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Tenofovir Emtricitabine Atazanavir Ritonavir

Tenofoviremtricitabineatazanavir Ritonavir

Abstract

In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens

Drug interactions

Owing to the numerous metabolic and transporter pathways in which it is involved, atazanavir/r is implicated in several drug–drug interactions. Only a few select interactions will be discussed in the context of this article. For a more thorough review of atazanavir drug interactions, consult the atazanavir prescribing information , antiretroviral treatment guidelines and/or an up-to-date antiretroviral drug interaction reference, such as the University of Liverpool HIV Drug Interaction website .

Tenofovir

The pharmacokinetic interaction between atazanavir and tenofovir was first described in 36 healthy volunteers receiving atazanavir 400 mg once daily . The addition of tenofovir decreased the atazanavir AUC and Cmin significantly by 25 and 40%, respectively, and thus should not be co-administered with unboostedatazanavir. When boosted with low-dose ritonavir, however, the interaction is largely overcome. Although some studies have documented a sustained decrease in atazanavir AUC by 25% (p = 0.05) when given with low-dose ritonavir in the presence of tenofovir ,others have found no significant difference in the atazanavirCmin or AUC Therefore, the impact, if any, of tenofovir on ritonavir-boosted atazanavir appears to be of low clinical significance in the absence of other drug interactions, and this combination has demonstrated optimal virologic efficacy in large, prospective, randomized controlled trials . The interaction may be bi-directional, as significant increases in tenofovirCmin and AUC in the presence of atazanavir have been reported [48]. These findings have not been consistently reproduced in all pharmaco-kinetic evaluations of tenofovir and atazanavir/r 300/100 mg in HIV-infected subjects [49,50]. The mechanism for this interaction is not fully elucidated, but may occur at the gut level and may be mediated by a drug-transporter pathway.

Rationale for ritonavir boosting & clinical efficacy

Several clinical trials and recent reviews have evaluated the efficacy of unboostedatazanavir in ART-naive and experienced patients. As current recommendations and routine clinical practice are to use ritonavir-boosted atazanavir in both ART-naive and -experienced patients, we primarily reviewed clinical trial efficacy data of atazanavir/r and comparisons with other ritonavir-boosted PI regimens (Table 3). If a patient has contraindications to ritonavir, then the provider should consider initiating an alternative cART regimen, such as a non-nucleoside reverse transcriptase inhibitor or integrase inhibitor-based therapy.

Patients and Methods

Retrospective chart reviews were conducted from July 2003 to March 2005 on treatment experienced HIV-1 infected patients residing in two active, urban clinical practices (San Francisco, California and Washington, D.C.). Patients included were required to have received at least one month of concomitant once daily TDF and ritonavir boosted ATV (ATV/r) following the change from other ART regimens. The major reason for this ART change was to reduce toxicities and/ or simplify therapy. At one site (Washington, D.C.), a small cohort of patients who received TDF with un-boosted-ATV (400 mg/day) were also included. This regimen was started before the pharmacokinetic drug interaction between TDF and ATV was identified.

The chart review included demographic information, HIV-1 RNA plasma concentrations, CD4 cell counts, clinical laboratory tests (including serum creatinine [SCr], total bilirubin, fasting lipids [total cholesterol, LDL cholesterol (LDL-c), HDL-cholesterol (HDL-c), triglycerides), prior and current ART, concurrent medications, and clinical adverse events as reported in the patient’s medical record. This research was approved by the University of California Committee on Human Research and a private Institutional Review Board in Wash DC.

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