scholarly journals Population Pharmacokinetic and Pharmacodynamic Analysis To Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Pavan Vaddady ◽  
Bhargava Kandala ◽  
Ka Lai Yee
Keyword(s):  
Transcriptase Inhibitor ◽  
Population Pharmacokinetic ◽  
People Living With Hiv ◽  
Shift Trial ◽  
Treatment Naïve ◽  
Post Hoc ◽  
Living With Hiv ◽  
Reverse Transcriptase Inhibitor ◽  
Parameter Values ◽  
Hiv 1

ABSTRACT Doravirine is a non-nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus type 1 (HIV-1) infection. A population pharmacokinetic (PK) model for treatment-naive participants in doravirine clinical studies was updated with data from switch participants in the DRIVE-SHIFT trial and used to estimate individual post hoc PK parameter values and evaluate the efficacy exposure-response relationship. The results support the 100-mg dose for people living with HIV switching to a doravirine-based regimen (This study has been registered at ClinicalTrials.gov under ClinicalTrials registration no. NCT02397096.)

scholarly journals INCIDENCE AND RISK FACTORS OF RENAL IMPAIRMENT IN HIV-1 INFECTED PATIENTS RECEIVING TENOFOVIR BASED ANTIRETROVIRAL THERAPY IN A SOUTH INDIAN HOSPITAL

2017 ◽  
Vol 9 (5) ◽  
pp. 152
Author(s):  
A. Pramod Kumar ◽  
G. Parthasarathi ◽  
A. P. Sudheer ◽  
S. N. Mothi ◽  
V. H. T. Swamy ◽  
...  
Keyword(s):  
Risk Factors ◽  
Renal Impairment ◽  
Real Life ◽  
Transcriptase Inhibitor ◽  
People Living With Hiv ◽  
South Indian ◽  
Severe Impairment ◽  
Living With Hiv ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Objective: To identify the incidence and risk factors of tenofovir (TDF) induced nephrotoxicity among People Living with HIV/AIDS (PLHA) receiving TDF-based anti-retroviral therapy (ART) in a South Indian Hospital.Methods: A retrospective cohort study was conducted among HIV-infected ART naïve patients taking TDF as part of either a first-line or second-line ART between July 2013 and June 2015 at Asha kirana Hospital Mysore, India.Results: A total of 380 patients have been initiated on TDF-based ART. Out of these, 335 patients were on tenofovir+lamivudine+efavirenz, 30 patients were on the tenofovir+lamivudine+nevirapine regimen and 25 patients were on tenofovir+lamivudine+atazanavir/ritonavir regimen. Renal impairment was documented for 35 patients with 9.21% incidence. 34% of renal impaired patients had a severe impairment with eGFR<30 ml/min. Elderly patients (>61 y) had higher chances of developing TDF toxicity compared to adult patients (P=0.0018). Other possible risk factors for TDF-induced renal impairment was CD4>200 (P=0.003). TDF was withdrawn and substituted with Nucleoside Reverse Transcriptase Inhibitor (NRTI) drug following the diagnosis of renal impairment.Conclusion: TDF-associated renal impairment was not uncommon in real-life practice and considered as a frequent complication during treatment with TDF. Risk factors for developing renal impairment include increasing age and CD4>200 cells.

Profiles of 2-Drug Regimen in People Living with HIV-1 in A Real World Setting: A Large-Scale Medical Claim Database Analysis in Japan

2020 ◽  
Author(s):  
Daniel J. Ruzicka ◽  
Mayuko Kamakura ◽  
Naho Kuroishi ◽  
Nobuyuki Oshima ◽  
Miyuki Yamatani ◽  
...  
Keyword(s):  
Large Scale ◽  
Transcriptase Inhibitor ◽  
Treatment Patterns ◽  
Claim Database ◽  
People Living With Hiv ◽  
Medical Claim ◽  
Living With Hiv ◽  
Reverse Transcriptase Inhibitor ◽  
Medical Claim Database ◽  
Hiv 1

Abstract Background Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and patient profiles associated with 2-ART are unclear. Methods This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of patient characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings.Results There were 94 patients identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n=3,993), the 2-ART cohort was older (mean age 54.4 vs 43.4 years), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (mean score 6.9 vs 5.3), more co-medications (mean 8.3 vs 5.0), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). Conclusion The profiles of patients on 2-ART in Japan were demonstrated to be complex. Most patients were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

scholarly journals Doravirine Exposure and HIV-1 Suppression after Switching from an Efavirenz-Based Regimen to Doravirine-Lamivudine-Tenofovir Disoproxil Fumarate

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Wayne Greaves ◽  
Hong Wan ◽  
Ka Lai Yee ◽  
Bhargava Kandala ◽  
Pavan Vaddady ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Tenofovir Disoproxil Fumarate ◽  
Phase 1 ◽  
Transcriptase Inhibitor ◽  
Phase 3 ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Shift Trial ◽  
Post Hoc ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Doravirine is a nonnucleoside reverse transcriptase inhibitor that has been approved for the treatment of HIV-1. In a phase 1 trial, doravirine exposure was transiently decreased when treatment was started immediately after the cessation of efavirenz treatment. In a post hoc subgroup analysis of participants who switched from an efavirenz-based regimen to doravirine-lamivudine-tenofovir disoproxil fumarate in the phase 3 DRIVE-SHIFT trial, doravirine plasma levels at week 4 were similar to noninduced levels, and HIV-1 suppression was maintained at weeks 24 and 48.

