Debate continues over interaction between ritonavir-boosted atazanavir and antacids

Three letters published in the March edition of The Journal of Acquired Immune Deficiency Syndromes have illustrated that there is still considerable uncertainty about whether it is safe for HIV-positive patients to take atazanavir (Reyataz) alongside stomach acid-reducing medications.

Since atazanavir is only absorbed properly from the stomach when the acidity level is high enough, some experts are concerned that patients also taking acid-reducing agents may not absorb enough atazanavir. This may put them at risk of low blood levels of the drug, leading to the development of drug resistance and treatment failure. Since up to half of all patients receiving atazanavir may also take acid-reducing drugs, a large number of patients could be affected by this interaction.

A number of small studies have examined the effects of acid-reducing agents on atazanavir levels. These drugs include proton pump inhibitors such as omeprazole (Losec) and histamine-2 blockers like ranitidine (Zantac). The results of these studies led atazanavir’s manufacturer, Bristol-Myers Squibb to recommend that omeprazole not be taken by patients taking atazanavir and that histamine-2 blockers be taken twelve hours apart from atazanavir.

Two studies presented last year found that the negative effects of proton pump inhibitors were also seen when atazanavir is boosted by low doses of ritonavir (Norvir). These included a study of 48 HIV-negative volunteers, as well as a smaller study of HIV-positive patients in Los Angeles (Agarwala 2005; Khanlou 2005).

Now, however, this conclusion has been called into question by two teams of doctors and pharmacists. The first team, led by Kari Furtek, conducted a retrospective review of the virological outcomes of the 76 HIV-positive patients taking ritonavir-boosted atazanavir at their clinic in Rockville, Maryland.

Ten of these patients were also taking a proton pump inhibitor, with nine patients taking rabeprazole (Pariet) and one taking omeprazole.

After a mean of 21.6 weeks, nine (90%) of the patients taking a proton pump inhibitor had viral loads below 500 copies/ml, compared to 55 (83%) of the 66 who were not taking a proton pump inhibitor. This difference was not statistically significant, suggesting that any differences in atazanavir blood levels may not necessarily translate into worse virological outcomes.

“Simultaneous use of atazanavir / ritonavir and proton pump inhibitors was not associated with a higher virologic failure rate than was observed in those not taking a proton pump inhibitor,” they conclude. “Although long-term studies involving both therapeutic drug monitoring and clinical response rates are needed to determine efficacy, it would seem that HIV-infected patients are less susceptible to this interaction. The reason for this is unclear.

“Although confusion remains on whether this interaction is clinically significant in HIV-infected patients, limited pharmacokinetic and clinical data suggest this interaction may not prohibit the use of these two agents in all patients,” they add.

Jean-Baptiste Guiard-Schmid and colleagues also call the negative effect of proton pump inhibitors on boosted atazanavir levels into question. They refer to a cohort study they carried out in 2005 which showed no effect of proton pump inhibitors on the minimum blood concentration of atazanavir in 92 HIV-positive patients taking ritonavir-boosted atazanavir, the opposite conclusion from the Los Angeles study (Guiard-Schmid 2005).

“Our conclusion is … completely different from that of Khanlou and Farthing because we observed that proton pump inhibitors seem to be compatible with boosted atazanavir therapy in clinical practice,” they write.

Their letter claims that the Los Angeles study’s findings are unreliable because the atazanavir levels reported are higher than those in previous studies of ritonavir-boosted atazanavir.

They suggest that this is due to blood samples being taken too soon after the last dose of atazanavir was taken by the patients. Samples should be taken 24 hours after the last dose, in order to get a measurement of the lowest blood concentration, just before the next dose is taken by the patient.

However, these claims are countered by the Los Angeles study’s original authors, Homayoun Khanlou and Charles Farthing, writing with Stan Louie. They state that their original study of HIV-positive patients from ten clinics was carried out correctly, but that the difficulty in interpreting the results of the conflicting studies is a result of the wide variability in atazanavir levels seen in different patients.

Despite their differing conclusions and opinions, the teams of doctors and pharmacists agree that further larger studies are required to understand the relationship between atazanavir and acid-reducing drugs in patients with HIV. Ideally, these should include a range of different measurements of atazanavir levels and compare these to virological outcomes.

Furtek and colleagues write, “until firm correlations between atazanavir minimum concentrations and virologic response are available, the long-term outcome of such a combination remains unclear. … Additional clinical data, including the use of a control group for comparison, are needed to make clinical decisions regarding this potential drug-drug interaction.”

Until the results of these larger trials are available, doctors with patients taking atazanavir and proton pump inhibitors should take care to either monitor atazanavir levels or continue to follow the current recommendation for patients taking atazanavir to avoid taking proton pump inhibitors.