High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen

Sunpath, Henry; Wu, Baohua; Gordon, Michelle; Hampton, Jane; Johnson, Brent A.; Moosa, Mahomed-Yunus S.; Ordóñez, Claudia E.; Kuritzkes, Daniel R.; Marconi, Vincent C.

doi:10.1097/qad.0b013e328356886d

Cited by 79 publications

(70 citation statements)

References 16 publications

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“…TDF-containing regimens have been shown to be better tolerated and have fewer side effects than d4T-containing ART but comparably effective. 61,62 However, amongst participants failing a TDF-containing regimen, we and others reported a high rate of the K65R mutation ( > 65% 63 and 46%, 64 respectively). This finding is under surveillance to assess if this is a unique association in subtype C.…”

Section: Discussionmentioning

confidence: 99%

Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

Marconi

Hampton

et al. 2013

AIDS Patient Care and STDs

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We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after ‡ 5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL) > 1000 copies/mL] and controls (2:1) if they had VL £ 1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF ( p < 0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.

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Section: Discussionmentioning

confidence: 99%

Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

Marconi

Hampton

et al. 2013

AIDS Patient Care and STDs

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“…Likewise, 9% of drug-naive subtype C-infected patients harbor tiny K65R minority species, while this is true for only 2% of subtype B-infected patients (44). Consequently, a relatively high number of subtype C patients have failed first-line therapy with the K65R mutation (49,50). The fact that G¡A mutations were the most common minority species detected here, combined with the fact that G¡A mutations are the most common type of HIV-1 drug resistance mutation, further underlines the critical role that mutational bias plays in the evolution of clinically relevant HIV-1 drug resistance.…”

Section: E138k and Hiv-1 Mutational Biasmentioning

confidence: 99%

Basis for Early and Preferential Selection of the E138K Mutation in HIV-1 Reverse Transcriptase

McCallum

Oliveira

Ibanescu

et al. 2013

Antimicrob Agents Chemother

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dE138K, a G¡A mutation in HIV-1 reverse transcriptase (RT), is preferentially selected by etravirine (ETR) and rilpivirine over other substitutions at position E138 that offer greater drug resistance. We hypothesized that there was a mutational bias for the E138K substitution and designed an allele-specific PCR to monitor the emergence of E138A/G/K/Q/R/V during ETR selection experiments. We also performed competition experiments using mutated viruses and quantified the prevalence of E138 minority species in drug-naive patients. E138K, as well as E138G, consistently emerged first during ETR selection experiments, followed by E138A and E138Q; E138R was never selected. Surprisingly, E138K was identified as a tiny minority in 23% of drug-naive subtype B patients, a result confirmed by ultradeep sequencing (UDS). This result could reflect a low fitness cost of E138K; however, E138K was one of the least fit substitutions at codon E138, even after taking into account the deoxynucleoside triphosphate pools of the cells used in competition experiments. Further UDS analysis revealed other minority species in a pattern consistent with the mutational bias of HIV RT. There was no evidence of APOBEC3-hypermutation in these selection experiments or in patients. Our results confirm the mutational bias of HIV-1 in patients and highlight the importance of G¡A mutations in HIV-1 drug resistance evolution.

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“…In particular, studies have proposed lower and higher propensities to develop K65R mutation for subtypes A and C, respectively. However, studies reporting subtype dependency of K65R selection were based mainly on observations from cell culture experiments or from patient populations with limited sample size or subtype distribution (3)(4)(5). Other studies failed to detect similar associations (6,7).…”

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confidence: 99%

HIV-1 Subtype Is an Independent Predictor of Reverse Transcriptase Mutation K65R in HIV-1 Patients Treated with Combination Antiretroviral Therapy Including Tenofovir

Theys

Vercauteren

Snoeck

et al. 2013

Antimicrob Agents Chemother

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Subtype-dependent selection of HIV-1 reverse transcriptase resistance mutation K65R was previously observed in cell culture and small clinical investigations. We compared K65R prevalence across subtypes A, B, C, F, G, and CRF02_AG separately in a cohort of 3,076 patients on combination therapy including tenofovir. K65R selection was significantly higher in HIV-1 subtype C. This could not be explained by clinical and demographic factors in multivariate analysis, suggesting subtype sequence-specific K65R pathways. Clinical relevance has been attributed to HIV-1 genomic diversity, classified in distinct groups and subtypes, since genetic variation can affect mutational pathways to drug resistance and possibly effectiveness of combination antiretroviral treatment (cART) (1, 2). The likelihood and rate of developing the lysine-toarginine resistance mutation at position 65 (K65R) of reverse transcriptase (RT) has been argued to vary depending on the viral subtype (3). In particular, studies have proposed lower and higher propensities to develop K65R mutation for subtypes A and C, respectively. However, studies reporting subtype dependency of K65R selection were based mainly on observations from cell culture experiments or from patient populations with limited sample size or subtype distribution (3-5). Other studies failed to detect similar associations (6, 7). While many clinical predictors of K65R selection have been identified to date (8, 9), a clear consensus on the role of genomic diversity is presently lacking. A large majority of K65R cases observed in recent years resulted from the administration of tenofovir (TDF) (10), which is currently the most widely used nucleoside RT inhibitor (NRTI) for first-line cART. Given the rising prevalence of non-B subtypes in Europe and treatment availability in other parts of the world, improved knowledge on subtype-specific K65R resistance pathways can be important in the planning of cART for HIV-1 non-B-infected patients.This study aimed specifically to evaluate the reported subtype-dependent selection of K65R rather than to identify novel predictors of its presence. We retrospectively investigated the emergence of K65R across different subtypes in a large TDFexperienced patient population, by integrating clinical and viral sequence data from eight countries (Belgium, Germany, Israel, Italy, Luxembourg, Portugal, Spain, and Sweden) in collaboration with the EuResist consortium. Viral isolates were obtained from genotypic resistance testing, recommended in case of therapy failure, while on treatment with a viral load high enough to allow successful sequencing. Together with information on demographics, treatment experience, and genotypic resistance profiles, we collected for each patient the most recent viral isolate while receiving TDF-based therapy, with a minimum of 30 days between the beginning of this therapy and the sampling date. When consecutive viral sequences were available, the first viral sequence containing K65R was selected. Patients were excluded if K65R was de...

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High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen

Cited by 79 publications

References 16 publications

Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

Basis for Early and Preferential Selection of the E138K Mutation in HIV-1 Reverse Transcriptase

HIV-1 Subtype Is an Independent Predictor of Reverse Transcriptase Mutation K65R in HIV-1 Patients Treated with Combination Antiretroviral Therapy Including Tenofovir

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