Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial

DeJesus, Edwin; Rockstroh, Jürgen K.; Henry, Keith; Molina, Jean Michel; Gathe, Joseph; Ramanathan, S.; Wei, Xuelian; Yale, Kitty; Szwarcberg, Javier; White, Kirsten; Cheng, Andrew; Kearney, Brian P.

doi:10.1016/s0140-6736(12)60918-0

Cited by 308 publications

(255 citation statements)

References 27 publications

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“…E92Q is a nonpolymorphic mutation that has been selected in patients receiving either EVG (40)(41)(42)(43)(44) or RAL (39,40,45) and is associated with virological failure on EVG-based regimens (45). The A54A/V, A265A/V, and V277V/M partial substitutions were selected under INSTI pressure, but only the A265 position is conserved among HIV integrases of different subtypes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3=-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased K m = and V max =/K m = for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV. IMPORTANCEOur goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.T he limitations of current highly active antiretroviral therapy (HAART) include the incidence of drug resistance observed in patients, issues of drug adherence, and numbers of newly acquired infections. The emergence of drug-resistant viruses can lead to increases in viral load and treatment failure, and such viruses can be transmitted to both healthy individuals as well as to untreated HIV-positive individuals, therefore threatening the long-term effica...

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Section: Discussionmentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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“…Clinical studies of INSTIs with or without FTC/TDF have shown durable efficacy (31)(32)(33)(34)(35)(36)(37)(38)(39). The INSTIs as a class and by themselves elicit a more rapid viral load decline than that observed for any other drug class.…”

Section: Discussionmentioning

confidence: 99%

“…Further, when dosed in a combination study of treatment-naive subjects receiving tenofovir and lamivudine (3TC) as a background regimen, subjects taking RAL had a more rapid decline in HIV-1 RNA than subjects taking the EFV-3TC-TDF regimen, although both arms reached the same reduction in viral load by week 24 (40). Clinical studies comparing EVG-COBI-FTC-TDF with EFV-FTC-TDF or ATV-ritonavir-FTC/TDF had the similar result of a transiently more rapid viral load suppression (36,37 In summary, the combinations of FTC-TFV with a third agent from one of the major drug classes, INSTIs, NNRTIs, or PIs, all showed additive to synergistic anti-HIV-1 activity in vitro. The strongest synergy was seen with the combinations of EVG or RAL with FTC-TFV, and this may contribute to the durable clinical antiviral efficacy observed for these drug regimens, which are both recommended as preferred INSTI-based regimens for ART-naive patients (49).…”

mentioning

confidence: 94%

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

Antimicrob Agents Chemother

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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 ...

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“…Stribild is the first and only integrase inhibitor-containing single-tablet regimen. Two independent, fully powered phase 3 noninferiority trials have compared Stribild with two current standard-of-care regimens for initial HIV treatment; these studies confirmed that Stribild has high efficacy and a good tolerability profile and is statistically noninferior to the two standardof-care regimens (DeJesus et al, 2012;Sax et al, 2012). The US Food and Drug Administration approved Stribild to treat HIV-1 infection in treatment-naive adults on August 27, 2012.…”

Section: Investigations Of Human Cytochrome P450 Enzymes Withmentioning

confidence: 96%

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

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This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drugmetabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b 5 . Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b 5 and P450 surfaces, showing that b 5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b 5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

show abstract

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial

Cited by 308 publications

References 27 publications

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

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

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

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