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Tuberculosis and Human Immunodeficiency Virus Coinfection
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Charisse Mandimika, Gerald Friedland
Integrase strand transfer inhibitors (INSTIs), including dolutegravir (DTG), raltegravir (RAL), and etravirine vary in their susceptibility to RIF metabolism induction. DTG is least affected although its use with RIF requires dose adjustment. Results from the INSPIRE study indicate that DTG 50 mg twice daily is effective and well-tolerated in HIV/TB coinfected adults receiving RIF-based TB therapy.86 In addition, when used with TB treatment, rates of IRIS were low and there were no new toxicity signals for DTG and no discontinuations. The DOLPHIN TB prevention trial,87 which tested the safety and pharmacokinetics of DTG with RPT/INH once weekly ×12 doses, showed this combination to be well-tolerated and that DTG at 50 mg daily maintained HIV viral suppression, despite a modest decrease in trough levels, not requiring dose adjustment. DTG is now the global recommended first choice ART for HIV and TB coinfection treatment. Among other INSTIs, both bictegravir and elvitegravir should not be used together with rifamycin-containing TB treatment because of subtherapeutic levels, and RAL requires a substantial dose increase to 800 mg BID when administered with RIF.
Investigational Antiviral Drugs
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
John Mills, Suzanne M. Crowe, Marianne Martinello
Bictegravir (GS-9883) is a novel integrase strand transfer inhibitor with low nM potency against wild-type HIV-1 that does not require boosting with ritonavir or cobicistat. It also displays an improved resistance profile relative to elvitegravir, raltegravir, and dolutegravir in patient isolates with high-level integrase inhibitor resistance, particularly for strains with mutations E92Q plus N155H or Q148R/H/K plus G140A/C/S. Bictegravir (in a dose of 50 mg) is being developed with emtricitabine (FTC) and TAF as a single-tablet regimen and is in several phase III clinical trials for the once-daily treatment of HIV-infected patients (NCT02397694, NCT02607930, and NCT02603107) (White et al., 2016).
Care of Critically Ill Patients with HIV
Published in Cheston B. Cunha, Burke A. Cunha, Infectious Diseases and Antimicrobial Stewardship in Critical Care Medicine, 2020
Joseph Metmowlee Garland, Andrew Levinson, Edward Wing
Integrase inhibitors (InSTIs) entered clinical care with the approval of raltegravir by the US FDA in 2007. They have quickly become the backbone of initial treatment regimens due to their excellent tolerability, relatively few drug-drug interactions, and low incidence of pre-existing resistance. All three currently available agents are part of first-line regimens. Raltegravir is well-absorbed and has a half-life of 9 hours. It is hepatically metabolized by glucuronidation and is not affected by even severe renal dysfunction, or moderate hepatic dysfunction. It has a good side effect profile, though drug-induced hypersensitivity syndrome (DIHS) and a creatine kinase elevation that can range from mild to frank rhabdomyolysis, have been observed. Headache, diarrhea, and nausea have also been observed with this drug. There are very few drug-drug interactions of clinical consequence besides rifampin and divalent cations, which inhibit oral absorption of all integrase inhibitors [51]. Elvitegravir is almost always prescribed as part of a combination pill of elvitegravir, cobicistat, emtricitabine, and TDF (Stribild, by Gilead), or elvitegravir, cobicistat, emtricitabine, and TAF (Genvoya, by Gilead). It has a half-life of 8.7 hours when administered with a CYP 3A4 inhibitor (such as cobicistat). It is hepatically metabolized and requires no adjustment for renal impairment. Because it must be co-administered with a CYP 3A4 inhibitor, there are a large number of drug-drug interactions to consider (see “cobicistat” section). Divalent cations, as discussed above, inhibit intestinal absorption of elvitegravir [52]. Dolutegravir has a half-life of 13–15 hours, allowing for once-daily dosing without boosting. It is metabolized through UGT1A1, with a minor contribution for CYP3A4. It does not require dose adjustment for renal disease. It does have some drug-drug interactions with other antivirals, including the uncommonly used protease inhibitors fosamprenavir and tipranavir, and the NNRTIs efavirenz and etravirine. Co-administration with rifampin requires dolutegravir dosing be increased to twice-daily. Antacids and other divalent cations should not be administered within 6 hours prior or 2 hours after dolutegravir. Side effects are rare but include insomnia, headache, and rare GI side effects. Dolutegravir has a high genetic barrier to resistance and is often used in patients with underlying resistance mutations [53]. Bictegravir, the newest integrase inhibitor, received FDA approval in 2018 and is marketed in a combination tablet with TAF and emtricitabine (Biktarvy, by Gilead). Similar to dolutegravir, it has a half-life of 18 hours, allowing for once-daily dosing. It is metabolized equally by both CYP3A4 and glucuronidation UGT 1A1. There is no dose-adjustment required for even advanced renal disease. Drug-drug interactions are expected to be relatively few because of its multiple pathways to metabolism, but data are not yet published confirming this. It has a high barrier to resistance. Side effects in early trials appear comparable to dolutegravir [54].
