Atazanavir and Acid-Lowering Therapy: DISCUSSION
Atazanavir requires a gastric pH below 4 for maximal dissolution and absorption. The manufacturer indicates in the product monograph that PPIs should not be administered with atazanavir and that PPIs may substantially decrease plasma concentrations of atazanavir, resulting in loss of therapeutic effect and development of resistance. Subtherapeutic levels of antiretroviral therapy can yield inadequate suppression of viral replication, increasing the risk of the viral mutation and subsequent drug resistance. Studies involving healthy adults offer proof that a pharmacokinetic drug interaction exists between atazanavir and acid- lowering medications, which potentially puts HIV-infected patients at risk of therapeutic failure. Case reports and retrospective and prospective analyses evaluating the interaction between acid-lowering agents and atazanavir have yielded conflicting results; of note, these studies have typically reported either the effects on pharma- cokinetics or the clinical outcome, but seldom both. All of the studies reviewed here are limited by small sample sizes and inability to correlate pharmacokinetic observations with long-term outcomes such as failure of the antiretroviral treatment. In terms of H2 receptor antagonists, Agarwala and others observed that the pharmacokinetic effects of famotidine on atazanavir could be minimized by temporally separating doses of the 2 drugs or by increasing the dose of atazanavir to 400 mg with ritonavir 100 mg. We found no published articles investigating the possible drug interaction between atazanavir and other antacids or buffered medications. PPIs have a greater impact on the pharma- cokinetics of atazanavir than shorter-acting acid-lowering agents, especially if given in higher doses. In the abstract presented by Luber and others, omeprazole 20 mg daily added to atazanavir had far less impact than was the case in previous studies using omeprazole 40 mg daily.
Several reasons may account for these conflicting results. Experts suggest that plasma concentrations in healthy subjects may not correlate with those of HIV-infected individuals and that HIV-infected patients may be less susceptible to this drug interaction because of a higher prevalence of hypochlorhydria. Another confounding factor is that many of the patients in these studies were receiving tenofovir as part of their antiretroviral regimen, a drug that has been shown to lower atazanavir levels. Atazanavir levels are highly variable and may not always correlate with viral response. Even though experts suggest maintaining the atazanavir trough concentration above 150 ng/mL, the minimum effective concentration of atazanavir has not been well established, especially in treatment- experienced patients.
Pharmacokinetic studies in healthy volunteers have clearly demonstrated that the bioavailability of atazanavir is compromised when acid-lowering agents are used concomitantly. Although the results of retrospective analyses and case reports are conflicting and do not strongly suggest that concomitant use of PPIs and atazanavir increases the risk of virologic or immunologic failure, long-term studies—especially in treatment- experienced patients—evaluating both pharmacokinetics and clinical response are required to establish the clinical relevance of this interaction. Until then, concomitant use of PPIs and atazanavir should be avoided if possible. If PPI therapy is necessary, the antiretroviral regimen should be changed to an alternative regimen not containing atazanavir, if possible. If the patient is limited to an atazanavir-containing regimen and an acid-lowering agent is required, therapy with an H2 receptor antagonist (with administration temporally spaced from the atazanavir) should be considered first. If PPI therapy is warranted while the patient is receiving atazanavir, the atazanavir should be boosted with ritonavir 100 mg daily and should be given at a minimum of 300 mg daily, the lowest effective dose of PPI should be prescribed, and the patient should be diligently monitored for virologic and immunologic failure. Therapeutic drug monitoring and resistance testing should be performed if treatment failure occurs. Inability to achieve adequate therapeutic levels may warrant an increase in the dose of atazanavir up to 400 mg daily, and evidence of drug resistance may dictate a change in the patient’s antiretroviral regimen. viagra plus