CROI 2016: Dolutegravir Is Safe and Highly Effective for Older Children with HIV

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Dolutegravir (Tivicay) plus an optimized background regimen is safe, well tolerated, and provides virological efficacy in HIV-infected children from 6 to 12 years of age at 48 weeks, Andrew Wiznia, presenting on behalf of the IMPAACT1093 study group, told participants at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston.

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Close to 80% (18 out of 23) of the children achieved virological success, defined as HIV RNA under 400 copies/mL, with 17 of the 23 (74%) having a viral load under 50 copies/mL.

Dolutegravir, an integrase inhibitor, is approved for treatment-naive and -experienced adults and adolescents 12 years of age and above. Found to have a high barrier to the development of drug resistance, it is an important option for adults and in particular adolescents and children who have failed treatment with other antiretrovirals, most notably in resource-poor settings.

There are 2.6 million children who are in need of antiretroviral therapy (ART). Almost half are currently on a sub-optimal regimen. Young children do respond well to ART, with high rates of virological suppression on first-line treatment. However, acquired drug resistance among young children after failure of a first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen is extremely high. Viral suppression may be achieved with a second line protease inhibitor-based regimen (lopinavir/ritonavir or Kaletra). However, while drug resistance mutations are limited among young children failing a first-line PI-based regimen, the potential for re-suppression when switching to an NNRTI is severely limited.

For children failing first- or second-line PI-based treatment in resource-poor settings, alternatives are lacking. The need to improve second- and third-line options is critical. Despite efforts, development of new drugs and appropriate formulations continues to be slow.

Integrase inhibitors may play an important role for children on a failing first-line PI-based regimen. Dolutegravir is of particular interest. It is well tolerated, taken once a day, and has a higher barrier to resistance than raltegravir. Determining the best sequencing of this class of drugs and improving their availability in resource-poor settings is key. Integral to this will be substantive price reduction and/or generic production. ViiV Healthcare agreed to licenses with the Medicines Patent Pool in 2014 that will allow generic production of dolutegravir for adults and children in lower- and middle-income countries.

IMPAACT 1093 is an ongoing Phase 1/2 multi-center open-label pharmacokinetic (PK), safety, and efficacy study of dolutegravir plus an optimized background regimen (OBR) for children and adolescents in age-defined cohorts.

HIV-infected treatment-experienced integrase-naive children 6 to 12 years of age on a failing antiretroviral regimen and with a viral load of or over 1000 copies/mL were enrolled into Stage 1 of the study, an intensive PK evaluation performed between days 5 and 10. The children received dolutegravir tablets (10, 25, or 50 mg) at 1 mg/kg once a day, based on defined weight bands, which were added to a stable failing regimen with an OBR added after the intensive PK or in Stage 2, where children received dolutegravir with an OBR at study entry.

The primary objective was to evaluate safety, tolerability, CD4 cell count, and viral load at week 48. Based on the Food and Drug Administration (FDA) logarithm, virological success was defined as a viral load under 400 copies/mL, with a secondary outcome of viral load under 50 copies/mL.

A total of 23 children were enrolled: 11 at Stage 1 and 12 at Stage 2. Of these, 21 (91%) completed the 48-week study period.

The median age of the children was 10 years, with a median weight of 30 kg. The majority were male and African American, 70% and 52%, respectively. Caucasians accounted for 17% and Hispanics for 26%. Median time on prior ART was 9.3 years, with close to half being triple-class experienced.

Median baseline CD4 cell count and percentage were 645 cells/mm3 and 24%, respectively. Median viral load at baseline was 5.0 log copies/mL. In accordance with pediatric weight band dosing at 1mg/kg, 1 child (weight >40 kg) received 70 mg, 5 children (weight >40 kg) received 50 mg, 6 (weight 30-40 kg) received 35 mg, 8 (weight 20-30 kg) received 25 mg, and 3 (weight 15-20 kg) received 20 mg once daily.

The preliminary 24-week study results presented in 2014 at CROI (abstract 118) showed adequate PK safety and efficacy.

Median CD4 cell count and percentage gain at week 48 were 387 cells/mm3 and 9%, respectively.

Dolutegravir was well tolerated. There were no grade 4 adverse events, serious adverse events, or discontinuation due to adverse events; 3 participants had unrelated abnormalities and 2 children went off the study, 1 due to virological failure and the other was lost to follow-up.

Dolutegravir with an optimized background regimen had a favorable safety profile in HIV-infected children aged 6 to 12 years and excellent and sustained virological efficacy with significant improvement in CD4 cell counts and percentages, the researchers concluded.

The study is continuing with evaluation of dolutegravir down to 4 weeks of age.

The future direction is weight-band dosing, avoiding an age-staggered approach that leads to the delay in approval for the youngest children, a discussion highlighted at the session. The study, Wiznia explained, inherited a structure of regulatory requirements involving age cohorts. The World Health Organization later issued recommendations for pediatric treatment using weight-band dosing. While switching patient populations in the middle of the study was not feasible, another version of the study is to be released in a month or so with another preparation of dolutegravir as a dispersible 5 mg tablet.

2/26/16

Reference

A Wiznia, C Alvero, T Fenton, et al. IMPAACT 1093: Dolutegravir in 6- to 12-Year-Old HIV-Infected Children: 48-Week Results. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 816.