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New MK-8591 Publication
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Long-Acting MK-8591 at IAS 2019, , New ART for Treatment, PrEP
CROI: Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis - (02/24/16) - up to one year PrEP protection potential
IAS/2019: First-in-Human Trial of MK-8591-Eluting Implants Demonstrates Concentrations Suitable for HIV Prophylaxis for at Least One Year
MK-8591 + Doravrine - a relatively New ART [NNRTI] - (12/20/19)
New MK-8591 Publication

the prevention of SIV infection demonstrated in rhesus macaques down to weekly doses as low as 0·1 mg/kg 21 supports a potential role for islatravir as a single agent for pre-exposure prophylaxis......Our trial showed that single oral doses of islatravir of 0·5–30 mg administered to treatment-naive adults with HIV-1 infection demonstrated potent antiretroviral activity and was generally well tolerated, with a single dose as low as 0·5 mg significantly suppressing HIV-1 plasma RNA by more than 1·0 log for at least 7 days. The results also suggest that higher doses of islatravir, of up to 30 mg, could extend the period of viral suppression achieved by a single dose to beyond 7 days.. Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. Islatravir is the first nucleoside reverse transcriptase translocation inhibitor (NRTTI), with structural and mechanistic features that distinguish it from currently marketed antiretroviral drugs. Islatravir is at least ten times more potent towards wild-type HIV-1 in human peripheral blood mononuclear cells (PBMCs) than other marketed antiretroviral drugs. It is also more potent against resistant variants than tenofovir alafenamide and more potent against common NRTI-resistant HIV-1 isolates than any approved NRTI is against wild-type HIV-1. 17, 18 Emergence of resistance to islatravir in selection experiments in vitro is through Met184Ile and Met184Val substitutions in reverse transcriptase, which confer 3·9 times and five times reduced susceptibility to islatravir in clinical isolates containing these mutations, respectively, compared with wild-type virus. 18 Islatravir exhibits high potency across a broad panel of NRTI resistant HIV-1 clinical isolates. 17 As monotherapy, islatravir has demonstrated the ability to suppress viraemia in macaques infected with simian immunodeficiency virus (SIV) for up to 6 months without recrudescence with resistant virus while on treatment and emergence of Met184 mutations only upon cessation of drug treatment. 19 Because of the high potency of islatravir, systemic concentrations of islatravir achieved at projected clinical doses in people are expected to suppress viruses that contain common NRTI resistance mutations fully, including those with Met184Ile/Val. Weekly dosing with oral islatravir protected male macaques against intrarectal SIV challenge. 21
Comment: Tough requirements for new antiretroviral drugs
December 17, 2019. Carmen de Mendoza, Vicente Soriano
Medical and social attention to HIV infection has declined globally and is increasingly focused on developing regions, where the epidemic is still largely uncontrolled. In North America and western Europe, AIDS is rarely in newspaper headlines or mentioned in television news. The success of antiretroviral therapy largely explains this change in the perception of HIV/AIDS, which was once a life-threatening disease but is now, more many, viewed as a chronic illness. Indeed, individuals on treatment currently benefit from life expectancies close to those of people who are HIV negative.
With the advent of safer and more effective antiretroviral agents, indications for treatment have expanded from advanced immunodeficiency, and now anyone with HIV should receive treatment as soon as possible. Furthermore, antiretrovirals are now recommended for people at risk of HIV as pre-exposure prophylaxis. 1 Long-acting formulations of antiretrovirals that will allow weekly or monthly prescriptions are on the horizon.2, 3 Clearly, there is a sense of victory and relief after major gaps in HIV/AIDS therapy have been filled. In this scenario, is there still any room for developing a new antiretroviral agent?
In the Lancet HIV, Dirk Schürmann and colleagues4 report the results of a phase 1b trial with islatravir (also known as MK-8591; previously known as EFdA), a first-in-class nucleoside reverse transcriptase translocation inhibitor.
Briefly, 30 antiretroviral-naive adults with HIV infection received one of five distinct single oral doses of the drug at one clinic in Berlin, Germany.4
The study was done between 2015 and 2017. Roughly a third of patients had drug-related adverse effects, but none of these effects were serious. The lowest dose, 0·5 mg, of islatravir suppressed plasma HIV RNA by more than 1 log10 copies per mL at 1 week. Given the safety, potency, and long intracellular half-life of the triphosphorylated active form of the drug (78 h), the authors propose further clinical development of islatravir.
