Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations

Background: Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. Methods: We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0–13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. Results: The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. Conclusions: The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments

Pregnant and breastfeeding women: A priority population for HIV viral load monitoring

With more than 18 million HIV-infected individuals having initiated antiretroviral therapy (ART) in low- and middle-income countries (LMICs) by the end of 2016, ensuring effective HIV care and treatment services is a global public health priority [1]. Viral load (VL) quantification provides a direct measure of the effectiveness of ART, with a consistently elevated VL suggesting poor adherence or treatment failure and the need for intervention. In turn, HIV VL monitoring is now recognised as a key component of ART services in LMICs in World Health Organization (WHO) guidelines, with an emphasis on scaling up access to VL testing for ART programmes [2]. Pregnant and postpartum women are an important population within ART programmes. In many countries, the majority of identified HIV-infected adults are women, and many women of reproductive age are diagnosed with HIV infection during pregnancy through prevention of mother-to-child transmission of HIV (PMTCT) services in antenatal care (ANC) [3]. With universal eligibility for ART for all HIV-infected pregnant and postpartum women (based on the WHO’s 2013 ‘Option B+’ policy [4]), many women of reproductive age initiating ART do so during pregnancy. PMTCT services extend through early infant diagnosis around 6–10 weeks postpartum until the cessation of breastfeeding and documentation of the infant’s final HIV testing status, which may extend well beyond 1 year postpartum based on the recently updated infant feeding recommendations [5]. With ongoing risk of HIV transmission throughout breastfeeding, maintaining ART adherence and viral suppression is especially crucial during this period. Although the importance of routine VL monitoring for HIV-infected individuals on ART is widely recognised [6], there has been minimal attention to VL monitoring in pregnancy and the postpartum period. Here we discuss key considerations for VL monitoring in pregnant and breastfeeding women in the context of expanding access to VL monitoring (summarised in Box 1)

Modeling the Impact of Retention Interventions on Mother-to-Child Transmission of HIV: Results From INSPIRE Studies in Malawi, Nigeria, and Zimbabwe

Six implementation research studies in Malawi, Nigeria, and Zimbabwe tested approaches for improving retention in care among women living with HIV. We simulated the impact of their interventions on the probability of HIV transmission during pregnancy and breastfeeding

Timing of antiretroviral therapy and adverse pregnancy outcomes : a systematic review and meta-analysis

BACKGROUND: Although life-long combination antiretroviral therapy (ART) is recommended for all HIV-infected individuals, there are limited data on pregnancy outcome with ART initiation pre-conception. We assessed the safety of ART initiated pre-conception versus post-conception on adverse pregnancy outcome. METHODS: We conducted a systematic review of studies from low-, middle-, and high-income countries. We searched Cochrane Central Register of Controlled Trials, EMBASE, LILACS, MEDLINE for randomized trials, quasi-randomized trials and prospective cohort studies conducted between 01 January 1980 to 01 June 2016). Risk ratios were pooled using a random-effects model. FINDINGS: Eleven studies were included (N=19,189 mother-infant pairs). Women initiating ART pre-conception compared to post-conception were significantly more likely to deliver preterm (pooled risk ratio[RR]=1·20, 95% confidence interval[CI] 1·01-1·14, 10 studies), very preterm (RR=1·53, 95%CI 1·22-1·92, two studies), or have low birth weight (LBW) infants (RR=1·30, 95%CI 1·04-1·62, two studies). Data on neonatal mortality was limited. We found no increase in very LBW (RR=0.18, 95% CI 0.02-1.51, one study), small for gestational age (SGA) (RR = 1·13, 95% CI 0·94-1·35, two studies), severe SGA (RR=1·09, 95%CI 0·82-1·45, one study), stillbirth (RR= RR=1·30, 95% CI 0·99-1·69, two studies) or congenital anomalies (RR= RR=1·24, 95% CI 0·61-2·49, one study). INTERPRETATION: The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but there remain limited, poor quality data on the extent/severity of these risks. We found elevated preterm delivery and low birth weight rates associated with pre-conception ART. As pre-conception ART rapidly increases globally, it will be critical to monitor for potential adverse pregnancy outcomes

HIV Testing for Children in Resource-Limited Settings: What Are We Waiting For?

Scott Kellerman and Shaffiq Essajee argue that the time has come to increase access to HIV testing for children, especially in sub-Saharan Africa

Is elimination of vertical transmission of HIV in high prevalence settings achievable?

Ameena Goga and colleagues argue that more realistic targets are needed to maintain momentum on reducing vertical transmission in countries with a high HIV prevalence.The South African Medical Research Council (SAMRC)http://www.bmj.com/thebmjam2020Paediatrics and Child Healt

Systematic review of the performance of HIV viral load technologies on plasma samples.

