matthias
INTRODUCTION: By 2020, 90% of all people diagnosed with HIV should receive long-term combination antiretroviral therapy (ART). In sub-Saharan Africa, this target is threatened by loss to follow-up in ART programmes. The proportion of people retained on ART long-term cannot be easily determined, because individuals classified as lost to follow-up, may have self-transferred to another HIV treatment programme, or may have died. We describe retention on ART in sub-Saharan Africa, first based on observed data as recorded in the clinic databases, and second adjusted for undocumented deaths and self-transfers. METHODS: We analysed data from HIV-infected adults and children initiating ART between 2009 and 2014 at a sub-Saharan African HIV treatment programme participating in the International epidemiology Databases to Evaluate AIDS (IeDEA). We used the Kaplan-Meier method to calculate the cumulative incidence of retention on ART and the Aalen-Johansen method to calculate the cumulative incidences of death, loss to follow-up, and stopping ART. We used inverse probability weighting to adjust clinic data for undocumented mortality and self-transfer, based on estimates from a recent systematic review and meta-analysis. RESULTS: We included 505,634 patients: 12,848 (2.5%) from Central Africa, 109,233 (21.6%) from East Africa, 347,343 (68.7%) from Southern Africa and 36,210 (7.2%) from West Africa. In crude analyses of observed clinic data, 52.1% of patients were retained on ART, 41.8% were lost to follow-up and 6.0% had died 5 years after ART initiation. After accounting for undocumented deaths and self-transfers, we estimated that 66.6% of patients were retained on ART, 18.8% had stopped ART and 14.7% had died at 5 years. CONCLUSIONS: Improving long-term retention on ART will be crucial to attaining the 90% on ART target. Naïve analyses of HIV cohort studies, which do not account for undocumented mortality and self-transfer of patients, may severely underestimate both mortality and retention on ART.
Stunting and growth velocity of adolescents with perinatally acquired HIV: differential evolution for males and females. A multiregional analysis from the IeDEA global paediatric collaboration.
(2019-Nov) Jesson, Julie; Schomaker, Michael; Malasteste, Karen; Wati, Dewi K.; Kariminia, Azar; Sylla, Miriam; Kouadio, Kouakou; Sawry, Shobna; Mubiana-Mbewe, Mwangelwa; Ayaya, Samuel; Vreeman, Rachel; McGowan, Catherine C.; Yotebieng, Marcel; Leroy, Valériane; Davies, Mary-Ann
INTRODUCTION: Stunting is a key issue for adolescents with perinatally acquired HIV (APH) that needs to be better understood. As part of the IeDEA multiregional consortium, we described growth evolution during adolescence for APH on antiretroviral therapy (ART). METHODS: We included data from sub-Saharan Africa, the Asia-Pacific, and the Caribbean, Central and South America regions collected between 2003 and 2016. Adolescents on ART, reporting perinatally acquired infection or entering HIV care before 10 years of age, with at least one height measurement between 10 and 16 years of age, and followed in care until at least 14 years of age were included. Characteristics at ART initiation and at 10 years of age were compared by sex. Correlates of growth defined by height-for-age z-scores (HAZ) between ages 10 and 19 years were studied separately for males and females, using linear mixed models. RESULTS: Overall, 8737 APH were included, with 46% from Southern Africa. Median age at ART initiation was 8.1 years (interquartile range (IQR) 6.1 to 9.6), 50% were females, and 41% were stunted (HAZ<-2 SD) at ART initiation. Males and females did not differ by age and stunting at ART initiation, CD4 count over time or retention in care. At 10 years of age, 34% of males were stunted versus 39% of females (p < 0.001). Females had better subsequent growth, resulting in a higher prevalence of stunting for males compared to females by age 15 (48% vs. 25%) and 18 years (31% vs. 15%). In linear mixed models, older age at ART initiation and low CD4 count were associated with poor growth over time (p < 0.001). Those stunted at 10 years of age or at ART initiation had the greatest growth improvement during adolescence. CONCLUSIONS: Prevalence of stunting is high among APH worldwide. Substantial sex-based differences in growth evolution during adolescence were observed in this global cohort, which were not explained by differences in age of access to HIV care, degree of immunosuppression or region. Other factors influencing growth differences in APH, such as differences in pubertal development, should be better documented, to guide further research and inform interventions to optimize growth and health outcomes among APH.
Temporal Trends in Co-trimoxazole Use Among Children on Antiretroviral Therapy and the Impact of Co-trimoxazole on Mortality Rates in Children Without Severe Immunodeficiency.
