With recent changes in global pediatric HIV policy to initiate treatment immediately after early infant diagnosis, there will be greater demand for feasible antiretroviral sequencing strategies that will support children through adulthood. This review will discuss HIV treatment (antiretroviral therapy) failure, regimen switching, and sequencing approaches in children.
Although children appear to acquire resistance mutations in a similar pattern to adults, they may develop virologic failure more rapidly; reports from Africa and Asia have already documented rates as high as 26% at 12 months of antiretroviral therapy. Ritonavir-boosted lopinavir is recommended after failure to nonnucleoside reverse transcriptase inhibitors; efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor after protease inhibitor failure. Approaches to sequencing nucleoside reverse transcriptase inhibitors are more complicated, as accumulated resistance mutations may render currently recommended combinations less potent. Salvage regimens are preferably selected after genotyping, and may require the use of expensive, novel boosted protease inhibitors and new drug classes (e.g., integrase inhibitors).
Data on drug resistance in children in low- and middle-income countries are emerging and will guide future sequencing strategies. Lack of access to treatment monitoring and second-line and salvage drugs are key limiting factors that need to be addressed in order to ensure ongoing treatment success.
[Show abstract][Hide abstract] ABSTRACT: To describe the global effort targeting the major causes of mortality in terms of "open" early phase clinical trials with drugs and biologicals.
Sixteen of the 20 leading causes of death were chosen; 9 of these were also amongst the top 10 causes of death in low-income countries. Studies were identified from the ClinicalTrials.gov database and included phase 1 and/or 2 "interventional" "open" trials, i.e. those recruiting or about to start recruitment. Trials were considered in terms of sponsorship [industry, universities and other organisations (UNO), and US federal agencies (NIH included)], genders and age groups included, and whether they were conducted with drugs and/or biologicals. The search was performed in March 2010.
A total of 2,298 (824 phase 1; 1,474 phase 2) trials were retrieved. Of these, 67% were on trachea, bronchus, and lung cancers (25%); diabetes mellitus (15%); colon and rectum cancers (14%); and HIV/AIDS (12%). In contrast, only 4% were trials on diarrhoeal disease, nephrosis and nephritis, liver cirrhosis, and prematurity and low birth weight. UNO were the first source of funding. Fifty-two percent of phase 1 non-cancer trials were on healthy volunteers. Twenty-nine percent of all trials were co-funded. There were 4.6 times as many drug trials as those with biologicals. Only 7% were conducted with a combination of drugs and biologicals, the majority (78%) on cancers. Discrimination in terms of gender or age group was not observed.
Four of the 16 diseases considered represented 2/3 of early phase trials. Cancers were a top priority for all sponsors. Increasing attention should be given to conditions with current and projected global high mortality rates that had few "open" early phase trials.
European Journal of Clinical Pharmacology 04/2011; 67(6):563-71. DOI:10.1007/s00228-011-1036-1 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Emergence of viral resistance is a major obstacle for antiretroviral treatment (ART) effectiveness. Human immunodeficiency virus type-1 (HIV-1) variants and drug-resistance mutations were identified in naive and antiretroviral drug-experienced children with virologic failure, in Honduras and El Salvador.
Methods: Dried blood spots (DBS) from 80 individuals (54 from Honduras, 26 from El Salvador) infected during their childhood between 1989 and 2009 were collected in 2009. The HIV pol region was amplified and sequenced to identify antiretroviral-resistant mutations according to the 2009 International AIDS Society. The genotypic drug resistance interpretation was performed using the Stanford algorithm. HIV-1 variants were characterized by phylogenetic analysis and subtyping tools.
Results: HIV-1 protease and reverse transcription sequences were obtained from DBS specimens in 71 and 66 patients, respectively, of the 80 patients. All children were native Central Americans carrying subtype B, with a mean age of 9 years, most were male (65%), perinatally infected (96%), with moderate/severe AIDS symptoms (70%), and receiving first line ART at the time of sequencing (65%). Diagnostic delay was frequently observed. Infected children from Honduras presented longer ART experience and clinical outcomes, and more frequent severe symptoms. Resistant variants infected 1 of 11 naive children from El Salvador but none of the perinatally infected naive children from Honduras. Resistance was higher among ART-exposed individuals in both countries and similar for protease inhibitors (16%), nucleoside reverse transcription inhibitors (44%–52%), and nonnucleoside reverse-transcription inhibitors (66.7%). One in 10 pretreated children in each country was infected with resistant viruses to the 3 drug families.
Conclusions: Our data support the need for continued surveillance of resistance patterns using DBS at national levels among naive and pretreated children to optimize the ART regimens.
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