Blip Frequency Research Articles

High efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in Black adults in the United States, including those with pre-existing HIV resistance and suboptimal adherence.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA<50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA<50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

Viral Blips Were Infrequent in HIV-1-Infected Virologically-Suppressed Adults Treated with Tenofovir Alafenamide or Tenofovir DF Rilpivirine-Containing Regimens

BackgroundDifferences between regimens in the frequency of transient episodes of viremia (viral blips) as well as the impact of these viral blips on the risk of virologic failure and resistance development is not fully understood. Here we investigate the frequency of viral blips in virologically-suppressed subjects switching to rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF) vs. maintaining R/F/tenofovir disoproxil fumarate (TDF) and the association of viral blips with clinical outcome through Week 48 of study GS-US-366-1216.MethodsGS-US-366-1216 is a randomized, double-blind, phase 3b study evaluating the safety and efficacy of switching to R/F/TAF from R/F/TDF in HIV-1-infected virologically-suppressed subjects. For the viral blip analysis, treated subjects with ≥1 post-baseline HIV-1 RNA value were included. All on-drug HIV-1 RNA data points and FDA snapshot outcome data through Week 48 were utilized. Plasma HIV-1 RNA was measured using the Roche Taqman 2.0 assay. A viral blip was defined as any post-baseline HIV-1 RNA value ≥50 c/mL preceded and followed by HIV-1 RNA <50 c/mL.ResultsOf the 627 subjects included in the analysis, 23 (3.7%) experienced ≥1 blip through Week 48 and were distributed similarly between treatment groups (10/315, 3.2% R/F/TAF; 13/312, 4.2% R/F/TDF; P = 0.53; median 6 viral load measurements per subject). Twenty subjects had single blips (8 R/F/TAF, 12 R/F/TDF) and 3 subjects experienced 2 blips each (2 R/F/TAF, 1 R/F/TDF). Of 26 total blip events, 19 (73%) were low-level at 50–199 c/mL. Among subjects with blips, 22/23 (96%) were virologic successes at Week 48 (9/10, 90% R/F/TAF; 13/13, 100% R/F/TDF), similar to those subjects without blips (568/604, 94% overall; 287/305, 94% R/F/TAF; 281/299, 94% R/F/TDF). One subject in the R/F/TAF group had 2 blips prior to experiencing virologic rebound with mutations also detected at baseline (determined by retrospective proviral DNA sequencing).ConclusionViral blips were infrequent among subjects switching to R/F/TAF or maintaining R/F/TDF through Week 48 of study GS-US-366-1216. No differences in blip frequency or virologic failure post-blip were observed between treatment groups. Most blips were low-level (<200 c/mL) and most subjects with blips remained suppressed through Week 48.Disclosures D. A. Wohl, Gilead Sciences Inc.: Consultant and Investigator, Consulting fee and Research grant; ViiV: Consultant and Investigator, Consulting fee and Research grant; Janssen: Consultant, Consulting fee; Bristol Myers Squibb: Consultant, Consulting fee; R. Kulkarni, Gilead Sciences, Inc.: Employee and Shareholder, Salary; W. Garner, Gilead Sciences, Inc.: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary; D. Porter, Gilead Sciences, Inc.: Employee and Shareholder, Salary

Virological Blips and Predictors of Post Treatment Viral Control After Stopping ART Started in Primary HIV Infection.

Background:Few individuals commencing antiretroviral therapy (ART) in primary HIV infection (PHI) maintain undetectable viremia after treatment cessation. Associated factors remain unclear given the importance of the phenomenon to cure research.Methods:Using CASCADE data of seroconverters starting ART in PHI (≤6 months from seroconversion), we estimated proportions experiencing viral blips (>400 copies followed by <400 copies HIV-RNA/mL without alteration of regimen) while on ART. We used Cox models to examine the association between time from ART stop to loss of control (2 consecutive measurements >1000 copies per milliliter) and magnitude and frequency of blips while on ART, time from seroconversion to ART, time on ART, adjusting for mean number of HIV-RNA measurements/year while on ART, and other confounders.Results:Seven hundred seventy-eight seroconverters started ART in PHI with ≥3 HIV-RNA measurements. Median interquartile range (IQR) ART duration was 16.2 (8.0–35.9) months, within which we observed 13% with ≥1 blip. Of 228 who stopped ART, 119 rebounded; time to loss of control was associated with longer interval between seroconversion and ART initiation [hazard ratio (HR) = 1.16 per month; 1.04, 1.28], and blips while on ART (HR = 1.71 per blip; 95% confidence interval = 0.94 to 3.10). Longer time on ART (HR = 0.84 per additional month; 0.76, 0.92) was associated with lower risk of losing control. Of 228 stopping ART, 22 (10%) maintained post treatment control (PTC), ie, HIV-RNA <50 copies per milliliter ≥24 months after ART cessation.Conclusion:HIV viral blips on therapy are associated with subsequent viral rebound on stopping ART among individuals treated in PHI. Longer duration on ART is associated with a greater chance of PTC.

