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 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 Simplification Therapy with Once‐Daily Emtricitabine, Didanosine, and Efavirenz in HIV‐1–Infected Adults with Viral Suppression Receiving a Protease Inhibitor–Based Regimen: A Randomized Trial

2005 ◽  
Vol 191 (6) ◽  
pp. 830-839 ◽  
Author(s):  
Jean‐Michel Molina ◽  
Valérie Journot ◽  
Laurence Morand‐Joubert ◽  
Patrick Yéni ◽  
Willy Rozenbaum ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Randomized Trial ◽  
Viral Suppression ◽  
Once Daily ◽  
Hiv 1

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 Protease Inhibitor Resistance Is Uncommon in HIV-1 Subtype C Infected Patients on Failing Second-Line Lopinavir/r-Containing Antiretroviral Therapy in South Africa

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Carole L. Wallis ◽  
John W. Mellors ◽  
Willem D. F. Venter ◽  
Ian Sanne ◽  
Wendy Stevens
Keyword(s):  
South Africa ◽  
Drug Resistance ◽  
Protease Inhibitor ◽  
Virologic Failure ◽  
Second Line ◽  
Resistance Mutations ◽  
Subtype C ◽  
Resistance Patterns ◽  
Main Barrier ◽  
Hiv 1

Limited data exist on HIV-1 drug resistance patterns in South Africa following second-line protease-inhibitor containing regimen failure. This study examined drug resistance patterns emerging in 75 HIV-1 infected adults experiencing virologic failure on a second-line regimen containing 2 NRTI and lopinavir/ritonavir. Ninety six percent of patients (n=72) were infected with HIV-1 subtype C, two patients were infected with HIV-1 subtype D and one with HIV-1 subtype A1. Thirty nine percent (n=29) of patients had no resistance mutations in protease or reverse transcriptase suggesting that medication non-adherence was a major factor contributing to failure. Major lopinavir resistance mutations were infrequent (5 of 75; 7%), indicating that drug resistance is not the main barrier to future viral suppression.

scholarly journals Enhanced Secretory Leukocyte Protease Inhibitor in Human Immunodeficiency Virus Type 1-Infected Patients

1999 ◽  
Vol 6 (6) ◽  
pp. 808-811 ◽  
Author(s):  
A. A. M. A. Baqui ◽  
Timothy F. Meiller ◽  
William A. Falkler
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
High Viral Load ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Secretory leukocyte protease inhibitor (SLPI) has been found to possess activity against the human immunodeficiency virus type 1 (HIV-1) in vitro at physiological concentrations. A study was undertaken to evaluate SLPI levels in human saliva and plasma among HIV-positive (HIV+) patients with various HIV-1 viral loads in comparison to uninfected controls. Whole blood in EDTA and unstimulated saliva samples were collected from 37 HIV+patients, of whom 20 had a history of intravenous drug abuse (IVDA). Control samples were collected from 20 appropriate age- and sex-matched HIV-1-negative individuals. SLPI was estimated from both saliva and serum samples by an enzyme-linked immunosorbent assay. HIV viral load was determined using a quantitative reverse transcription-PCR. SLPI levels were increased 16.7% in plasma and 10.3% in saliva among HIV+ patients in comparison to uninfected controls. SLPI levels were increased 5.9% in saliva and 3.9% in plasma among HIV+ patients with a high viral load (>10,000 copies/ml) as compared to patients with a low viral load (<400 copies/ml). Only 23% of patients with a high viral load used combination therapy with protease inhibitor drugs, whereas 92.9% of HIV+ patients with a low viral load used protease inhibitors. SLPI levels did not differ significantly among the IVDA patients, patients with different viral loads, or patients using protease inhibitor drugs. There was a statistically significant increase in SLPI levels in saliva among HIV patients in comparison to non-HIV-infected controls. An increase in SLPI levels among HIV+ patients may be a natural consequence of HIV pathogenesis and an important factor in preventing oral transmission of HIV, but this increase may not be evident during plasma viremia in patients with a high viral load.

scholarly journals Incidence of CXCR4 tropism and CCR5-tropic resistance in treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1 and 2 trials

2019 ◽  
Vol 27 ◽  
pp. 204020661989570
Author(s):  
Becky Jubb ◽  
Marilyn Lewis ◽  
Lynn McFadyen ◽  
Paul Simpson ◽  
Julie Mori ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Demographic Data ◽  
Virologic Response ◽  
Viral Escape ◽  
Background Therapy ◽  
Resistance Rates ◽  
Post Hoc ◽  
Hiv 1 ◽  
Selection Of ◽  
Baseline Demographic

Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials. Resistance was assessed relative to number of active drugs in participants’ optimized background therapy, pharmacokinetic adherence markers, Baseline demographic data, HIV-1 RNA and CD4+ counts. For participants with R5 virus confirmed ( post hoc) at Screening, Baseline genotypic weighted optimized background therapy susceptibility scores (gwOBTSS) were assigned where possible. Through Week 48, 219/392 (56%) participants with an assigned gwOBTSS achieved a virologic response. Of those remaining, 48/392 (12%) had CXCR4-using virus; 58/392 (15%) had R5 virus (maraviroc sensitive: n = 35/392, 9%; maraviroc resistant: n = 18/392, 5%; undeterminable: n = 5/392, 1%) and 67/392 (17%) had no failure tropism result. When optimized background therapy provided limited support to maraviroc (gwOBTSS <2), 143/286 (50%) responded to therapy, while 76/106 (72%) participants with gwOBTSS ≥2 responded ( p < 0.001). Resistance rates were highest for participants with gwOBTSS <2, accounting for 45/48 (94%) of total CXCR4-using emergence and 18/18 (100%) of total CCR5-tropic resistance. R5 viruses from participants with gwOBTSS ≥2 ( n = 10) were exclusively maraviroc sensitive; five of these participants had pharmacokinetic and/or pill-count markers of non-adherence. When co-administered with a fully active background regimen, maraviroc did not readily generate resistance in the clinical setting. Trial registry name: ClinicalTrials.gov ( https://clinicaltrials.gov/ ), NCT00098722 and NCT00098306

scholarly journals Virological and Pharmacological Parameters Predicting the Response to Lopinavir-Ritonavir in Heavily Protease Inhibitor-Experienced Patients

2005 ◽  
Vol 49 (5) ◽  
pp. 1720-1726 ◽  
Author(s):  
Anne-Geneviève Marcelin ◽  
Isabelle Cohen-Codar ◽  
Martin S. King ◽  
Philippe Colson ◽  
Emmanuel Guillevic ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Drug Exposure ◽  
Virologic Response ◽  
Therapeutic Drug ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Hiv Rna ◽  
Inhibitor Resistance ◽  
Hiv 1

ABSTRACT The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of −1.50 log10 copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C min concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

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