Once-daily FTC, ddI, and efavirenz in children and adolescents

Easy to take once a day regimens seem particularly desirable for paediatric HIV treatment, both for children and their caregivers. It is expected that a once a day strategy will improve adherence and, in turn, efficacy.

In an oral presentation, Ross McKinney, on behalf of the PACTG Protocol 1021 team, presented results from an open label, phase I/II paediatric study of the antiretroviral drug regimen, FTC, ddI and efavirenz.

A group of 37 drug naive, (having previously received perinatal prophylaxis was allowed in the study) patients were enrolled between September 2001 and October 2002. Twenty-one children were between 3 and 12 years and 16 adolescents 13 to 21 years. The group was followed for at least 96 weeks on an intent-to-treat basis. The data cut off for these results was August 2004.

At baseline. the overall median absolute CD4 count of the group was 310 cells/mm³, CD4 percentage was 17% and viral load 47,775 copies/mL. The study included intensive PK at weeks 2, 8 and 12 at a time of discontinuation. The investigators reported anticipated AUCs with FTC and ddI. For efavirenz AUCs were below anticipated for children </= 12 years receiving the oral solution (oral 30.8 h ug/mL, caps 46.5 ug/mL, adolescent patients 61 ug/mL), which led to a dose increase in this group.

Overall, 10/37 patients discontinued treatment. The only adverse events leading to discontinuation were 2 rashes (one grade 3, one grade 2) during the first two weeks of therapy. Three patients discontinued due to virological failure (attributed to adherence). The remaining discontinuations were non treatment-related: 2 adolescents were incarcerated; 2 found the study visits inconvenient and 1 moved out of the country.

Two patients had grade 3 symptoms attributed to the study regimen (rash; dizziness which resolved in week 1). Only one possibly drug-related adverse event was severe (grade 4 hypoglycemia). There were no deaths.

The investigators reported that virologic outcomes showed promise, with 32/37 (85%) patients achieving viral loads <400 RNA copies/mL, and 26/37 (72%) <50 copies/mL at week 96. At week 96 the median absolute CD4 was 673 cells/mm³ and CD4 percentage was 32%

Dr McKinney reported: A once-daily regimen of FTC, ddI, and EFV proved to be safe and effective in this 37 subject, 2-year phase I/II study. By intent-to-treat analysis, 72% of subjects demonstrated sustained HIV viral load suppression to <50 copies/mL through week 96.

Questions from the floor included, whether failures could be attributed to under dosing, to which Dr McKinney explained that this was more likely to be the result of poor adherence. There was also a remark that there seemed to be no difference in the response to treatment across age groups in this small study and these results were particularly impressive for adolescents.

Comment

What little adult data there is on ddI/3TC (or FTC)/EFV is virologically good. However, it has never really become popular, largely because of the ddI/food issue, and because of concerns regarding ddI toxicity. The results of the UK Nocte study (Combivir/EFV versus ddI/3TC/EFV) should be presented later this year, although this study is powered to address adherence rather than virological efficacy.

McKinney R, Rathore M, Hu C et al. Phase I/II study of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: PACTG Protocol 1021. 13th CROI, Denver, 2006. Abstract 17.