How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use

Elliot, Emilie R; Chirwa, Mimie; Boffito, Marta

doi:10.1097/qco.0000000000000327

Cited by 27 publications

(26 citation statements)

References 33 publications

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“…A VL at three months may allow for earlier detection of adherence problems. This may be particularly relevant as integrase inhibitors are increasingly being used in first‐line regimens in LMIC and result in more rapid suppression of VL when compared to Efavirenz‐based regimens .…”

Section: Discussionmentioning

confidence: 99%

Routine versus Targeted Viral Load Strategy among Patients Starting Antiretroviral in Hanoi, Vietnam

et al. 2019

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Introduction HIV viral load (VL) testing is recommended by the WHO as the preferred method for monitoring patients on antiretroviral therapy (ART). However, evidence that routine VL (RVL) monitoring improves clinical outcomes is lacking. Methods We conducted a prospective, randomized controlled trial of RVL monitoring every six months versus a targeted VL (TVL) strategy (routine CD4 plus VL testing if clinical or immunological failure) in patients starting ART between April 2011 and April 2014 at Bach Mai Hospital in Hanoi. Six hundred and forty‐seven subjects were randomized to RVL (n = 305) or TVL monitoring (n = 342) and followed up for three years. Primary endpoints were death or WHO clinical Stage 4 events between six and thirty‐six months of ART and rate of virological suppression at three years. Results Overall, 37.1% of subjects were female, median age was 33.4 years (IQR: 29.5 to 38.6), and 47% had a CD4 count ≤100 cells/mm3 at time of ART initiation. Approximately 44% of study events (death, LTFU, withdrawal, or Stage 4 event) and 68% of deaths occurred within the first six months of ART. Among patients on ART at six months, death or Stage 4 event occurred in 3.6% of RVL and 3.9% of TVL (p = 0.823). Survival analysis showed no significant difference between the groups (p = 0.825). Viral suppression at 36 months of ART was 97.2% in RVL and 98.9% in TVL (p = 0.206) at a threshold of 400 copies/mL and was 98.0% in RVL and 98.9% in TVL (p = 0.488) at 1000 copies/mL. In ITT analysis, 20.7% in RVL and 21.9% in TVL (p = 0.693) were unsuppressed at 1000 copies/mL. Conclusions We found no significant difference in rates of death or Stage 4 events and virological failure in patients with RVL monitoring compared to those monitored with a TVL strategy after three years of follow‐up. Viral suppression rates were high overall and there were few study events among patients alive and on ART after six months, limiting the study's power to detect a difference among study arms. Nonetheless, these data suggest that the choice of VL monitoring strategy may have less impact on patient outcomes compared to efforts to reduce early mortality and improve ART retention.

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Section: Discussionmentioning

confidence: 99%

Routine versus Targeted Viral Load Strategy among Patients Starting Antiretroviral in Hanoi, Vietnam

et al. 2019

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“…However, it should be recognized that the safety concerns cannot be univocally ascribed to dolutegravir, except for the observed increment in serum transaminases in one liver transplant recipient, an uncommon effect already reported for dolutegravir [10]. Four additional patients experienced increased serum creatinine, which is a known "cosmetic" effect of dolutegravir [3,4]. Indeed, dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [2].…”

Section: Discussionmentioning

confidence: 93%

“…1b), despite prompt cyclosporine dose adjustments (ranging from 50 to 125 mg twice daily). Patients 6 and 10 experienced increased serum creatinine concentrations (from 1.3 to 1.8 mg/dL and from minimal dependence on CYP3A-mediated metabolism, high potency and high genetic barrier [3,4]. However, data on the use of dolutegravir in real-life transplant settings are limited and exclusively involve kidney transplant recipients [5][6][7][8][9].…”

Section: Resultsmentioning

confidence: 99%

“…Liver transplantation is now considered a safe procedure in select HIV-positive patients with end-stage hepatic disease because of the advent of potent antiretroviral therapies (ART) [1,2]. Moreover, potential concerns related to drug-drug interactions (DDIs) between immunosuppressive agents and ART have been overcome by the availability of booster-free, integrase inhibitor-based regimens, which are now considered first-line ART according to international guidelines [3,4]. Indeed, raltegravir is exclusively metabolized by uridine 5′-diphospho-glucuronosyltransferase and is neither an inducer nor an inhibitor of cytochrome P450 (CYP)-3A4 and 3A5, the phase I enzymes mainly involved in the metabolism of calcineurin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, raltegravir is exclusively metabolized by uridine 5′-diphospho-glucuronosyltransferase and is neither an inducer nor an inhibitor of cytochrome P450 (CYP)-3A4 and 3A5, the phase I enzymes mainly involved in the metabolism of calcineurin inhibitors. Conversely, elvitegravir requires the coadministration of cobicistat, a pharmaco-enhancer specifically designed to inhibit the CYP3A-mediated metabolism that is likely to affect the metabolism of both cyclosporine and tacrolimus and eventually increase their toxicity [3,4]. Dolutegravir, a recent integrase inhibitor, may represent an attractive option for HIV-positive liver transplant recipients because of its…”

Section: Introductionmentioning

confidence: 99%

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Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings

et al. 2020

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Background and Objectives Liver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART). Objective We aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital. Methods We searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. Results Ten HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable. Conclusions The management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.

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Antiviral Agents

Santos,

Reyna Quito

2023

ClinMicroNow

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There are five classes of antiviral agents for the treatment of human immunodeficiency virus type 1 (HIV‐1): nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), nonucleoside reverse transcriptase inhibitors, protease inhibitors (PIs), entry/fusion inhibitors, and integrase strand transfer inhibitors. PIs are commonly used in combined antiretroviral therapy regimens in combination with NRTI and/or NtRTIs for maximum antiretroviral activity and to minimize the development of resistance. Integrase Strand Transfer Inhibitors a class of antiretroviral drugs, target the HIV‐1 integrase enzyme that mediates transfer of the reverse‐transcribed HIV‐1 DNA into the host chromosome. The common target for antiviral drugs active against both viruses is the reverse transcriptase function of the HIV and hepatitis B virus (HBV) replication enzymes. Chronic HBV infection plays an important role in the morbidity and mortality of HIV‐infected patients. Most of the antiviral compounds that are approved to treat the eight human herpesviruses are nucleoside or nucleotide analogues, which inhibit DNA replication.

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How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use

Abstract: All three InSTIs have impressive data on efficacy, tolerability and safety. The unique differences of each InSTI's pharmacokinetics and pharmacodynamics lend themselves to various clinical scenarios, enabling us as clinicians to provide better patient-centred care.

Cited by 27 publications

References 33 publications

Routine versus Targeted Viral Load Strategy among Patients Starting Antiretroviral in Hanoi, Vietnam

Routine versus Targeted Viral Load Strategy among Patients Starting Antiretroviral in Hanoi, Vietnam

Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings

Antiviral Agents

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