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Low-Level Pretreatment NNRTI Mutation May Imperil Virologic Response
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
South African women with typically undetectable levels of the K103N nonnucleoside (NNRTI) resistance mutation before steady therapy with nevirapine or efavirenz ran a higher risk of virologic failure than women without K103N [1]. Some of the women had taken single-dose nevirapine earlier, but some had not. The role of the mutation itself versus other factors that influence virologic response was not clear in this observational epidemiologic study.
Earlier work shows that single-dose nevirapine to prevent mother-to-child transmission of HIV can evoke the K103N mutation, which renders the virus resistant to nevirapine or efavirenz. But mutations induced by single-dose nevirapine fade over time [2] and appear not to jeopardize response to a nonnucleoside regimen begun 6 months (from Jules: or greater may be required; it may take variable time to fade) after single-dose nevirapine [3]. Standard genotyping can miss mutations that make up less than 20% of a person's viral population, but such low-frequency mutations can emerge under drug pressure.
To gauge the impact of covert K103N on treatment with nevirapine or efavirenz plus stavudine (d4T) and lamivudine (3TC), Gillian Hunt (National Institute of Communicable Diseases, Johannesburg) and collaborators studied 94 women who took single-dose nevirapine 18 to 36 months before starting their triple regimen and 60 previously pregnant women who had no record of taking single-dose nevirapine before starting a nonnucleoside regimen. The investigators used ultrasensitive allele-specific PCR (AS-PCR) to search pretreatment viral samples for K103N, and they used standard genotyping to look for mutations in women with a poor virologic response.
Almost all women in both groups responded well to the first months of nonnucleoside therapy. At 24 weeks the probability of reaching a viral load below 50 copies measured 0.975 in the nevirapine-exposed women and 0.913 in the unexposed women, a nonsignificant difference (P = 0.21). Nor did the two groups differ in risk of viral rebound by week 78 (P = 0.57).
AS-PCR spotted K103N in 10 of 94 women (10.6%) who took single-dose nevirapine and in 9 of 60 (15%) who did not and reported taking no antiretrovirals before the nonnucleoside regimen. Among the 19 women with pretreatment K103N, 11 (57.8%) had a poor virologic response to their nonnucleoside regimen, either failing to get their viral load under 50 copies or failing to keep it there for 78 weeks. But 7 women (36.8%) who had K103N before treatment kept their viral loads undetectable for 78 weeks. (One women with K103N before treatment stopped coming for visits.)
Ultimately, 30 women in both the nevirapine-exposed and -unexposed groups had a poor response to triple therapy. AS-PCR saw K103N in only 11 of them (36.7%) before they started therapy. That result, the investigators suggested, could mean other low-level pretreatment mutations affected response to nevirapine or efavirenz. Still, the probability of poor viral control at week 78 was 0.609 among women with pretreatment K103N versus 0.151 among women without that mutation, a highly significant difference (P < 0.001).
Curiously, Hunt and coworkers did not probe the myriad other reasons that influence success or failure of antiretroviral regimens. Daniel Kuritzkes of Boston's Brigham and Women's Hospital suggested that the study group is big enough to allow for multivariate analysis weighing factors such as pretreatment viral load and adherence. Such an analysis might reveal that pretreatment K103N does not independently predict poor response.
Standard genotyping of the first failure sample disclosed different resistance patterns in women who took single-dose nevirapine and in those who did not. K103N turned up in failure samples of 9 of 18 nevirapine-exposed women but in only 1 of 10 unexposed women (50% versus 10%). The 3TC-induced M184V or M184I mutation arose in 7 of 10 women who did not take single-dose nevirapine versus 6 of 18 who did (70% versus 33%). Most women in both groups had at least one major nonnucleoside mutation, including 13 of 18 nevirapine-exposed women (72%) and 8 of 10 unexposed women (80%).
Although this study involved pregnant African women, the possibility of low-frequency K103N in people who never took a nonnucleoside has clear risk implications for anyone starting a regimen containing nevirapine or efavirenz. Hunt speculated that some of these women may have forgotten taking single-dose nevirapine or may not have been told they were getting it. Alternatively, they could have been infected with the mutant virus or the mutation may have emerged without drug pressure. The newest nonnucleoside, etravirine, usually controls virus bearing only the K103N nonnucleoside mutation [4,5].
References
1. Hunt G, Coovadia A, Abrams JE, et al. Low frequency K103N mutations are strongly associated with inadequate virological responses to non-nucleoside reverse transcriptase inhibitor based therapy. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 120.
2. Flys TS, Donnell D, Mwatha A, et al. Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission. J Infect Dis. 2007;195:711-715.
3. Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007;356:135-147.
4. Vingerhoets J, Buelens A, Peeters M, et al. Impact of baseline NNRTI mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2. XVI International HIV Drug Resistance Workshop. June 12-16, 2007. Barbados. Abstract 32.
5. Vingerhoets J, Janssen K, Welkenhuysen-Gybels J, et al. Impact of baseline K103N or Y181C on the virological response to the NNRTI TMC125: analysis of study TMC125-C223. XV International HIV Drug Resistance Workshop. June 13-17, 2006. Sitges, Spain. Abstract 17.
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