Antiretroviral drugs: Critical issues and recent advances

Abstract

Human immunodeficiency virus (HIV) infection is now recognized as a chronic illness. Although the success of highly active antiretroviral therapy is beyond question, several issues still persist. Since the drugs cannot eradicate the virus, cure is not yet possible, and patients have to maintain a lifelong adherence with the risk of toxic effects, drug-drug interactions and drug resistance. A clear understanding of the viral replication and its interaction with host cell factors has led to the development of a large number of effective antiretroviral drugs (ARVs). New drugs in the existing class such as apricitabine, elvucitabine and etravirine have shown promising results against HIV isolates resistant to first line drugs. These drugs have offered a new choice for patients with drug resistant disease. However, the impact of their long term use on safety is yet to be assessed. Novel drugs with unique mechanism of action such as CD4 receptor attachment inhibitors, maturation inhibitors, pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived growth factor inhibitors are still under development. Currently, ARVs, especially tenofovir and emtricitabine, are also being evaluated for prevention of sexual transmission of HIV-1. The initial results of an HIV prevention trial network are encouraging and have recommended the use of ARVs for pre-exposure prophylaxis. Thus, ARVs form the key component of HIV prevention and treatment strategy. This article discusses the challenges associated with HIV-1 treatment and updates several major advances in the development of ARVs.

Gold(I) complex of 1,1′-bis(diphenylphosphino) ferrocene–quinoline conjugate: a virostatic agent against HIV-1

“…To date, there are only two compounds that have been approved for entry inhibition and these are maraviroc which is a CCR5 inhibitor and enfurvirtide which is a fusion inhibitor (Desai et al 2012). There is scope for complex 3 to be developed into a member of this class of antiretroviral drugs.…”

Recent Advance of the Hepatitis B Virus Inhibitors: A Medicinal Chemistry Overview

“…To overcome these shortcomings of existing nucleos(t) ide analogs, currently several novel anti-HBV agents, recently several researchers undertook a new round of (48), CMX157 (49) and so on (Figure 11) [107][108][109][110][111][112][113][114][115][116]. Lagociclovir valactate (43,, invented by Medvir AB company, is a prodrug of the nucleoside analogue 3'-fluoro-2', 3'-dideoxyguanosine (FLG) and has high oral bioavailability in humans and potent activity against HBV [117][118][119].…”

Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

“…As a gauge of compound stability, we determined the antiviral activity of PD after storage under different conditions for different periods of time. PD was diluted in buffered DPBS (pH 4,6,8,10) or cervical fluids (a pool of fluids from 3 donors 5-fold diluted in DPBS; Lee Biosolutions, St. Louis, MO) to achieve a final concentration of 30 M. DPBS was buffered to the desired pH using hydrochloric acid or sodium hydroxide. Diluted drug was incubated at the desired temperature for 0, 8, 24, or 48 h. After the temperature incubation, the drug mixture was further diluted to 1, 0.1, and 0.05 M in complete growth medium and used for incubation with VSV-G lentiviral pseudoparticles (VSV-Gpp; harboring either pTRIP-Gluc or NL4-3.Luc viral supernatant diluted 500-fold in complete growth medium) at 37°C for 30 min.…”

“…The last consideration derives from the presence of rare preexisting drug-resistant viral variants, as well as drug-resistant HIV variants, from patients who underwent previous antiretroviral treatment that can bypass the microbicidal barrier and transmit to target cells. Most current anti-HIV microbicide candidates in clinical trials are formulated on the basis of existing antiretroviral drugs and target well-studied viral proteins such as HIV protease (PR), reverse transcriptase, and HIV envelope protein (Env) (6)(7)(8)(9)(10). In the CAPRISA 004 clinical trial involving 1% tenofovir gel, HIV type 1 (HIV-1) acquisition was reduced by ϳ38% in all woman and by 54% in woman who used the gel 80% or more of the time (11).…”