Multimonth Prescription of Antiretroviral Therapy Among Children and Adolescents: Experiences From the Baylor International Pediatric AIDS Initiative in 6 African Countries.

BACKGROUND: To reach 90-90-90 targets, differentiated approaches to care are necessary. We describe the experience of delivering multimonth prescription (MMP) schedules of antiretroviral therapy (ART) to youth at centers of excellence in 6 African countries. METHODS: We analyzed data from electronic medical records of patients aged 0-19 years started on ART. Patients were eligible to transition from monthly prescribing to MMP when clinically stable [improving CD4, viral load (VL) suppression, or minimal HIV-associated morbidity] and ART adherent (pill count 95%-105%). Patients were classified as transitioned to MMP after 3 consecutive visits at intervals of >56 days. We used survival analysis to describe death and lost to follow-up. We described adherence and acceptable immunologic response by CD4 using 6-month and VL suppression (<400 copies per milliliter) using 12-month intervals. RESULTS: Twenty-two thousand six hundred fifty-eight patients aged 0-19 years received ART and 14,932 (66%) transitioned to MMP between 2003 and 2015. Of these 2.6% were lost to follow-up and 2.0% died. Median duration of MMP was 3.9 (interquartile range: 2.2-5.9) years. There were significant differences in survival (P < 0.0001) between age groups, worst among those younger than 1 year and 15-19 years. The frequency of favorable clinical endpoints was high throughout the first 5 years of MMP, by year ranging from 87% to 94% acceptable immunologic response, 75% to 80% adherent, and 79% to 85% VL suppression. CONCLUSIONS: These analyses from 6 African countries demonstrate that youth on ART who transitioned to MMP overall maintained favorable outcomes in terms of death, retention, adherence, immunosuppression, and viral suppression. These results reassure that children and adolescents, who are clinically stable and ART adherent, can do well with reduced visit frequencies and extended ART refills.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

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.

The Pediatric AIDS Corps: a 5-year evaluation.

BACKGROUND: The Baylor College of Medicine International Pediatric AIDS Initiative at Texas Children's Hospital created a global health corps named the Pediatric AIDS Corps (PAC) in June 2005. This report provides descriptive details and outputs for PAC over its first 5 years. METHODS: Demographic data were gathered about PAC physicians employed from July 2006 to June 2011. A 21-question survey was used to query PAC physicians about their experiences in the program. Data concerning clinical experiences and educational programs also were reviewed. RESULTS: A total of 128 physicians were employed with PAC. The median duration served was 22.7 months. Eighty-seven percent indicated that experience affected their future career choice, with half continuing to work with children and families living in resource-limited areas after they left PAC. Patient care was identified as the most rewarding part of their work (73%), whereas deaths (27%) were the most difficult. Baylor College of Medicine International Pediatric AIDS Initiative enrollment of HIV-infected children and adolescents into care and treatment increased from 6107 to 103 731 with the addition of PAC physicians. Approximately 500 local health care professionals per quarter benefited from HIV clinical attachments that were not available before PAC arrival. PAC physicians visited outreach sites providing in-depth HIV mentoring of local health care professionals, leading to 37% of the sites becoming self-sufficient. CONCLUSIONS: The positive evaluation by the PAC and the scale-up of clinical and educational programs support the recent calls for the development of a national global health corps program.

Nine-year follow-up of HIV-infected Romanian children and adolescents receiving lopinavir/ritonavir-containing highly active antiretroviral therapy.

INTRODUCTION: Many Romanian children were infected nosocomially with human immunodeficiency virus (HIV) in the late 1980s. The Romanian-American Children's Center of Excellence in Constanta continues to follow approximately 450 of these patients. In 2001, 414 of these patients were initiated on triple therapy including lopinavir/ritonavir. Data from this cohort treated through August 2006 were published in April 2007 demonstrating that the treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of >4 years. The current article describes the results of continued analysis of this cohort through end 2010. The objective of the study was to determine the long-term clinical outcomes of children and adolescents commenced on antiretroviral therapy (ART) including lopinavir/ritonavir. METHODS: Data were extracted retrospectively from the charts of the 336 patients remaining on lopinavir/ritonavir in August 2006. The following outcomes were analyzed: mortality, current patient status, viral load (VL), CD4 counts and reasons for discontinuation of lopinavir/ritonavir. RESULTS: The median age at initiation of lopinavir/ritonavir was 14.0 years (range 5.4 to 20.0 years). The median time on lopinavir/ritonavir treatment was 7.5 years (interquartile range 5.7 to 8.6 years). Overall mortality was 13.5%. Of the original 414 patients started on lopinavir/ritonavir in 2001, 199 (48.1%) remained on this therapy at the end of 2010 and of these 63.8% had undetectable viral load. CONCLUSION: Despite initial suboptimal ART, a significant proportion of patients subsequently treated with a lopinavir/ritonavir based regimen remained on this therapy for up to nine years.

