Residual viraemia does not influence 1 year virological rebound in HIV-infected patients with HIV RNA persistently below 50 copies/mL

Gianotti, Nicola; Galli, Laura; Racca, Sara; Salpietro, Stefania; Cossarini, Francesca; Spagnuolo, Vincenzo; Barda, Beatrice; Canducci, Filippo; Clementi, Massimo; Lazzarin, Adriano; Castagna, Antonella

doi:10.1093/jac/dkr422

Cited by 27 publications

(33 citation statements)

References 7 publications

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“…The precise incidence rates of VLLV are, however, poorly characterized, as studies have differed in terms of the pVL assay used, as well as patient population characteristics, such as type and duration of cART (7,42,43).…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…when routine viral load (VL) is found between quantitation limit and detection limit) [16]. This also represents one of the suspected causes of virological failure [17,18], immunological suboptimal gain [18] or persistent immune activation [19], but this is also currently debated [20][21][22].…”

Section: Cd38mentioning

confidence: 99%

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Saison

Ferry

Demaret

et al. 2014

Clinical and Experimental Immunology

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SummaryThe mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (Tregs) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4 + T cell count (> or < 500/mm 3 ). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4 + lymphocytes, including Treg subsets, and CD8 + T cells was performed. Percentages of activated CD4 + T cells, Tregs, effector Tregs and terminal effector Tregs were found to be significantly elevated in iIR. Neither the percentage of activated CD8+ T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4 + T cell count and percentage of Tregs were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4 + and CD8+ T cells, Treg percentages and very low-level viraemia. Causative interactions between Tregs and CD4 + T cells should now be explored prospectively in a large patients cohort.

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“…Altogether, over 264 extendedly discontinuous treatment years, HIV escaped control in 18 instances, amounting to 7 escapes per 100 highly discontinuous treatment years, within the range of viral escapes noted in a number of 7 days per week combinations (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), yet lower than on unremitting PI monotherapy (45)(46)(47)(48). Congruent with the tentative exploratory nature of our prescriptions, 14 of the 18 escapes could reasonably be linked to unfitting prescriptions or EA (Table 3).…”

Section: Iccarre 4 Day Per Week Treatment: Not a Single Hiv Escapementioning

confidence: 67%

“…Yet, not just any medicinal treatment simplification will do; the alleviation of triplecombination therapy with 2 drugs as maintenance therapy, 7 days per week, once failed radically (65)(66)(67)(68), and ritonavirboosted PI monotherapies, 7 days per week, have yet to match (45-48) current triple combination standards virologically (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

Section: Treatment Outcomes Following Viral Escapesmentioning

confidence: 99%

Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project

et al. 2015

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Short, intraweekly cycles of anti‐HIV combinations have provided intermittent, effective therapy (on 48 patients) (1). The concept is now extended to 94 patients on treatment, 4 days per week or less, over a median of 2.7 discontinuous treatment years per patient. On suppressive combinations, 94 patients volunteered to treatment, 5 and 4 days per week, or reduced stepwise to 4,3,2, and 1 days per week in 94, 84, 66, and 12 patients, respectively, on various triple, standard, antiviral combinations, or nonregistered, quadruple, antiviral combinations. Ninety‐four patients on treatment 4 days per week aggregated 165 intermittent treatment years; no viral breakthrough was observed over 87 average treatment weeks per patient, 63 of 94 having passed 2.5 intermittent treatment years on any of the antiviral combinations prescribed. On the hyperintermittent treatment of 3, 2, and 1 days per week, HIV RNA surged >50 copies, 4 weeks apart, in 18 instances (6.8 viral escapes/100 hyperdiscontinuous maintenance years). Viral escapes could have been a result of erratic adherence (EA) to regimen or follow‐up (3 patients)—drug taken at half of the daily recommended dosage (8 patients) and/or overlooked archival‐resistant HIVs from antecedent treatment failures (6 patients). Aside from the above circumstances, HIV unexpectedly rebounded in 3 patients on 2 days per week treatment and 1 patient on 1 day per week treatment, posting 2.2 intrinsic viral escapes/100 highly discontinuous treatment years. All 18 escapes were eventually reversed by 7 days per week salvage combinations, and 11 of 18 patients have been back for a second course of intermittent therapy, 4 days per week or less. Both cell‐activation markers on the surface of T lymphocytes and cell‐bound HIV DNA levels remained stable or declined. CD4/CD8 ratios rose to ≤1 in 35% of patients, whereas CD4 counts went ≤500/μl in 75%. These values were previously 7 and 40%, respectively, on 7 days per week therapy. In our aging, long, HIV‐enduring, multitreated patient cohort, treatment 4 days per week and less over 421 intermittent treatment years reduced prescription medicines by 60%—equivalent to 3 drug‐free/3 virus‐free remission year per patient—actually sparing €3 million on just 94 patients at the cost of 2.2 intrinsic viral failure/100 hyperintermittent treatment years. At no risk of viral escape, maintenance therapy, 4 days per week, would quasiuniversally offer 40% cuts off of current overprescriptions.—Leibowitch, J., Mathez, D., de Truchis, P., Ledu, D., Melchior, J. C., Carcelain, G., Izopet, J., Perronne, C., David, J. R. Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project. FASEB J. 29, 2223‐2234 (2015). http://www.fasebj.org

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Residual viraemia does not influence 1 year virological rebound in HIV-infected patients with HIV RNA persistently below 50 copies/mL

Abstract: Residual viraemia assessed by kPCR was not associated with virological rebound during 1 year of follow-up. However, the patients attaining <1 HIV RNA copy/mL showed a small but statistically significant improvement in CD4+ cell recovery.

Cited by 27 publications

References 7 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

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project

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