Studies presented at CROI suggest the presence of minority variants that are resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may impair virological response to an NNRTI-based treatment. After exposure to single-dose nevirapine (sdNVP), minority resistant variants were found in children, particularly those infected in utero, and in mothers, although the frequency was reduced in those receiving additional short-course zidovudine and lamivudine postpartum. However, sdNVP exposure with or without resistance detected by standard assays was not associated with virological or immunological failure, as the median delay between exposure for the prevention of mother-to-child transmission (PMTCT) of HIV and the initiation of NNRTI-containing treatment was >6 months, which is consistent with the results of a recently published study.(1) Details of the presentations are given below. Presentations Low-Frequency Mutations
Abstract: Johnson J, Li JF, Wei X, et al. Low-frequency Mutations Substantially Increase the Prevalence of Transmitted Drug Resistance and Greatly Strengthen the Relationship between Resistance Mutations and Virologic Failure. Abstract 639.
Description: Retrospective sensitive testing on baseline samples from drug-naive persons who participated in treatment studies with efavirenz/lamivudine + abacavir or zidovudine was conducted on blinded plasma-virus samples from 101 individuals with virologic failure (>50 HIV RNA copies/mL by 48 weeks) and 158 individuals with treatment successes.
Results: Drug-naive people with minority resistance mutations at initiation of treatment were 8.1 times more likely to experience treatment failure than those without mutations, independent of viral loads and CD4 counts, suggesting that the presence of resistant variants at low frequency may have implications upon the virological response. Nevirapine Resistance among Mozambican Infants
Abstract: Micek M, Blanco M, Matediane E, et al. Nevirapine-resistant HIV-1 among Mozambican Infants Infected in Utero vs Intra-partum or Early Postpartum. Abstract 92.
Description: Eighteen infants who received sdNVP with their mothers were tested for HIV infection at birth and at 2, 4, 6, and 8 weeks of age using DNA polymerase chain reaction (PCR) assays of HIV-1 pol, and they were assessed for NVP resistance using sensitive assays.
Results: Twelve infants were infected in utero, and all had resistance mutations detected, whereas 2 of the 6 remaining infants who were infected intrapartum or early postpartum had NVP-resistant mutations. TOPS Trial (South Africa)
Abstract: Palmer S, Boltz V, Maldarelli F, et al. Addition of Short-course Combivir to Single-dose Nevirapine Reduces the Selection of NPV-resistant HIV-1 with Infrequent Emergence of 3TC-resistant Variants. Abstract 763.
Description: A subset of samples from mothers at 6 weeks postpartum from the TOPS trial (South Africa) was analyzed with allele-specific PCR to detect NVP- and lamivudine-resistant variants at frequencies as low as 0.1%.
Results: NVP-resistant variants were found in 71%, 25%, and 25% of the samples from the sdNVP arm, sdNVP + zidovudine/lamivudine (4 days) arm, and sdNVP + zidovudine/lamivudine (7 days) arm, respectively. The addition of zidovudine/lamivudine reduced also the frequency of NVP-resistant mutations in the virus population. Lamivudine-resistant variants were found in only 1 mother among 40. Short-Course Zidovudine/Lamivudine or Single-Dose Nevirapine Regimens
Abstract: Coffie P, Ekouevi D, Chaix ML, et al. Short-course Zidovudine and Lamivudine or single-dose Nevirapine-containing PMTCT Compromises 12-Month Response to HAART in African Women, Abidjan, Côte d'Ivoire (2003-2006). Abstract 93LB.
Description: Women enrolled in the MTCT-Plus care and treatment program in Côte d'Ivoire who initiated antiretroviral therapy (ART) with stavudine/zidovudine + lamivudine + NVP/efavirenz postpartum or in previous pregnancy were followed for at least 12 months. Virological failure (plasma HIV RNA >500 copies/mL 12 months after initiation of therapy) and immunological failure (>30% fall from peak CD4+ count) responses were assessed, as were their association with the presence of viral resistance at 4 weeks postpartum detected by standard genotyping assays.
Results: PMTCT-acquired lamivudine resistance was associated with a poorer 12-month virological response but not with immunological failure (median interval between PMTCT exposure and initiation of ART: 15 months). NVP resistance after sdNVP exposure was not associated with virological or immunological failure at 12 months (median interval between PMTCT exposure and initiation of ART: 21 months). The most important and consistent factor in predicting virological and immunological failure was poor adherence to ART. References
- Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007 Jan 11;356(2):135-47.