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  18th HIV Drug Resistance Workshop
June 9-12 2009
Ft Myers Florida
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NNRTI/PI Regimen More Prone to Resistance Than Standard Triple Combos
  Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Treatment with a nonnucleoside (NNRTI) plus a protease inhibitor (PI)--without nucleosides--resulted in emergence of more resistance mutations than did treatment with a standard nucleoside-containing regimen in ANRS trial 121 (Hippocampe) [1]. That finding confirmed results of an earlier AIDS Clinical Trials Group (ACTG) study [2]. In the ANRS trial, people with a high pretreatment viral load and with low efavirenz levels during treatment were especially prone to emergence of NNRTI-related mutations.
ANRS 121 randomized 117 previously untreated people to efavirenz or nevirapine plus ritonavir-boosted lopinavir (533/133 mg twice daily) or indinavir (600/100 mg twice daily) (n = 60), to an NNRTI plus two nucleosides (n = 28), or to standard-dose boosted lopinavir or indinavir plus two nucleosides (n = 29) [3]. All licensed nucleosides except stavudine and zalcitabine were allowed. Median pretreatment CD4 count was about 200 across the three study arms, and median starting viral load about 100,000 copies.
The study ended early when the proportion of people who remained on their assigned regimen with a viral load below 50 copies proved significantly lower in the NNRTI/PI group. At study week 24, 60% in that group, versus 82.5% in the nucleoside-containing groups, had a sub-50-copy viral load while remaining on their original regimen.
For the resistance analysis [1], Anne-Genevieve Marcelin and coworkers defined failure as a viral load above 50 copies or a change from the assigned regimen by week 48. In people whose regimen failed, the investigators looked for resistance-related mutations in reverse transcriptase, protease, and gag (where cleavage site mutations have been linked to PI resistance).
After 48 weeks, 24 of 117 study participants (20.5%) met failure criteria, 28.3% in the NNRTI/PI group and 12.2% in the nucleoside-containing arms. Marcelin and colleagues detected no nucleoside-related mutations at failure in any study arm. Three people (12.5% of 24 failures) had PI-related mutations, all of them in the NNRTI/PI group. Among 7 people with NNRTI-related mutations (29% of 24 failures), all but 1 were taking the NNRTI/PI regimen.
If one assumes nobody with missing genotypic data had resistance mutations, numbers of patients with virologic failure and one or more mutations were 8 of 60 in the NNRTI/PI group (13%), 0 of 29 in the nucleoside/PI group, and 1 of 28 (4%) in the nucleoside/NNRTI group (P = 0.03 for the NNRTI/PI group versus either of the other two groups).
Most people in whom NNRTI mutations emerged at failure had a pretreatment viral load above 100,000 copies (P = 0.05), and all had an efavirenz concentration below 1100 ng/mL at week 12 (P = 0.01). Emergence of NNRTI mutations did not correlate with pretreatment CD4 count, pretreatment HIV DNA load, or lopinavir trough concentration at failure.
Gag cleavage site mutations did not contribute to the higher failure rate with an NNRTI plus a boosted PI.
Marcelin and coworkers speculated that poor adherence or treatment interruptions in the NNRTI/PI group rapidly resulted in functional NNRTI monotherapy because the NNRTIs studied have much longer half-lives than the PIs used. They concluded that the nucleoside-sparing strategy "should not be recommended as [an] antiretroviral first-line regimen, particularly in patients with high viral load and susceptible to ... adherence problems."
After 112 weeks of follow-up, ACTG study A5142 investigators found no virologic response difference between efavirenz plus lopinavir/ritonavir and either of those two agents plus two nucleosides in 753 previously untreated people [2]. Time to virologic failure was longer with efavirenz plus two nucleosides than with lopinavir/ritonavir plus two nucleosides. As in ANRS 121, emergence of resistance mutations was more common in the NNRTI/PI group than in the other two groups.
1. Marcelin AG, Soulie C, Assoumou L, et al. NRTI-sparing regimen (NNRTI+PI) was more likely to be associated with drug resistance compared with NNRTI+NRTI or PI+NRTI in the randomized ANRS 121 trial. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 52.
2. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095-2106.
3. Duvivier C, Ghosn J, Assoumou L, et al. Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother. 2008;62:797-808.