Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

BACKGROUND: In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiation of ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to substitute drugs or interrupt therapy. This review, an update of a previous review, aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 3 years of age. OBJECTIVES: To evaluate 1) when to start ART in young children (less than 3 years); 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens; and 3) whether alternative strategies should be used to optimize antiretroviral treatment in this population: induction (initiation with 4 drugs rather than 3 drugs) followed by maintenance ART, interruption of ART and substitution of PI with NNRTI drugs once virological suppression is achieved on a PI-based regimen. SEARCH METHODS: Search methodsWe searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform). SELECTION CRITERIA: We identified RCTs that recruited perinatally HIV-infected children under 3 years of age without restriction of setting. We rejected trials that did not include children less than 3 years of age, did not provide stratified outcomes for those less than 3 years or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes. MAIN RESULTS: A search of the databases identified a total of 735 unique, previously unreviewed studies, of which 731 were excluded to leave 4 new studies to incorporate into the review. Four additional studies were identified in conference proceedings, for a total of 8 studies addressing when to start treatment (n=2), what to start (n=3), whether to substitute lopinavir/ritonavir (LPV/r) with nevirapine (NVP) (n=1), whether to use an induction-maintenance ART strategy (n=1) and whether to interrupt treatment (n=1).Treatment initiation in asymptomatic infants with good immunological status was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller pilot trial, median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure at 24 weeks was 1.79 (95%CI 1.33, 2.41) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0001) with no clear difference in the effect observed for children younger or older than 1 year. The hazard for virological failure at 24 weeks was overall 1.84 (95%CI 1.29, 2.63) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0008) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life.Infants starting a LPV/r regimen and achieving sustained virological suppression who then substituted LPV/r with NVP after median 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was greater among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002).Children undergoing an induction-maintenance ART approach with a 4-drug NNRTI-based regimen for 36 weeks, followed by 3-drug ART, had significantly greater CD4 rise than children receiving a standard 3-drug NNRTI-based ART at 36 weeks (mean difference 1.70 [95%CI 0.61, 2.79] p=0.002) and significantly better viral load response at 24 weeks (OR 1.99 [95%CI 1.09, 3.62] p=0.02). However, the immunological and virological benefits were short-term.The one trial of treatment interruption that compared children initiating continuous ART from infancy with children interrupting ART was terminated early because the duration of treatment interruption was less than 3 months in most infants. Children interrupting treatment had similar growth and occurrence of serious adverse events as those in the continuous arm. AUTHORS' CONCLUSIONS: ART initiation in asymptomatic children under 1 year of age reduces morbidity and mortality, but it remains unclear whether there are clinical benefits to starting ART in asymptomatic children diagnosed with HIV infection between 1-3 years.The available evidence shows that a LPV/r-based first-line regimen is more efficacious than a NVP-based regimen, regardless of PMTCT exposure status. New formulations of LPV/r are urgently required to enable new WHO recommendations to be implemented. An alternative approach to long-term LPV/r is substituting LPV/r with NVP once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of routine viral load testing.A 4-drug induction-maintenance approach showed short-term virological and immunological benefits during the induction phase but, in the absence of sustained benefits, is not recommended as a routine treatment strategy. Treatment interruption following early ART initiation in infancy was challenging for children who were severely immunocompromised in the context of poor clinical immunological condition at ART initiation due to the short duration of interruption, and is therefore not practical in ART treatment programmes where close monitoring is not feasible.

How much should we expect? Family caregiving of AIDS patients in rural Uganda.

The aim of this study was to measure the burden of care for family caregivers of AIDS patients. A cross-sectional exploratory design was used to describe the care experiences of family caregivers of AIDS care recipients. A questionnaire was used to interview 120 family caregivers of AIDS patients from four rural areas in western Uganda. The questions asked were related to 12 domains of family caregiving. Care burden scores of caregivers were calculated. It was found that care burden scores were high in all domains except those regarding relationships within the families and substance abuse. Serious work overload and low health status were reported. The high burden of caregiving puts family caregivers at risk for decreased health status and increased social isolation and depression.

