scholarly journals Impact of HIV subtype on response and resistance in antiretroviral-naïve adults comparing treatment with once daily versus twice daily ritonavir boosted fosamprenavir in combination with Abacavir/Lamivudine

2011 ◽  
Vol 2 (1) ◽  
pp. 1
Author(s):  
Lisa L. Ross ◽  
Marjorie D. Robinson ◽  
Giampiero Carosi ◽  
Adriano Lazzarin ◽  
Hans-Juergen Stellbrink ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Resistance Mutation ◽  
Virologic Response ◽  
Fixed Dose ◽  
Combination Tablet ◽  
Once Daily ◽  
Hiv Rna ◽  
Subtype B ◽  
The Impact ◽  
Hiv 1

The impact of HIV-1 subtype on resistance mutation selection and on virologic response to fosamprenavir in combination with once-daily (QD) versus twice-daily (BID) dosing of ritonavir was examined in a prospective, open label, randomized study in antiretroviral-naïve, HIV-1 infected subjects. We studied APV109141 compared QD fosamprenavir/ritonavir (1400mg/100mg) to BID fosamprenavir/ritonavir (700mg/100mg), administered in combination with a QD fixed-dose abacavir/lamivudine (600 mg/300 mg) combination tablet through 48 weeks in ART-naïve subjects. HIV genotypes were obtained from all subjects at screen. Subjects with virologic failure (VF) were also genotyped at baseline and VF. HIV subtypes observed in the ITT (n=214) population were A or AE or AG circulating recombinant forms (CRFs) 19%; B 62%; BF or BG CRFs 2%; C or CPX CRFs 7%; D 2%; F1 7%; G <1%. By TLOVR (ITT-exposed), 86/106 (81%) of subjects on QD study arm and 87/106 (82%) in the BID arm achieved plasma HIV-RNA<400 copies/mL at Week 48. Three subjects met VF criteria, 2 receiving QD fosamprenavir/ritonavir; 1 receiving BID fosamprenavir/ritonavir; (HIV subtype B, F1 A1, respectively). Baseline drug resistance was detected in 2/3 VFs: Subject 1-RT: K103K/N, T215C; major PI: V82A, L90M; and Subject 2-RT: M41L, L74V. Only virus from one subject with VF selected for any treatment-emergent mutation (Subject 1; M184V). Post-VF, Subject 3 (subtypeA1) suppressed HIV-RNA >400 copies/mL through 48 weeks. Subtype appeared to have no preferential impact on virologic response or selection for specific resistance mutations in subjects receiving fosamprenavir/ritonavir. Virologic failure rate was rare (3 subjects; each from different subtypes). At VF, virus from only one subject selected any HIV NRTI mutation (M184V); none selected major protease mutations.

scholarly journals 936. Evaluating the Impact of Polypharmacy on Virologic Success in People with HIV

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S501-S502
Author(s):  
Humberto R Jimenez ◽  
Naana Boachie ◽  
Sangwon Park ◽  
Jin Suh
Keyword(s):  
Hiv Transmission ◽  
Virologic Failure ◽  
Descriptive Analysis ◽  
Virologic Response ◽  
Transmission Risk ◽  
Pill Burden ◽  
Cross Sectional ◽  
Hiv Rna ◽  
Aids Diagnosis ◽  
The Impact

Abstract Background As people with HIV (PWH) have experienced reductions in antiretroviral pill burden, there has been an increase in medications to manage non-AIDS-related co-morbidities. Previous studies have linked virologic failure to an increased pill burden. This study assessed whether polypharmacy and other variables affect success of HIV management in our population. Methods A retrospective, cross-sectional analysis of PWH receiving care at a Ryan White-funded clinic in New Jersey was performed. Eligible patients were ≥18 years old, had ≥2 visits in 2019 and were receiving antiretroviral therapy (ART). The primary endpoints were to determine the effect polypharmacy (defined as 5 or more non-ART pills per day) on virologic response rates (HIV RNA < 200 copies/mL). Secondary endpoints accounted for the impact of age, gender, race/ethnicity, HIV transmission risk factor, and AIDS diagnosis on virologic response. A descriptive analysis of comorbidities and medication classes was also completed. Logistic regression, chi square and student’s t test were used for statistical analysis. Results 964 patients were included in the analysis, with 355 (37%) meeting the criteria for polypharmacy. Most patients were male (60%) and the mean age was 49 years of age. The racial/ethnic breakdown was 46% Hispanic, 45% Black and 8% White. Polypharmacy was associated with higher rates of virologic success compared to those with a lower pill burden: 94% vs 86% had an HIV RNA < 200 copies/mL (P=0.0003), respectively. ART pill burden was statistically, but not clinically higher among those with polypharmacy (1.34 vs 1.45, P=0.025). Virologic response was found to be higher among Hispanics and Whites in comparison to Black patients (OR 2.2, CI 1.4-3.5 and 3.0, CI 1.1-8.2). Patients with an AIDS diagnosis were less likely to achieve virologic response (OR 0.64, CI 0.42-0.99). Conclusion Patients with polypharmacy were more likely to achieve virologic success than paitents with a low pill burden in our population. Disclosures Humberto R. Jimenez, PharmD, BCPS, AAHIVP, Gilead (Speaker’s Bureau)

