A Randomized Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate for Initial Treatment of HIV-1 Infection

Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n ‫؍‬ 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n ‫؍‬ 40), lopinavir-ritonavir 400 and 100 mg twice daily (n ‫؍‬ 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n ‫؍‬ 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. Infection with HIV is a worldwide health problem, with an estimated burden of 34 million infected patients. With the introduction of highly active antiretroviral therapy (HAART), it has been possible to manage infections and prevent the occurrence of AIDS and HIV-related complications (1, 2). HAART is based on the coadministration of drugs that target several important HIV enzymes or cell coreceptors, including reverse transcriptase, integrase, protease, and CCR5. Currently, protease inhibitor (PI)-based regimens are often adopted for HIV treatment (3, 4). Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction o...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

“…In a 48-week head-to-head comparison with the fixed-dose combination of TDF, emtricitabine, and efavirenz (5) or TDF and emtricitabine combined with RTV-boosted atazanavir (7), a noninferior efficacy and differentiated safety profile for TDF-FTC-EVG-COBI was observed. Recent data from the 96-week analyses of both trials established the longer-term robust and durable efficacy of this regimen (6,9). Minor elevation in serum creatinine attributed to the direct inhibitory effect of COBI on renal organic cation transporters has been noted in clinical studies with the TDF-FTC-EVG-COBI regimen (5,7,18).…”

Section: Discussionmentioning

confidence: 97%

Evaluation of the Effect of Cobicistat on theIn VitroRenal Transport and Cytotoxicity Potential of Tenofovir

Stray

Bam

Birkuš

et al. 2013

A once-daily single-tablet antiretroviral regimen containing tenofovir (TFV) disoproxil fumarate, emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI) is an approved combination for the treatment of patients infected with HIV. COBI and TFV have been reported to interact with distinct transporters in renal proximal tubules; while TFV is renally eliminated by a combination of glomerular filtration and tubular secretion via anion transporters OAT1, OAT3, and MRP4, COBI inhibits renal cation transporters, particularly MATE1, resulting in a measurable decrease in the tubular secretion of creatinine. To investigate the potential for a renal drug-drug interaction between TFV and COBI in vitro, the uptake of TFV in the presence and absence of COBI was determined in fresh human renal cortex tissue and in cells expressing the relevant renal transporters. At concentrations exceeding clinical protein-unbound plasma levels, COBI did not significantly inhibit the transport of TFV by the anion transporters OAT1, OAT3, and MRP4 (50% inhibitory concentrations [IC 50 s] of >15, 6.6, and 8.5 M, respectively). Conversely, TFV had little or no effect on the cation transporters OCT2 and MATE1 (IC 50 > 100 M). Consistent with studies using individual transporters, no increase in the accumulation of TFV in freshly isolated human renal cortex tissue or renal proximal tubule cells (RPTECs) was observed in the presence of COBI. Finally, COBI alone or in combination with FTC and EVG did not affect the sensitivity to TFV of cultured primary RPTECs or cells coexpressing OAT1 and MRP4. These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction. STRIBILD, an antiretroviral single-tablet regimen, consists of two nucleoside/nucleotide HIV reverse transcriptase inhibitors, tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine, combined with the integrase strand transfer inhibitor elvitegravir and the pharmacokinetic enhancer cobicistat (COBI), which effectively blocks the CYP450-mediated metabolic clearance of elvitegravir (1-4). Once-daily treatment with this regimen showed noninferior and durable efficacy and safety in treatmentnaive HIV-infected patients when compared head-to-head with either efavirenz (5, 6)-or atazanavir (7-9)-containing once-daily treatment regimens. A small, early, and nonprogressive increase in the levels of serum creatinine due to a COBI-mediated blockade of creatinine active tubular secretion without an effect on glomerular filtration or overall renal function has been observed during clinical trials (10).The orally administered prodrug TDF is unstable in plasma and is rapidly hydrolyzed, releasing the parent nucleotide TFV. TFV is renally eliminated by a combination of glomerular filtration and active tubular secretion via renal transporters (11-15). TFV is taken up into proximal tubules by renal organic anion transporter 1 (OAT1) and OAT3, and its luminal efflux is mediated by ABC efflux pum...

“…As an example, the E92Q substitution, which has been shown to be prevalent in patients failing EVG-based therapy (23)(24)(25)(26)(27)(28), was associated with the highest level of resistance against this drug when introduced into stHIV-1. In agreement with our studies on the role of the G118R substitution in HIV-1 (29), this substitution was the only one that conferred moderate-level resistance in stHIV-1 against DTG (change, 6.4-fold).…”

Section: Discussionmentioning

confidence: 99%

Simian-Tropic HIV as a Model To Study Drug Resistance against Integrase Inhibitors

Wares

Hassounah

Mésplède

et al. 2015

Drug resistance represents a key aspect of human immunodeficiency virus (HIV) treatment failure. It is important to develop nonhuman primate models for studying issues of drug resistance and the persistence and transmission of drug-resistant viruses. However, relatively little work has been conducted using either simian immunodeficiency virus (SIV) or SIV/HIV recombinant viruses for studying resistance against integrase strand transfer inhibitors (INSTIs). Here, we used a T-cell-tropic SIV/HIV recombinant virus in which the capsid and vif regions of HIV-1 were replaced with their SIV counterparts (simian-tropic HIV-1 [stHIV-1] (SCA,SVIF) ) to study the impact of a number of drug resistance substitutions in the integrase coding region at positions E92Q, G118R, E138K, Y143R, S153Y, N155H, and R263K on drug resistance, viral infectivity, and viral replication capacity. Our results show that each of these substitutions exerted effects that were similar to their effects in HIV-1. Substitutions associated with primary resistance against dolutegravir were more detrimental to stHIV-1 (SCA,SVIF) infectiousness than were resistance substitutions associated with raltegravir and elvitegravir, consistent with data that have been reported for HIV-1. These findings support the role of stHIV-1 (SCA,SVIF) as a useful model with which to evaluate the role of INSTI resistance substitutions on viral persistence, transmissibility, and pathogenesis in a nonhuman primate model.