IgA antibodies to human immunodeficiency virus in serum, saliva and urine for early diagnosis of immunodeficiency virus infection in Ugandan infants.

The value of HIV-1 IgA antibodies for early diagnosis of HIV infection in infants in serum, saliva and urine was investigated at Mulago Hospital, Kampala. Sensitivity and specificity in serum of HIV-infected infants at different ages were: 0 to 1 months, 88 and 95%; 1 to 3 months, 88 and 97%; 4 to 6 months, 80 and 96%. They decreased between 67 and 77% and 80 to 91%, respectively, in older age groups. Sensitivity for saliva was lower (53 to 79%) and urine only 37 to 62%, although specificity was reasonably high (>85%). The high proportion of infants with raised HIV IgA in the first months of life (88%) may represent prenatal infection. Sensitivity of serum and especially salivary and urinary HIV IgA is too low to be of practical value for early diagnosis of HIV infection in infants.

Optimization of antiretroviral therapy in HIV-infected children under 3 years of age: a systematic review.

BACKGROUND: Treatment of young HIV-infected children is challenging because of rapid disease progression, high viral loads and few drug options. This review was undertaken to update evidence on the management of young HIV-infected children and to inform the development of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries. DESIGN: A systematic review and meta-analysis. METHODS: We identified and critically assessed randomized controlled trials that evaluated treatment strategies in perinatally HIV-infected infants and young children (aged <3 years). RESULTS: Eight studies were included. Antiretroviral therapy (ART) initiation in asymptomatic infants led to 74% reduction in mortality or disease progression [hazard ratio 0.36, 95% confidence interval (CI) 0.18-0.74, P = 0.0002]. Regardless of previous exposure to prevention of mother to child transmission (PMTCT), treatment failure at 24 weeks was more likely in children starting nevirapine-based than in those starting lopinavir/ritonavir (lopinavir/r)-based ART (hazard ratio 1.79, 95% CI 1.33-2.41, P = 0.0001). Infants starting lopinavir/r-based ART and substituting lopinavir/r with nevirapine once virologic suppression was achieved were less likely to experience viral load more than 50 copies/ml (hazard ratio 0.62, 95% CI 0.41-0.92, P = 0.02) but more likely to have confirmed virologic failure (>1000 copies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.36-43.94, P = 0.002). Children receiving induction-maintenance ART (four-drug NNRTI-based regimen for 36 weeks followed by three-drug ART) showed better short-term immunologic and virologic responses, but no long-term benefits. The only trial comparing continuous ART from infancy with interrupted ART beyond infancy was terminated early because the duration of treatment interruption was less than 3 months in most infants. CONCLUSION: ART initiation in asymptomatic infants reduces morbidity and mortality. Lopinavir/r-based first-line ART is superior to nevirapine-based regimens in young children, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substituting lopinavir/r with nevirapine following virologic suppression may be feasible where viral load testing is available. Considering current evidence, induction-maintenance and treatment interruption strategies are not recommended. This review contributed to the evidence base for the 2013 WHO guidelines on antiretroviral therapy, which recommend that all children below 3 years start lopinavir/r-based ART and that lopinavir/r can be substituted with nevirapine once sustained virologic suppression is achieved.

Scaling up pediatric HIV care and treatment in Africa: clinical site characteristics associated with favorable service utilization.