Enthusiasm unabated, we think it worth considering the convenience of developing such a drug. We identified at least four important caveats. The first refers to safety. The phase 1b study ended in 2017, and no serious adverse events were reported during the short follow-up of a single oral dose. Longer exposure to the drug and longer follow-up would be needed to explore safety issues adequately. Given that islatravir is an adenosine analogue, like didanosine, worrisome metabolic effects in the middle or long term should be excluded, including lipoatrophy, lactic acidosis, neuropathies, 5 and non-cirrhotic portal hypertension.6
Second, the claim for a unique distinct mechanism of action for islatravir needs to show clinical meaning, especially regarding an absence of cross-resistance with already marketed nucleoside or nucleotide reverse transcriptase inhibitors. Although in-vitro experiments have highlighted a high barrier to resistance for islatravir, with a characteristic Met184Ile/Val substitution that only results in a five times loss of drug potency, only studies testing a prolonged exposure to the drug as monotherapy will show whether the addition of more mutations could significantly impair islatravir inhibitory activity. Notably, several reverse transcriptase mutations, including Lys65Arg, Leu74Val, and Gln151Met, render viruses hypersusceptible to islatravir.7 In this regard, islatravir could be a preferred option in patients with these drug-resistant viruses.
Third, women should be part of trials to avoid controversies such as occurred after the recent US Food and Drug Administration approval of emtricitabine plus tenofovir alafenamide for HIV prevention in at-risk uninfected adults “excluding those who have receptive vaginal sex”.
The drug has not been authorised for most sexually active women because of paucity of data, 8 acknowledging that differences in drug concentrations between rectal and vaginal mucosa could affect its efficacy on HIV prevention. In addition, given that most people who now need HIV therapy are living in developing countries, where the proportion of women of childbearing age is higher than in high-income countries, studies of teratogenicity of islatravir should be prioritised.
Finally, in sub-Saharan Africa, where more than 75% of people with HIV are living, HIV-2 is present alone or as coinfection with HIV-1. Therefore, for the achievement of the UNAIDS 90-90-90 goal, 1 therapeutic effort must include HIV-2,9 because problems arising from mismanaging patients with HIV-2 could hamper the expected success.10 Therfore, the in-vivo activity of islatravir against HIV-2 isolates must be determined.
In summary, islatravir is a promising new antiretroviral oral drug that preliminarily depicts a good safety profile, high potency, and long half-life. Because most currently approved HIV drugs are already given as single pills once a day, the challenges of lifelong drug compliance are already well addressed by existing medications. What would be the added value of islatravir? Among others, we identified four areas of interest: improved middle-term and long-term safety, high resistance barrier, high efficacy in women and children, and HIV-2 activity. We believe that positioning the drug advantageously in these niches would push its clinical development.
Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. Recent and potential advances in HIV therapy include simplification of oral once-daily regimens from three to two drugs, injectable formulations that facilitate infrequent dosing, and new classes of medication with differentiated mechanisms of action. Two-drug regimens, such as dolutegravir plus rilpivirine and dolutegravir plus lamivudine, have demonstrated non-inferiority to standard three-drug regimens in specific populations, 7, 8 and intramuscular cabotegravir plus rilpivirine is being assessed as a potential regimen that is administered every 2 months. 9 Several new classes of molecules, including a subcutaneously injected HIV capsid inhibitor 10 and parenterally administered broadly neutralising antibodies, 11 might also have the potential to be administered less frequently than current regimens. Islatravir (also known as ISL, MK-8591, and 4′-ethynyl-2-fluoro-2′-deoxyadenosine; previously known as EFdA) has characteristics that potentially allow it to manifest all of these potential advances.
Long-Acting MK-8591 at IAS 2019, , New ART for Treatment, PrEP
EFdA / MK-8591 - HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection - (08/05/16)
.....Significant gender inequalities limit the ability of women to access and exercise HIV prevention options resulting in earlier acquisition of infection, higher transmission rates and increased mother-to-child transmission of HIV. Collectively, our in vivo results demonstrating 4'-ethynyl-2-fluoro-2'-deoxyadenosine's excellent efficacy in preventing both vaginal and oral HIV transmission together with its relatively low toxicity and high potency against drug-resistant HIV strains support 4'-ethynyl-2-fluoro-2'-deoxyadenosine as a potential PrEP agent for use in women and infants, two of the most vulnerable populations at risk for acquiring HIV.
EACS 2019: Islatravir Efficacy and Safety for Selected Demographic and Baseline Subgroups From a Phase 2 Trial In Treatment-naïve Adults With HIV-1 Infection....http://www.natap.org/2019/EACS/EACS_81.htm


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