Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 ...weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing.
ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing.
Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34–50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI −0·6–2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred.
The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1.
ViiV Healthcare and Janssen.
Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated ...with virologic failure at Week 48 were evaluated post hoc . Design and methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination. Results: Overall, 1.25% ( n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated ( P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35). Conclusion: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m 2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.
Objectives
Physicians could request compassionate use of oral and long‐acting (LA) cabotegravir + rilpivirine for people living with HIV‐1 under a single‐patient request programme supported by ViiV ...Healthcare and Janssen. Outcomes are reported.
Methods
Eligibility criteria included need for parenteral therapy, no primary resistance mutations to cabotegravir or rilpivirine, and established retention in care. Demographic, efficacy, and safety data were obtained from standardized programme applications and quarterly clinical updates. Individuals received a loading dose of LA cabotegravir 600 mg + rilpivirine 900 mg, followed by LA maintenance doses of 400 mg/600 mg every 4 weeks; some received lead‐in oral cabotegravir and rilpivirine.
Results
Through July 2020, 35 people living with HIV‐1 had data available. The most frequent reason for compassionate use request was chronic non‐adherence due to psychological conditions (n = 15). Of 35 people living with HIV‐1, 28 had detectable viremia (median viral load 60 300 copies/mL) and seven were virologically suppressed at programme entry; 16/28 and 6/7 achieved or maintained virological suppression at data cutoff, respectively. Seven people living with HIV‐1 discontinued for incomplete virological response, six with detectable viremia at initiation; six and four had new reverse transcriptase and integrase mutations at discontinuation, respectively. Six non‐fatal serious adverse events were reported, two considered possibly treatment related. Four deaths were reported; none were treatment related. One individual reported two pregnancies and continued LA dosing.
Conclusions
Most people living with HIV‐1 had advanced disease and achieved (16/28) or maintained (6/7) virological suppression with LA therapy. Cabotegravir LA + rilpivirine LA as compassionate use provided a valuable treatment option for individuals with adherence issues with oral therapy and advanced disease.
In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure ...to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number NCT01054573.).
OBJECTIVE:To compare the distribution of R5-like and X4-like HIV-1envelope sequences in plasma and peripheral blood mononuclear cell (PBMC).
METHODS:Clonal sequencing of the HIV-1 glycoprotein 120 ...region was performed on PBMC DNA and plasma RNA of 11 HIV-1 subtype B-infected patients with high probability of carrying X4 virus. Coreceptor use was predicted using the position-specific scoring matrix (PSSM).
RESULTS:A total of 330 and 427 clonal envelope sequences were obtained from PBMC and plasma, respectively. PSSM interpretation revealed the presence of a mixture of predicted X4 and R5 sequences in 10 patients and pure R5 sequences in 1. The X4 sequences were significantly more represented in PBMC (with an average of 52.2% of the clonal proviral sequences scored X4) compared with plasma (19.7% X4 sequences) (P < 0.0001). At the single patient level, the higher representation of X4 sequences in PBMC reached statistical significance (P < 0.002) in 6 individuals.
CONCLUSIONS:Mixtures of X4 and R5 sequences with highly divergent PSSM scores are present in both plasma and PBMC, but a shift toward a more abundant representation of X4-like PSSM scores in PBMC-derived DNA was apparent. Additional studies are needed to evaluate the clinical importance of these findings with regard to tropism prediction and the use of CCR5 anatagonists.
Background and aims
Direct‐acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection have resulted in high rates of sustained virologic response (SVR) following 8 to 24 weeks of treatment. ...However, difficult‐to‐cure/cirrhotic patients typically require a longer treatment duration and less is known regarding the long‐term durability of SVR or effect on liver disease progression; to assess this, the IMPACT study followed patients for a 3‐year period after end of treatment.
Methods
The Phase II, open‐label, nonrandomized IMPACT study assessed the efficacy, safety, and pharmacokinetics of the combination of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/4‐infected, treatment‐naïve/‐experienced cirrhotic patients with portal hypertension or decompensated liver disease. Patients from a single site in the United States were assigned to one of two groups by Child–Pugh (CP) score: CP A, CP score less than 7 and evidence of portal hypertension; CP B, CP score of 7 to 9. All patients received simeprevir 150 mg, daclatasvir 60 mg, and sofosbuvir 400 mg once‐daily for 12 weeks between September 2014 and August 2015. All 40 patients included in the study (male, 63%; median age, 58.5 years) achieved SVR 12 and 24 weeks after end of treatment, and the combination was well tolerated.
Results
All patients who reached the 3‐year follow‐up timepoint maintained SVR (CP A, 15/15; CP B, 18/18). CP scores and Model for End‐stage Liver Disease scores remained relatively stable, and mean FibroScan and FibroTest scores declined. No new safety signals were identified.
Conclusions
In the IMPACT study, virologic response to simeprevir, sofosbuvir, and daclatasvir was durable over 3 years (ClinicalTrials.gov number: NCT02262728).
The registrational phase III clinical trials of the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) rilpivirine (RPV) in combination with two nucleoside/nucleotide RT inhibitors (NRTIs) ...found a unique genotypic resistance pattern involving the NNRTI mutation E138K with the NRTI mutation M184I. Eighty percent of subjects used emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF); a single tablet regimen of FTC/RPV/TDF is in development.
HIV-1 with E138K and/or M184V or I mutations were constructed and phenotyped in MT-2 cells and the PhenoSense and Antivirogram assays. Viral fitness was determined using growth competitions. Molecular models of the mutants were constructed from the RT-RPV crystal structure.
The E138K mutant showed low-level reduced susceptibility to RPV (2.4-fold), but full susceptibility to FTC and tenofovir (TFV). Viruses with M184V or M184I showed high-level resistance to FTC and full susceptibility to RPV and TFV. Addition of M184I, but not M184V, to E138K, further decreased susceptibility to RPV and maintained FTC resistance. The E138K and M184V or I single and double mutants showed decreased replication fitness compared with wild type. M184V outcompeted M184I when compared directly and in the background of E138K. E138K + M184I was less fit than either E138K or M184I alone. Removing a salt bridge between E138/K101 is implicated in resistance to RPV.
The higher frequency of E138K and M184I among RPV + FTC/TDF virologic failures is due to reduced susceptibility of the single mutants to RPV and FTC and the enhanced resistance to RPV for the double mutant at the cost of decreased viral fitness.
Ultra-deep sequencing (UDS) of amplicons is a major application for next-generation sequencing tech nologies, even more so for the 454 Genome Sequencer FLX. Especially for this application, errors ...that might be introduced during any of the sample processing or data analysis steps should be avoided or at least recognized, as they might lead to aberrant sequence variant calling. Since 454 pyrosequencing relies on PCR-driven target amplification, it is key to differentiate errors introduced during the amplification step from genuine minority variants. Thereto, optimal primer design is imperative because primer selection, primer dimer formation, and nonspecific binding may all affect the quality and outcome of amplicon-based deep sequencing. Also, other intrinsic PCR characteristics including amplification drift and the formation of secondary structures may influence sequencing data quality. We illustrate these phenomena using real life case studies and propose experimental and analytical evidence-based solutions for effective practice. Furthermore, because accuracy of the DNA polymerase is vital for reliable UDS results, a comparative analysis of error profiles from seven different DNA polymerases was performed and experimentally as-sessed in parallel by 454 sequencing. Finally, intra and interrun variability evaluation of the 454 sequencing protocol revealed highly reproducible results in amplicon-based UDS.
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