TASER-P
Study title
Prospective Monitoring of Second-line Antiretroviral Therapy Failure and Resistance in Children
Study Code
TASER-P
Network
TREAT Asia
Study PI
Prof. Virat Sirisanthana, M.D.
Study Co PI
Linda Aurpibul, M.D.
Tavitiya Sudjaritruk, MD, ScM
Study sites
Indonesia
- Cipto Mangunkusumo Hospital, Jakarta
Thailand
- HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok
- Faculty of Medicine Srinakarin Hospital, Khon Kaen University, Khon Kaen
- RIHES, Chiang Mai University, Chiang Mai
- Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok
Vietnam
- Children’s Hospital 1, Ho Chi Minh City
- Children’s Hospital 2, Ho Chi Minh City
- National Hospital of Pediatrics, Hanoi
Funding agency
amfAR, Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) through an unrestricted grant from ViiV Healthcare.
Study design
Multicenter, observational cohort study
Study objective
Primary Objective
To monitor for resistance development and resistance patterns in children failing second-line ART over 72 weeks
Secondary Objectives
- To determine the frequency of virologic suppression defined as HIV-RNA
- To determine the frequency of virologic suppression defined as HIV-RNA 1000 copies/ml over 168 weeks
- To assess HIV drug resistance patterns by virtual phenotyping
- To evaluate predictors of virologic failure
- To correlate ARV drug levels between plasma and hair samples
- To correlate hair ARV levels with virologic response and measures of adherence
Number of enrolled participants (overall/at RIHES)
HIV-positive children
For Faculty of Medicine and Research Institutes for Health Sciences (RIHES), Chiang Mai University enrolled 24 HIV-positive children to the study.
Year: started
October 2010
Year: expected to finish
May 2014
Significance
First-line Treatment Failure: Prevalence, Predictors and Resistance Pattern in Children
There are an estimated 2 million children living with HIV in the world with 200,000 of them on antiretroviral therapy. The World Health Organization recommends using two NRTIs (nucleoside reverse transcriptase inhibitors) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) as first-line treatment. Data from individual cohorts in Thailand, Uganda Cambodia and also data from a meta-analysis of 1457 children in resource limited settings showed that 70-81% of children had viral suppression at one year after first-line treatment. However, children in resource-limited settings are increasingly experiencing treatment failure, as defined by virologic, immunologic, and/or clinical criteria. In a recent study from the UK and USA of children who were treated with first-line NNRTI and protease inhibitor (PI)-based therapy, 23% failed virologically over four years. Virologic failure after 12 months of ART has been reported in as much as 40% of children on first-line treatment. The number of children who are becoming resistant to first-line ART and need more advanced treatment regimens is growing.
Pediatric studies have reported several factors associated with virological failure. Male sex and use of nevirapine as supposed to efavirenz were strong predictive factors. Having advanced HIV disease, low CD4 and high HIV RNA prior to starting first-line ART may also be risk factors for failure.
There are few studies of HIV resistance mutations in children failing first-line NNRTI therapy in resource-limited settings. Mutations occur when active viral replication persists in the presence of ARV pressure. The extent of resistance development depends on whether failure is detected early or late. Early treatment failure is usually associated with few NRTI mutations and may be captured when routine (i.e., every 1000 copies/ml) after NNRTI-based ART. Major resistance mutations were found in 57% of children, including 33% with K103N, 10% with Y181C, and 38% with thymidine analog mutations (TAM). A similar study of 40 children in Northern Thailand with virologic failure (HIV RNA >1000 copies/ml after 24 weeks of ART) found 95% (N=37 of 39 genotyped) of them with NNRTI resistance mutations, including 33% with K103N and 56% with Y181C/I. NRTI mutations included M184V (82%), any TAM (18%), and K65R (10%). Another study from Thailand, the HIV-NAT 086 study, of 120 children failing first-line NNRTI-based therapy who did not have routine viral load monitoring, almost all children had some NRTI, lamivudine and NNRTI resistance, about one-third had multi-NRTI drug resistance, and 5% had K65R.
