A range of new antiretroviral drugs are in development for adolescents with HIV, a population which may have extensive experience of antiretroviral therapy and resistance to some of the most commonly used drugs, the 19th International AIDS Conference (AIDS 2012) in Washington DC heard on July 24.
Etravirine (Intelence), a non-nucleoside reverse transcriptase inhibitor (NNRTI) could offer an important alternative to nevirapine (Viramune). Many children will have experience of an NNRTI such as nevirapine as used in prevention of mother-to-child transmission (PMTCT) so making second-or third-line treatment options difficult, especially in resource-poor settings.
While these findings bring long-awaited and welcome new developments they also serve to highlight the divide, not only between adults and children, but also between children in resource-rich settings and those in resource-poor settings.
Dolutegravir (DTG) is a new integrase inhibitor being developed by Viiv Healthcare for once-daily dosing.
IMPAACT P1093 is an ongoing Phase 1/2 open-label PK safety-dose-finding study of dolutegravir (DTG) plus OBG in children aged from 6 weeks to under 18 years.
DTG weight-based fixed doses at 1.0 mg per kg once a day were evaluated. Background regimens were optimised following intensive PK evaluation.
Of the ten adolescents, seven were female with a mean age of 14 years and weight of 57.3 kg; nine received 50mg DGT and one 35mg daily. Median baseline CD4 cell percentages and viral load were 21.5% (IQR: 18.4-26) and 4.40log10 copies/ml (IQR: 4.17-4.84), respectively. After four weeks of dosing, 70% (7/10) had a viral load under 40 copies/ml with a median decrease from baseline CD4 cell percentage of 2.8 log10 copies/ml, 95% CI:-3.1, -2.6).
Presenting the findings, Dr Rohan Hazra noted DTG was well-tolerated in adolescents over a short-term dosing period, offering an attractive treatment option in this population.
Longer-term safety data are being assessed in this ongoing study. Dr Hazra concluded that these results support further DTG investigations at the selected dose and these are starting in a younger paediatric cohort (6 to 12 years).
In a difficult-to-treat antiretroviral treatment-experienced population comprising two cohorts (6 to under 12 years and over 12 to under 18 years), the efficacy, safety and resistance profiles of etravirine at 5.2 mg/kg taken twice a day with an optimised background regimen (OBG) at 48 weeks were comparable to those seen in treatment-experienced adults (in the DUET study), Dr Gareth Tudor-Williams reported on behalf of the PIANO study at the same session.
All participants in this 48 week Phase II, open-label trial had a baseline viral load of at least 500 copies/ml. All participants received an OBG comprising a ritonavir-boosted protease inhibitor plus nucleotide reverse transcriptase inhibitors and optional enfuvirtide (T-20) and/or raltegravir.
In total, 75% (76) completed the trial, most stopping because of adverse events, with rash being the most frequent. Of the remaining participants, 65% were adherent – according to a questionnaire, but the pill count showed only 39% adherence. Forty-six per cent of the children and 35% of the adolescents had adherence rates of 95% or more.
Overall, 56% attained undetectable viral load (under 50 copies/ml). Children did better than adolescents with the former reaching an undetectable viral load at a median of 16 weeks and the latter at 24 weeks.
In all, 41 (41%) had virologic failure, 30 of whom had available genotyping at 48 weeks. Of these, 60% (18) developed common NNRTI resistance mutations.
Raltegravir, used in combination with other antiretrovirals, in HIV-infected treatment-experienced children aged two to 18 years was well tolerated with good viral and immunological responses at 48 weeks, Dr Sharon Nachman, presenting on behalf of IMPAACT P1066, reported in the final session.
Initial findings from this ongoing Phase 1/11 open-label, multicentre trial on the safety, tolerability, pharmacokinetics and efficacy of raltegravir in two formulations (film-coated tablet and chewable) at 24 weeks led to the US Food and Drug Administration approval for children aged two and older in January 2012, and were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections (CROI).
Three age cohorts were enrolled in sequence with cohort 1 enrolled first: 12 to 18 years; cohort 2: 6 to under 12 years; and cohort 3: 2 to under 6 years.
At 48 weeks, an overall virologic response was seen in close to 80% of the 96 subjects, with 56.7% having achieved an undectable viral load (under 50 copies/ml) and a mean CD4 cell count increase of 155.7 cells/mm3.
While serious adverse events were seen in close to half (46) of all subjects, none required drug discontinuation, nor did they result in any deaths.
Findings from this study have been used to obtain licensing approval for these regimens in HIV-positive young people in the US.
Hazra R et al. Pharmacokinetics, safety and efficacy of dolutegravir (DGT); S/GSK1349572) in HIV-1 positive adolescents: preliminary analysis from IMPAACT P1093. 19th International AIDS Conference, abstract TUAB0203, Washington DC, July 2012.
Tudor-Williams G et al. Safety and efficacy of etravirine in HIV -1-infected, treatment-experienced children and adolescents: PIANO 48-week results. 19th International AIDS Conference, abstract TUAB 0204, Washington DC, July 2012.
Nachman S et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through 48, 19th International AIDS Conference, abstract TUAB0205, Washington DC, July 2012.