Potency of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Used in Combination with Other Human Immunodeficiency Virus NNRTIs, NRTIs, or Protease Inhibitors

GW678248, a novel nonnucleoside reverse transcriptase inhibitor, has been evaluated for anti-human immunodeficiency virus activity in a variety of in vitro assays against laboratory strains and clinical isolates. When GW678248 was tested in combination with approved drugs in the nucleoside and nucleotide reverse transcriptase inhibitor classes or the protease inhibitor class, the antiviral activities were either synergistic or additive. When GW678248 was tested in combination with approved drugs in the nonnucleoside reverse transcriptase inhibitor class, the antiviral activities were either additive or slightly antagonistic. Clinical isolates from antiretroviral drug-experienced patients were selected for evaluation of sensitivity to GW678248 in a recombinant virus assay. Efavirenz (EFV) and nevirapine (NVP) had >10-fold increases in their 50% inhibitory concentrations (IC 50 s) for 85% and 98% of the 55 selected isolates, respectively, whereas GW678248 had a >10-fold increase in the IC 50 for only 17% of these isolates. Thus, 81 to 83% of the EFV-and/or NVP-resistant viruses from this data set were susceptible to GW678248. Virus populations resistant to GW678248 were selected by in vitro dose-escalating serial passage. Resistant progeny viruses recovered after eight passages had amino acid substitutions V106I, E138K, and P236L in the reverse transcriptase-coding region in one passage series and amino acid substitutions K102E, V106A, and P236L in a second passage series.

Section: Antiviral Activity Of Gw678248 In Mt-4 Cells and Humanmentioning

confidence: 91%

Anti-Human Immunodeficiency Virus Type 1 Activity of the Nonnucleoside Reverse Transcriptase Inhibitor GW678248 in Combination with Other Antiretrovirals against Clinical Isolate Viruses and In Vitro Selection for Resistance

Hazen¹,

Harvey²,

Clair³

et al. 2005

“…Synergy has previously been reported between NRTIs and NNRTIs which target the same viral enzyme. Zidovudine and efavirenz were shown to be synergistic in cell culture, and studies of etravirine combined with zidovudine suggested synergy, though additive effects were reported when etravirine was combined with other NRTI drugs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine, and tenofovir) and representatives of the PIs and the currently marketed NNRTIs (2,26). The synergistic interaction between NRTIs and NNRTIs has been associated with the ability of the NNRTI to inhibit ATP-mediated removal of the NRTI and so prolong its MOA (7).…”

Section: Discussionmentioning

confidence: 99%

Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

Corbau¹,

Mori²,

Phillips

et al. 2010

The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC 50 s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.

“…Combinations that show antagonism should be avoided, and combinations that show synergy may have added benefit in vivo. There have been a number of studies showing that combinations of NRTIs plus NNRTIs inhibit HIV-1 infection more efficiently than the additive effect expected for the individual drugs studied alone, thus demonstrating synergy in vitro (2)(3)(4)(5)(6)(7)(8)(9). For example, combinations of efavirenz (EFV)-TFV, EFV-FTC, rilpivirine (RPV)-TFV, and RPV-FTC have shown moderate to strong antiviral synergy against HIV-1 in cell culture (3,10).…”

mentioning

confidence: 99%

The Combined Anti-HIV-1 Activities of Emtricitabine and Tenofovir plus the Integrase Inhibitor Elvitegravir or Raltegravir Show High Levels of SynergyIn Vitro

Kulkarni

Hluhanich

McColl

et al. 2014

Highly active antiretroviral therapy (HAART) is the current standard of care for HIV infection and involves treatment with a combination of three or more antiretroviral agents. Generally, these are combinations of two or more drug classes which target different steps of the HIV-1 replication cycle. The most extensively studied anti-HIV-1 drug combinations are those of nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). NRTIs are competitive inhibitors of HIV-1 RT that cause chain termination of viral DNA polymerization and form the two-drug backbone of most regimens. The third agents are chosen from the different drug classes, consisting of NNRTIs (noncompetitive inhibitors of HIV-1 RT), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). The first single-tablet regimen containing an INSTI was recently approved and consists of the two NRTIs emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF), an oral prodrug of TFV; the INSTI elvitegravir (EVG); and the pharmacoenhancer cobicistat (COBI), which increases EVG concentrations (1).Combinations of antiviral inhibitors can directly affect the antiviral potency of their counterparts in an additive, antagonistic, or synergistic manner. Determination of the in vitro antiviral interactions between inhibitors used together in patients is an important component of the drug development process. Combinations that show antagonism should be avoided, and combinations that show synergy may have added benefit in vivo. There have been a number of studies showing that combinations of NRTIs plus NNRTIs inhibit HIV-1 infection more efficiently than the additive effect expected for the individual drugs studied alone, thus demonstrating synergy in vitro (2-9). For example, combinations of efavirenz (EFV)-TFV, EFV-FTC, rilpivirine (RPV)-TFV, and RPV-FTC have shown moderate to strong antiviral synergy against HIV-1 in cell culture (3,10). Studies have also shown that some combinations within a drug class, such as two or more NRTIs, can act synergistically in vitro (11)(12)(13)(14)(15)(16)(17). In-depth studies have been performed on the combination of FTC and TFV, and these two drugs show synergy (by median-effect analysis, combination index range of 0.52 to 0.56) to strong synergy (by MacSynergy analysis, synergy volumes of 153 to 181 nM 2 %) against HIV-1 in cell culture (3, 10). This has been partially explained by a positive metabolic interaction between FTC and TFV that leads to higher levels of phosphorylation to the active metabolites when dosed in combination and more efficient trapping of TFV in a dead-end chainterminated complex (3, 10, 17). Combinations of NRTIs or NNRTIs with INSTIs have also shown additive to synergistic effects in vitro (18,19). As combination therapies are the standard of care in HIV treatment, it is important to understand how newer inhibitors in different classes work in combination with existing therapies. This study evaluates the in vitro anti-HIV activity ...