BACKGROUND: To improve pediatric enrollment and retention in HIV treatment programs in Africa, we examined factors associated with service utilization within the Elizabeth Glaser Pediatric AIDS Foundation program in Côte d'Ivoire, Mozambique, South Africa, Tanzania and Zambia. METHODS: We retrospectively reviewed characteristics of clinical sites providing HIV treatment services within our program. For each site, favorable pediatric program outcomes were defined as a cumulative number or percentage of pediatric enrollment in care or antiretroviral therapy (ART) more than the pooled median value or an attrition rate less than 10%. We compared proportions of sites with favorable outcomes among those with or without selected characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were determined using logistic regression analyses, accounting for potential confounding factors. RESULTS: Over 4 years, 33,331 children were enrolled, including 18,255 on ART, across 220 sites. Characteristics associated with favorable pediatric enrollment were nutritional support (aOR = 8.9; CI: 2.8 to 28.4), linkages with associations of people living with HIV (aOR = 4.2; CI: 1.8 to 9.5), early infant diagnosis (aOR = 3.3; CI: 1.5 to 7.1), and on-site prevention of mother-to-child transmission services (aOR = 3.1; CI: 1.0 to 11.1). Similarly, linkages with people living with HIV, early infant diagnosis, and prevention of mother-to-child transmission were associated with high proportion of children on ART younger than 2 years of age. Home-based care was associated with low pediatric attrition rates (aOR = 2.9; CI: 1.4 to 5.8). CONCLUSIONS: Certain site characteristics were associated with favorable pediatric enrollment and retention in our program. Expanding these characteristics to improve pediatric HIV treatment in Africa warrants further evaluation.

PEPFAR scale-up of pediatric HIV services: innovations, achievements, and challenges.

HIV/AIDS has had a profound impact on children around the world since the start of the epidemic. There are currently 3.4 million children under the age of 15 years living with HIV globally, and more than 450,000 children currently receiving lifesaving antiretroviral treatment. This article describes efforts supported by the President's Emergency Plan for AIDS Relief (PEPFAR) to expand access to treatment for children living with HIV in high-burden countries. The article also highlights a series of case studies that illustrate the impact that the PEPFAR initiative has had on the pediatric HIV epidemic. Through its support of host governments and partner organizations, the PEPFAR initiative has expanded HIV testing and treatment for pregnant women to reduce vertical transmission of HIV, increased access to early infant diagnosis for HIV-exposed infants, improved training and resources for clinicians who provide pediatric care and antiretroviral treatment, and, through public-private partnerships with pharmaceutical manufacturers, helped increase the number of medications available for the treatment of HIV-infected children in resource-limited settings.

AIDS-related stigma: perceptions of family caregivers and health volunteers in western Uganda.

This article reports the findings from a qualitative research study carried out in four areas in western Uganda. Opinions about AIDS-related stigma were elucidated from four focus group discussions with health volunteers of a home-based care program for HIV/AIDS and from 16 in-depth interviews with family caregivers of AIDS patients. While the health volunteers emphasized that AIDS-related stigma is still very strong, the family caregivers said that positive changes have occurred and discrimination against AIDS patients and their family members has eased. The difference in the perception of AIDS-related stigma between health volunteers and family caregivers needs further confirmation through additional studies specifically designed to answer this question. It should also be investigated whether the healthcare system itself contributes to AIDS-related stigma in this environment.

Family caregivers in rural Uganda: the hidden reality.

We conducted 16 in-depth interviews with family caregivers of AIDS patients in three rural districts in western Uganda. They were selected from a client visitation list of the home-based care program for AIDS patients, based on volunteer participation. Family caregivers reported huge problems associated with providing the necessary psychological, social, and economic care. They also said that the physical and emotional demands of caregiving are overwhelming daily challenges. Most support to AIDS patients provided by family, friends, and the churches. The study highlights the great burden of caregivers, in sub-Saharan Africa who most often are elderly women and young girls. This study examine, the burden and related health issues of family caregivers, primarily women, for AIDS patients in Uganda. It was part of a broad research project using qualitative methods on family caregiving in the home environment in sub-Saharan Africa. As the requirements for family care giving are often overwhelming for women under the conditions as they exist in Uganda and in other developing countries, it constitutes a gender issue of great importance that has not been appreciated fully in the international literature. Family caregiving is also of international relevance, as HIV/AIDS is a global pandemic of previously unknown proportions. In many poor countries, family caregiving is the most common and often the only care that AIDS patients receive, because clinic-based care often is not available close to home or is not affordable. Therefore, family caregiver support programs to alleviate this burden are essential for all those countries where HIV/AIDS is prevalent. Family caregiver burden encompasses medical, social, and economic issues at the household level, which requires an interdisciplinary approach in order to fully understand and appreciate the different dimensions of the family caregiver burden and its negative impact on the lives of so many women in so many countries.