*9.2.3. MK-1439*

MK-1439 is a new and effective drug against a variety of HIV-1 mutants that are resistant to NNRTIs [157]. Preclinical studies (Phase l clinical trial) that are currently in progress show that this drug has a good pharmacokinetic profile, with the possibility of a daily dose in low concentrations to obtain an optimal effect. Additionally, it has good absorption, low potential for toxicity and the ability to be used with other antiretroviral agents. MK-1439 showed good results in cases where the K103N mutation of HIV-1 leads to resistance to treatment with nevirapine and efavirenz, as well as in the occurrence of the Y1818C mutation, which leads to a lower susceptibility in treatment with nevirapine, rilpivirine and etravirine*. In vitro* data suggest that MK-1439 has beneficial properties for additional development as a new antiviral drug; however, no data are available about its potential impact on lipid metabolism [163-164].

New NNRTIs class drugs are in various experimental stages such as BILR 355 BS (Phase Ila), (+)-Calanolide A (Phase I), GSK 2248761 (Phase Ilb), MK-4965 (Phase I), MK-6186 (Phase I), RDEA806 (Phase Ila), and UK-453061 (Phase Ilb). These new drugs have not been approved by the FDA and still require different clinical trials to be launched as drugs available for the treatment of HIV-1 infection. Currently, no scientific information regarding their possible effects on lipid metabolism is available.

#### **9.3. Fusion/entry inhibitors**

The HIV-1 envelope (Env) glycoprotein complex, which is composed of three receptor-binding gp120 subunits and three fusion protein gp41 subunits, mediates virus entry by fusing viral and cellular membranes and offers an attractive target for developing antiviral agents [165, 166]. In succession to enfuvirtide/T-20, a number of design strategies have been applied to develop new peptide-based fusion inhibitors with improved stability, bioavailability and potency [166, 167]. There are several drug classes that are in two experimental phases. Albuvirtide (FB006M), T649, T2634, T2544, T1249, SC34EK, and SC29EK are in the class of fusion inhibitors. BMS 663068, BMS 626529, vicriviroc (SCH 417690), and cenicriviroc (TAK-652, TBR-652) are in the class of entry inhibitors. These and other drugs are in experi‐ mental stages and/or have been suspended, and there are no initial and/or conclusive data about their potential toxic effects and the impact on lipid metabolism.

#### **9.4. InSTIs**

Cobicistat (GS-9350) is a new InSTIs drug recently approved by the FDA (2012). This drug, like ritonavir, has the ability to inhibit hepatic enzymes that metabolize other drugs used to treat HIV-1 infection, such as raltegravir [168]. Cobicistat has become increasingly important, and its use has been associated with elvitegravir, permitting it to have higher blood concentrations with use of smaller doses, which theoretically allows for greater suppression of viral replication with elvitegravir, having fewer adverse effects. Cobicistat has been employed in combination with elvitegravir/emtricitabine/tenofovir (Stribild®) [168, 169]. Cobicistat is a potent inhibitor of CYP3A enzymes, which will concurrently affect administered medications metabolized by this pathway. It also inhibits intestinal transport proteins, increasing the overall absorption of several drugs including atazanavir, darunavir, and tenofovir alafenamide fumarate (TAF). Phase III trials of the cobicistat-containing combination antiretroviral therapy regimens in ART-naïve patients have shown a small elevation of serum fasting lipid, with a relative increase in the levels of TC and TG, in addition to bilirubin elevations, jaundice, nausea and diarrhea [168-170]. Other drugs of the InSTI class are experimental, such as MK2048. It is a drug that acts by inhibiting integrase enzyme four times longer and shows superior efficacy to raltegra‐ vir. Additionally, it is being investigated for use as part of PrEP [171]. In turn, BI224436 is the first non-catalytic site integrase inhibitor (NCINI) with capacity to inhibit HIV-1 replication. This inhibition of HIV-1 replication occurs via its attachment to a conserved allosteric pocket of the HIV integrase enzyme. This makes the drug distinct in its mechanism of action compared to raltegravir and elvitegravir, which bind at the catalytic site [172, 173]. Another experimental drug is GSK744 (S/GSK1265744, Cabotegravir®), which has a structure similar to that of carbamoyl and omizanddolutegravir. In investigational studies, the agent has been packaged into nanoparticles (GSK744LAP), which confer an exceptionally long half-life of 21–50 days following a single dose. In theory, this would make suppression of HIV-1 possible when dosing as infrequently as once every three months. These drugs do not have sufficient data on their toxicity profile and/or on lipid metabolism; however, they have been previously considered to have low metabolic toxicity [174, 175].