scholarly journals Integrated Resistance Analysis of CERTAIN-1 and CERTAIN-2 Studies in Hepatitis C Virus-Infected Patients Receiving Glecaprevir and Pibrentasvir in Japan

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Preethi Krishnan ◽  
Gretja Schnell ◽  
Rakesh Tripathi ◽  
Jill Beyer ◽  
Thomas Reisch ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virologic Failure ◽  
Virologic Response ◽  
Fixed Dose ◽  
Resistance Testing ◽  
Combination Regimen ◽  
Resistance Analysis ◽  
Number Of Patients ◽  
The Impact

ABSTRACT Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high sustained virologic response 12 weeks postdosing (SVR12) rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure rate (1.2%). There were no virologic failures among direct-acting antiviral (DAA)-treatment-naive genotype 1a (GT1a) (n = 4)-, GT1b (n = 128)-, and GT2 (n = 97)-infected noncirrhotic patients treated for 8 weeks or among GT1b (n = 38)- or GT2 (n = 20)-infected patients with compensated cirrhosis treated for 12 weeks. Two of 33 DAA-experienced and 2 of 12 GT3-infected patients treated for 12 weeks experienced virologic failure. Pooled resistance analysis, grouped by HCV subtype, treatment duration, prior treatment experience, and cirrhosis status, was conducted. Among DAA-naive GT1b-infected patients, the baseline prevalence of NS3-D168E was 1.2%, that of NS5A-L31M was 3.6%, and that of NS5A-Y93H was 17.6%. Baseline polymorphisms in NS3 or NS5A were less prevalent in GT2, with the exception of the common L/M31 polymorphism in NS5A. Among DAA-experienced GT1b-infected patients (30/32 daclatasvir plus asunaprevir-experienced patients), the baseline prevalence of NS3-D168E/T/V was 48.4%, that of NS5A-L31F/I/M/V was 81.3%, that of the NS5A P32deletion was 6.3%, and that of NS5A-Y93H was 59.4%. Common baseline polymorphisms in NS3 and/or NS5A had no impact on treatment outcomes in GT1- and GT2-infected patients; the impact on GT3-infected patients could not be assessed due to the enrollment of patients infected with diverse subtypes and the limited number of patients. The glecaprevir-pibrentasvir combination regimen allows a simplified treatment option without the need for HCV subtyping or baseline resistance testing for DAA-naive GT1- or GT2-infected patients. (The CERTAIN-1 and CERTAIN-2 studies have been registered at ClinicalTrials.gov under identifiers NCT02707952 and NCT02723084, respectively.)

scholarly journals Pharmacotherapy of HIV: A Focus on Atazanavir/Ritonavir a Potent and Convenient Once Daily Ritonavir Boosted Protease-Inhibitor for HIV-1 Infected Adults

2009 ◽  
Vol 1 ◽  
pp. CMT.S1088
Author(s):  
Clotilde Allavena ◽  
Stéphanie Trancart ◽  
Lise Cuzin
Keyword(s):  
Protease Inhibitor ◽  
Virologic Failure ◽  
High Viral Load ◽  
Virologic Response ◽  
Important Place ◽  
Once Daily ◽  
Unconjugated Hyperbilirubinemia ◽  
Gastrointestinal Tolerability ◽  
Hiv 1 ◽  
Better Than

Atazanavir is the first azapeptide protease inhibitor. As a consequence of metabolism by the Cytochrome P450 system and excretion by drug-transporters such as P-Glycoprotein, drug interactions are considerable. They can be used to improve efficacy (ritonavir boosting) but may also cause adverse effects. Efficacy of ATV/RTV has been shown to be comparable to lopinavir/ritonavir in antiretroviral naïve patients, providing even better results in patients with high viral load. Efficacy has also been demonstrated in maintenance therapy in antiretroviral-experienced patients, and in patients with previous virologic failure, providing the best virologic response when the virus harbors less than four resistance PI mutations. The gastrointestinal tolerability and the lipid profile are better than with other PIs. The major side effect is a jaundice caused by unconjugated hyperbilirubinemia that rarely leads to discontinuation. ATV/RTV simple administration as well as tolerability may be linked with better treatment adherence. ATV/RTV is simple, potent and well tolerated. Thus it takes an important place in the treatment of HIV-infected patients, preferentially in antiretroviral-naïve or moderately pretreated populations.

