Protease Inhibitors

Agents: atazanavir (ATV), darunavir (DRV), ritonavir (boosting dose: /r), fosamprenavir  (FPV), saquinavir (SQV), indinavir (IDV),  nelfinavir (NFV), tipranavir (TPV), ritonavir (full dose: RTV)

Combinations: lopinavir/ritonavir (LPV/r, Kaletra)

The introduction of the protease inhibitors (PIs)  was a major advance in antiretroviral therapy. Combination regimens with PIs were the beginning of the era of “highly active antiretroviral therapy” (HAART) and have had a major impact on prolonging lifespan among HIV-infected individuals. (Note: the term HAART has largely fallen out of favor.) PIs are now entering their third genera-tion, with more-potent agents with fewer acute toxicities; however, long-term toxicities are arising as a concern. A key advance has been the introduction of “boosting”: using the (normally undesirable) potent inhibition of drug-metabolizing enzymes displayed by ritonavir to increase the serum concentrations and half-lives of other PIs. Boosting is now routine for essentially all PIs: patients take an additional pill of a low dose of ritonavir along with their PI (typically indicated as “/r”, as in ATV/r).  The drug Kaletra (lopinavir/ritonavir) is the only agent where the boosted ritonavir is co-formulated into the same pill.

Spectrum

Only current clinical use is for HIV.

Adverse Effects

Cardiovascular: That patients with HIV were living long enough to suffer from heart attacks and strokes was viewed (somewhat perversely)  as a sign of the success of potent antiretroviral therapy, particularly PIs. However, the possibility of cardiovascular adverse effects is now recognized as a substantial problem. PIs appear to interact with conventional cardio-vascular risk factors to increase risk for myocardial infarction and stroke beyond that expected from just prolonging lifespan. Atazanavir and darunavir may confer somewhat lower risk compared with other PIs. Management is with all the mainstays of cardio-vascular risk prevention (diet, exercise, drugs).

Gastrointestinal: All PIs are pretty hard on the GI tract (nausea, vomiting, diarrhea). Taking the  drugs with food may reduce the symptoms somewhat. Many patients find the effects  more tolerable with time. Severe cases may require administration with anti-emetics or antidiarrheals.

Hepatotoxicity: The potential for hepatotoxicity exists with all PIs, ranging from asymptomatic transaminase elevations to clinical hepatitis. Risk may be highest with boosted tipranavir.

Metabolic: One means by which PIs increase cardiovascular risk is through adverse effects on the lipid profile. The PIs are also associated with lipohypertrophy (fat accumulation in abdomen, breasts, and neck).

Nephrotoxicity: Renal toxicity caused by certain PIs precipitating in the kidneys or ureters has been reported. This toxicity is most common with the now infrequently used agent indinavir, and it is reported rarely with atazanavir and fosamprenavir. Adequate fluid intake is recommended for prevention.

Important Facts

• Compared with the NNRTIs, PIs are more robust to antiviral resistance. Typically, several mutations in the target enzyme are required to confer high-level resistance. Thus, PI-based regimens may be slightly more “forgiving” of less than perfect adherence—although, of course,  that’s probably not the message to convey to your patients.

• The PIs pose tremendous drug interaction challenges. They are all substrates of the common drug-metabolizing enzymes and thus can have their concentrations substantially increased or decreased by drugs that inhibit or induce these enzymes. Ritonavir is one of the most potent inhibitors of the cytochrome P450 enzyme sys-tem; hence its use in boosting levels of the other PIs (at the boosting doses used, it has minimal direct antiviral effect). Generally, co-administering other drugs that are P450 substrates  (such as statins, macrolides, benzodiazepines,  and calcium channel blockers) with ritonavir leads to increased serum concentrations of these drugs. However, more unpredictable effects can occur, perhaps as a result of shunting to alternative pathways or mixed inhibition/induction, leading to the reduction in serum levels of P450 substrates (as can be seen withvoriconazole and methadone). The bottom line: for patients on PIs, carefully screen all of their medications for drug interactions using the most up-to-date references.

What They’re Good For

Several PI-based combinations are among the preferred regimens for treatment of initial HIV infection. They are also often used in salvage regimens for patients with resistant virus. Their durable viral suppression needs to be balanced against their long-term toxicities (particularly cardiovascular effects), and patients should be prepared to make appropriate lifestyle changes.

Don’t Forget!

Only atazanavir and fosamprenavir can be used un-boosted (and this is generally not recommended). If there’s not a little ritonavir in the regimen, some-thing is probably wrong.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.