In the Journals

NRTIs safe, effective in pediatric HIV patients

Recent data on three nucleoside reverse-transcriptase inhibitors demonstrated low toxicity and good clinical, immunological and virological responses in HIV-infected children and adolescents from Africa, according to a recent study.

“CHAPAS-3 shows primarily that children respond well to all [nucleoside reverse-transcriptase inhibitor (NRTI)/non-nucleoside reverse-transcriptase inhibitor (NNRTI)] recommended fixed-dose combinations in 2013 WHO guidelines with minimal drug toxicity,” Veronica Mulenga, MSc, from the department of pediatrics at University Teaching Hospital in Lusaka, Zambia, and colleagues wrote.

Mulenga and colleagues randomly assigned 478 children from sub-Saharan Africa to open-label Zerit (stavudine, Bristol-Myers Squibb) (n = 156), Retrovir (zidovudine, ViiV Healthcare; n = 158) or Ziagen (abacavir, ViiV Healthcare; n = 164) in combination with Epivir (lamivudine, ViiV Healthcare) and either nevirapine or Sustiva (efavirenz, Bristol-Myers Squibb). The patients were enrolled between Nov. 8, 2010 and Dec. 28, 2011.

The cohort was stratified by age (aged younger than 5 years vs. aged 5 years and older), ART history, NNRTI (nevirapine vs. efavirenz) and clinical center. Lipodystrophy measurements and hematology, biochemistry and CD4 tests were conducted at weeks 6, 12, 24, and every 24 weeks thereafter. The primary outcome was grade 2 or higher clinical adverse events, or grade 3 or 4 adverse events.

Most of the patients were ART-naive (76%) and aged younger than 5 years (71%), and more patients received nevirapine (74%) than efavirenz. The median follow-up was 2.3 years among those who completed the study (5% absent), and 98% of scheduled visits were completed with no significant difference in adherence between groups.

More than 900 grade 2 to 4, or grade 3 or 4 adverse events were reported in 312 patients, including 67% of those assigned stavudine, 65% assigned zidovudine and 64% assigned abacavir. Most of the adverse events (n = 634) were grade 2.

Nearly 200 serious adverse events occurred in 132 patients regardless of treatment. Four percent of patients who received stavudine, 8% who received zidovudine and 3% who received abacavir experienced grade 2 or 4 events that were possibly related to NRTIs, the researchers wrote. Nine of 19 reported deaths and five of 14 WHO grade 3 or 4 events occurred within 12 weeks of ART initiation and were likely related to “pre-enrollment disease severity,” the researchers wrote.

Fourteen patients substituted their ART regimen due to toxicities. Among them, four patients experienced anemia, three had neutropenia and one had leucopenia. Eight of these patients initially received zidovudine (P = .03).

At 48 weeks, ART-naive patients in the stavudine (85%), zidovudine (80%) and abacavir (81%) arms had a viral load less than 400 copies per mL, and most patients who previously received ART maintained suppression. The findings were similar across all groups at the end of follow-up, the researchers said.

Mulenga and colleagues concluded, however, that abacavir was favored over the other agents because it is dosed once-daily and had fewer hypersensitivity reactions and a greater resistance profile.

“Its only disadvantage is that it has a higher cost than zidovudine and stavudine,” they wrote. “Potential future triple abacavir-based combinations with efavirenz or [Tivicay, ViiV Healthcare (dolutegravir)] could further simplify and improve durability of once-daily first-line ART for children.”

In a related commentary, Harry Moultrie, MSc, faculty of health sciences at the University of the Witwatersrand in Johannesburg, South Africa, and Annelies Van Rie, MD, PhD, of the department of epidemiology and social medicine at the University of Antwerp in Belgium, wrote the findings refute previous observational studies that showed abacavir had reduced efficacy.

“These data are reassuring and support clinicians and policymakers in their implementation of the current WHO guidelines, which recommend abacavir plus lamivudine as the preferred NRTI backbone for pediatric ART,” they wrote. – by Stephanie Viguers

Disclosures: Moultrie, Mulenga and Van Rie report no relevant financial disclosures.

