<i>In Utero</i> HIV Infection Is Associated with an Increased Risk of Nevirapine Resistance in Ugandan Infants Who Were Exposed to Perinatal Single Dose Nevirapine

Church, Jessica D.; Mwatha, Anthony; Bagenda, Danstan; Omer, Saad B.; Donnell, Deborah; Musoke, Philippa; Nakabiito, Clemensia; Eure, Chineta; Bakaki, Paul M.; Matovu, Flavia; Thigpen, Michael C.; Guay, Laura; McConnell, Michelle S.; Fowler, Mary Glenn; Jackson, J. Brooks; Eshleman, Susan H.

doi:10.1089/aid.2009.0003

Cited by 15 publications

(7 citation statements)

References 15 publications

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“…Both genotyping kits were extensively tested and validated (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). While the ViroSeq HIV-1 kit is still on the market, Siemens discontinued selling and supporting the TruGene HIV-1 kit in 2014.…”

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confidence: 99%

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

et al. 2015

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HIV genotyping is a critical tool for antiviral drug resistance testing that has revolutionized HIV care and advanced HIVrelated research. Routine antiretroviral (ARV) drug resistance testing is useful in choosing an optimal treatment regimen and monitoring its efficiency in clinical practice (1-12). HIV genotyping has been used successfully in research on HIV transmission clusters and HIV transmission dynamics (13-35).Initial broadly used ARV regimens included combinations of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). To monitor the emergence of drug resistance mutations associated with NRTIs and NNRTIs, HIV genotyping targeted viral sequences spanning an approximately 1,000-to 1,300-bp region of the HIV-1 genome encoding viral protease and partial RT, using viral RNA as a template for amplification. While the RNA-based approach works well in antiretroviral therapy (ART)-naive individuals, it is less successful if levels of viral replication are low, such as in individuals on ART. The sequence length of traditional RNAbased HIV genotyping for drug resistance is relatively short and does not cover the HIV-1 region encoding viral integrase or the viral envelope, hindering analysis of drug resistance mutations associated with integrase strand transfer inhibitors or entry inhibitors. The global scale up of ARV treatment and successful introduction of integrase strand transfer inhibitors and entry inhibitors into clinical trials and clinical practice necessitate modification of traditional methods of HIV genotyping.Two commercial genotyping assays, ViroSeq HIV-1 from Abbott Molecular and TruGene HIV-1 from Siemens Molecular Diagnostics, have been widely used for analysis of HIV-1-associated drug resistance. Both genotyping kits were extensively tested and validated (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). While the ViroSeq HIV-1 kit is still on the market, Siemens discontinued selling and supporting the TruGene HIV-1 kit in 2014. The ViroSeq HIV-1 kit covers the entire protease-coding region and the RT region encoding the first 320 amino acids. The TruGene HIV-1 sequences span the protease (amino acids 4 to 99)-and RT (amino acids 40 to 240)-coding regions. The CDC supplies WHO-designated and CDC-supported President's Emergency Plan for AIDS Relief (PEPFAR) Genotyping Laboratories with the ATCC HIV-1 Drug Resistance Genotyping kit (46) for drug resistance testing. Many experienced genotyping laboratories have developed their own in-house amplification and sequencing protocols (11,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56), including identification of minor viral variants that are normally missed by commercial genotyping kits (57-61). All of these approaches generally include smaller and more restricted regions for testing HIV-1 drug resistance.Recently, the protocol developed by Gall et al. (62)

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confidence: 99%

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

et al. 2015

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“…Importantly, we also found that a substantial proportion (38%) of infants infected in utero who received single-dose nevirapine maintained nevirapine resistance at levels detected by standard population sequencing at 6 months of age compared with 18% of those infected between birth and 14 weeks of age; however, this was not statistically different, but may be limited by the small sample size. Together, these findings highlight differences in the pathogenesis of HIV infection based on timing of infection in children [37][38][39] and emphasize the need to consider timing of infection in the management of HIV-infected children in resource-constrained settings by improving access to HIV testing, including drug resistance testing.…”

Section: Discussionmentioning

confidence: 88%

Slower Clearance of Nevirapine Resistant Virus in Infants Failing Extended Nevirapine Prophylaxis for Prevention of Mother-to-Child HIV Transmission

Persaud

Bedri

Ziemniak

et al. 2011

AIDS Research and Human Retroviruses

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Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6-12 months of single-dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high-throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p ¼ 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD-or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug-resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens.

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“…Furthermore, this study included only infants with in utero HIV infection. Infants who are HIV-infected in utero are more likely to acquire NVP resistance after sdNVP compared to infants who acquire HIV infection at or after birth [3]. …”

Section: Discussionmentioning

confidence: 99%

“…Administration of NVP-based prophylaxis to infants with undiagnosed HIV infection puts those infants at risk for acquiring NVP resistance. When sdNVP is used for prophylaxis, infants with in utero HIV infection are more likely to develop NVP resistance than infants with intrapartum or postnatal HIV infection [3]. In the SWEN study, Ugandan infants with in utero HIV infection who received either sdNVP or sdNVP plus daily NVP up to 6 weeks of age were at high risk of developing NVP resistance [4].…”

Section: Introductionmentioning

confidence: 99%

Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero

Lidström

Hoover³

et al. 2010

Aids

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BACKGROUND-In the PEPI-Malawi trial, most women received single dose nevirapine (sdNVP) at delivery, and infants in the extended study arms received sdNVP plus 1 week of daily zidovudine (ZDV), followed by either extended daily NVP or extended daily NVP+ZDV up to 14 weeks of age. While extended NVP prophylaxis reduces the risk of postnatal HIV transmission, it may increase the risk of NVP resistance among infants who are HIV-infected despite prophylaxis.

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In Utero HIV Infection Is Associated with an Increased Risk of Nevirapine Resistance in Ugandan Infants Who Were Exposed to Perinatal Single Dose Nevirapine

Cited by 15 publications

References 15 publications

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

Slower Clearance of Nevirapine Resistant Virus in Infants Failing Extended Nevirapine Prophylaxis for Prevention of Mother-to-Child HIV Transmission

Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero

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