Suchergebnisse

There has been significant progress towards the goal of eliminating vertical transmission of HIV by 2015. However, a question that remains is how we can most effectively prevent late postnatal transmission of HIV through infant feeding. Guidelines published by the World Health Organization in 2010 have been widely adopted. These guidelines place strong emphasis on exclusive breastfeeding, in some countries over‐turning a prior emphasis on formula feeding. Where available, provision of antiretroviral treatment for HIV‐positive mothers or prophylaxis for infants offers additional protection against vertical transmission through infant feeding. However, merely changing guidelines is not sufficient to change practice, particularly with regard to culturally sanctioned forms of feeding, such as mixed feeding. This commentary highlights structural, social and contextual barriers to effective implementation of the guidelines and suggests ways to address some of these barriers.

AbstractIntroductionThe objective of this commentary is to review considerations for implementing routine viral load (VL) monitoring programmes for HIV‐infected infants and children living in low‐ and middle‐income countries (LMIC). Since 2013, the World Health Organization (WHO) guidelines recommend VL testing as the preferred monitoring approach for all individuals treated with ART in order to assess treatment response, detect treatment failure and determine the need to switch to a second‐line regimen in a timely manner. More recently, WHO guidelines from 2016 identify HIV‐infected infants and children as a priority group for routine VL monitoring.DiscussionThere are a number of reasons why HIV‐infected infants and children should be prioritized for routine VL monitoring. Data from national VL monitoring programmes as well as systematic reviews and meta‐analyses from LMIC indicate rates of viral suppression are lower for infants and children compared to adults. The number of antiretroviral drugs and palatable formulations suitable for young children are limited. In addition, emotional and developmental issues particular to children can make daily medication administration difficult and pose a challenge to adherence and achievement of sustained viral suppression. VL monitoring can be instrumental for identifying those in need of additional adherence support, reducing regimen switches and preserving treatment options. The needs of infants and children warrant consideration in all aspects of VL monitoring services. If capacity for paediatric venipuncture is not assured, platforms that accept dried blood spot specimens are necessary in order for infants and children to have equitable access. Healthcare systems also need to prepare to manage the substantial number of infants and children identified with elevated VL, including adherence interventions that are appropriate for children. Establishing robust systems to evaluate processes and outcomes of routine VL monitoring services and to support drug forecasting and supply management is essential to determine best practices for infants and children in LMIC.ConclusionsThe particular concerns of HIV‐infected infants and children warrant attention during all phases of planning and implementation of VL monitoring services. There are a number of key areas, including frequency of monitoring, blood specimen type and adherence challenges, where specific approaches tailored for infants and children may be required.

Background: Great strides have been made in decreasing paediatric human immunodeficiency virus (HIV) infections, especially in sub-Saharan Africa. In South Africa, new paediatric HIV infections decreased by 84% between 2009 and 2015. This achievement is a result of a strong political will and the rapid evolution of the country's prevention of mother-to-child transmission (PMTCT) guidelines.Objectives: In this paper we report on the implementation of a large PMTCT programme in Soweto, South Africa.Methods: We reviewed routinely collected PMTCT data from 13 healthcare facilities, for the period 2002-2015. Antiretroviral therapy (ART) coverage among pregnant women living with HIV (PWLHIV) and the mother-to-child transmission (MTCT) rate at early infant diagnosis were evaluated.Results: In total, 360 751 pregnant women attended the facilities during the review period, and the HIV prevalence remained high throughout at around 30%. The proportion of PWLHIV presenting with a known HIV status increased from 14.3% in 2009 when the indicator was first collected to 45% in 2015, p < 0.001. In 2006, less than 10% of the PWLHIV were initiated on ART, increasing to 88% by 2011. The MTCT rate decreased from 6.9% in 2007 to under 1% from 2013 to 2015, p < 0.001.Conclusion: The achievements in decreasing paediatric HIV infections have been hailed as one of the greatest public health achievements of our times. While there are inherent limitations with using routinely collected aggregate data, the Soweto data reflect progress made in the implementation of PMTCT programmes in South Africa. Progress with PMTCT has, however, not been accompanied by a decline in HIV prevalence among pregnant women.

