Genotypic Resistance in HIV‐1–Infected Patients with Persistently Detectable Low‐Level Viremia while Receiving Highly Active Antiretroviral Therapy

Nettles, Richard E.; Kieffer, Tara L.; Simmons, Rachel P.; Cofrancesco, Joseph; Moore, Richard D.; Gallant, Joel E.; Persaud, Deborah; Siliciano, Robert F.

doi:10.1086/423388

Cited by 72 publications

(54 citation statements)

References 24 publications

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“…(i) Antiretroviral resistance increases with persistent LLV. ARV drug resistance is well documented in patients with a viremia level of Ͻ1,000 cpm (Table 4), though the reported prevalence varies depending on ART experience, virological suppression/failure, duration of viremia, and treatment regimen (45,(68)(69)(70)(71)(72)(73)(74)(75). In one of the largest studies (n ϭ 1,001), genotyping of clinical samples between 1999 and 2006 in the United Kingdom revealed at least one drug resistance mutation (DRM) in 60% and 72% of samples, with pVLs of Ͻ300 cpm and 300 to 999 cpm, respectively (70).…”

Section: Figmentioning

confidence: 99%

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Ryscavage

Kelly

et al. 2014

Antimicrob Agents Chemother

118

101

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A goal of HIV therapy is to sustain suppression of the plasma viral load below the detection limits of clinical assays. However, widely followed treatment guidelines diverge in their interpretation and recommended management of persistent viremia of low magnitude, reflecting the limited evidence base for this common clinical finding. Here, we review the incidence, risk factors, and potential consequences of low-level HIV viremia (LLV; defined in this review as a viremia level of 50 to 500 copies/ml) and verylow-level viremia (VLLV; defined as a viremia level of <50 copies/ml detected by clinical assays that have quantification cutoffs of <50 copies/ml). Using this framework, we discuss practical issues related to the diagnosis and management of patients experiencing persistent LLV and VLLV. Compared to viral suppression at <50 or 40 copies/ml, persistent LLV is associated with increased risk of antiretroviral drug resistance and overt virologic failure. Higher immune activation and HIV transmission may be additional undesirable consequences in this population. It is uncertain whether LLV of <200 copies/ml confers independent risks, as this level of viremia may reflect assay-dependent artifacts or biologically meaningful events during suppression. Resistance genotyping should be considered in patients with persistent LLV when feasible, and treatment should be modified if resistance is detected. There is a dearth of clinical evidence to guide management when genotyping is not feasible. Increased availability of genotypic assays for samples with viral loads of <400 copies/ml is needed.

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Section: Figmentioning

confidence: 99%

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Ryscavage

Kelly

et al. 2014

Antimicrob Agents Chemother

118

101

View full text Add to dashboard Cite

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“…For multidrug-resistant variants to emerge during ART, either viral variants with multiple drug resistance mutations that exist prior to therapy must be selected during treatment or ongoing, low-level virus replication and recombination must allow the necessary multiple mutations to accumulate on single viral genomes. Many studies have demonstrated that suboptimal therapy results in the selection of drug-resistant variants as a consequence of incomplete viral suppression (15,17,21,24,32,33,42). For example, the widespread and rapid resistance to monotherapy and dual-drug combination therapy (6,13,16,19,25,30,35,37,41) and the emergence of nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) resistance mutations after single-dose nevirapine to prevent mother-to-child transmission of HIV during childbirth in resource-limited settings (12,20,26) support the hypothesis that preexisting resistance and ongoing replication during suboptimal treatment result in the selection of drug-resistant virus and virologic failure.…”

mentioning

confidence: 99%

Genetic Diversity of Simian Immunodeficiency Virus Encoding HIV-1 Reverse Transcriptase Persists in Macaques despite Antiretroviral Therapy

Kearney

Spindler

Shao

et al. 2011

J Virol

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The impact of antiretroviral therapy (ART) on the genetics of simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) populations has been incompletely characterized. We analyzed SIV genetic variation before, during, and after ART in a macaque model. Six pigtail macaques were infected with an SIV/HIV chimeric virus, RT-SHIV mne , in which SIV reverse transcriptase (RT) was replaced by HIV-1 RT. Three animals received a short course of efavirenz (EFV) monotherapy before combination ART was started. All macaques received 20 weeks of tenofovir, emtricitabine, and EFV. Plasma virus populations were analyzed by single-genome sequencing. Population diversity was measured by average pairwise difference, and changes in viral genetics were assessed by phylogenetic and panmixia analyses. After 20 weeks of ART, viral diversity was not different from pretherapy viral diversity despite more than 10,000-fold declines in viremia, indicating that, within this range, there is no relationship between diversity and plasma viremia. In two animals with consistent SIV RNA suppression to <15 copies/ml during ART, there was no evidence of viral evolution. In contrast, in the four macaques with viremias >15 copies/ml during therapy, there was divergence between preand during-ART virus populations. Drug resistance mutations emerged in two of these four animals, resulting in virologic failure in the animal with the highest level of pretherapy viremia. Taken together, these findings indicate that viral diversity does not decrease with suppressive ART, that ongoing replication occurs with viremias >15 copies/ml, and that in this macaque model of ART drug resistance likely emerges as a result of incomplete suppression and preexisting drug resistance mutations.