HIV and childhood disability: a case-controlled study at a paediatric antiretroviral therapy centre in Lilongwe, Malawi.

BACKGROUND: As paediatric antiretroviral therapy (ART) is rapidly scaled up in Southern Africa, Human Immunodeficiency Virus (HIV) infection is becoming a chronic illness. Children growing up with HIV may begin to encounter disabilities. The relationship between HIV, disability and the need for rehabilitation has added an additional element that needs to be addressed by paediatric HIV treatment programmes. STUDY OBJECTIVES: 1) Estimate the prevalence of disabilities in HIV-infected and HIV-uninfected children in Lilongwe, Malawi. 2) Examine types of disability and associated clinical and socio-demographic factors. 3) Identify needs, opportunities and barriers for rehabilitation in Malawi. METHODS: A case-controlled study of 296 HIV-infected children aged 2-9 years attending an ART centre in Lilongwe (cases) and their uninfected siblings (controls) was conducted. Disability was assessed using the WHO Ten Question Screen (TQS). Socio-demographic and clinical data were collected using a parent-proxy questionnaire and medical records. RESULTS: Of 296 case and control pairs recruited, 33% (98) versus 7% (20) screened positive for a disability (OR 8.4, 4.4-15.7) respectively. Of these 98 HIV-infected cases, 6%, 36%, 33%, 53%, 46% and 6% had a vision, hearing; physical, learning/comprehension, speech or seizure-related disability respectively and 51% had multiple coexisting disabilities. HIV-infected cases with a disability were more likely to be WHO stage III or IV at enrolment (71% vs. 52%, OR 2.7, 1.5-4.2), to have had TB (58% vs. 39%, OR 2.3, 1.4-3.8) and to have below-average school grades (18% vs. 2%, OR 11.1, 2.2-54.6) than those without. Sixty-seven percent of cases with a disability had never attended any rehabilitative service. Twenty-nine percent of caregivers reported facing stigma and discrimination because of the child's disability. CONCLUSION: This study reveals the magnitude of disability among HIV-infected children and the large unmet need for rehabilitation services. This expanding issue demands further investigation to provide an evidence base for holistic care for disabled children living with HIV.

Mortality and clinical outcomes in HIV-infected children on antiretroviral therapy in Malawi, Lesotho, and Swaziland.

OBJECTIVE: To determine mortality and immune status improvement in HIV-infected pediatric patients on antiretroviral treatment (ART) in Malawi, Lesotho, and Swaziland. METHODS: We conducted a retrospective cohort study of patients aged <12 years at ART initiation at 3 sites in sub-Saharan Africa between 2004 and 2009. Twelve-month and overall mortality were estimated, and factors associated with mortality and immune status improvement were evaluated. RESULTS: Included in the study were 2306 patients with an average follow-up time on ART of 2.3 years (interquartile range 1.5-3.1 years). One hundred four patients (4.5%) died, 9.0% were lost to follow-up, and 1.3% discontinued ART. Of the 104 deaths, 77.9% occurred in the first year of treatment with a 12-month mortality rate of 3.5%. The overall mortality rate was 2.25 deaths/100 person-years (95% confidence interval [CI] 1.84-2.71). Increased 12-month mortality was associated with younger age; <6 months (hazard ratio [HR] = 8.11, CI 4.51-14.58), 6 to <12 months (HR = 3.43, CI 1.96-6.02), and 12 to <36 months (HR = 1.92, CI 1.16-3.19), and World Health Organization stage IV (HR = 4.35, CI 2.19-8.67). Immune status improvement at 12 months was less likely in patients with advanced disease and age <12 months. CONCLUSIONS: Despite challenges associated with pediatric ART in developing countries, low mortality and good treatment outcomes can be achieved. However, outcomes are worse in younger patients and those with advanced disease at the time of ART initiation, highlighting the importance of early diagnosis and treatment.

The Pediatric AIDS Corps: responding to the African HIV/AIDS health professional resource crisis.

Health professional capacity for delivery of HIV/AIDS care and treatment is severely constrained across sub-Saharan Africa. African health professional expertise in pediatrics is in particularly short supply. Here we describe a Pediatric AIDS Corps program that was designed to place pediatricians and other physicians in Africa on a long-term basis to expand existing health professional capacity for pediatric and family HIV/AIDS care and treatment. In the first 2 years of this program, 76 physicians were placed in 5 African countries that have been hit hard by HIV/AIDS. Enrollment of HIV-infected children in care more than quadrupled over a 24-month period, to 26 590. We believe that this pilot program can serve as a model for larger-scale efforts to immediately expand access for African children and families to life-saving HIV/AIDS care and treatment.

Education and preparation of physicians entering an international pediatric AIDS program: the Pediatric AIDS Corps.

