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AIDS 2012: Adolescent Antiretroviral Options Expanding

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A range of new antiretroviral drugs are in development for adolescents with HIV, a population which may have extensive experience with antiretroviral therapy and resistance to some of the most commonly used drugs, researchers reported at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC. Related presentations covered new treatments for HIV-infected infants and children.

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Dolutegravir (not yet approved) and raltegravir (Isentress) offer the potential for options involving a whole new class of drugs -- integrase inhibitors -- for highly treatment-experienced adolescents.

Etravirine (Intelence), a non-nucleoside reverse transcriptase inhibitor (NNRTI) could offer an important alternative to nevirapine (Viramune). Many children will have experience with an NNRTI such as nevirapine used for prevention of mother-to-child transmission, 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

Dolutegravir is a new integrase inhibitor being developed by ViiV Healthcare with once-daily dosing.

IMPAACT P1093 is an ongoing Phase 1/2 open-label PK safety/dose-finding study of dolutegravir plus optimized background therapy in children aged from 6 weeks to under 18 years.

Dolutegravir weight-based fixed doses of 1.0 mg per kg once-daily were evaluated. Background regimens were optimized following intensive PK evaluation.

Of the 10 adolescents in the study, 7 were female with a mean age of 14 years and weight of 57.3 kg; 9 received 50 mg dolutegravir and 1 received 35 mg daily. Median baseline CD4 cell percentages and viral load were 21.5% and 4.4 log copies/mL, respectively. After 4 weeks of dosing, 70% (7/10) had a viral load under 40 copies/mL with a median decrease from baseline of 2.8 log copies/mL.

Presenting the findings, Rohan Hazra noted that dolutegravir 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. Hazra concluded that these results support further dolutegravir investigations at the selected dose and these are starting in a younger pediatric cohort (6 to 12 years).

Etravirine

In a difficult-to-treat antiretroviral treatment-experienced population comprising 2 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-daily with an optimized background regimen at 48 weeks were comparable to those seen in treatment-experienced adults (in the DUET study), Gareth Tudor-Williams reported on behalf of the PIANO study at the same session.

All participants in this 48 week Phase 2, open-label trial had a baseline viral load of at least 500 copies/mL. All participants received an optimized background regimen comprising a ritonavir-boosted protease inhibitor plus nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide (T-20, Fuzeon) and/or raltegravir.

In total, 75% (76 patients) 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 pill counts showed only 39% adherence. 46% of the children and 35% of the adolescents had adherence rates of 95% or more.

Overall, 56% of patients 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 participants (41%) had virologic failure, 30 of whom had available genotyping at 48 weeks. Of these, 60% (18) developed common NNRTI resistance mutations.

Raltegravir

Raltegravir, used in combination with other antiretrovirals, in HIV-infected treatment-experienced children aged 2 to 18 years was well tolerated with good viral and immunological responses at 48 weeks, Sharon Nachman, presenting on behalf of IMPAACT P1066, reported in the final session.

Initial findings from this ongoing Phase 1/2 open-label, multicenter trial of the safety, tolerability, pharmacokinetics, and efficacy of raltegravir in 2 formulations (film-coated tablet and chewable) at 24 weeks led to U.S. Food and Drug Administration approval for children aged 2 years and older in January 2012, and were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections

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 virological response was seen in close to 80% of the 96 subjects, with 56.7% having achieved an undetectable viral load (under 50 copies/mL) and a mean CD4 cell count increase of 156 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.

8/14/12

References

R Hazra, R Viani, E Acosta, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DGT); S/GSK1349572) in HIV-1 positive adolescents: preliminary analysis from IMPAACT P1093. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUAB0203.

G Tudor-Williams, P Cahn, K Chokephaibulkit, et al. Safety and efficacy of etravirine in HIV -1-infected, treatment-experienced children and adolescents: PIANO 48-week results. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUAB0204.S.

S. Nachman, E Acosta, N Zheng, et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract TUAB0205.