Diversity of HIV-1 subtypes and transmitted drug-resistance mutations among minority HIV-1 variants in a Turkish cohort

2021 ◽  
Vol 19 ◽  
Author(s):  
Rabia Can Sarinoglu ◽  
Uluhan Sili ◽  
Ufuk Hasdemir ◽  
Burak Aksu ◽  
Guner Soyletir ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Transmitted Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Treatment Naïve ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Background: The World Health Organization (WHO) recommends the surveillance of transmitted drug resistance mutations (TDRMs) to ensure the effectiveness and sustainability of HIV treatment programs. Objective: Our aim was to determine the TDRMs and evaluate the distribution of HIV-1 subtypes using and compared next-generation sequencing (NGS) and Sanger-based sequencing (SBS) in a cohort of 44 antiretroviral treatment-naïve patients. Methods: All samples that were referred to the microbiology laboratory for HIV drug resistance analysis between December 2016 and February 2018 were included in the study. After exclusions, 44 treatment-naive adult patients with a viral load of >1000 copies/mL were analyzed. DNA sequencing for reverse transcriptase and protease regions was performed using both DeepChek ABL single round kit and Sanger-based ViroSeq HIV-1 Genotyping System. The mutations and HIV-1 subtypes were analyzed using the Stanford HIVdb version 8.6.1 Genotypic Resistance software, and TDRMs were assessed using the WHO surveillance drug-resistance mutation database. HIV-1 subtypes were confirmed by constructing a maximum-likelihood phylogenetic tree using Los Alamos IQ-Tree software. Results: NGS identified nucleos(t)ide reverse transcriptase inhibitor (NRTI)-TDRMs in 9.1% of the patients, non-nucleos(t)ide reverse transcriptase inhibitor (NNRTI)-TDRMs in 6.8% of the patients, and protease inhibitor (PI)-TDRMs in 18.2% of the patients at a detection threshold of ≥1%. Using SBS, 2.3% and 6.8% of the patients were found to have NRTI- and NNRTI-TDRMs, respectively, but no major PI mutations were detected. M41L, L74I, K65R, M184V, and M184I related to NRTI, K103N to NNRTI, and N83D, M46I, I84V, V82A, L24I, L90M, I54V to the PI sites were identified using NGS. Most mutations were found in low-abundance (frequency range: 1.0% - 4.7%) HIV-1 variants, except M41L and K103N. The subtypes of the isolates were found as follows; 61.4% subtype B, 18.2% subtype B/CRF02_AG recombinant, 13.6% subtype A, 4.5% CRF43_02G, and 2.3% CRF02_AG. All TDRMs, except K65R, were detected in HIV-1 subtype B isolates.. Conclusion: The high diversity of protease site TDRMs in the minority HIV-1 variants and prevalence of CRFs were remarkable in this study. All minority HIV-1 variants were missed by conventional sequencing. TDRM prevalence among minority variants appears to be decreasing over time at our center.

scholarly journals Impact of HIV-1 Resistance-associated Mutations on Susceptibility to Doravirine: Analysis of Real-world Clinical Isolates

2021 ◽  
Author(s):  
Ernest Asante-Appiah ◽  
Johnny Lai ◽  
Hong Wan ◽  
Dongmei Yang ◽  
Elizabeth Anne Martin ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Fold Change ◽  
Clinical Isolates ◽  
Transmitted Drug Resistance ◽  
People Living With Hiv ◽  
Relative Fold Change ◽  
Reverse Transcriptase Inhibitor ◽  
The Impact ◽  
Hiv 1

Background: Clinical management of human immunodeficiency virus type-1 (HIV-1) infection may be negatively impacted by either acquired or transmitted drug resistance. Here, we aim to extend our understanding of the impact of resistance-associated mutations (RAMs) on the susceptibility of clinical isolates to the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine. Methods: Clinical isolates from people living with HIV-1 undergoing routine testing for susceptibility to doravirine and other approved NNRTIs (etravirine, rilpivirine, efavirenz, and nevirapine) were collected from August 2018 to August 2019. Susceptibility in the presence/absence of NNRTI and nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations was determined using cut-offs for relative fold-change in inhibition (ratio of the 50% inhibitory concentration [IC 50 ] of patient virus compared with the IC 50 of a wild-type reference strain). Biological cut-offs of 3- to 15-fold-change were investigated for doravirine, with pre-established cut-offs used for the other NNRTIs. Results: Of 4,070 clinical isolates, 42.9% had ≥1 NNRTI RAM. More isolates were susceptible to doravirine (92.5–96.7%) than to etravirine (91.5%), rilpivirine (89.5%), efavirenz (81.5%), or nevirapine (77.5%). Based on a 3-fold cut-off, doravirine susceptibility was retained in 44.7–65.8% of isolates resistant to another NNRTI and 28.5% of isolates resistant to all other tested NNRTIs. The presence of NRTI RAMs including thymidine analog mutations was associated with doravirine hypersusceptibility in some isolates, particularly in the absence of NNRTI RAMs. Conclusion: These results support the favorable resistance profile of doravirine, and are of particular importance given the challenge posed by both acquired and transmitted resistance.

scholarly journals Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242405
Author(s):  
Dwight E. Yin ◽  
Christina Ludema ◽  
Stephen R. Cole ◽  
Carol E. Golin ◽  
William C. Miller ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Continuous Therapy ◽  
Time To Treatment ◽  
Treatment Naïve ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Background Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. Methods We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. Results The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88–1.61 (adjusted HR 1.24, 95% CI 0.91–1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84–1.48 (adjusted HR 1.13, 95% CI 0.84–1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. Conclusions Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

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