The Reverse Transcriptase 67N 70R 215Y Genotype Is the Predominant TAM Pathway Associated with Virologic Failure among HIV Type 1C-Infected Adults Treated with ZDV/ddI-Containing HAART in Southern Africa

Novitsky, Vlad; Wester, Carolyn; DeGruttola, Victor; Bussmann, Hermann; Gaseitsiwe, Simani; Thomas, Ann; Moyo, Sikhulile; Musonda, Rosemary; Widenfelt, Erik van; Marlink, Richard; Essex, Max

doi:10.1089/aid.2006.0298

Cited by 65 publications

(66 citation statements)

References 53 publications

(55 reference statements)

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“…48 This appears to be specific to the d4T/ddI exposure in this country since similar results were not found in other subtype C studies in South Africa, Malawi, and India where other drug regimens were used. 49 A 2005 meta-analysis of 3686 persons with non-B subtypes and 4769 with B subtypes found that 55 known treatmentassociated mutations that were observed in subtype B were also found in non-B subtypes, and the converse was true for 61/67 mutations observed in non-B subtypes.…”

Section: Hiv-1 Subtype On Drug Resistance Mutations In Nigeriasupporting

confidence: 75%

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Chaplin

Eisen

Idoko

et al. 2011

AIDS Research and Human Retroviruses

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A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR) ¼ 0.35; p ¼ 0.022]. Subtype A patients showed a 42.5-fold increased risk (AOR ¼ 42.5, p ¼ 0.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AOR ¼ 2.40, p ¼ 0.036) and V106I (AOR ¼ 6.15, p ¼ 0.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AOR ¼ 3.16; p ¼ 0.003) and a decreased risk for A98G (AOR ¼ 0.48, p ¼ 0.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings.

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Section: Hiv-1 Subtype On Drug Resistance Mutations In Nigeriasupporting

confidence: 75%

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Chaplin

Eisen

Idoko

et al. 2011

AIDS Research and Human Retroviruses

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“…Studies in our laboratory have shown that in a didanosine-containing regimen (along with AZT and efavirenz or nevirapine), 67N, 70R, and 215Y were the most common mutations seen together (17). The same study showed that the 41L mutation was rare compared to what was expected from the subtype B data; in fact, it did not occur in this study at all.…”

mentioning

confidence: 40%

“…Mutations occur randomly, but the more fit amino acids are more likely to persist and be seen clinically due to their ability to outcompete the rest of the viral reservoir. These data do not explain why this pathway was seen more than TAM-1 or TAM-2 in Botswana, but the published results (17) are based on a restricted number of patients.…”

Section: Discussionmentioning

confidence: 74%

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Armstrong¹,

Lee²,

Essex³

2009

J Virol

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In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture. Different viruses were distinguished by sequence tags in nef and a quantitative-PCR assay. The 67N and 70R accessory mutations gave an advantage over the WT in subtype C, but these mutations in subtype B had replication capacities similar to that of the WT. Of the triple mutants examined, the TAM-1 types, 41L210W215Y, were the most fit in both subtypes, but only in subtype C was the replication capacity the same as that of the WT. The TAM-2 mutants, 67N70R215F, had the slowest replication in both clones. The mixed TAM pathway mutant, 67N70R215Y, in subtype C had a significant advantage over the TAM-2 mutant, but this was not seen in subtype B. When the WT viruses were competed with each other, the subtype B RT had enhanced replication relative to subtype C. The increased capacities of the 67N and 70R mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B.Human immunodeficiency virus type 1 (HIV-1) remains a leading cause of morbidity and mortality worldwide. With the advent of highly active antiretroviral therapy (HAART), the life expectancy for those on treatment has increased dramatically. Given HIV-1's ability to replicate and mutate quickly, drug resistance has been a significant problem since treatment began. While drug resistance has been studied extensively in the developed world, HIV-1 subtypes that affect developing countries are rarely targeted for drug resistance research (9).Sub-Saharan Africa continues to bear the bulk of the burden of the HIV-1 epidemic, with 22.5 million infections out of the 33.2 million global infections (22). However, the developed world has begun to take notice by contributing unprecedented amounts of money and expertise to combat the epidemic. Much of the support for developing countries has gone toward drug treatment programs for those in need, making research into drug resistance of paramount importance. As more and more people get the treatment they require, drug resistance will increasingly play a major role in the epidemic in these hard-hit areas, where expertise and laboratory tests for clinical monitoring are often not available.Some in vivo data point to different patterns of resistance between subtypes. Brenner et al. (3) have shown for subtype C that the 65R mutation occurs faster in cell culture in response to tenofovir pressure than it does in subtype B. A study from Brazil looked at 160 sequences from treatment-experienced HIV-1-infected individuals (21). It was found that subtype C viruses accumulated drug resistance mutations at a lower rate than subtype B i...