The Pediatric AIDS Corps (PAC) are a group of physicians that were hired to provide clinical care and treatment to children and their families infected with HIV/AIDS and to help educate local health care professionals in the management of children with HIV/AIDS located in the high prevalence areas of sub-Saharan Africa. Prior to their departure the PAC were required to participate in a 4-week educational training program that included travel and tropical medicine and HIV infections in children, teaching skills, bioethics, and good clinical practice in human research training. Evaluation of the program was done using a 50-question pretest/posttest design, a standard postcourse evaluation, and a PAC focus group follow-up. Fifty-two physicians were hired who had been trained in the following specialties: pediatrics (77%), medicine/pediatrics (9%), family medicine (8%), and internal medicine (6%). Posttest scores improved by a mean of 10 points for all PAC physicians (p < 0.001) but those that had been in Africa for 5 months or more prior to the course continued to score higher than the other participants. Reviewing the results by category demonstrated significant improvement in all areas (p < or = 0.002) except for general pediatrics for the HIV/AIDS infected patients (p = 0.124) and psychosocial issues (p = 0.376). Changes for the next training were implemented based upon the information obtained from the PAC focus group. The foundation provided by this educational course was an important beginning for the PAC physicians. Other groups providing specialized care to patients in developing countries might consider a similar educational program.

Long-term follow-up of 414 HIV-infected Romanian children and adolescents receiving lopinavir/ritonavir-containing highly active antiretroviral therapy.

BACKGROUND: There are no published reports of the long-term safety and effectiveness of highly active antiretroviral therapy for children and adolescents living in resource-limited settings or of large cohorts of HIV-infected children and adolescents treated long-term (>48 weeks) with lopinavir/ritonavir-containing highly active antiretroviral therapy. OBJECTIVES: The purpose of this work was to evaluate the long-term outcomes of treatment of HIV-infected children and adolescents with lopinavir/ritonavir-containing highly active antiretroviral therapy in a resource-limited setting. METHODS: We studied an inception cohort of 414 HIV-infected children receiving lopinavir/ritonavir-containing highly active antiretroviral therapy between November 2001 and August 2006 at the Romanian-American Children's Center in Constanta, Romania. The center provides comprehensive primary and HIV specialty care and treatment to all known HIV-infected children and adolescents living in Constanta. We measured safety and effectiveness by the percentage of children remaining on treatment, rates of mortality, and changes in plasma HIV RNA concentrations and CD4+ lymphocyte counts. RESULTS: The study population consisted predominantly of antiretroviral drug-experienced older children and adolescents with advanced HIV disease. Treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of >4 years. Thirty-seven deaths occurred; the death rate compared favorably to prospectively collected historical data. The most recent on-treatment plasma HIV RNA concentration was <400 copies per milliliter in 192 of 265 children tested. The mean baseline CD4+ lymphocyte count was 292 cells per microliter (n = 299); the mean change from baseline was +266 (n = 284), +317 (n = 260), +343 (n = 176), and +270 cells per microliter (n = 121) after 1, 2, 3, and 4 years of treatment, respectively. CONCLUSIONS: Highly active antiretroviral therapy can be administered safely and effectively to children and adolescents in resource-limited settings. Lopinavir/ritonavir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiretroviral drug-experienced older children and adolescents with advanced HIV disease.

Comprehensive pediatric human immunodeficiency virus care and treatment in Constanta, Romania: implementation of a program of highly active antiretroviral therapy in a resource-poor setting.

BACKGROUND: Relatively few human immunodeficiency virus (HIV)-infected children worldwide have access to care and treatment. The Romanian-American Children's Center, a collaborative project of a U.S. health care institution and the Romanian government, has established a comprehensive program of highly active antiretroviral therapy for children in Constanta, Romania. OBJECTIVES: To describe the design and outcomes of a program of pediatric HIV/acquired immunodeficiency syndrome (AIDS) care and treatment in a resource-poor setting. SETTING: Outpatient center providing comprehensive primary and HIV/AIDS specialty care and treatment to all known HIV-infected children living in Constanta County, Romania. OUTCOMES: As of August 2003, a total of 452 children were receiving highly active antiretroviral therapy. Therapy has been well-tolerated, with approximately 90% of children continuing to receive treatment after a median duration of follow-up of 67 weeks. Normal weight and height growth velocities have been observed among treated children. Marked decreases have been observed in rates of hospitalization and mortality. The mean change in CD4+ lymphocyte count for 173 children who have both a baseline count and at least 1 follow-up count is +284 cells/microL (P < 0.0001). CONCLUSIONS: Highly active antiretroviral therapy can be administered safely and effectively to children in a resource-poor setting, with outcomes comparable with those observed in U.S. pediatric antiretroviral clinical trials.

Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection.

OBJECTIVE: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection. METHODS: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated. RESULTS: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml. CONCLUSIONS: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.