**10. Pre-Exposure Prophylaxis (PrEP)**

*9.2.3. MK-1439*

effects on lipid metabolism is available.

**9.3. Fusion/entry inhibitors**

**9.4. InSTIs**

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].

146 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

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

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

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

about their potential toxic effects and the impact on lipid metabolism.

In addition to known HAART regimens demonstrated in HIV-1 patients, new drugs and formulations have been developed to prevent infection by HIV-1. This new approach based on PrEP has shown promising results when administered as oral drugs, vaginal microbicides (VM), and rectal microbicides (RM). PrEP is an important tool for the prevention of HIV-1 infection, and can be combined with condom provision, counseling, and the diagnosis and treatment of sexually transmitted infection (STI), thus providing even greater protection than when used alone [176, 177]. Different clinical trials based on PrEP, have shown reductions in HIV-1 infection rates among men who have sex with men (MSM), and heterosexual HIVserodiscordant couples, who were prescribed daily oral antiretroviral PrEP with a fixed-dose combination of TDF and emtricitabine (FTC) (Truvada®). The isolated use of TDF also demonstrated safety and efficacy in clinical trials among injecting drug users (IDU) and among men and women in heterosexual HIV-discordant couples [177-180] (Table 5).
