The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to &lt; 400 copies/ml

Easterbrook, Philippa; Ives, Natalie; Waters, Anele; Mullen, Jane; O’Shea, Siobhan; Peters, Barry; Gazzard, Brian

doi:10.1097/00002030-200207260-00009

Cited by 68 publications

(84 citation statements)

References 15 publications

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“…Prolonged breaks in adherence may thus represent islands of infectivity where host infectiousness relates positively to pretreatment SPVL. Finally, viral “blips” (brief and intermittent periods of detectable viral load despite adherence to ART) are observed more often in hosts with high baseline SPVL (Havlir et al., 2001; Leierer et al., 2015), and infections with large or frequent blips are more likely to experience virologic failure (Easterbrook et al., 2002; Grennan et al., 2012; Laprise, De Pokomandy, Baril, Dufresne, & Trottier, 2013) and achieve higher viral rebound upon treatment interruption (Castro et al., 2013). These observations span drug types, host populations and viral clades, but collectively support the intuitive assumption that infections with high SPVL are more infectious than those with low SPVL when imperfectly treated.…”

Section: Discussionmentioning

confidence: 99%

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Mideo

2017

Evolutionary Applications

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Average HIV‐1 virulence appears to have evolved in different directions in different host populations since antiretroviral therapy first became available, and models predict that HIV drugs can select for either higher or lower virulence, depending on how treatment is administered. However, HIV virulence evolution in response to “leaky” therapy (treatment that imperfectly suppresses viral replication) and the use of preventive drugs (pre‐exposure prophylaxis) has not been explored. Using adaptive dynamics, we show that higher virulence can evolve when antiretroviral therapy is imperfectly effective and that this evolution erodes some of the long‐term clinical and epidemiological benefits of HIV treatment. The introduction of pre‐exposure prophylaxis greatly reduces infection prevalence, but can further amplify virulence evolution when it, too, is leaky. Increasing the uptake rate of these imperfect interventions increases selection for higher virulence and can lead to counterintuitive increases in infection prevalence in some scenarios. Although populations almost always fare better with access to interventions than without, untreated individuals could experience particularly poor clinical outcomes when virulence evolves. These findings predict that antiretroviral drugs may have underappreciated evolutionary consequences, but that maximizing drug efficacy can prevent this evolutionary response. We suggest that HIV virulence evolution should be closely monitored as access to interventions continues to improve.

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Section: Discussionmentioning

confidence: 99%

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Mideo

2017

Evolutionary Applications

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“…After adjustment for these factors, none of the other markers of A study in patients with CD4 counts 4200 cells/mL found that time with undetectable viraemia was a significant predictor of clinical progression [30]. In addition, previous studies have found that patients with a history of persistent low-level viraemia (51-1000 copies/mL) were more likely to experience virological failure [31], as were those with intermittent viraemia above 400 copies/mL, compared with those who sustained an undetectable viral load [32]. However, some studies have shown that, although moderate viraemia and viral rebounds may increase your risk of future rebounds, this may not translate into an increased risk of clinical disease progression [33,34].…”

Section: Discussionmentioning

confidence: 99%

History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change^*

et al. 2010

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ObjectivesHIV-infected persons experience different patterns of viral suppression after initiating combination antiretroviral therapy (cART). The relationship between such differences and risk of virological failure after starting a new antiretroviral could help with patient monitoring strategies. MethodsA total of 1827 patients on cART starting at least one new antiretroviral from 1 January 2000 while maintaining a suppressed viral load were included in the analysis. Poisson regression analysis identified factors predictive of virological failure after baseline in addition to traditional demographic variables. Baseline was defined as the date of starting new antiretrovirals. ResultsFour hundred and fifty-one patients (24.7%) experienced virological failure, with an incidence rate (IR) of 7.3 per 100 person-years of follow-up (PYFU) [95% confidence interval (CI) 6.7-8.0]. After adjustment, patients who had rebounded in the year prior to baseline had a 2.4-times higher rate of virological failure after baseline (95% CI 1.77-3.26; Po.0001), while there was no increased incidence in patients whose last viral rebound was 43 years prior to baseline [Incidence rate ratio (IRR) 1.06; 95% CI 0.75-1.50; P 5 0.73] compared with patients who had never virally rebounded. Patients had an 86% (95% CI 1.36-2.55; Po.0001), 53% (95% CI 1.06-2.04; P 5 0.02) and 5% (95% CI 0.80-1.38; P 5 0.72) higher virological failure rate after baseline if they were virally suppressed o50%, 50-70% and 70-90% of the time they were on cART prior to baseline, respectively, compared with those virally suppressed 490% of the time. DiscussionIntensive monitoring after a treatment switch is required in patients who have rebounded recently or have a low percentage of time suppressed while on cART. Consideration should be given to increasing the provision of adherence counselling. IntroductionTreatment guidelines for HIV-1 infection state that suppression of viral load below the level of quantification (normally 50 HIV-1 RNA copies/mL) is one of the key goals of combination antiretroviral therapy (cART) and should be one of the deciding factors when planning a patient's treatment strategy [1][2][3][4]. However, a substantial number of patients fail to achieve viral suppression in the first 6 DOI: 10.1111DOI: 10. /j.1468DOI: 10. -1293DOI: 10. .2009 (2010), 11, 469-478 469 months after starting cART [5] and many others go on to experience viral rebound at some time thereafter [6]. With increasing numbers of episodes of viral failure, the goal of viral suppression becomes harder to achieve [7]. Patients experience different immunological and virological responses after initiating cART [5,8,9]. In clinical practice, earlier studies found that around 70-80% of patients starting cART achieve an undetectable viral load [10]. This proportion has increased in recent years [11][12][13]; however, viral replication is still not fully controlled in all patients at all times. Previous analyses have found that a patient is most likely to fail in the first few mon...

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“…Another study that specifically evaluated sustained viral rebound at 50 to 400 cpm found no association with a prior blip (14). The four studies that found an association between viral blips and subsequent virologic failure included either a pVL of Ն400 cpm in the definitions of viral blip (34,53,54) or considered a single blip of Ͼ500 cpm to be virologic failure (5). Thus, studies to date agree that the risk of subsequent virologic failure (including persistent viremia in the LLV range) is not significantly increased among patients with isolated low-amplitude viral blips (Ͻ400 or Ͻ500 cpm).…”

Section: Figmentioning

confidence: 99%

“…There does not appear to be a clinically meaningful impact of either VLLV or persistent viremia of Ͻ400 cpm on the CD4 ϩ T-cell trajectory (26,31,39,45,47,49,51,80), while a few studies have signaled that the trajectory may be affected by viremia of Ͼ400 cpm (31,37,53).…”

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

112

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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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The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml

Cited by 68 publications

References 15 publications

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change^*

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

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The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml

Cited by 68 publications

References 15 publications

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change*

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

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History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change^*