Boosted HCV proteases in the STAT-C era - what can we learn from HIV?

I'm far from a pharmacologist and nowhere near being an expert in pharmacokinetics, but my rudimentary view, based on this report Jules Levin did on a session addressing ritonavir boosted HCV PIs from the 5th International Workshop on Hepatitis C Resistance and New Compounds last summer in Boston, is that we certainly could learn a thing or two taught from the lessons of boostings past. Boosting HIV protease inhibitors with a sub-therapeutic dose of ritonavir was a break through in the fight against HIV. Boosted PIs allowed for a 'PK cushion' when it came to trough levels... that is, when the PI was at its lowest concentration in the body - usually just before the next dose - it was still well above the IC50 of the virus thanks to the metabolic inhibition provided by ritonavir. This cushion prevented sub-therapeutic levels of the drug which could lead to viral resistance. As an added benefit, this also allowed for less frequent dosing and a sometimes drastic reduction in pill count - hopefully, one could argue - leading to an improvement in patient adherence. The dark side of ritonavir boosting is the remote possibility that even a sub-therapeutic dose could lead to the development of HIV resistance, tolerability is still an issue, increased trigylcerides, kidney toxicity and the fact that an essential metabolic enzyme, CYP 450, an enzyme responsible for the metabolism of many common drugs, not just HIV protease inhibitors, was effectively being inhibited as long as the patient was on therapy. Drug-drug interactions are a major problem in boosted PI HIV therapy, and will continue to be.

So all of the above might be applicable to ritonavir-boosting of HCV protease inhibitors as well… at least some of them. Telaprevir, despite what was shown in vitro, doesn’t respond to ritonavir boosting in vivo, at least for the long haul. Experts are still speculating on the exact reasons why – perhaps an inhibition/induction mechanism on the part of Telaprevir or some secondary mechanism of metabolism. The good news is that some initial data shows Telaprevir may not actually need to be boosted in a majority of patients, still showing some remarkably good mean concentration levels at trough even with q12h dosing. What still hasn’t been shown – at least to my knowledge – is the range of intra-patient variability from that mean. From the HIV PI history books, we know that there is usually a wide range of variability when it comes to pharmacokinetics dependent on a range of host factors. Even though it looks like HCV resistance might not mean a whole lot in the long run - the jury is still out – if the risk of being on the wrong end of that PK curve can be avoided, then it should certainly be a priority to do so.

Danoprevir and ABT-450, among others, are HCV protease inhibitors that appear to benefit from ritonavir boosting or even require it. In fact, Roche changed the dosing in their INFORM-2 Phase I trial of Danoprevir to include ritonavir boosting - but we need to see more data before the final judgment. Where the therapies for HIV and HCV differ, however, is that the HCV patient will only be on a boosted PI regimen for a short period of time, vs the HIV patient who is on the drug indefinitely so some of the long term metabolic effects of being on a boosted PI may be avoided. Still, drug-drug interactions are a concern as is the safety of a patient on a boosted HCV protease inhibitor with renal and/or liver insufficiency.

Could the benefits outweigh the risks in using ritonavir to boost HCV PIs? It’s definitely a tough call at this point and any judgment would be highly theoretical given the relative shortage of data in this area. As new data emerges, we’ll get a better idea of any clinical benefit or potential safety risks for the HCV patient in this brave new era of STAT-C therapy. My semi-educated gut feeling is that boosted PIs will offer some benefit with providing a “PK cushion” thus a leg-up in preventing resistance… but will that be enough to actually prevent resistance given a rapidly replicating virus that can make every conceivable combination of mutations in the course of one day? Does a boosted HCV PI plus a nuc or non-nuke backbone present enough of a barrier to prevent resistance given the variables such as intra-patient PK variability, drug interactions and adherence issues? Will interferon and ribiviran still be needed to shore-up any gaps left by STAT-C therapy? How about next generation metabolic blockers like Gilead's Cobicistat now in development? Only time - and solid empirical data - will tell.