Human pharmacokinetics prediction with an in vitro–in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy® for the treatment of HIV-1 infection
Published in Xenobiotica, 2022
Raju Subramanian, Jianhong Wang, Bernard Murray, Joseph Custodio, Jia Hao, Scott Lazerwith, Kelly MacLennan Staiger, Judy Mwangi, Hailing Sun, Jennifer Tang, Kelly Wang, Gerry Rhodes, Samantha Wijaya, Heather Zhang, Bill J. Smith
Bictegravir (BIC; Figure 1) is a potent small-molecule human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to resistance in vitro (Tsiang et al. 2016; Santoro et al. 2020). Biktarvy®, the once-daily, single-tablet, fixed-dose combination comprising BIC (50 mg), emtricitabine (FTC; 200 mg), and tenofovir alafenamide (TAF; 25 mg) has demonstrated good safety and tolerability, noninferior efficacy, and no treatment-emergent resistance in multiple phase 2 and 3 studies in HIV-1 infected, treatment-naive adults and in phase 3 switch studies in HIV-1 infected, virologically suppressed adults (Gallant et al. 2017; Sax, DeJesus et al. 2017; Sax, Pozniak et al. 2017; Daar et al. 2018; Molina et al. 2018). Biktarvy is indicated as a complete regimen for the treatment of HIV-1 infection in patients who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/ml) and on a stable antiretroviral regimen, with no history of treatment failure and no known resistance to any component of Biktarvy (EMA 2018). This therapy has no restrictions for food and few for drug-drug interactions (DDIs). Biktarvy is a preferred regimen for initial HIV-1 therapy and for patients switching regimens (European AIDS Clinical Society 2021; Panel on Antiretroviral Guidelines for Adults and Adolescents 2021).
Human and nonclinical disposition of [14C]bictegravir, a potent integrase strand-transfer inhibitor for the treatment of HIV-1 infection
Published in Xenobiotica, 2022
Raju Subramanian, John Ling, Jianhong Wang, Kelly Wang, Jia Hao, Haolun Jin, Yurong Lai, Bernard Murray, Samantha Wijaya, Heather Zhang, Bill J. Smith
Bictegravir (BIC; Figure 1) is a potent small-molecule human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to resistance in vitro (Tsiang et al. 2016; Santoro et al. 2020). Biktarvy, the fixed-dose combination (FDC) tablet comprising BIC (50 mg), emtricitabine (FTC; 200 mg), and tenofovir alafenamide (TAF; 25 mg) is approved for the treatment of HIV-1 infection. Biktarvy is indicated as a complete regimen for the treatment of HIV-1 infection in patients who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/ml) and on a stable antiretroviral regimen, with no history of treatment failure and no known substitutions associated with resistance to the individual components of Biktarvy (EMA (European Medicines Agency) 2018).
Antiretroviral treatment for HIV infection: Swedish recommendations 2019
Published in Infectious Diseases, 2020
Jaran Eriksen, Christina Carlander, Jan Albert, Leo Flamholc, Magnus Gisslén, Lars Navér, Veronica Svedhem, Aylin Yilmaz, Anders Sönnerborg
Since the previous update [2], several new drugs have become available as generics with significantly lower prices. Bictegravir (BIC) is a new integrase inhibitor available only as a combination tablet with tenofovir alafenamide (TAF) and emtricitabine (Biktarvy®). BIC + TAF + emtricitabine (FTC) has been shown to be equivalent to dolutegravir (both in combination with abacavir (ABC) + lamivudine (3TC) and TAF + FTC) in terms of efficacy and side effects when given to treatment-naïve patients [3,4]. Doravirine is a new NNRTI available both as a single substance (Pifeltro®) and in combination with TDF and 3TC (Delstrigo®). Doravirine + TDF + 3TC fixed combination has been shown to be equivalent to efavirenz + TDF + FTC and doravirine as a single substance equivalent to darunavir/r (combined with 2 NRTIs) in the treatment of previously untreated patients [5,6]. A lower frequency of CNS side effects was seen compared to efavirenz. Darunavir/cobicistat (800/150 mg) is now available in fixed combination with TAF + FTC (Symtuza®). Symtuza® has been compared to darunavir/cobicistat + TDF/FTC when given to treatment-naïve patients, and as switch therapy in stable patients compared to patients remaining on boosted PIs + TDF/FTC [7,8]. The non-inferiority criteria were met in both studies. Juluca® is a new fixed combination tablet of two previously available drugs, the INSIT dolutegravir and the NNRTI rilpivirine. This combination tablet has been shown to be similar in switch therapy compared to continued standard regimens in virally suppressed patients [9].