The emergence of treatment failure and drug resistance in children on ART emphasizes the urgency for developing evidence-based second-line and salvage treatment strategies. Pediatric treatment is complicated by a number of factors, including having fewer numbers of ARVs approved by drug safety agencies and the lack of pediatric formulations. This further shortens the list of available second-line ARVs as compared to adults.
Second-line and Salvage Treatment in Children
In the TREAT Asia Pediatric Program, a regional network of primarily referral-level clinical sites in Asia, 20% of children were already on their second regimens in early 2008. For second-line therapy, WHO recommends using two NRTIs plus one PI and specifically to replace zidovudine or stavudine with abacavir. This frequently is used in combination with lamivudine or didanosine, and lopinavir/ritonavir. Despite the growing number of children on second-line therapy worldwide, there are limited data on efficacy of second-line PI therapy in children after NRTI-NNRTI failure. Currently available data on small cohorts of children from developed and developing countries have demonstrated between 67% to 92% with HIV RNA below 50 copies/ml. The HIV-NAT 017 study treated children with a double-boosted PI regimen of saquinavir and lopinavir/ritonavir, and reported 78% of children having HIV RNA below 50 copies/ml at two years. In a multicenter retrospective study from Thailand, 241 children failing first-line therapy were treated with single-boosted PI or double-boosted PI. It was found that the overall rate of HIV RNA suppression below 50 copies/ml was excellent, with approximately 80% of children achieving viral undetectable. Despite this favorable viral suppression rate, there will be at least 20% of children who will experience treatment failure. Data on PI-based second line are lacking in other Asian countries.
There are currently no options for third-line/salvage regimens for children in resource-limited settings. New drugs and drug classes including darunavir, etravirine, tipranavir, raltegravir and maraviroc will be needed to ensure treatment success as children age into adulthood. Of the new drugs, only darunavir (for age ≥6 years) and tipranavir (for age ≥2 years) are approved for use in children by the US FDA, but are not routinely available outside of high-income settings.
Darunavir/ritonavir showed good efficacy in the DELPHI study that enrolled 80 highly ART-experienced children ages 6-17 years old. At 24 weeks, 50% had HIV RNA below 50 copies/ml21. Tipranavir/ritonavir was used to treat 115 children ages 2-18 years with 3-class failure and 34.5% had HIV RNA below 50 copies/ml. Etravirine is being studied in an ongoing 48-week phase II trial, the PIANO trial, of 100 treatment-experienced children. Raltegravir is being studied in the ongoing IMPAACT P1066 study of 140 children aged 4 weeks to 19 years. There is a study of maraviroc in 125 experienced CCR5-Tropic children with ≥ 2 class failure aged 2-18 years.
There are no data on the resistance patterns of children failing second-line therapy in resource-limited settings to guide clinical management and ARV procurement. Clinicians need evidence-based guidelines for how to manage children with treatment failure, and access to the drugs necessary to construct potent and durable third-line regimens. This study will help to identify which ARV candidates should be prioritized for pediatric use in resource-limited settings.
Assessment of Antiretroviral Drug Level in Blood and Hair
Studying ARV pharmacokinetics can provide important insights into how Asian children respond to therapy and potential drug toxicities. Many factors can affect drug absorption, disposition and elimination. These include gender, age, genetics, weight, drug-drug interaction and food. Measuring drug concentrations has proven beneficial in a number of investigations: determining appropriate drug dosing when there is a need to use drugs with potential interactions, for populations with different body builds or different ethnicities, and when studying equivalence between branded and generic drugs.
Therapeutic drug monitoring (TDM) is the measurement of drug concentrations in plasma at a particular time point in order to assess for adherence and potential toxicity from high drug levels. However, a limitation of TDM on plasma is that it reflects current blood levels (a “snapshot” of exposure), but not ARV exposure over time. Determining ARV levels in hair can reflect plasma concentrations over weeks to months, and may provide a novel method for predicting therapeutic responses. Gandhi M, et al. demonstrated that PI levels in hair samples were the strongest independent predictor of virologic response in multivariate models for patients on PI-based regimens. Studies in African children have been initiated using this laboratory technology, but have not yet been conducted in Asia. The TASER-Pediatrics will study the potential correlation between TDM by plasma and hair samples, as compared with self-reported adherence for the first time in Asian children.
