Antiretroviral agents in pediatric HIV infection

"Although the pathogenesis of human immunodeficiency virus (HIV) infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, there are unique considerations needed for HIV-infected infants, children, and adolescents, including a) acquisition of infection through perinatal exposure for many infected children; b) in utero exposure to zidovudine (ZDV) and other antiretroviral medications in many perinatally infected children; c) differences in diagnostic evaluation in perinatal infection; d) differences in immunologic markers (e.g., CD4+ T-lymphocyte count) in young children; e) changes in pharmacokinetic parameters with age caused by the continuing development and maturation of organ systems involved in drug metabolism and clearance; f) differences in the clinical and virologic manifestations of perinatal HIV infection secondary to the occurrence of primary infection in growing, immunologically immature persons; and g) special considerations associated with adherence to treatment for children and adolescents. This report addresses the pediatric-specific issues associated with antiretroviral treatment and provides guidelines to health-care providers caring for infected infants, children, and adolescents.""April 17, 1998.""These guidelines were developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children convened by the National Pediatric and Family HIV Resource Center ... the Health Resources and Services Administration ... and the National Institutes of Health ... The Co-Chairs of the Working Group were James Oleske ... and Gwendolyn B. Scott ..."--P. ii."U.S. Government Printing Office: 1998-633-228/67064 Region IV."--P. [4] of cover.Includes bibliographical references (p. 28-31)

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.

BACKGROUND: For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. OBJECTIVES: To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy. DESIGN: Open, randomised, non-inferiority trial. SETTING: Europe, Thailand, Uganda, Argentina and the USA. PARTICIPANTS: Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of  12 months. INTERVENTIONS: Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART). MAIN OUTCOME MEASURES: Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age. RESULTS: In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial. CONCLUSIONS: Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information

Perinatal HIV transmission and the cost-effectiveness of screening at 14 weeks gestation, at the onset of labour and the rapid testing of infants

<p>Abstract</p> <p>Background</p> <p>Preventing HIV transmission is a worldwide public health issue. Vertical transmission of HIV from a mother can be prevented with diagnosis and treatment, but screening incurs cost. The U.S. Virgin Islands follows the mainland policy on antenatal screening for HIV even though HIV prevalence is higher and rates of antenatal care are lower. This leads to many cases of vertically transmitted HIV. A better policy is required for the U.S. Virgin Islands.</p> <p>Methods</p> <p>The objective of this research was to estimate the cost-effectiveness of relevant HIV screening strategies for the antenatal population in the U.S. Virgin Islands. An economic model was used to evaluate the incremental costs and incremental health benefits of nine different combinations of perinatal HIV screening strategies as compared to existing practice from a societal perspective. Three opportunities for screening were considered in isolation and in combination: by 14 weeks gestation, at the onset of labor, or of the infant after birth. The main outcome measure was the cost per life year gained (LYG).</p> <p>Results</p> <p>Results indicate that all strategies would produce benefits and save costs. Universal screening by 14 weeks gestation and screening the infant after birth is the recommended strategy, with cost savings of $1,122,787 and health benefits of 310 LYG. Limitations include the limited research on the variations in screening acceptance of screening based on specimen sample, race and economic status. The benefits of screening after 14 weeks gestation but before the onset of labor were also not addressed.</p> <p>Conclusion</p> <p>This study highlights the benefits of offering screening at different opportunities and repeat screening and raises the question of generalizing these results to other countries with similar characteristics.</p