Selection and Persistence of Viral Resistance in HIV-Infected Children After Exposure to Single-Dose Nevirapine

Martinson, Neil; Morris, Lynn; Gray, Glenda; Moodley, Deshendran; Pillay, Visva; Cohen, S. M.; Dhlamini, Puleng; Puren, Adrian; Bhayroo, Schene; Steyn, Jan; McIntyre, James

doi:10.1097/qai.0b013e31802b920e

Cited by 77 publications

(59 citation statements)

References 18 publications

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“…Reports of the 106A mutation have been rare in subtype C, but they do occur (11,12,27,29,31,38); however, the functionality of these subtype C 106A mutant RTs is unknown. The 106M mutation appears in the same studies at least three times as often as the 106A mutation in the same cohorts.…”

Section: Discussionmentioning

confidence: 99%

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Armstrong

Lee

Essex

2011

Antimicrob Agents Chemother

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Single-dose nevirapine (NVP) is quite effective in preventing transmission of the human immunodeficiency virus (HIV) from mother to child; however, many women develop resistance to NVP in this setting. Comparing outcomes of clinical studies reveals an increased amount of resistance in subtype C relative to that in other subtypes. This study investigates how nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations of subtype C affect replication capacity. The 103N, 106A, 106M, 181C, 188C, 188L, and 190A drug resistance mutations were placed in a reverse transcriptase (RT) that matches the consensus subtype C sequence as well as the HXB2 RT, as a subtype B reference. The replicative fitness of each mutant was compared with that of the wild type in a head-to-head competition assay. The 106A mutant of subtype C would not grow in the competition assay, making it the weakest virus tested. The effect of the 106M mutation was weaker than those of the 181C and 188C mutations in the consensus C RT, but in subtype B, this difference was not seen. To see if the 106A mutation in a different subtype C background would have a different replicative profile, the same NNRTI resistance mutations were added to the MJ4 RT, a reference subtype C molecular clone. In the context of MJ4 RT, the 106A mutant was not the only mutant that showed poor replicative fitness; the 106M, 188C, and 190A mutants also failed to replicate. These results suggest that NNRTIs may be a cost-effective alternative for salvage therapy if deleterious mutations are present in a subtype C setting.The emergence of drug-resistant mutants is common among HIV-infected patients undergoing antiviral therapy. Clinically, the standard practice is to drop the antiviral to which the resistance has developed from the treatment regimen in such drug failure cases. However, a notable exception to this is the continuing use of lamivudine (3TC) as a salvage regimen because the 184V mutation linked to 3TC treatment has decreased replication ability relative to that of the wild type (WT) in subtype B (7). Mechanistically, Back et al. (2) found that the 184V mutant is less processive than wild-type RT under conditions of limiting deoxynucleoside triphosphates (dNTPs), and in primary lymphoid cells, the mutant is less fit than wildtype virus. These studies were extended further in vivo by Paredes et al. (35), who looked at multidrug-resistant virus from patients who were ending 3TC treatment. They used an allele-specific PCR assay to track the reversion of the M184V sequence and found that there was a fitness cost of 4 to 8% for the 184V mutation compared to that of the viral sequence that grew without 3TC drug pressure. Taken together, these studies illustrate how clinical management of HIV-infected patients can benefit from the study of the fitness cost of HIV drugresistant mutants.The use of antiretroviral drugs is increasing in the developing world. In particular, the use of single-dose nevirapine (NVP) has been shown to be an effective means of mitigat...

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Section: Discussionmentioning

confidence: 99%

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Armstrong

Lee

Essex

2011

Antimicrob Agents Chemother

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“…For instance, although K103N is the predominant mutation in mothers, infants exposed to SDNVP showed predominantly Y181C mutations (37). One explanation is that NVP resistance mutations arise largely de novo in infants, and only a small proportion are transmitted by the mothers (38).…”

Section: Discussionmentioning

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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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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“…However, this extended half-life also means that once treatment is stopped, viral replication can occur in a setting of suboptimally suppressive drug concentrations, creating an ideal situation for the emergence of drug resistance. Indeed, selection by NVP of drug resistance-conferring mutations in the RT of the replicating plasma virus pool was observed in 15 to 50% of the mothers (11,14,16,30,35) and in 45 to 87% of the infants (15,16,38) as assessed by populationbased sequencing. All of these studies found K103N to be the most prevalent amino acid substitution observed for women with NVP-resistant virus.…”

mentioning

confidence: 99%

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Ambrose

Palmer

Boltz

et al. 2007

J Virol

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Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does notclear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

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Selection and Persistence of Viral Resistance in HIV-Infected Children After Exposure to Single-Dose Nevirapine

Cited by 77 publications

References 18 publications

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

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

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

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