Purpose of the studyVirological outcomes and resistance patterns in children initiating protease inhibitor (PI)‐based antiretroviral therapy (ART) immediately following HIV‐1 diagnosis are not well described. Challenges include maintaining adherence in asymptomatic patients with very high pre‐ART viral loads. The CHER trial compared deferred but continuous ART (arm 1) with early limited ART (arms 2 and 3).MethodsLPV/r+ZDV+3TC was commenced either immediately (in 250 of 252 children randomized in arms 2 and 3) or at clinical/immunological progression (103 of 125 children in arm 1). Interruption of ART occurred after 40 (arm 2) or 96 weeks (arm 3) and re‐initiation with LPV/r + ZDV + 3TC was based on immunologic/clinical criteria. Viral load was measured on all children with a stored specimen at their last visit, having been on initial or restarted ART following interruption (arms 2 and 3) for at least 24 weeks. Children in arms 1, 2 and 3 not initiating ART due to death (16, 0, 0), LTFU (2, 2, 0) or other reason (4, 0, 0) are excluded. Resistance testing was performed on samples with a viral load (VL) ≥1000 c/mL together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and PI inhibitor mutations were analyzed using a validated in‐house population‐based sequencing assay and the IAS 2011 mutation list.Summary of resultsA total of 377 infants were enrolled; median was age 7.4 (interquartile range (IQR) 6.7 to 8.9) weeks and median baseline viral load was log10 5.7. By end of study (June 2011), 353/377 children had started LPV/r + ZDV + 3TC. Median (IQR) age at ART initiation in arms 1, 2 and 3 was 26.1 (19.9 to 40), 7.4 (6.6 to 8.7) and 7.5 (6.6 to 9.0) weeks. Median (IQR) duration on ART was 240 (216 to 252), 243 (200 to 260) and 240 (194 to 257) weeks in arms 1, 2 and 3, respectively. HIV‐1 RNA was <400 c/mL in 88/101 (87%), 95/113 (84%) and 97/117 (83%) (P=0.96). Twenty‐two of thirty‐two children with VL >1000 c/mL (2/5, 8/14, 12/13 in arms 1, 2 and 3) have had resistance tests to date; nine (41%) had mutations. There were seven with M184V mutations (1, 4, 2 in arms 1, 2 and 3); two with major PI mutations (V82A/L76V) (one in each of arms 1 and 2); and two with major NNRTI mutations (K103N/M230L) (one in each of arms 2 and 3). Two of ten children tested to date had NNRTI mutations prior to starting PI‐based triple therapy.ConclusionsVirological response on ART was excellent in this large cohort of infants initiating LPV/r+ZDV+3TC at a very young age, with no differences between randomized strategies, suggesting that planned interruption after early limited ART does not adversely affect virological outcomes. Overall, approximately 40% of those on ART with VL>1000 c/mL had a resistance mutation; PI mutations were infrequent, despite around 5 years on therapy. Ongoing work will investigate impact of length of time with detectable viral load on risk of developing resistance.

BACKGROUND: Great strides have been made in decreasing paediatric human immunodeficiency virus (HIV) infections, especially in sub-Saharan Africa. In South Africa, new paediatric HIV infections decreased by 84% between 2009 and 2015. This achievement is a result of a strong political will and the rapid evolution of the country's prevention of mother-to-child transmission (PMTCT) guidelines. OBJECTIVES: In this paper we report on the implementation of a large PMTCT programme in Soweto, South Africa. METHODS: We reviewed routinely collected PMTCT data from 13 healthcare facilities, for the period 2002–2015. Antiretroviral therapy (ART) coverage among pregnant women living with HIV (PWLHIV) and the mother-to-child transmission (MTCT) rate at early infant diagnosis were evaluated. RESULTS: In total, 360 751 pregnant women attended the facilities during the review period, and the HIV prevalence remained high throughout at around 30%. The proportion of PWLHIV presenting with a known HIV status increased from 14.3% in 2009 when the indicator was first collected to 45% in 2015, p < 0.001. In 2006, less than 10% of the PWLHIV were initiated on ART, increasing to 88% by 2011. The MTCT rate decreased from 6.9% in 2007 to under 1% from 2013 to 2015, p < 0.001. CONCLUSION: The achievements in decreasing paediatric HIV infections have been hailed as one of the greatest public health achievements of our times. While there are inherent limitations with using routinely collected aggregate data, the Soweto data reflect progress made in the implementation of PMTCT programmes in South Africa. Progress with PMTCT has, however, not been accompanied by a decline in HIV prevalence among pregnant women.

ObjectiveTo describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa.DesignThis was a programmatic cohort study.MethodsElectronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi‐square, two‐sample t‐test and Kaplan–Meier methods.ResultsA total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2–9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% <25% or absolute CD4<1500 cells/mm3 or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2–11.9) weeks in Cape Town and 8.6 (IQR: 7.7–10.0) weeks in Soweto infants (p<0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (p<0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36–0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05–2.71).ConclusionsART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality.

AbstractIntroductionEarly antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV‐infected (HIV‐positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long‐term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV‐infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART‐Def); immediate time‐limited ART for 40 weeks (ART‐40W) or 96 weeks (ART‐96W). ART was restarted in the time‐limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants.MethodsA prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery‐Buktenica developmental tests for visual motor integration at 60 months. HIV‐exposed uninfected (HEU) and HIV‐unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms.ResultsIn this study, 28 ART‐Def, 35 ART‐40W, 33 ART‐96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART‐Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV‐infected children (mean standard scores: 75.8 ART‐Def, 79.8 ART‐40W, 75.9 ART‐96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)).ConclusionsEarly locomotor delay in the ART‐Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV‐infected children on early time‐limited ART were similar to uninfected controls, apart from visual perception where HIV‐infected children scored lower. Poorer visual perception performance warrants further investigation.

Research in rapidly-evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study's standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this paper, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the "PROMISE" (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study's standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other; and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.