BACKGROUND: Viral load (VL) monitoring is the standard of care in developing country settings for detecting HIV treatment failure. Since 2010 the World Health Organization has recommended a phase-in approach to VL monitoring in resource-limited settings. We conducted a systematic review of the accuracy and precision of HIV VL technologies for treatment monitoring. METHODS AND FINDINGS: A search of Medline and Embase was conducted for studies evaluating the accuracy or reproducibility of commercially available HIV VL assays. 37 studies were included for review including evaluations of the Amplicor Monitor HIV-1 v1.5 (n = 25), Cobas TaqMan v2.0 (n = 11), Abbott RealTime HIV-1 (n = 23), Versant HIV-1 RNA bDNA 3.0 (n = 15), Versant HIV-1 RNA kPCR 1.0 (n = 2), ExaVir Load v3 (n = 2), and NucliSens EasyQ v2.0 (n = 1). All currently available HIV VL assays are of sufficient sensitivity to detect plasma virus levels at a lower detection limit of 1,000 copies/mL. Bias data comparing the Abbott RealTime HIV-1, TaqMan v2.0 to the Amplicor Monitor v1.5 showed a tendency of the Abbott RealTime HIV-1 to under-estimate results while the TaqMan v2.0 overestimated VL counts. Compared to the Amplicor Monitor v1.5, 2-26% and 9-70% of results from the Versant bDNA 3.0 and Abbott RealTime HIV-1 differed by greater than 0.5log10. The average intra and inter-assay variation of the Abbott RealTime HIV-1 were 2.95% (range 2.0-5.1%) and 5.44% (range 1.17-30.00%) across the range of VL counts (2log10-7log10). CONCLUSIONS: This review found that all currently available HIV VL assays are of sufficient sensitivity to detect plasma VL of 1,000 copies/mL as a threshold to initiate investigations of treatment adherence or possible treatment failure. Sources of variability between VL assays include differences in technology platform, plasma input volume, and ability to detect HIV-1 subtypes. Monitoring of individual patients should be performed on the same technology platform to ensure appropriate interpretation of changes in VL. Prospero registration # CD42013003603

MRC Clinical Trials Unit, UK

www.ias-cipher.org

Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis.

BACKGROUND: Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID. METHODS AND FINDINGS: Thirteen peer reviewed HIV VL publications and five HIV EID papers were included. Depending on the technology and the viral load distribution in the study population, the percentage of DBS samples that are within 0.5 log of VL in plasma ranged from 52-100%. Because the input sample volume is much smaller in a blood spot, there is a risk of false negatives with DBS. Sensitivity of DBS VL was found to be 78-100% compared to plasma at VL below 1000 copies/ml, but this increased to 100% at a threshold of 5000 copies/ml. Unlike a plasma VL test which measures only cell free HIV RNA, a DBS VL also measures proviral DNA as well as cell-associated RNA, potentially leading to false positive results when using DBS. The systematic review showed that specificity was close to 100% at DBS VL above 5000 copies/ml, and this threshold would be the most reliable for predicting true virologic failure using DBS. For early infant diagnosis, DBS has a sensitivity of 100% compared to fresh whole blood or plasma in all studies. CONCLUSIONS: Although limited data are available for EID, DBS offer a highly sensitive and specific sampling strategy to make viral load monitoring and early infant diagnosis more accessible in remote settings. A standardized approach for sampling, storing, and processing DBS samples would be essential to allow successful implementation. TRIAL REGISTRATION: PROSPERO Registration #: CRD42013003621

How are countries in sub-Saharan African monitoring the impact of programmes to prevent vertical transmission of HIV?

Vertical transmission of HIV can occur during pregnancy, delivery, or through breast feeding. The main driver of vertical transmission is a high maternal viral load. Between 2002 and 2016, low and middle income countries (LMICs) in sub-Saharan Africa with high HIV prevalence improved their policies to prevent vertical transmission of HIV. In 2002, national policies recommended single dose nevirapine at the onset of labour, with limited or no breast feeding. By 2016, all Global Plan priority countries in sub-Saharan Africa (where 90% of the world’s HIV positive pregnant women live) had adopted Option B+ with promotion of breast feeding. Option B+ was a dramatic policy change recommending lifelong triple antiretroviral therapy (ART) for all pregnant and lactating women living with HIV. The aim is to protect the child from HIV infection, ensure the mother’s future health, and prevent horizontal transmission of HIV.The South African Medical Research Council (SAMRC)http://www.bmj.com/thebmjam2020Paediatrics and Child Healt