A Phase 3, Open-label, Dose Escalation Study to Determine the Pharmacokinetics of Atazanavir Administered With RIfampicin to HIV Positive Adults on sEcond-line ART Regimen With Suppressed HIV-1 Viral Load (DERIVE)

Background and Justification

Both HIV and TB can successfully be managed using the currently available medications with the latter being curable. However, due to the detrimental drug-drug interaction (DDI) between RIF and the bPIs, there is a challenge in the management of the two conditions concurrently in persons who need both classes of drugs. RIF is a strong inducer of the hepatic enzyme cytochrome P450 (CYP) 34A which metabolizes several agents including the PI drugs thereby reducing their bioavailability. While rifabutin, an alternative rifamycin is associated with less DDI with bPI and maybe a better alternative to RIF in such circumstances, its cost, toxicity and lack of co-formulated preparations renders it to be a less likely sustainable option especially in LRS.

Though data published in 2008 showed a high incidence of adverse events when higher adjusted doses of LPV/r were used to overcome the DDI effect with RIF among healthy volunteers, data in 2012 among HIV-infected adults treated with adjusted doses of LPV/r co-administered with RIF-based TB treatment showed the drug was well tolerated with no significant adverse events. The major difference is that the 2012 study was conducted among HIV infected patients, that were already on normal doses of LPV/r and RIF at the time of enrolment who underwent PI dose escalation unlike the 2008 study among healthy volunteers who received the RIF and shortly after higher than normal doses of LPV/r in short succession with no step-wise phase to allow compensation. Similarly to LPV, ATV is affected by the inducing effect of RIF on the drug metabolizing enzyme cytochrome P450 (CYP) 34A, thereby significantly reducing its bioavailability to sub-therapeutic levels when co-administered in standard doses with RIF.

Several studies exploring the interaction between ATV/r and RIF have reached similar conclusions to the experience with LPV/r and RIF: A study in healthy volunteers given RIF first, then ATV/r first at standard dose with proposed dose escalation was halted when the first three participants developed hepatotoxicity. It was noted that the pre-induction of giving RIF first could have caused this problem. This argument is supported by a study conducted by Burger and colleagues where participants were first given ATV/r before the addition of RIF and where no hepatotoxicity occurred; in that study, the dose escalation evaluated was insufficient to overcome the interaction, but concluded that further evaluation was safe and appropriate. Similarly, Acosta and colleagues concluded that increased unboosted ATV was safe for co-administration with RIF, but that higher doses are required to overcome the DDI. No studies have yet evaluated this interaction in HIV-infected individuals.

It is notable that all of the currently available PIs have been associated with transient and usually asymptomatic elevations in serum aminotransferase levels, and ATV has been associated with mild-to-moderate elevations in indirect and total bilirubin concentration. All studied PIs are rare causes of clinically apparent, acute liver injury. The protease inhibitors are heterogeneous molecules with little structural similarity, most of which are peptide-like and resemble the short peptide that is cleaved by the viral protease; for this reason, the patterns of liver toxicity will differ between drugs of this class.