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“…To our knowledge this is the first study to observe ''combined'' TAM-2 pathway (215F) and TAM-1 pathway (210W) associated mutations in this setting. Such variation has been reported in an adult subtype C cohort failing zidovudine/didanosinecontaining ART in Botswana, 19 but additional data are needed to determine if such variation is common in CRF01_ AE-infected children and its effect.…”

Section: Coetzer Et Almentioning

confidence: 89%

“…Mounting evidence suggests that naturally occurring polymorphisms among non-B subtypes can influence susceptibility to antiretroviral drugs, 15 such as the higher incidence of nevirapine-resistant mutations K103N and Y181C in subtype C from South Africa 16,17 or the thymidine analogue mutations (TAM) pathway variation 18 observed in subtype C from Botswana. 19 Most of these studies focus on adults, and whether specific pediatric variations exist is less clear. 7,20 CRF01_AE is the most common HIV variant in Southeast Asia, accounting for 5% of all global HIV-1 infections.…”

Section: Introductionmentioning

confidence: 99%

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

Coetzer

Westley

DeLong

et al. 2013

AIDS Research and Human Retroviruses

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Antiretroviral therapy in resource-limited settings is monitored clinically and immunologically according to WHO guidelines. Frequent misclassification of virologic failure is reported, mostly in adults, leading to early therapy switch or late failure diagnosis. Pediatric treatment monitoring and resistance data upon first-line failure are limited, particularly when the 2010-WHO pediatric guidelines are used without routine viral load monitoring. We previously reported high treatment failure misclassification rates by pediatric 2010 guidelines in Cambodian children on first-line therapy. Here we determine the extent and patterns of resistance, with yearly viral load and 6-monthly CD4. Drug resistance mutations were determined using the IAS-USA 2011 list. Predicted resistance interpretation was determined with Stanford Database tools. Fifty-one children with available genotypes met inclusion criteria. All but one (subtype B) were CRF01_AE. The most common regimen was stavudine, lamivudine, and nevirapine (96%), taken for a median of 2.2 years. Resistance was seen in 98%; 96% to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs); 51% with ‡ 4 mutations. The most common NRTI mutations were 184V/I and 67N and the most common NNRTI mutations were 181C/Y/I/V and 190A/S. A total of 22% had multiresistant mutations and 18% had predicted high-level resistance to subsequent therapy options didanosine, abacavir, etravirine, and tenofovir. In 98% of Cambodian children misclassified as nonfailing first-line therapy by 2010 guidelines, 51% had extensive drug resistance to current and 18% to subsequent antiretroviral therapy. Affordable routine viral load monitoring allowing for early and more accurate treatment failure diagnosis is desperately needed in resource-limited settings.

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The Reverse Transcriptase 67N 70R 215Y Genotype Is the Predominant TAM Pathway Associated with Virologic Failure among HIV Type 1C-Infected Adults Treated with ZDV/ddI-Containing HAART in Southern Africa

Cited by 65 publications

References 53 publications

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

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