(2019-Nov-06) Boettiger, David C.; Law, Matthew G.; Sohn, Annette H.; Davies, Mary-Ann; Wools-Kaloustian, Kara; Leroy, Valeriane; Yotebieng, Marcel; Vinikoor, Michael J.; Vreeman, Rachel; Amorissani-Folquet, Madeleine; Edmonds, Andrew; Fatti, Geoffrey; Batte, James; Renner, Lorna; Adedimeji, Adebola ; Kariminia, Azar
BACKGROUND: Co-trimoxazole is recommended for all children with human immunodeficiency virus. In this analysis, we evaluate trends in pediatric co-trimoxazole use and survival on co-trimoxazole in children using antiretroviral therapy (ART). METHODS: We used data collected between January 1, 2006, and March 31, 2016, from the International Epidemiology Databases to Evaluate AIDS. Logistic regression was used to evaluate factors associated with using co-trimoxazole at ART initiation. Competing risk regression was used to assess factors associated with death. RESULTS: A total of 54113 children were included in this study. The prevalence of co-trimoxazole use at ART initiation increased from 66.5% in 2006 to a peak of 85.6% in 2010 and then declined to 48.5% in 2015-2016. A similar trend was observed among children who started ART with severe immunodeficiency. After adjusting for year of ART initiation, younger age (odds ratio [OR], 1.18 for <1 vs 1 to <5 years of age [95% confidence interval (CI), 1.09-1.28]), lower height-for-age z score (OR, 1.15 for less than -3 vs greater than -2 [95% CI, 1.08-1.22]), anemia (OR, 1.08 [95% CI, 1.02-1.15]), severe immunodeficiency (OR, 1.25 [95% CI, 1.18-1.32]), and receiving care in East Africa (OR, 8.97 vs Southern Africa [95% CI, 8.17-9.85]) were associated with a high prevalence of co-trimoxazole use. Survival did not differ according to co-trimoxazole use in children without severe immunodeficiency (hazard ratio, 1.01 for nonusers versus users [95% CI, 0.77-1.34]). CONCLUSIONS: Recent declines in co-trimoxazole use may not be linked to the current shift toward early ART initiation. Randomized trial data might be needed to establish the survival benefit of co-trimoxazole in children without severe immunodeficiency.
Temporal trends in the characteristics of children at antiretroviral therapy initiation in southern Africa: the IeDEA-SA Collaboration.
(2013) Davies, Mary-Ann; Phiri, Sam; Wood, Robin; Wellington, Maureen; Cox, Vivian; Bolton-Moore, Carolyn; Timmerman, Venessa; Moultrie, Harry; Ndirangu, James; Rabie, Helena; Technau, Karl; Giddy, Janet; Maxwell, Nicola; Boulle, Andrew; Keiser, Olivia; Egger, Matthias ; Eley, Brian
BACKGROUND: Since 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration. METHODOLOGY/PRINCIPAL FINDINGS: Data from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick's test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<-3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines. CONCLUSIONS/SIGNIFICANCE: Between 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children.
The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.
(2018-Mar) Slogrove, Amy L.; Schomaker, Michael; Davies, Mary-Ann; Williams, Paige; Balkan, Suna; Ben-Farhat, Jihane; Calles, Nancy; Chokephaibulkit, Kulkanya; Duff, Charlotte; Eboua, Tanoh F.; Kekitiinwa-Rukyalekere, Adeodata; Maxwell, Nicola; Pinto, Jorge; Seage, George; Teasdale, Chloe A.; Wanless, Sebastian; Warszawski, Josiane; Wools-Kaloustian, Kara; Yotebieng, Marcel; Timmerman, Venessa; Collins, Intira J.; Goodall, Ruth; Smith, Colette; Patel, Kunjal; Paul, Mary; Gibb, Diana; Vreeman, Rachel; Abrams, Elaine J.; Hazra, Rohan; Van Dyke, Russell; Bekker, Linda-Gail; Mofenson, Lynne ; Vicari, Marissa; Essajee, Shaffiq; Penazzato, Martina; Anabwani, Gabriel; Mohapi, Edith Q.; Kazembe, Peter N.; Hlatshwayo, Makhosazana; Lumumba, Mwita; Goetghebuer, Tessa; Thorne Claire; Galli, Luisa; van Rossum, Annemarie; Giaquinto, Carlo; Marczynska, Magdalena; Marques, Laura; Prata, Filipa; Ene, Luminita; Okhonskaia, Liubov; Rojo, Pablo; Fortuny, Claudia; Naver, Lars; Rudin, Christoph; Le Coeur, Sophie; Volokha, Alla; Rouzier, Vanessa; Succi, Regina; Sohn, Annette; Kariminia, Azar; Edmonds, Andrew; Lelo, Patricia; Ayaya, Samuel; Ongwen, Patricia; Jefferys, Laura F.; Phiri, Sam; Mubiana-Mbewe, Mwangelwa; Sawry, Shobna; Renner, Lorna; Sylla, Mariam; Abzug, Mark J.; Levin, Myron; Oleske, James; Chernoff, Miriam; Traite, Shirley; Purswani, Murli; Chadwick, Ellen G.; Judd, Ali; Leroy, Valériane
BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
Trends in CD4 and viral load testing 2005 to 2018: multi-cohort study of people living with HIV in Southern Africa.
(2020-Jul) Zaniewski, Elizabeth; Ostinelli, Cam H. D.; Chammartin, Frédérique; Maxwell, Nicola; Davies, Mary-Ann; Euvrard, Jonathan; van Dijk, Janneke; Bosomprah, Samuel; Phiri, Sam; Tanser, Frank; Sipambo, Nosisa; Muhairwe, Josephine ; Fatti, Geoffrey; Prozesky, Hans; Wood, Robin; Ford, Nathan; Fox, Matthew P.; Egger, Matthias
INTRODUCTION: The World Health Organization (WHO) recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa. METHODS: We analysed data from 14 HIV treatment programmes in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in 2005 to 2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count <200 cells/mm RESULTS: Among 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017; the probability declined by 14% each year (odds ratio (OR) 0.86; 95% CI 0.86 to 0.86). Frequency of CD4 testing also declined. The percentage starting ART with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018; each year the probability declined by 20% (OR 0.80; 95% CI 0.80 to 0.81). VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested, but fewer than 2% were tested in the other four countries. The probability of VL testing after ART start increased only modestly each year (OR 1.06; 95% CI 1.05 to 1.06). The percentage with unsuppressed VL was 8.6%. There was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99 to 1.01). CONCLUSIONS: CD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub-Saharan Africa.