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“…Commercial assays require Ն1,000 copies/ml, but noncommercial, modified commercial, and proprietary GART assays have successfully detected resistance at much lower levels (1,3,4,(6)(7)(8). Since 2001, the Infectious Diseases Laboratory at the Veterans Affairs Medical Center in Washington, D.C., has performed genotypic testing using the TruGene HIV type 1 (HIV-1) genotyping kit/OpenGene DNA sequencing system (Bayer HealthCare LLC, Tarrytown, NY).…”

mentioning

confidence: 99%

Performance of the TruGene Human Immunodeficiency Virus Type 1 Genotyping Kit and OpenGene DNA Sequencing System on Clinical Samples Diluted to Approximately 100 Copies per Milliliter

Gale

Kan

Shinol

2006

Clin Vaccine Immunol

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The TruGene human immunodeficiency virus type 1 (HIV-1) genotyping kit/OpenGene DNA sequencing system (Bayer HealthCare, Tarrytown, NY) reliably produced clinically acceptable resistance profiles for reverse transcriptase and protease inhibitors on patient samples diluted to ϳ100 copies/ml following extraction with the QIAamp viral RNA minikit (QIAGEN Inc., Valencia, CA). One modification of the standard protocol was made to guarantee PCR amplification: a centrifugation step to concentrate virus was added before RNA extraction. For genotypic antiretroviral resistance testing, no significant differences in the identification and sensitivity of detection for codon mutations, base mutations, and multibase sites were found between the original and diluted samples.Genotypic antiretroviral resistance testing (GART) is a routine tool in the management of human immunodeficiency virus (HIV) patients on highly active antiretroviral therapy (2). Commercial assays require Ն1,000 copies/ml, but noncommercial, modified commercial, and proprietary GART assays have successfully detected resistance at much lower levels (1,3,4,(6)(7)(8). Since 2001, the Infectious Diseases Laboratory at the Veterans Affairs Medical Center in Washington, D.C., has performed genotypic testing using the TruGene HIV type 1 (HIV-1) genotyping kit/OpenGene DNA sequencing system (Bayer HealthCare LLC, Tarrytown, NY). We observed that this commercial assay was consistently able to genotype clinical samples well below 1,000 copies/ml. We designed this study to validate genotypic testing at very low viral loads because an earlier recognition of resistance to antiretroviral agents may well enhance the clinician's opportunity to alter therapy, prevent the emergence of added resistance, and better preserve future treatment options.(Results of this study were presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., 16 to 19 December 2005.) MATERIALS AND METHODSPeripheral blood was drawn by venipuncture into EDTA tubes, kept at room temperature, and centrifuged within 4 h of drawing at 1,000 ϫ g for 15 min. Plasma was stored at Ϫ80°C and thawed in a 10 to 15°C water bath for 15 min before use. Twenty consecutive clinical GART specimens were chosen for the presence of HIV RNA with multiple mutations leading to complex resistance profiles and with Ͼ1,000 copies/ml (median, 13,933 copies/ml; range, 1,032 to 345,560 copies/ml; Versant HIV-1 RNA 3.0 assay [bDNA]; Bayer HealthCare). The samples were diluted in human serum-based dilution matrix (AcroMetrix Corporation, Benecia, CA) or HIV-negative plasma to ϳ100 copies/ml (median, 136 copies/ml; range, Ͻ75 to 254 copies/ml) ( Table 1). The diluted samples were stored and thawed in the same manner as the original samples before processing.Viruses in the diluted sample were only when PCR amplification failed concentrated: one milliliter was centrifuged at 23,500 ϫ g and 4°C for 75 min in a 2-ml microtube (PN 72.693.005; Sarstedt Inc., Newton, NC), and 800 l of sup...

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Genotypic Resistance in HIV‐1–Infected Patients with Persistently Detectable Low‐Level Viremia while Receiving Highly Active Antiretroviral Therapy

Abstract: The finding that clinically significant resistance mutations were present in some but not all patients with persistent viremia (range, 50-400 copies/mL) highlights the need to improve the sensitivity of current clinical assays for detection of drug resistance.

Cited by 72 publications

References 24 publications

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Significance and Clinical Management of Persistent Low-Level Viremia and Very-Low-Level Viremia in HIV-1-Infected Patients

Genetic Diversity of Simian Immunodeficiency Virus Encoding HIV-1 Reverse Transcriptase Persists in Macaques despite Antiretroviral Therapy

Performance of the TruGene Human Immunodeficiency Virus Type 1 Genotyping Kit and OpenGene DNA Sequencing System on Clinical Samples Diluted to Approximately 100 Copies per Milliliter

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