Low-Abundance Drug-Resistant Viral Variants in Chronically HIV-Infected, Antiretroviral Treatment–Naive Patients Significantly Impact Treatment Outcomes

Simen, Birgitte B.; Simons, Jan Fredrik; Hullsiek, Katherine Huppler; Novak, Richard M.; MacArthur, Rodger D.; Baxter, John D.; Huang, Chunli; Lubeski, Christine K.; Turenchalk, Gregory S.; Braverman, Michael; Desany, Brian; Rothberg, Jonathan M.; Egholm, Michael; Kozal, Michael J.

doi:10.1086/596736

Cited by 364 publications

(470 citation statements)

References 19 publications

Supporting

Mentioning

448

Contrasting

Unclassified

Order By: Relevance

“…These results were also limited by the inability of bulk sequencing technology to detect low-frequency variants that had been shown to affect treatment outcomes, [48][49][50][51][52][53] and that patients with HPLC-MS/ MS detectable pretherapy plasma drug levels were included in all virologic outcome analyses because HPLC-MS/MS was not performed on plasma samples with wildtype viruses. Our results agreed with reports that subtype-D infection was not associated with a worse virologic outcome, 54,55 which implied that the observed difference in suppression was not biased by subtype differences.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Lee

Bangsberg

Muzoora

et al. 2014

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Few reports have examined the impact of HIV-1 transmitted drug resistance (TDR) in resource-limited settings where there are fewer regimen choices and limited pretherapy/posttherapy resistance testing. In this study, we examined TDR prevalence in Kampala and Mbarara, Uganda and assessed its virologic consequences after antiretroviral therapy initiation. We sequenced the HIV-1 protease/reverse transcriptase from n = 81 and n = 491 treatment-naive participants of the Uganda AIDS Rural Treatment Outcomes (UARTO) pilot study in Kampala (AMU 2002(AMU -2004 and main cohort in Mbarara (MBA 2005(MBA -2010. TDR-associated mutations were defined by the WHO 2009 surveillance mutation list. Posttreatment viral load data were available for both populations. Overall TDR prevalence was 7% (Kampala) and 3% (Mbarara) with no significant time trend. There was a slight but statistically nonsignificant trend indicating that the presence of TDR was associated with a worse treatment outcome. Virologic suppression (£ 400 copies/ml within 6 months posttherapy initiation) was achieved in 87% and 96% of participants with wildtype viruses versus 67% and 83% of participants with TDR (AMU, MBA p = 0.2 and 0.1); time to suppression (log-rank p = 0.3 and p = 0.05). Overall, 85% and 96% of study participants achieved suppression regardless of TDR status. Surprisingly, among the TDR cases, approximately half still achieved suppression; the presence of pretherapy K103N while on nevirapine and fewer active drugs in the first regimen were most often observed with failures. The majority of patients benefited from the local HIV care system even without resistance monitoring. Overall, TDR prevalence was relatively low and its presence did not always imply treatment failure.

show abstract

Section: Discussionmentioning

confidence: 99%

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Lee

Bangsberg

Muzoora

et al. 2014

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

show abstract

“…9,24 In addition, we recently reported that such a technique is applicable to all PCR products. Grossmann et al 25 published a study where this assay was applied to sequence CEBPA, a gene with high GC content.…”

Section: Discussionmentioning

confidence: 99%

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories

et al. 2011

View full text Add to dashboard Cite

Massively parallel pyrosequencing allows sensitive deep sequencing to detect molecular aberrations. Thus far, data are limited on the technical performance in a clinical diagnostic setting. Here, we investigated as an international consortium the robustness, precision and reproducibility of amplicon nextgeneration deep sequencing across 10 laboratories in eight countries. In a cohort of 18 chronic myelomonocytic leukemia patients, mutational analyses were performed on TET2, a frequently mutated gene in myeloproliferative neoplasms. Additionally, hotspot regions of CBL and KRAS were investigated. The study was executed using GS FLX sequencing instruments and the small volume 454 Life Sciences Titanium emulsion PCR setup. We report a high concordance in mutation detection across all laboratories, including a robust detection of novel variants, which were undetected by standard Sanger sequencing. The sensitivity to detect low-level variants present with as low as 1-2% frequency, compared with the 20% threshold for Sanger-based sequencing is increased. Together with the output of high-quality long reads and fast run time, we demonstrate the utility of deep sequencing in clinical applications. In conclusion, this multicenter analysis demonstrated that amplicon-based deep sequencing is technically feasible, achieves high concordance across multiple laboratories and allows a broad and in-depth molecular characterization of cancer specimens with high diagnostic sensitivity.

show abstract

“…In the absence of adequate monitoring, the increased access to ART might lead to spread of transmitted and acquired drug-resistant HIV-1, resulting in reduced effectiveness of these drugs. Drug-resistant viruses have been reported to become the major circulating virus populations in infected individuals, with subsequent failure of therapy in treatment-naive patients [12,44,45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Knowledge of ART resistance is described as a predictor of immunologic, virologic, and clinical outcomes of therapy [10]. Consequently, the identification of HIVDR in treatment-naive patients is critical to maximize the detection of transmitted drug resistance, guide the selection of treatment regimen to suppress HIV-1 replication, and ultimately prevent resistance-associated virologic failure [9,11,12]. The prevalence of HIVDR among ART-naive people in the United States and Europe has been estimated to be 10%-15% [11,13].…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Low-Abundance Drug-Resistant Viral Variants in Chronically HIV-Infected, Antiretroviral Treatment–Naive Patients Significantly Impact Treatment Outcomes

Cited by 364 publications

References 19 publications

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories

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

Contact Info

Product

Resources

About