The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance

Gifford, Robert J.; Liu, Tommy F.; Rhee, Soo-Yon; Kiuchi, Mark; Hué, Stéphane; Pillay, Deenan; Shafer, Robert W.

doi:10.1093/bioinformatics/btp134

Cited by 164 publications

(142 citation statements)

References 16 publications

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“…14 Transmitted drug resistance was defined according to the CPR, an algorithm specifically designed for the epidemiologic surveillance of HIV-1 tDRM. 8 The prevalence of tDRM detected in this population was 4.9%, which was somewhat lower than that previously reported for adults and children in other regions of Brazil, which used the Stanford CPR criteria for these estimates. 15 However, if all DRAMs are included, we found a prevalence of 43.9% DRAM in the pol sequences.…”

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confidence: 70%

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Molecular Characterization of the Human Immunodeficiency Virus Type 1 in Women and Their Vertically Infected Children

Nunes

GiovanettiMarta

Almeida

et al. 2015

AIDS Research and Human Retroviruses

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Approximately 35 million people worldwide are infected with human immunodeficiency virus (HIV) around 3.2 million of whom are children under 15 years. Mother-to-child-transmission (MTCT) of HIV-1 accounts for 90% of all infections in children. Despite great advances in the prevention of MTCT in Brazil, children are still becoming infected. Samples from 19 HIV-1-infected families were collected. DNA was extracted and fragments from gag, pol, and env were amplified and sequenced directly. Phylogenetic reconstruction was performed. Drug resistance analyses were performed in pol and env sequences. We found 82.1% of subtype B and 17.9% of BF recombinants. A prevalence of 43.9% drug resistance-associated mutations in pol sequences was identified. Of the drug-naive children 33.3% presented at least one mutation related to protease inhibitor/ nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NRTI/NNRTI) resistance. The prevalence of transmitted drug resistance mutations was 4.9%. On env we found a low prevalence of HR1 (4.9%) and HR2 (14.6%) mutations.

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confidence: 70%

“…Transmitted drug resistance mutations (tDRM) were analyzed using the Calibrated Population Resistance (CPR) tool. 8 The gp41 env mutations associated with fusion inhibitor were defined based in the International AIDS Society-USA/IAS-USA database 9 and the Stanford Database (http://hivdb.stanford.edu).…”

mentioning

confidence: 99%

Molecular Characterization of the Human Immunodeficiency Virus Type 1 in Women and Their Vertically Infected Children

Nunes

GiovanettiMarta

Almeida

et al. 2015

AIDS Research and Human Retroviruses

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“…The other differences between the consensus C and MJ4 RT sequences appear to be common substitutions in subtype C RTs except for 39A and 248T. These two amino acid substitutions appear to be unique to MJ4, although there is some variability at these positions in the extended consensus sequence (15,39).…”

Section: Discussionmentioning

confidence: 92%

“…In addition, the resistance mutations 106M, 188C, and 190A do not seem to lie anywhere near the 296 residue in p66 or p51. Changes at the 296 residue appear to be quite rare, with not a single instance of an N residue occurring in the Stanford Drug Resistance Database among all submitted subtype C sequences (15,39). The 334H substitution used in the consensus RT reflects the Botswana consensus sequence; however, the H residue is found in 28% of all subtype C sequences, and the Q amino acid is found in 33%, as well as being seen in MJ4.…”

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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“…DNA sequencing was performed using ABI Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). Drug resistance mutations were identified based on the published 2009 WHO list for surveillance of transmitted resistance [27,28,29] as well as the Stanford HIV Drug Resistance Database [30].…”

Section: Hiv-1 Drug Resistance Mutationsmentioning

confidence: 99%

Screening for antiretroviral drug resistance among treatment-naive human immunodeficiency virus type 1-infected individuals in Lebanon

Mokhbat

Melhem

El‐Khatib

et al. 2014

J Infect Dev Ctries

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Introduction: Antiretroviral therapy (ART) has been successful at decreasing the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 drug resistance (HIVDR) among ART-naive patients has been documented to compromise the success of initial therapy. This study was conducted to determine the prevalence of HIVDR mutations among newly diagnosed drug-naive HIV-infected individuals in Lebanon. Methodology: Plasma samples from 37 newly diagnosed participants at various stages of HIV-1 infection were used to determine HIV-1 RNA viral load, isolate viral RNA, and amplify DNA by RT-PCR. Purified PCR products were used to perform genotypic resistance tests. Results: The prevalence of resistance mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRT), and protease inhibitors (PI) were 5.4%, 10.8%, and 8%, respectively. The major mutations detected in the study participants conferred resistance to NRTIs and NNRTIs recommended for HIV-1 treatment. No significant relationship between HIV-1 viral load of participants and the mode of HIV-1 transmission or between the occurrence of HIVDR and the mode of transmission was found. Conclusions: To our knowledge, this is the first study on HIVDR mutations among newly diagnosed HIV-infected persons in Lebanon. The overall prevalence of HIVDR mutations detected in our study was 16%. Our results are important for evaluating the utility of the standard first-line regimens in use, determining the feasibility of HIVDR testing before the initiation of ART, as well as minimizing the emergence and transmission of HIVDR.

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The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance

Cited by 164 publications

References 16 publications

Molecular Characterization of the Human Immunodeficiency Virus Type 1 in Women and Their Vertically Infected Children

Molecular Characterization of the Human Immunodeficiency Virus Type 1 in Women and Their Vertically Infected Children

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

Screening for antiretroviral drug resistance among treatment-naive human immunodeficiency virus type 1-infected individuals in Lebanon

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