Nevirapine Resistance in Women and Infants after First versus Repeated Use of Single‐Dose Nevirapine for Prevention of HIV‐1 Vertical Transmission

Flys, Tamara; McConnell, Michelle S.; Matovu, Flavia; Church, Jessica D.; Bagenda, Danstan; Khaki, Leila; Bakaki, Paul M.; Thigpen, Michael C.; Eure, Chineta; Fowler, Mary Glenn; Eshleman, Susan H.

doi:10.1086/590160

Cited by 24 publications

(24 citation statements)

References 16 publications

(23 reference statements)

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“…The outcomes of NNRTI-based therapies are thus expected to be similar in NVP-naïve patients and patients in whom therapy is initiated long after SDNVP. Indeed, two studies found no substantial increase in the risk of mother-to-child transmission with repeated usage of SDNVP (18,36), possibly because the median duration between pregnancies in the latter studies was Ͼ20 months, during which period NVP resistance mutations selected following the first SDNVP may have faded to the preexposure levels. Similarly, the risk of failure of NNRTI-based therapy was enhanced when therapy was initiated within 6 months of SDNVP, but no significant enhancement in the risk was observed when therapy was initiated more than 12 months after SDNVP (33,60).…”

Section: Discussionmentioning

confidence: 98%

“…NVP resistance mutations may also be archived in latently infected cells (64), which have half-lives of ϳ44 months (55). The rapid selection and persistence of NVP resistance mutations following SDNVP may compromise the efficacy of SDNVP during subsequent pregnancies, may adversely impact outcomes of subsequent antiretroviral therapies containing NNRTIs, and may result in the transmission of drug-resistant strains of HIV-1 (18,27,33,36,38,60).…”

mentioning

confidence: 99%

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Estimating Frequencies of Minority Nevirapine-Resistant Strains in Chronically HIV-1-Infected Individuals Naïve to Nevirapine by Using Stochastic Simulations and a Mathematical Model

Gadhamsetty¹,

Dixit

2010

J Virol

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Nevirapine forms the mainstay of our efforts to curtail the pediatric AIDS epidemic through prevention of mother-to-child transmission of HIV-1. A key limitation, however, is the rapid selection of HIV-1 strains resistant to nevirapine following the administration of a single dose. This rapid selection of resistance suggests that nevirapine-resistant strains preexist in HIV-1 patients and may adversely affect outcomes of treatment. The frequencies of nevirapine-resistant strains in vivo, however, remain poorly estimated, possibly because they exist as a minority below current assay detection limits. Here, we employ stochastic simulations and a mathematical model to estimate the frequencies of strains carrying different combinations of the common nevirapine resistance mutations K103N, V106A, Y181C, Y188C, and G190A in chronically infected HIV-1 patients naïve to nevirapine. We estimate the relative fitness of mutant strains from an independent analysis of previous competitive growth assays. We predict that single mutants are likely to preexist in patients at frequencies (ϳ0.01% to 0.001%) near or below current assay detection limits (>0.01%), emphasizing the need for more-sensitive assays. The existence of double mutants is subject to large stochastic variations. Triple and higher mutants are predicted not to exist. Our estimates are robust to variations in the recombination rate, cellular superinfection frequency, and the effective population size. Thus, with 10 7 to 10 8 infected cells in HIV-1 patients, even when undetected, nevirapine-resistant genomes may exist in substantial numbers and compromise efforts to prevent mother-to-child transmission of HIV-1, accelerate the failure of subsequent antiretroviral treatments, and facilitate the transmission of drug resistance.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Estimating Frequencies of Minority Nevirapine-Resistant Strains in Chronically HIV-1-Infected Individuals Naïve to Nevirapine by Using Stochastic Simulations and a Mathematical Model

Gadhamsetty¹,

Dixit

2010

J Virol

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“…1 However, where this prophylaxis fails, the HIV-infected infants have been demonstrated to develop resistance mutations to nonnucleoside reverse transcriptase inhibitors (NNRTIs). [2][3][4][5] These resistance mutations have been detected in the mothers too. [6][7][8] There have been varying reports on the clinical implications of these mutations in HIV-infected children, with reports of virologic failure 9 and good response, 10 when the HIV-infected children are started on antiretroviral therapy (ART).…”

Section: Introductionmentioning

confidence: 98%

Response to Nonnucleoside Reverse Transcriptase Inhibitor-Based Therapy in HIV-Infected Children with Perinatal Exposure to Single-Dose Nevirapine

