Rate and Determinants of Residual Viremia in Multidrug-Experienced Patients Successfully Treated with Raltegravir-Based Regimens

Abstract

Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.

Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment

“…Because residual HIV in individuals on effective suppressive ART shows only limited genetic diversification over-time, with no new appearance of ART resistance mutations (Bailey et al , 2006; Wong et al , 1997), it is unlikely that this virus arises from active virus replication in an unidentified tissue. In some studies, however, residual viremia can be reduced (but not eliminated) upon intensification of treatment (Baroncelli et al , 2015). Together these considerations suggest that other persistently-infected cells, in addition to memory T cells, contribute to stable residual viremia and chronic inflammatory diseases in patients on effective ART.…”

HIV‐1 DNA dynamics and variations in HIV‐1 DNA protease and reverse transcriptase sequences in multidrug‐resistant patients during successful raltegravir‐based therapy

“…An ultrasensitive method based on a modified real time PCR assay (VERSANT® HIV‐1 RNA 1.0 kPCR, Siemens Healthcare Diagnostics, Berkeley, CA), was used. The modified method had a detection limit of 2.5 HIV‐1 RNA copies/ml [Baroncelli et al, ]. Analysis were performed after 12 and 24 months from the beginning of the RAL‐based regimen.…”

Different Pathways Leading to Integrase Inhibitors Resistance

“…Despite their great efficiency to inhibit the integration step, INSTIs are unable to impair the late stages of the viral replication cycle, and thus they can’t prevent new infections. Clinical studies have not only shown that low-level viremia can persist in patients with undetectable plasma HIV RNA (Maldarelli et al, 2007) including patients treated with RAL-based regimens (Baroncelli et al, 2015), but also that RAL intensification is unable to suppress this persistent residual viremia and is associated with an increase in circular uDNA (Dinoso et al, 2009; Buzon et al, 2010b; Gandhi et al, 2010; McMahon et al, 2010; Hatano et al, 2011; Vallejo et al, 2012). An evolution of HIV-1 envelope sequences despite potent antiviral therapy has previously been shown (Gunthard et al, 1999; Martinez et al, 1999) with the emergence of a NRTI resistance mutation (Martinez et al, 1999).…”