Dolutegravir
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 in Kucers’ The Use of Antibiotics, 2017
Dolutegravir is a human immunodeficiency virus (HIV) integrase strand–transfer inhibitor (INSTI), consisting of a chiral nonracemic tricyclic carbamoyl pyridone–containing heterocycle core and a benzyl carboxamide moiety. Dolutegravir was discovered using a pharmacophore-based design approach to construct a bioisostere of the integrase phosphodiester substrate. As such, dolutegravir was designed to bind two divalent magnesium ions within the integrase catalytic active site, which effectively prevents the productive integration of viral and host deoxyribonucleic acid (DNA) substrates through inhibition of the second biochemical step catalyzed by HIV integrase known as strand transfer. Dolutegravir has no appreciable inhibition of the first biochemical step catalyzed by integrase known as 3’ processing, which is consistent with the two-metal binding mechanism of action (Johns et al., 2013). Dolutegravir is a specific inhibitor of HIV-1 and HIV-2 and has some antiviral activity against select non-HIV viruses, as described in section 2a, Routine susceptibility.
Antimicrobials during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
Dolutegravir is an anti-HIV drug. In 116 women who used the drug during pregnancy, there was no significant increase in the frequency of congenital anomalies (Antiretroviral Registry, 2018). Among 426 women in Botswana who took dolutegravir during the first trimester, there were four neural tube defects (Crawford et al., 2020). In another 396 women who used the drug with efavirenz (another anti-HIV agent), there were no neural tubes defects, and no increased frequency of congenital anomalies.
Care of Critically Ill Patients with HIV
Cheston B. Cunha, Burke A. Cunha in Infectious Diseases and Antimicrobial Stewardship in Critical Care Medicine, 2020
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].
Safety implications of combined antiretroviral and anti-tuberculosis drugs
Published in Expert Opinion on Drug Safety, 2020
Maddalena Cerrone, Margherita Bracchi, Sean Wasserman, Anton Pozniak, Graeme Meintjes, Karen Cohen, Robert J Wilkinson
Due to its high potency and genetic barrier to resistance, dolutegravir is the drug of choice for the treatment of HIV recommended by the WHO. Nevertheless, its administration with RIF is currently recommended at the double dose of 50 mg twice daily. Adding an extra dose can represent a challenge to its implementation in low and middle-income countries, due to potential for decreased patient adherence and increased cost. Preliminary data on using the standard dolutegravir 50 mg daily dose together with RIF in healthy volunteers are promising [43], hence assessing the safety and efficacy of the standard dose of dolutegravir of 50 mg once daily in PLWH infected with TB as a next step is a research priority to accelerate dolutegravir global implementation. More data informing on the most appropriate dose of raltegravir to adopt in patients with HIV-associated TB are also needed in order to expand its use in this population. Tenofovir alafenamide is gradually replacing tenofovir disoproxil fumarate in many of the newly approved ART combinations and also as pre-exposure prophylaxis option for HIV [219] in light of its safer profile in terms of nephrotoxicity and bone health. Drug interaction and efficacy studies in patients with HIV-associated TB are necessary to expand the access to patients on TB treatment, especially when concomitant renal impairment is present.
Dolutegravir monotherapy: an option for highly adherent HIV1-infected naive patients with relatively low zenith HIV-RNA?
Published in Infectious Diseases, 2019
Massimiliano Lanzafame, Sebastiano Rizzardo, Daniela Piacentini, Emanuela Lattuada, Sheila Chiesi, Sandro Vento
Dolutegravir, thanks to its potency and tolerability, has been tried as monotherapy in virologically suppressed HIV1-infected patients [3]. The results of several randomized clinical trials and clinical cohort studies have shown a high rate of resistance after virological failure, discouraging this approach [3]. However, in our hands dolutegravir monotherapy has been effective in naive patients with a zenith HIV-RNA below 100,000 copies/ml [4]. Around 40% of naive patients in Italy indeed have, at the start of antiretroviral therapy, a zenith HIV-RNA lower than 100,000 copies/ml [5], and a personalized antiretroviral therapy with fewer than three antiretroviral drugs could be used to treat this subset with a relatively low viral load. In an attempt to clarify the possible reasons underlying the virological success in our naive patients treated with dolutegravir monotherapy, we retrospectively analyzed two cohorts of naive HIV1-infected patients followed at the Outpatient Clinic of the Infectious Diseases Unit, G.B. Rossi Hospital in Verona, comparing age, mean TCD4+ cell count, mean zenith HIV RNA and mean length of follow-up (from the first observation in our Centre to the start of HAART).
Efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide in the treatment of HIV-1
Published in Expert Opinion on Pharmacotherapy, 2018
Eugènia Negredo, Bonaventura Clotet
Cobicistat, like ritonavir, is a pharmacokinetic booster, with similar inhibitory effects on CYP3A4, CYP2D6, P-gp, and other transporters [14,19], so it shares most of its drug interactions. However, inhibition by cobicistat seems to be more selective than with ritonavir, and cobicistat has no inducer effects [12,14,19]. Given its greater specificity, in the presence of inducers such as etravirine, rifamycins, or anticonvulsants, cobicistat may not be as effective as ritonavir in terms of inhibiting CYP3A4 [20]. On the other hand, cobicistat is a more potent inhibitor of intestinal P-gp transporter than ritonavir, which explain the greater dabigatran exposure with cobicistat but not with ritonavir [21]. As mentioned above, cobicistat is not associated with enzyme-inducing properties, including uridine diphosphate-glucuronosyltransferase (UGT) [19]. A recent pharmacokinetic switch study in 12 HIV-infected patients on dolutegravir 50 mg daily plus DRV/r 800/100mg daily illustrates this point. After patients were switched to DRV/c 800/150 mg daily with dolutegravir, DRV exposures remained stable, but DTG Ctrough increased 100%. The authors hypothesized that dolutegravir exposures might have decreased secondary to ritonavir induction of glucuronidation. Switching to cobicistat removed the UGT induction effect, resulting in increased dolutegravir concentrations [22].
Related Knowledge Centers
- Antiviral Drug
- Hyperglycemia
- Liver Disease
- Allergy
- Diarrhea
- Pregnancy
- HIV/AIDS
- Post-Exposure Prophylaxis
- Breastfeeding
- Integrase Inhibitor