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Fortificación con ritonavir:
¿Medicina esencial o un burdo atajo?

It is now common practice for companies to improve the bioavailability of new anti-HIV therapies by combining them with a booster dose of Norvir (ritonavir). This extends the drug’s half life in the blood which reduces either the number of pills, the number of doses, or both. It can also eliminate food restrictions for some HIV drugs. In many cases, using Norvir allows a company to present their drug as a “once daily” product, with some obvious advantages for patients.

Researchers summarize these advantages by saying that Norvir boosting makes other protease inhibitors work better. However, improved bioavailability and simplified dosing are not the whole story. The rest of the story is typically not discussed and largely avoided in public discussions of new drugs. The unspoken, dark side of Norvir boosting harms patients in several ways.

The most obvious harm is that it excludes some patients from using the new product if they cannot tolerate Norvir. Even at the reduced doses used for boosting, many cannot use Norvir without experiencing significant and sometimes dangerous liver toxicity. “One-sixth of the standard dose” of Norvir may make it sound harmless, but ritonavir has a greater effect on how the body processes fats and sugars than any other protease inhibitor. The net result is sometimes too much for a patient to bear with drug side effects. Also, at least one drug, Aptivus, requires a large 400mg dose of Norvir as its booster. At this dose, a much wider range of people are not likely to tolerate it.

Second, using Norvir boosting greatly adds to the cost of therapy. While people who use federal payer programs such as Medicaid and ADAP were able to escape the infamous 400% increase in the price of Norvir imposed by Abbott in 2004, people with private insurance were not. Tens of thousands of people with HIV rely on private insurance programs, whose premiums—although declining in growth in the last two years—are increasing at an annual rate three times that of the general population. Even in federal payer programs, using Norvir at the old, lower price represents a significant cost addition to the price of an overall regimen.

There is also some concern over what will happen to the government price of Norvir when its manufacturer, Abbott Labs, reformulates the drug. The new “Meltrex” version will eliminate the need for refrigeration, thus extending its use especially in areas where refrigeration is difficult to attain. It’s unclear if the current version’s price for Medicaid and ADAP will extend to the new formula.

Third, a little known fact is that when companies develop new drugs with Norvir boosting right from the start, they must pay a royalty to Abbott Labs for using it. Although companies are required to keep the cost of this royalty private, some suggest that it is substantial and thus affects the price. Abbott disputes this, insisting the royalty is very small, but since no one will announce the cost publicly, we can’t say who is telling the truth. Whatever the amount, Norvir boosting adds directly to the cost of therapy in two distinct ways, one of which is invisible to the patient but nonetheless real. It forces a company developing a new drug to charge a higher price to incorporate the cost of the royalty. (This royalty does not apply to older protease inhibitors that were approved without ritonavir boosting but then added it to improve their performance.)

Finally, there is good reason to be concerned from a purely medical point of view. Norvir boosting works in two ways. First, it improves absorption of many drugs in the gut. While this helps the protease inhibitor that it’s boosting, it may also cause unintended increases in the absorption of other drugs used at the same time. Doctors must then take considerable care to make sure they don’t give the patient any other drugs that might be affected by this.

Second, and more importantly, Norvir works by the crude process of shutting off a natural function of the liver, called the CYP3A4 pathway. The pathway is there for good reasons. It is the product of literally millions of years of evolution. Its function is to rid the body of lipophilic compounds—substances that bind to lipids or fat. When this pathway is suppressed or shut down, lipids and compounds that normally bind to them remain in the bloodstream. Many of these are toxic; some are drugs. Most protease inhibitors fall in this category, and therefore using Norvir causes them to remain in the blood stream much longer than normal, and so too any other lipophilic compounds that the body would normally get rid of quickly. The consequences of doing this are not wholly known.

Should we be so casual about shutting this clearance process down, simply to allow a greater half life for a drug that the body perceives as toxic? It may sound crazy when described this way, but this is exactly what happens with Norvir boosting. Unfortunately, pharmaceutical companies only look at the issue from the narrow perspective of what will make their drugs work better, or appear more attractive to patients. When there was no other choice for people with HIV and no drugs that worked well enough without shutting down this process, it was easy to argue in favor of Norvir boosting. Now as there are alternatives, this “wisdom” must be revisited.

Norvir boosting has become an easy way out for companies. Rather than taking on the harder task of building better formulations that do not require boosting, companies have fallen into the habit of just using Norvir. All the problems associated with Norvir boosting are passed along to the patients in the form of side effects, and to the payers, in the form of higher costs. Companies that use the boosting strategy simply point the finger of blame at Abbott Labs when anyone complains. This is unfair and by no means in a patient’s best interests. Companies that use Norvir boosting are responsible for the problems it creates. Abbott Labs doesn’t force anyone to use it.

Certainly, having a once daily drug offers some advantages, but many studies suggest that there’s little difference in adherence between once and twice daily dosing. As well, there are other ways to improve the half life of drugs in the body. Companies should look to other options, including time release formulations, different buffers, formulations that are metabolized in other ways, etc.

Perhaps most importantly in the short run, companies should not be so quick to seek the perceived advantage of once daily dosing when it comes at the price of increased side effects and the higher cost of therapy. At the very least, companies should study alternative dosing schedules that use more frequent dosing or larger doses to achieve the desired effect. In the case of drugs like Gilead’s integrase inhibitor GS-9137, it is not too late to start studies that use alternate formulas or dosing schedules.

Why not at least give the patient a choice? Those who insist on once daily dosing can use the Norvir-boosted regimen; others can opt for an alternative. Having two choices would increase the potential market for GS-9137 by making the drug available to people who cannot tolerate Norvir at any dose.

It is no secret that many companies are currently searching for an alternative to Norvir that might achieve the same results. While this is encouraging on some levels, it is important that companies not merely seek products that duplicate exactly what Norvir does. It seems logical to expect that products which work by interfering with the same CYP3A4 pathway are likely to create the same side effects. Hopefully, companies have already recognized this. There are better, more humane ways to improve a drug’s bioavailability and durability in the blood stream, and that’s where researchers should be looking.