scholarly journals Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Ka Lai Yee ◽  
Aziz Ouerdani ◽  
Anetta Claussen ◽  
Rik de Greef ◽  
Larissa Wenning
Keyword(s):  
Virologic Failure ◽  
Phase 1 ◽  
Fixed Dose ◽  
Response Analysis ◽  
Population Pharmacokinetic ◽  
Phase 3 ◽  
Once Daily ◽  
Intrinsic Factors ◽  
Exposure Response ◽  
Hiv 1

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

scholarly journals Impact of HIV-1 CRF55_01B infection on the evolution of CD4 count and plasma HIV RNA load in men who have sex with men prior to antiretroviral therapy

2021 ◽  
Author(s):  
Lan Wei ◽  
Hao Li ◽  
Xing Lv ◽  
Chenli Zheng ◽  
Guilian Li ◽  
...  
Keyword(s):  
Viral Load ◽  
Antiretroviral Therapy ◽  
Cd4 Count ◽  
Transmission Risk ◽  
Mixed Effect ◽  
Cd4 Cell Count ◽  
Hiv Rna ◽  
Subtype B ◽  
The Impact ◽  
Hiv 1

Abstract Background CRF55_01B is a newly identified HIV-1 circulating recombinant form originated from MSM in China. However, its impact on the disease progression and transmission risk has not been investigated. This study aimed to determine the impact of CRF55_01B infection on viral dynamics and immunological status, so as to provide implications for future prevention, treatment, or target interventions. Linear mixed effect models were applied to evaluate CD4 cell count decline and viral load increase by subtype.Results Of the 3418 blood samples, 1446 (42.3%) were CRF07_BC, 1169 (34.2%) CRF01_AE, 467 (13.7%) CRF55_01B, 249 (7.3%) type B, and 87 (2.5%) other subtypes (CRF_08BC, CRF_01B, C). CRF55_01B had replaced subtype B as the third predominant strain since 2012 in Shenzhen, China. CRF55_01B-infected MSM showed lower median of CD4 count than CRF07_BC-infected MSM (349.5 [IQR, 250.2~474.8] vs 370.0 [IQR, 278.0~501.0], P<0.05). CRF55_01B infection was associated with slower loss of CD4 count than CRF01_AE (13.6 vs 23.3 [cells/μL]¹/²/year, P<0.05)among MSM with initial CD4 count of 200~350 cells/μL. On the other hand, those infected with CRF55_01B showed higher median plasma HIV RNA load (5.4 [IQR, 5.0~5.9]) than both CRF01_AE (5.3 [IQR, 4.8~5.7], P<0.05) and CRF07_BC (5.0 log10 [IQR, 4.5~5.5], P<0.001) at the initiation of antiretroviral therapy. Furthermore, the annual increasing rate of viral load for CRF55_01B infection was significantly higher than that of CRF07_BC (2.0 vs 0.7 log10 copies/ml/year, P<0.01).Conclusions The relatively lower CD4 count and faster increase of plasma HIV RNA load of CRF55_01B-infected MSM without antiretroviral therapy suggest that CRF55_01B may lead to longer asymptomatic phase and higher risk of HIV transmission. Strengthened surveillance, tailored prevention strategies and interventions, and in-depth research focusing on CRF55_01B are urgently needed to forestall potential epidemic.

scholarly journals Impact of Integrase Sequences From HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine

2022 ◽  
Author(s):  
Jerry L. Jeffrey ◽  
Marty St. Clair ◽  
Ping Wang ◽  
Chunfu Wang ◽  
Zhufang Li ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Fold Change ◽  
Effective Capacity ◽  
Virologic Suppression ◽  
Subtype B ◽  
Long Acting ◽  
Breakthrough Experiments ◽  
The Impact ◽  
Hiv 1

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine vs daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

scholarly journals HIV Viral Rebound Due to a Possible Drug–Drug Interaction between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Calcium-Containing Products: Report of 2 Cases

2019 ◽  
Vol 18 ◽  
pp. 232595821882165 ◽  
Author(s):  
S. Lena Kang-Birken ◽  
Dena El-sayed ◽  
John Prichard
Keyword(s):  
Drug Interaction ◽  
Calcium Salt ◽  
Fixed Dose ◽  
Viral Rebound ◽  
Once Daily ◽  
Hiv Rna ◽  
Drug Drug Interaction ◽  
Tenofovir Alafenamide ◽  
Hiv 1 ◽  
Rapid Emergence

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a potent fixed-dose, once-daily regimen for HIV-1 treatment and has rare emergence of drug resistance. We report a potential drug–drug interaction in 2 female patients both receiving treatment for HIV and cerebral toxoplasmosis: one case between E/C/F/TAF with calcium carbonate and a second case involving leucovorin as calcium salt. Both cases resulted in rise in HIV RNA levels and emergence of M184 V mutation and resistance to elvitegravir and raltegravir. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation from coadministration of E/C/F/TAF and calcium.

