Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated.
ABSTRACT Conventional sequence analysis detects human immunodeficiency virus (HIV)-1 drug resistance mutations in approximately 40% of women shortly after they receive intrapartum single-dose nevirapine (SD-NVP). Using sensitive real-time polymerase chain reaction assays for the K103N and Y181C resistance mutations, we tested genotyped virus before and after SD-NVP in 50 South African women infected with HIV-1 subtype C. By sequence analysis, 40 women had no detectable resistance mutations, and an additional 6 women were negative for Y181C after SD-NVP. We found K103N in 16 (40%) of 40 women and Y181C in 5 (11%) of 46 women at 6-36 weeks postpartum. Clonal sequencing confirmed K103N in 5 of 5 representative samples and Y181C in 4 of 4 samples. Four of the 5 women with newly identified Y181C also had K103N. These findings indicate that resistance mutations emerged in at least 65% of the women after SD-NVP and emphasize the importance of further research to determine the clinical implications.
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ABSTRACT: Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ~95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ~12% of all global HIV infections, whereas non-B subtype HIV infections that account for ~88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes.Viruses 09/2014; 6(9):3535-3562. · 3.28 Impact Factor
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ABSTRACT: Introduction: We assessed the rate of treatment failure of HIV-infected children after 12 months on antiretroviral treatment (ART) in the Paediatric IeDEA West African Collaboration according to their perinatal exposure to antiretroviral drugs for preventing mother-to-child transmission (PMTCT). Methods: A retrospective cohort study in children younger than five years at ART initiation between 2004 and 2009 was nested within the pWADA cohort, in Bamako-Mali and Abidjan-Côte d'Ivoire. Data on PMTCT exposure were collected through a direct review of children's medical records. The 12-month Kaplan-Meier survival without treatment failure (clinical or immunological) was estimated and their baseline factors studied using a Cox model analysis. Clinical failure was defined as the appearance or reappearance of WHO clinical stage 3 or 4 events or any death occurring within the first 12 months of ART. Immunological failure was defined according to the 2006 World Health Organization age-related immunological thresholds for severe immunodeficiency. Results: Among the 1035 eligible children, PMTCT exposure was only documented for 353 children (34.1%) and remained unknown for 682 (65.9%). Among children with a documented PMTCT exposure, 73 (20.7%) were PMTCT exposed, of whom 61.0% were initiated on a protease inhibitor-based regimen, and 280 (79.3%) were PMTCT unexposed. At 12 months on ART, the survival without treatment failure was 40.6% in the PMTCT-exposed group, 25.2% in the unexposed group and 18.5% in the children with unknown exposure status (p=0.002). In univariate analysis, treatment failure was significantly higher in children unexposed (HR 1.4; 95% CI: 1.0-1.9) and with unknown PMTCT exposure (HR 1.5; 95% CI: 1.2-2.1) rather than children PMTCT-exposed (p=0.01). In the adjusted analysis, treatment failure was not significantly associated with PMTCT exposure (p=0.15) but was associated with immunodeficiency (aHR 1.6; 95% CI: 1.4-1.9; p=0.001), AIDS clinical events (aHR 1.4; 95% CI: 1.0-1.9; p=0.02) at ART initiation and receiving care in Mali compared to Côte d'Ivoire (aHR 1.2; 95% CI: 1.0-1.4; p=0.04). Conclusions: Despite a low data quality, PMTCT-exposed West African children did not have a poorer 12-month response to ART than others. Immunodeficiency and AIDS events at ART initiation remain the main predictors associated with treatment failure in this operational context.Journal of the International AIDS Society 06/2014; 17(1):18737. · 4.21 Impact Factor
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ABSTRACT: An Oligonucleotide Ligation Assay (OLA) designed to detect Human Immunodeficiency Virus type-1 (HIV)-drug-resistance to the nevirapine (NVP) selected mutations K103N, Y181C, V106M and G190A was used to evaluate 200 archived dried blood spots (DBS) from infected infants participating in the Zimbabwean Early Infant Diagnosis (EID) Program. Consensus sequencing of specimens with indeterminate OLA results was performed to identify genetic sequence polymorphisms that appeared to compromise performance of the OLA. When consistent patterns of polymorphisms were observed the probes were redesigned, and DBS specimens with indeterminate OLA results were retested with the new Zimbabwe-specific (ZW) probes. OLA results obtained in Zimbabwe were compared to repeat testing in a US reference laboratory. 188/200 (94%) DBS yielded PCR amplification of HIV pol. ZW probes reduced indeterminate OLA results from 5.2% to 2.8% of codons evaluated (p=0.02), with 98.2% concordance between results obtained in the Zimbabwean and US laboratories. Optimization of OLA probes to accommodate polymorphisms in regional HIV variants improved OLA performance, and comparison to the USA results showed successful implementation of the OLA in Zimbabwe for detection of NVP resistance mutations in DBS specimens.Journal of Virological Methods 09/2014; · 1.88 Impact Factor