scholarly journals Unanticipated Effects of New Drug Availability on Antiretroviral Durability: Implications for Comparative Effectiveness Research

2016 ◽  
Vol 3 (2) ◽  
Author(s):  
Ellen F. Eaton ◽  
Ashutosh R. Tamhane ◽  
Greer A. Burkholder ◽  
James H. Willig ◽  
Michael S. Saag ◽  
...  
Keyword(s):  
Undetectable Viral Load ◽  
Strand Transfer ◽  
Extrinsic Factors ◽  
Drug Availability ◽  
New Drug ◽  
Kaplan Meier ◽  
Initial Regimen ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Dynamic Treatment

Abstract Background.  Durability of antiretroviral (ARV) therapy is associated with improved human immunodeficiency virus (HIV) outcomes. Data on ARV regimen durability in recent years and clinical settings are lacking. Methods.  This retrospective follow-up study included treatment-naive HIV-infected patients initiating ARV therapy between January 2007 and December 2012 in a university-affiliated HIV clinic in the Southeastern United States. Outcome of interest was durability (time to discontinuation) of the initial regimen. Durability was evaluated using Kaplan-Meier survival analyses. Cox proportional hazard analyses was used to evaluate the association among durability and sociodemographic, clinical, and regimen-level factors. Results.  Overall, 546 patients were analyzed. Median durability of all regimens was 39.5 months (95% confidence interval, 34.1–44.4). Commonly prescribed regimens were emtricitabine and tenofovir with efavirenz (51%; median duration = 40.1 months) and with raltegravir (14%; 47.8 months). Overall, 67% of patients had an undetectable viral load at the time of regimen cessation. Discontinuation was less likely with an integrase strand transfer inhibitor (adjusted hazards ratio [aHR] = 0.35, P = .001) or protease inhibitor-based regimen (aHR = 0.45, P = .006) and more likely with a higher pill burden (aHR = 2.25, P = .003) and a later treatment era (aHR = 1.64, P < .001). Conclusions.  Initial ARV regimen longevity declined in recent years contemporaneous with the availability of several new ARV drugs and combinations. Reduced durability mostly results from a preference for newly approved regimens rather than indicating failing therapy, as indicated by viral suppression observed in a majority of patients (67%) prior to regimen cessation. Durability is influenced by extrinsic factors including new drug availability and provider preference. Medication durability must be interpreted carefully in the context of a dynamic treatment landscape.

scholarly journals HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Dario Oliveira Passos ◽  
Dmitry Lyumkis ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Strand Transfer ◽  
First Line ◽  
Preclinical Development ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

scholarly journals Might dolutegravir be part of a functional cure for HIV?

2016 ◽  
Vol 62 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Mark A. Wainberg ◽  
Ying-Shan Han ◽  
Thibault Mesplède
Keyword(s):  
First Generation ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Functional Cure ◽  
Viral Reservoirs ◽  
Genetic Barrier ◽  
Clinical Resistance ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.

scholarly journals Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Kara S McGee ◽  
Nwora Lance Okeke ◽  
Christopher B Hurt ◽  
Mehri S McKellar
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Transmitted Drug Resistance ◽  
Strand Transfer ◽  
Naive Patient ◽  
Immunodeficiency Virus ◽  
Integrase Strand Transfer Inhibitors ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Transmitted drug resistance to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals is very rare. We present a case of a treatment-naive female patient with human immunodeficiency virus harboring resistance to all INSTIs, including bictegravir and dolutegravir.

scholarly journals Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy

2019 ◽  
Vol 70 (7) ◽  
pp. 1267-1274 ◽  
Author(s):  
Kassem Bourgi ◽  
Peter F Rebeiro ◽  
Megan Turner ◽  
Jessica L Castilho ◽  
Todd Hulgan ◽  
...  
Keyword(s):  
Weight Gain ◽  
Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Care Clinic ◽  
Art Initiation ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Restricted Cubic Splines

Abstract Background Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)–based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. Methods Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)–, and nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. Results Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. Conclusions Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

scholarly journals Cost-Efficacy of Antiretroviral Regimens Recommended in Treatment-Naive HIV-Infected Adults. A Single Center Experience

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 956
Author(s):  
Raluca Jipa ◽  
Iulia Nedelcu ◽  
Eliza Manea ◽  
Anca Damalan ◽  
Adriana Hristea
Keyword(s):  
Similar Efficacy ◽  
Strand Transfer ◽  
Software Application ◽  
Single Center Experience ◽  
Combined Antiretroviral Therapy ◽  
Treatment Naïve ◽  
Cost Efficacy ◽  
Transfer Inhibitor ◽  
The Cost ◽  
Integrase Strand Transfer Inhibitor

We aimed to assess the prescription trends of combined antiretroviral therapy (cART) in one infectious diseases department and the cost-efficacy (C/E) of different regimens used in treatment-naïve patients. The C/E was assessed with a software application developed by a group of researchers in Spain. The efficacy was already calculated in the application. The costs included the local cost of antiretrovirals and other direct costs specific to our institution. In the software application, the C/E reference regimen was ABC/3TC/DTG. In total, 181 HIV-infected patients were diagnosed and initiated cART during 2015–2019. The proportion of patients treated with integrase-strand transfer inhibitor (INSTI)-based regimens increased from 2015–2018 (54%) to the end of 2019 (81%). The relative C/E ranged from 0.90 to 1.28 for the evaluated INSTI-based regimens. Among INSTI-based regimens, ABC/3TC/DTG and TAF/FTC/EVG/c are the regimens with similar efficacy and relative C/E.