Recent data on three nucleoside reverse-transcriptase inhibitors demonstrated low toxicity and good clinical, immunological and virological responses in HIV-infected children and adolescents from Africa, according to a recent study.

“CHAPAS-3 shows primarily that children respond well to all [nucleoside reverse-transcriptase inhibitor (NRTI)/non-nucleoside reverse-transcriptase inhibitor (NNRTI)] recommended fixed-dose combinations in 2013 WHO guidelines with minimal drug toxicity,” Veronica Mulenga, MSc, from the department of pediatrics at University Teaching Hospital in Lusaka, Zambia, and colleagues wrote.

Mulenga and colleagues randomly assigned 478 children from sub-Saharan Africa to open-label Zerit (stavudine, Bristol-Myers Squibb) (n = 156), Retrovir (zidovudine, ViiV Healthcare; n = 158) or Ziagen (abacavir, ViiV Healthcare; n = 164) in combination with Epivir (lamivudine, ViiV Healthcare) and either nevirapine or Sustiva (efavirenz, Bristol-Myers Squibb). The patients were enrolled between Nov. 8, 2010 and Dec. 28, 2011.

The cohort was stratified by age (aged younger than 5 years vs. aged 5 years and older), ART history, NNRTI (nevirapine vs. efavirenz) and clinical center. Lipodystrophy measurements and hematology, biochemistry and CD4 tests were conducted at weeks 6, 12, 24, and every 24 weeks thereafter. The primary outcome was grade 2 or higher clinical adverse events, or grade 3 or 4 adverse events.

Most of the patients were ART-naive (76%) and aged younger than 5 years (71%), and more patients received nevirapine (74%) than efavirenz. The median follow-up was 2.3 years among those who completed the study (5% absent), and 98% of scheduled visits were completed with no significant difference in adherence between groups.

More than 900 grade 2 to 4, or grade 3 or 4 adverse events were reported in 312 patients, including 67% of those assigned stavudine, 65% assigned zidovudine and 64% assigned abacavir. Most of the adverse events (n = 634) were grade 2.

Nearly 200 serious adverse events occurred in 132 patients regardless of treatment. Four percent of patients who received stavudine, 8% who received zidovudine and 3% who received abacavir experienced grade 2 or 4 events that were possibly related to NRTIs, the researchers wrote. Nine of 19 reported deaths and five of 14 WHO grade 3 or 4 events occurred within 12 weeks of ART initiation and were likely related to “pre-enrollment disease severity,” the researchers wrote.

Fourteen patients substituted their ART regimen due to toxicities. Among them, four patients experienced anemia, three had neutropenia and one had leucopenia. Eight of these patients initially received zidovudine (P = .03).

At 48 weeks, ART-naive patients in the stavudine (85%), zidovudine (80%) and abacavir (81%) arms had a viral load less than 400 copies per mL, and most patients who previously received ART maintained suppression. The findings were similar across all groups at the end of follow-up, the researchers said.

Mulenga and colleagues concluded, however, that abacavir was favored over the other agents because it is dosed once-daily and had fewer hypersensitivity reactions and a greater resistance profile.

“Its only disadvantage is that it has a higher cost than zidovudine and stavudine,” they wrote. “Potential future triple abacavir-based combinations with efavirenz or [Tivicay, ViiV Healthcare (dolutegravir)] could further simplify and improve durability of once-daily first-line ART for children.”

In a related commentary, Harry Moultrie, MSc, faculty of health sciences at the University of the Witwatersrand in Johannesburg, South Africa, and Annelies Van Rie, MD, PhD, of the department of epidemiology and social medicine at the University of Antwerp in Belgium, wrote the findings refute previous observational studies that showed abacavir had reduced efficacy.

“These data are reassuring and support clinicians and policymakers in their implementation of the current WHO guidelines, which recommend abacavir plus lamivudine as the preferred NRTI backbone for pediatric ART,” they wrote. – by Stephanie Viguers

Disclosures: Moultrie, Mulenga and Van Rie report no relevant financial disclosures.