Suppressing effect of Ca^{2+} blips on puff amplitudes by inhibiting channels to prevent recovery.

As local signals, calcium puffs arise from the concerted opening of a few nearby inositol 1,4,5-trisphospate receptor channels to release Ca^{2+} ions from the endoplasmic reticulum. Although Ca^{2+} puffs have been well studied, little is known about the modulation of cytosolic basal Ca^{2+} concentration ([Ca^{2+}]_{Basal}) on puff dynamics. In this paper we consider a puff model to study how the statistical properties of puffs are modulated by [Ca^{2+}]_{Basal}. The puff frequency and lifetime trivially increase with the increasing [Ca^{2+}]_{Basal}, but an unexpected result is that the puff amplitude and the maximum open-channel number of the puff show decreasing relationship with the increasing [Ca^{2+}]_{Basal}. The underlying dynamics is related not only to the increasing puff frequency which gives a shorter recovery time, but also to the increasing frequency of blips with only one channel open. We indicate that Ca^{2+} blips cause the channels to be inhibited and prevent their recovery during interpuff intervals, resulting in the suppressing effect on puff amplitudes. With increasing [Ca^{2+}]_{Basal}, more blips occur to cause more channels to be inhibited, leaving fewer channels available for puff events. This study shows that the blips may play relevant functions in global Ca^{2+} waves through modulating puff dynamics.

Intermittent viraemia and immune reconstitution in patients with more than 10-15 years of antiretroviral therapy: baseline values still matter.

IntroductionData on patients with long-term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T-cell nadir or pre-treatment viraemia do have an impact on ART success after more than a decade of treatment.MethodsELBE is a cross-sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub-analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia (50–1000 copies/mL, defined as “blips”) during the last five years.ResultsFrom a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one “blip” while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre-treatment viraemia compared to patients without blips (5.30 versus 5.06 log copies/mL, p=0.0003). In patients with a pre-treatment viraemia of more than 100,000, 50,000–100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS-defining illness or the CD4 T-cell nadir was not associated with a higher frequency of blips. However, CD4 T-cell nadir was a strong predictor for current CD4 T-cell counts. In patient groups with a CD4 T-cell nadir of 0–99, 100–199, 200–349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268).ConclusionsIn this large group of positively selected HIV+ patients with long-term exposure to ART of at least 10–15 years, high pre-treatment viraemia was still associated with a higher frequency of intermittent transient viraemia (“blip”). A low CD4 T-cell nadir remained associated with a lower CD4 cell recovery. The clinical implications of these findings remain to be evaluated.

Frequency and Relative Prevalence of Calcium Blips and Puffs in a Model of Small IP3R Clusters

In this work, we model the local calcium release from clusters with a few inositol 1,4,5-trisphosphate receptor (IP3R) channels, focusing on the stochastic process in which an open channel either triggers other channels to open (as a puff) or fails to cause any channel to open (as a blip). We show that there are linear relations for the interevent interval (including blips and puffs) and the first event latency against the inverse cluster size. However, nonlinearity is found for the interpuff interval and the first puff latency against the inverse cluster size. Furthermore, the simulations indicate that the blip fraction among all release events and the blip frequency are increasing with larger basal [Ca2+], with blips in turn giving a growing contribution to basal [Ca2+]. This result suggests that blips are not just lapses to trigger puffs, but they may also possess a biological function to contribute to the initiation of calcium waves by a preceding increase of basal [Ca2+] in cells that have small IP3R clusters.

