Johnson JA, Li JF, Morris L, Martinson N, Gray G, McIntyre J, et al. Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated

Johns Hopkins University, Baltimore, Maryland, United States
The Journal of Infectious Diseases (Impact Factor: 6). 08/2005; 192(1):16-23. DOI: 10.1086/430741
Source: PubMed


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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    • "). Despite numerous scientific reports of selection of nevirapine (NVP)-resistance mutations (Eshleman et al., 2005a,b; Halvas et al., 2010; Johnson et al., 2005; Martinson et al., 2007; Micek et al., 2010) data from Zimbabwean infants are sparse. These data are unavailable due primarily to the unaffordable cost of consensus sequencing, the sequencing method used most commonly to assess HIV drug resistance (HIV-DR) (Beck et al., 2002; Bennett et al., 2008). "
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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; 210. DOI:10.1016/j.jviromet.2014.09.005 · 1.78 Impact Factor
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    • "Thai children residing in orphanages have shown better clinical profiles at presentation and lower mortality than those living with parents or relatives [11]. Long-term viral suppression in children is influenced not only by clinical factors but also psychosocial issues [7], [12]–[14] including vulnerabilities to poverty and stigma [15], risk of a range of psychosocial problems is often heightened in adolescence [16]. "
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    ABSTRACT: Background The Thai HIV programme is a leader in the public health approach to HIV treatment. Starting at transmission of HIV and ending with transition to adult services this paper assesses the paediatric HIV treatment continuum from three perspectives: service-user, provider and policy maker, to understand what works well and why. Methods A qualitative research design was used to assess and triangulate the stakeholder perspectives. Semi-structured interviews were conducted with ART service-users (n = 35), policy actors (n = 20); telephone interviews with prior caregivers of orphans (n = 10); and three focus group discussions with service-providers (hospital staff and volunteers) from a district, provincial and a university hospital. Findings Children accessing HIV care were often orphaned, cared for by elderly relatives and experiencing multiple vulnerabilities. Services were divided into three stages, 1. Diagnosis and linkage: Despite strong policies there were supply and demand-side gaps in the prevention of mother-to-child transmission ‘cascade’ preventing early diagnosis and/or treatment. 2. Maintenance on ART - Children did well on treatment; caregivers took adherence seriously and valued the quality of services. Drug resistance, adherence and psychosocial issues were important concerns from all perspectives. 3. Adolescents and transition: Adolescent service-users faced greater complexity in their physical and emotional lives for which providers lacked skills; transition from the security of paediatric clinic was a daunting prospect. Dedicated healthcare providers felt they struggled to deliver services that met service-users' diverse needs at all stages. Child- and adolescent-specific elements of HIV policy were considered low priority. Conclusions Using the notion of the continuum of care a number of strengths and weaknesses were identified. Features of paediatric services need to evolve alongside the changing needs of service users. Peer-support volunteers have potential to add continuity and support at all stages. It is critical that adolescents receive targeted support, particularly during transition to adult services.
    PLoS ONE 06/2014; 9(6):e99061. DOI:10.1371/journal.pone.0099061 · 3.23 Impact Factor
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    • "Often, this result occurred prior to treatment and despite the absence of resistance mutations [10–13]. Very sensitive PCR detection procedures, which reveal resistance due to minority species, have revealed a higher incidence of NVP resistance (K103N, Y181C) in 70–87% of individuals with subtype C compared with 42% of individuals with subtype A [14–16]. "
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    ABSTRACT: The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.
    06/2012; 2012(4):256982. DOI:10.1155/2012/256982
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