Use of a lopinavir/ritonavir (LPV/r) based regimen compared to a nevirapine-based regimen in infants not exposed to single-dose nevirapine (sdNVP) was superior and the differences for viral failure, drug discontinuation and death at six months were significant (p = 0.001) Paul Palumbo reported at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) last week.
However, better improvements were seen in CD4 cell counts and growth over time in the nevirapine-based cohort suggesting further study is needed.
Palumbo was reporting on behalf of the IMPAACT P1060 cohort 2 trial, a multi-site randomised prospective study in sub-Saharan Africa and India begun in March 2010.
Previous findings from the IMPAACT cohort 1 study, run parallel to the cohort 2 study, found LPV/r to be better in reducing viral load than nevirapine in infants exposed to single-dose nevirapine.
288 HIV-positive infants, not exposed to maternal or infant nevirapine, from 10 sites were enrolled by March 2010. Infants were randomised to get zidovudine, lamivudine and nevirapine or LPV/r. A one-year follow-up had been planned but in October 2010 (at six months) the Data Safety and Monitoring Board recommended un-blinding the study because of the significance of the interim results.
Median baseline viral load and CD4 percentage were 535,632 copies/ml and 15%, respectively. Median follow-up was 72 weeks.
At six months 40.8% in the nevirapine arm and 19.3% in the LPV/r arm had viral failure (defined as < 1 log10 decline from baseline to 12-24 weeks or viral load less than 400 copies/ml), a difference of 21.5% (p = 0.001); five infants and one infant died in the nevirapine and LPV/r arms, respectively; and 26 and 15 discontinued drugs in the nevirapine and LPV/r arms, respectively.
Significant differences in virological failure and death seen at six months continued throughout the follow-up period.
Paul Palumbo noted that the OCTANE study found no significant difference between lopinavir/ritonavir and nevirapine arms, but said that the results of the IMPAACT study argued for extending the recommendation of lopinavir-based ART to all infants, and extending it up to three years of age.
He also noted the need for development of new first-, second- and third-line paediatric drug options.
Responding to questions after the presentation Palumbo noted that the very high and rapid failure rate in the nevirapine arm might be attributable to the currently recommended practice of stepping up nevirapine dosing during the first two weeks of treatment. Inadequate drug coverage could result in a failure of viral suppression in infants with very high viral load, he suggested.
Targeted viral load and treatment switching in nevirapine-exposed infants with HIV
Infant treatment is complicated by exposure to single-dose nevirapine after delivery; infants who become infected despite prophylaxis have a high risk of acquiring nevirapine-resistant virus.
Infant treatment with a nevirapine-containing antiretroviral regimen may result in treatment failure if resistance is present. As a consequence, regimens containing lopinavir/ritonavir have been recommended by the World Health Organization for the treatment of infants exposed to nevirapine prophylaxis.
However continuation of a protease inhibitor (PI)-based regimen limits second-line options, is expensive and presents adherence challenges, particularly because of its taste. In addition the long-term toxicities are unknown, notably its effect at the critical developmental stage in newborns.
For these reasons there is still a need to determine whether there are circumstances in which nevirapine-based ART can be used in infants and children previously exposed to single-dose nevirapine.
Louise Kuhn of the Mailman School of Public Health, Columbia University, presented final results from NEVEREST, a large randomised study which compared switching to nevirapine-based ART to continuous lopinavir-based ART in infants below two years of age who had achieved a viral load below 400 copies/ml for at least three months on lopinavir-based ART.
The study randomised 195 children, 95 to stay on lopinavir/ritonavir and 96 to switch to nevirapine.
The study measured viral load at 4, 16, 24, 36, 52, 64 and 76 weeks after switching. 3020 and 3425 child-months of follow-up in the switch and control groups, respectively were available for analysis.
At three years after the switch 40.5% of children in the switch group had a viral load under 50 copies/ml compared to 31.3% in the control group, (p = 0.01). However 23.9% of those in the switch group had a viral load greater than 1000 copies/ml (failure) compared to 11.1% in the control group (p = 0.01). At every time point infants who stayed on lopinavir/ritonavir had a greater likelihood of viral failure (viral load above 50 copies/ml) (p = 0.02).
However infants in the nevirapine arm were signficantly more likely to have a confirmed viral load above 1000 copies/ml (p = 0.008). All of these failures were detected in the first 12 months after switching, and 59% had been detected by 6 months. Failure was significantly associated with the detection of pre-existing NNRTI (non-nucleoside reverse transcriptase inhibitors) mutations (p = 0.02).
The researchers concluded that targeted viral load testing, at six months and one year could identify all switch failures.
Dr Kuhn noted in the absence of pre-treatment drug-resistance testing targeted viral load testing is necessary for the switch strategy to be effective, However, she cautioned that without such testing the strategy should not be attempted.
She stressed that it is important given the paucity of paediatric treatment options to think not only about treatment regimens in themselves but also about how regimens are used, the sequencing and potential for the strategic use of viral load and drug resistance testing.
Abstracts and webcast
You can view the abstracts from this research on the official conference website:
Abstract 128: www.retroconference.org/2011/Abstracts/41025.htm
Abstract 129LB: www.retroconference.org/2011/Abstracts/42501.htm
You can also watch a webcast of the presentations made at this conference session, including the speakers Paul Palumbo and Louise Kuhn.
Webcast from MTCT and HIV in Children.
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Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI-based regimen. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 128, 2011.
Palumbo P et al. NVP- vs. LPV/r-based ART among HIV+ infants in resource-limited settings: The IMPAACT P1060 trial. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 129LB, 2011.