Musiime

Ssali²,

Kayiwa³

et al. 2009

AIDS Research and Human Retroviruses

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We set out to investigate whether there are clinically significant consequences when children with perinatal exposure to single-dose nevirapine are initiated on a nonnucleoside reverse transcriptase inhibitor (NNRTI) containing a highly active antiretroviral therapy (HAART) regimen. We carried out a chart and database review of 104 HIV-infected children, who had initiated HAART with an NNRTI at JCRC and were less than or equal to 5 years of age, 35 (33.7%) of whom had prior exposure to perinatal single-dose nevirapine. We studied the viral load and CD4 percentage at baseline, at week 24, and at week 48 after the start of HAART in children exposed and not exposed to perinatal single-dose nevirapine, as well as the results of genotypic resistance testing done for the children who had failed to achieve virologic suppression on HAART. At weeks 24 and 48 after initiating HAART, children not exposed to single-dose nevirapine were 3.28 times [OR = 3.28, 95% CI: (1.37 to 9.20), p = 0.0167] and 3.47 times [OR = 3.47, 95% CI: (1.28 to 9.37), p = 0.0091] more likely to achieve virologic suppression compared to children exposed to single-dose nevirapine, respectively. However, the CD4 cell response at weeks 24 and 48 was not worse in the children exposed to single-dose nevirapine. In 10 children with perinatal exposure to single-dose nevirapine, NNRTI resistance mutations, mostly K103N, Y181C, and G109A, were identified. HIV-infected children with perinatal exposure to single-dose nevirapine are less likely to achieve short-term virologic suppression when started on an NNRTI-containing regimen, when compared to those who were not exposed to it, probably because the exposure predisposes them to developing NNRTI resistance mutations.

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“…Following reuse of sdNVP at median intervals of 21-32 months (Martinson et al 2007b(Martinson et al , 2009McConnell et al 2007;Walter et al 2008), the proportion with NVP resistance mutations after the first compared to subsequent sdNVP did not differ at 6 weeks Flys et al 2008), 6 months (Flys et al 2008), and 12 months (Flys et al 2008) by consensus sequencing Flys et al 2008) or by more sensitive assays (Flys et al 2008). Similarly, in infected infants the proportion of NVP resistance mutations was similar at 6 weeks (Flys et al 2008).…”

Section: Reuse Of Sdnvp In Subsequent Pregnancies: Hiv Transmission Amentioning

confidence: 85%

HIV Drug Resistance in Mothers and Infants Following Use of Antiretrovirals to Prevent Mother-to-Child Transmission

Olson¹,

Ton²,

Frenkel³

2014

Handbook of Antimicrobial Resistance

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In the United States and other resource-rich nations, combination antiretroviral therapy (ART) that suppresses viral replication below the limits of detection in the plasma is standard of care for prevention of mother-to-child transmission of HIV (PMTCT). In many resource-limited communities, financial and infrastructure limitations preclude ART for pregnancy. Instead, abbreviated PMTCT regimens of short-term antiretrovirals (ARV) (mono-or dual therapy) that do not suppress viral replication to undetectable levels are recommended. While these less costly approaches achieve significant decreases in the rates of MTCT, selection of HIV drug resistance (HIV-DR) has been detected in both mothers and infected infants. This chapter reviews prominent studies that provide insight into HIV-DR related to use of ARV for PMTCT and discusses how recent findings and therapeutic advances have led to policy changes and new directions in this developing field.

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Nevirapine Resistance in Women and Infants after First versus Repeated Use of Single‐Dose Nevirapine for Prevention of HIV‐1 Vertical Transmission

Cited by 24 publications

References 16 publications

Estimating Frequencies of Minority Nevirapine-Resistant Strains in Chronically HIV-1-Infected Individuals Naïve to Nevirapine by Using Stochastic Simulations and a Mathematical Model

Estimating Frequencies of Minority Nevirapine-Resistant Strains in Chronically HIV-1-Infected Individuals Naïve to Nevirapine by Using Stochastic Simulations and a Mathematical Model

Response to Nonnucleoside Reverse Transcriptase Inhibitor-Based Therapy in HIV-Infected Children with Perinatal Exposure to Single-Dose Nevirapine

HIV Drug Resistance in Mothers and Infants Following Use of Antiretrovirals to Prevent Mother-to-Child Transmission

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