The amplitudes of viral blips in HIV-1 infected patients treated with antiretroviral therapy are power-law distributed

We previously reported that in patients treated with highly active antiretroviral therapy (HAART) who achieve viral load (VL) suppression, low fluctuations of viral load over the threshold of detection (viral blips) more than 4 weeks apart occur at random, with a frequency that does not change with longer times of observation. The etiology of viral blips is currently unknown, but viral blip frequency inversely correlates with the decay of the latent reservoir, whose stability has been proposed as the major hurdle to HIV eradication. We show here that the distribution of viral blip amplitudes observed in a group of 272 patients successfully treated with highly active antiretroviral therapy appears to be power-law distributed. Such a distribution can be theoretically generated by randomly sampling the arrival of asynchronous and overlapping elementary pulses of viremia, with asymptotic exponential decay of kinetics, thus suggesting that the low fluctuations of viremia observed in patients during HAART treatment is, in part, a discrete phenomenon consistent with random activation of latently infected cells or release of virus and infected cells into the blood compartment from unknown sites of active viral replication.

Intermittent HIV-1 Viremia (Blips) and Drug Resistance in Patients Receiving HAART

Many patients infected with human immunodeficiency virus type 1 (HIV-1) and receiving highly active antiretroviral therapy experience intermittent episodes of detectable viremia ("blips"), which may raise concerns about drug resistance, lead to costly repeat measurements of viral RNA, and sometimes trigger alterations in therapy. To test the hypothesis that blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia. Between June 19, 2003, and February 9, 2004, patients receiving therapy underwent intensive sampling (every 2-3 days) over 3 to 4 months to define the frequency, magnitude, and duration of blips and their association with drug levels and other clinical variables. Blips were defined as HIV-1 RNA measurements greater than or equal to 50 copies/mL preceded and followed by measurements less than 50 copies/mL without a change in treatment. To determine whether blips result from or lead to drug resistance, an ultrasensitive genotyping assay was used to detect drug resistance mutations before, during, and after blips. Patients were 10 HIV-1-infected asymptomatic adults recruited by clinicians and followed up in the Moore Clinic at the Johns Hopkins Hospital. Patients had suppression of viremia to below 50 copies/mL while receiving a stable antiretroviral regimen for 6 months or longer. At each time point, plasma HIV-1 RNA levels were measured in 2 independent laboratories and drug resistance mutations were analyzed by clonal sequencing. With the intensive sampling, blips were detected in 9 of 10 patients. Statistical analysis was consistent with random assay variation around a mean viral load below 50 copies/mL. Blips were not concordant on independent testing and had a short duration (median, <3 days) and low magnitude (median, 79 copies/mL). Blip frequency was not associated with demographic, clinical, or treatment variables. Blips did not occur in relation to illness, vaccination, or directly measured antiretroviral drug concentrations. Blips were marginally associated (P = .08) with reported episodes of nonadherence. Most importantly, in approximately 1000 independent clones sequenced for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or shortly after blips. Most blips in this population appear to represent random biological and statistical variation around mean HIV-1 levels below 50 copies/mL rather than clinically significant elevations in viremia.

Viral blip dynamics during highly active antiretroviral therapy.

Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e., plasma VL measurements of >50 copies/ml, in 123 HAART-treated patients monitored for a mean of 2.6 years (range, 5 months to 5.3 years). The mean (+/- the standard deviation) blip frequency was 0.09 +/- 0.11/sample, with about one-third of patients showing no viral blips. The mean viral blip amplitude was 158 +/- 132 human immunodeficiency virus type 1 (HIV-1) RNA copies/ml. Analysis of the blip frequency and amplitude distributions suggest that two blips less than 22 days apart have a significant chance of being part of the same episode of viremia. The data are consistent with a hypothetical model in which each episode of viremia consists of a phase of VL rise, followed by two-phase exponential decay. Thus, the term "viral blip" may be a misnomer, since viral replication appears to be occurring over an extended period. Neither the frequency nor the amplitude of viral blips increases with longer periods of observation, but the frequency is inversely correlated with the CD4(+)-T-cell count at the start of therapy, suggesting that host-specific factors but not treatment fatigue are determinants of blip frequency.