Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

Abstract

In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety.

Dolutegravir Plus Lamivudine Two-Drug Regimen: Safety, Efficacy and Diagnostic Considerations for Its Use in Real-Life Clinical Practice—A Refined Approach in the COVID-19 Era

“…Notably, suboptimal DTG levels were recorded in all of them [ 16 , 22 ]. Emergent mutations included T66I, G118R, Q148R/K, I151V, E157Q, G163E, R263R/K, for the most part associated with a low-level DTG-resistance in vitro [ 24 , 25 , 26 ]. The copresence of M184V plus R263K was observed in three out of six cases, and this same mutational pattern was also described in a recent case of failure to a bictegravir (BIC)-containing 3DR (M184I/V+R263K, 33% prevalence) [ 27 ].…”

Rational pharmacological approach to clinical studies for the treatment of SARS-COV-2 infection

“…The use of drugs in the class of HIV Protease Inhibitors and Integrase inhibitors, as well as the use of more than 1 Reverse Transcriptase Inhibitor per therapeutic regimen reinforce the argument. A therapeutic strategy centered on action on multiple targets using different drugs is a logical path for proposing clinical studies aimed at evaluating treatment strategies for viral infections causing illnesses that had not been treated [20]. Enfermagem Brasil 2020;19(4Supl):S42-S49…”

Pyrroles as Privileged Scaffolds in the Search for New Potential HIV Inhibitors

“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 19 adherence and tolerability to treatment, is imperative. These aspects are also essential for decreasing the selection of drug-resistant viral strains, which are currently one of the significant problems of therapy [6,8]. In addition, several drawbacks have been developed due to cART, including long-term toxicity and drug-drug interactions [9].…”

“…The available anti-HIV drugs target the essential HIV enzymes reverse transcriptase (RT), integrase (IN), and protease. However, other stages of HIV infection can be addressed, for example, entry and capsid inhibitors [ 5 , 6 ]. There is no cure for this disease or a vaccine to help to avoid HIV transmission, and drug-based therapy is the only means to control infection progress [ 7 ].…”

“…Despite the success of viral load suppression and increased patient survival due to the correct administration of cART, the development of new drugs and formulations of combined fixed doses (CFDs), and long-releasing formulations with better patient adherence and tolerability to treatment, is imperative. These aspects are also essential for decreasing the selection of drug-resistant viral strains, which are currently one of the significant problems of therapy [ 6 , 8 ]. In addition, several drawbacks have been developed due to cART, including long-term toxicity and drug–drug interactions [ 9 ].…”