HIV-1 Subtype B/B′ and Baseline Drug Resistance Mutation Are Associated With Virologic Failure

2015 ◽  
Vol 68 (3) ◽  
pp. 289-297 ◽  
Author(s):  
Yijia Li ◽  
Lijun Gu ◽  
Yang Han ◽  
Jing Xie ◽  
Huanling Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virologic Failure ◽  
Resistance Mutation ◽  
Drug Resistance Mutation ◽  
Subtype B ◽  
Hiv 1

scholarly journals 2508. Virologic Suppression in Patients Switched to BIC/TAF/FTC with Baseline NRTI and/or INSTI Resistance

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S870-S870
Author(s):  
Kayla M Natali ◽  
Rahul Tilani ◽  
Jihad Slim
Keyword(s):  
Second Generation ◽  
Virologic Response ◽  
Cd4 Count ◽  
Fixed Dose ◽  
Virologic Suppression ◽  
Combination Tablet ◽  
Hiv Rna ◽  
Dose Combination ◽  
The Mean ◽  
M184v Mutation

Abstract Background BIC/TAF/FTC is the first fixed-dose combination tablet to contain both a second-generation INSTI and TAF and has therefore become a popular treatment option for HIV. Historically, patients with NRTI mutations were placed on four-drug, NRTI-retaining regimens or two-drug, NRTI-sparing regimens. Recently, data have emerged supporting the use of second-generation INSTIs with tenofovir/FTC in the setting of the M184V mutation alone. There is a paucity of data, however, evaluating the use of BIC/TAF/FTC in the setting of NRTI and/or INSTI mutations. This study assessed the role of BIC/TAF/FTC in patients with baseline NRTI and/or INSTI mutations. Methods This was an observational retrospective study conducted at an inner city HIV clinic. Patients were eligible if they were switched to BIC/TAF/FTC with confirmed adherence and had either the M184V mutation alone, M184V plus another NRTI mutation(s), an INSTI mutation alone, or both NRTI and INSTI mutation(s) at the time of ART switch. We evaluated virologic response (HIV RNA < 200 copies/mL) and duration of BIC/TAF/FTC therapy. Results There were 16 patients eligible for analysis. Among the patients, 69% were male and 31% were female. The majority of patients were Black (81%). The mean age was 63 years (SD ± 8.6). Thirteen patients were virologically suppressed (HIV RNA < 200 copies/mL) at baseline. The mean CD4 count at baseline was 630.4 cells/mm3 (SD ± 297.1). Mutations at baseline were as follows: M184V alone (25%), M184V plus another NRTI mutation(s) (56.25%), INSTI mutation alone (12.5%), NRTI and INSTI mutation(s) (6.25%). BIC/TAF/FTC mean duration of therapy was 10.5 months (range 6–14 months). The mean CD4 count of the patients switched to BIC/TAF/FTC was 687 cells/mm3 (SD ± 20.7). All patients switched to BIC/TAF/FTC achieved or maintained virologic suppression (HIV RNA < 200 copies/mL) with a mean HIV RNA of 26.25 copies/mL (SD ± 14.1). Fifteen of those switched to BIC/TAF/FTC had an undetectable HIV RNA level (HIV RNA < 50 copies/mL). Conclusion While a larger cohort and longer follow-up period is needed, BIC/TAF/FTC may maintain virologic suppression in patients with select baseline NRTI and/or INSTI mutations. Disclosures All authors: No reported disclosures.

scholarly journals Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Rashmi Mehta ◽  
Allen Wolstenholme ◽  
Kristin Di Lullo ◽  
Caifeng Fu ◽  
Shashidhar Joshi ◽  
...  
Keyword(s):  
Statistical Power ◽  
Drug Regimen ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Combination Tablet ◽  
Reference Treatment ◽  
Dose Combination ◽  
Hiv 1 ◽  
Test Treatment ◽  
Separate Tablets

ABSTRACTA complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review ofCmaxvariability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, andCmax(test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n= 5) and 3% (n= 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.)

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