Important note: Information in this article was accurate in March 2004. The state of the art may have changed since the publication date. 
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The session on “Transmission, Selection, and Persistence of Drug-Resistant HIV” at the 11th CROI featured several abstracts highlighting the increasing problem of transmission of drug-resistant HIV, and, most importantly, the stable persistence of drug-resistant viral variants in the plasma of patients who either deferred antiretroviral therapy after primary infection, discontinued NNRTIs following treatment failure, or received single dose nevirapine (NVP) for prevention of mother-to-child-transmission (PMTCT).
Persistence of Resistance Following Primary Infection
Using standard genotypic assays in a longitudinal study of 12 patients found to have been infected with resistant virus during primary infection, Little and colleagues demonstrated that the NNRTI-resistant variants (K103N ± 181C [N =7/12]; Y188L [N =1/12]) were the predominant variants that were transmitted [Abstract 36LB]. The mean time to the detection of a wild-type mixture was 375 days. The majority (11/12) of patients continued to have mixtures of wild-type and resistant virus detectable in plasma for years; complete replacement by wild-type virus was only seen in 1 of the 12 patients 1,019 days following infection. This study demonstrates the fitness of the NNRTI-resistant variants and their ability to be transmitted and predominate at high frequencies in plasma for years. However, it should be noted that NRTI- and PI-resistant variants also persisted for long periods of time. The mean time to reversion of any NRTI mutation was 362 days, and for protease inhibitor mutations it was 517 days, with 4 patients showing no appearance of wild-type virus, even in a mixture, for follow-periods ranging from 64 to 689 days.
Persistence of Resistance in Chronic Infection
Even when wild-type virus in plasma replaces NNRTI-resistant virus, the resistant mutants persist and therefore can reemerge when NNRTIs are reintroduced. Studies by Palmer and colleagues showed that when more sensitive allele-specific RT-PCR genotypic assays are used, NNRTI-resistant variants can be detected in plasma, at levels of approximately 15%, for up to 5-years in the absence of selective pressure [Abstract 37]. In an analysis of data from the ACTG 398 trial, in which PI-experienced and NRTI-experienced participants were treated with a regimen of abacavir, efavirenz, adefovir, and a dual-PI combination, Mellors, and colleagues assessed whether NNRTI-resistant virus present at low-levels (detectable only by more sensitive geno-typing methods such as single genome sequencing (SGS) and a Ty1/HIV-RT yeast system) contributed to treatment failure [Abstract 39]. In this trial, NNRTI-naïve patients did well on this salvage regimen, while NNRTI-experienced patients had similarly poor responses, regardless of whether NNRTI mutations were detectable on standard genotyping. Mellors then went on to show that at the time of failure the NNRTI-resistant virus in these patients clustered phylogenetically with the NNRTI-resistant virus detected at low-levels by SGS prior to the initiation of the study regimen. Based on these findings he concluded that NNRTI drug resistance, present at levels not detectable by standard genotyping, could contribute to treatment failure when drug-selective pressure is reapplied in a salvage therapy setting.
Persistence of Resistance and NNRTI Levels With PMTCT
The efficacy of single dose NVP for PMTCT was again demonstrated in this session. Data presented from a large clinical trial in Thailand (N =1844) showed that single dose NVP provided significant additional benefit when added to a regimen of AZT given to the mother starting at 28-weeks gestation and to the infant for 1 week after birth [Lallemant M, et al. Abstract 40LB]. In fact, the efficacy of this two-drug strategy was similar to that of HAART regimens in other PMTCT trials. However, other presentations during this session confirmed that the benefits of single dose NVP come with a price for mothers and for infants who ultimately become infected. Two abstracts explored the virologic consequences of single-dose NVP for PMTCT in two large trials conducted in South Africa [Martinson N, et al. Abstract 38], and Thailand [Jourdain G, et al. Abstract 41LB]. The first study confirmed previous findings by Eshleman and colleagues [AIDS 2001;5:1951] demonstrating the emergence of NNRTI resistant variants following the use of single-dose NVP given to women in labor. Thirty-nine percent of the women and 42% of the infected infants had detectable NNRTI- resistant virus in plasma 6 weeks after NVP exposure. As previously reported by Eshleman, the distribution of the various NNRTI-resistant variants was different in the mothers and their infants. K103N was the predominant mutation (31%) in the mothers, while Y181C (32%) predominated in the infants. Furthermore, in the study reported by Jourdain, the authors found that in women receiving NVP for PMTCT, NVP levels remained detectable in plasma for weeks.
Other studies presented at CROI demonstrated the persistence of NNRTI drug levels in other settings [Taylor S, et al. Abstract 131], and also found that efavirenz clearance rates are lower in blacks and Hispanics than whites [Ribaudo H, et al. Abstract 132], which appears to be explained by racial differences in CYP2B6 G516T poly-morphisms (see Lucas G, “The Treatment of Experienced Patients and Resistance Mechanisms”, p 6 and to be covered in detail in the next issue). These studies provide a basis for the high rates of resistance observed following limited exposure (single dose) to NVP in women and infants, and also raise concern about the timing of discontinuation of NVP when it is part of a failed regimen. Importantly, the authors also showed that in women treated with NVP-containing HAART regimens, there was a trend towards lower virologic responses (VL <50 c/mL) at 6-months in those who had detectable NNRTI resistance following single dose NVP (34%) compared with those who had no prior NVP exposure (75%). However, there was a suggestion that re-introducing NVP more than 6-months after exposure to single dose NVP may be associated with better response to therapy, which may be reflective of the diminishing proportion of viral quasispecies with detectable resistance over time following single dose NVP. Clearly, further data are needed regarding the kinetics of NVP resistance mutations following single dose NVP, including the prevalence of minority resistant quasispecies over time, and archiving of resistant virus within cellular reservoirs.
These results are not particularly surprising given what we know about NNRTI pharmacokinetics and the permanent nature of drug resistance. The conservative assumption has always been that resistance is clinically relevant, regardless of whether it occurs in the setting of primary infection, HAART, or PMTCT. The implications for resource poor countries are less clear, however, since single dose NVP is a practical and cost-effective way to reduce perinatal transmission. One response to these studies has been to urge that pregnant women be treated with standard HAART regimens, as they are in the developed world. This would almost certainly reduce transmission of resistant virus to the infant and would probably be more beneficial to the mothers as well. However, giving a NVP-containing regimen throughout pregnancy could increase the risk of serious hepatotoxicity, which is more common among women, especially those with high CD4 counts. Moreover, the problem of prolonged drug levels and low genetic barrier to resistance following discontinuation of NNRTIs is not solved by using combination therapy; there may still be a risk of resistance with discontinuation of temporary NNRTI-based HAART regimens. Protease inhibitors may be a better choice, either for PMTCT or to provide a pharmacologic “tail” while NNRTI levels fall, but they are prohibitively expensive in many parts of the world. This is clearly an evolving controversy, and in many cases, scientific data will have to take a back seat to political, economic, and practical considerations. Given present-day realities, NVP may remain the most feasible option for PMTCT for most women in resource-poor settings.
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