Is immune recovery different depending on the use of integrase strand transfer inhibitor-, non-nucleoside reverse transcriptase- or boosted protease inhibitor-based regimens in antiretroviral-naive HIV-infected patients?

2019 ◽  
Author(s):  
Yusnelkis Milanés-Guisado ◽  
Alicia Gutiérrez-Valencia ◽  
Juan Manuel Muñoz-Pichardo ◽  
Antonio Rivero ◽  
Maria Trujillo-Rodriguez ◽  
...  
Keyword(s):  
Viral Load ◽  
Repeated Measures ◽  
Integrase Inhibitor ◽  
Undetectable Viral Load ◽  
Cd4 Count ◽  
Strand Transfer ◽  
Treatment Groups ◽  
Hiv Rna ◽  
The Third ◽  
Transfer Inhibitor

Abstract Objectives To analyse whether integrase inhibitor (InSTI)-based regimens achieve better immunological recovery than NNRTI- or boosted PI (bPI)-based regimens as initial ART. Methods In a retrospective analysis, we selected patients who initiated ART with two NRTIs plus an InSTI, an NNRTI or a bPI and maintained both the same ‘third drug’ and an HIV-RNA <50 copies/mL in ≥95% of determinations once undetectable viral load had been achieved. We compared CD4+ count, %CD4+ and CD4+/CD8+ ratio recovery over 2 years. Data were analysed using mixed-effects regression models for repeated measures. Results Of the 836 patients included, 208, 481 and 147 initiated with InSTI, NNRTI and bPI, respectively. For CD4+, %CD4+ and CD4+/CD8+ two main slopes were identified: from month 0 to month 6, with the highest increments; and from month 6 to month 24, with smaller increases every semester. Although the patients on InSTI achieved undetectable viral load faster, for CD4+ and %CD4+ there were no differences in the slopes of change according to the third drug either for the first phase (P = 0.137 and P = 0.393, respectively) or from month 6 onwards (P = 0.834 and P = 0.159, respectively). The increase in CD4+/CD8+ was slightly higher for bPI compared with InSTI (difference of 0.0119, 95% CI 0.0020–0.0205; P = 0.018), but clinically negligible. From month 6 onwards, no differences were found between treatment groups (P = 0.176). Conclusions Immune restoration measured as CD4+ count, %CD4+ and CD4+/CD8+ increases was independent of the third antiretroviral drug class used when given with two NRTIs.

scholarly journals Emergent Resistance to Dolutegravir Among INSTI-Naïve Patients on First-line or Second-line Antiretroviral Therapy: A Review of Published Cases

2020 ◽  
Vol 7 (6) ◽  
Author(s):  
Muge Cevik ◽  
Chloe Orkin ◽  
Paul E Sax
Keyword(s):  
Virological Failure ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Poor Adherence ◽  
Clinical Aspects ◽  
Strand Transfer ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract None of the licensing studies of dolutegravir (DTG) reported any treatment-emergent resistance among DTG-treated individuals, though virological failure in treatment-naïve and treatment-experienced, integrase strand transfer inhibitor (INSTI)–naïve individuals has been reported in clinical practice. While the spectrum of dolutegravir-selected mutations and their effects on clinical outcome have been described, the clinical characteristics of these rare but important virological failure cases are often overlooked. In this perspective piece, we focus on key clinical aspects of emergent resistance to DTG among treatment-naïve and treatment-experienced INSTI-naïve patients, with an aim to inform clinical decision-making. Poor adherence and HIV disease factors contribute to emergent drug resistance, even in regimens with high resistance barriers. Patients with severe immunosuppression or poor adherence are under-represented in licensing studies, and these patients may be at higher risk of treatment failure with DTG resistance, which requires close clinical and laboratory follow-up.

Raltegravir: Its use in the Treatment of HIV Infection

2009 ◽  
Vol 1 ◽  
pp. CMT.S32
Author(s):  
Marianne Harris
Keyword(s):  
Hiv Infection ◽  
Safety Data ◽  
Resistance Testing ◽  
Strand Transfer ◽  
Antiretroviral Agents ◽  
First Line Therapy ◽  
Effective Option ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of HIV infection. Administered orally in doses of 400 mg twice daily, it is well-tolerated and has minimal drug-drug interactions with coadministered antiretrovirals and other agents. In clinical trials including treatment-experienced and treatment-naïve HIV-infected adults, raltegravir in combination with other antiretroviral agents has demonstrated a rapid and potent virologic effect and a generally benign safety profile. Like other antiretrovirals, raltegravir should ideally be given with two additional agents to which the patient's virus is susceptible based on results of resistance testing. In this context, raltegravir offers a safe and effective option as a component of combination therapy in treatment-experienced patients who are infected with HIV-1 strains showing evidence of resistance to other antiretroviral agents. Pending the availability of longer-term efficacy and safety data, raltegravir cannot currently be recommended as part of first-line therapy for treatment-naïve patients.

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