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  11th International Workshop on Clinical Pharmacology of HIV Therapy
Sorrento, Italy
April 7-9, 2010
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What Will It Take To Replace Ritonavir as the Prime PK Booster?
...Debate Ritonavir v GS9350

  11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
HIV pharmacologists and clinicians, led by Richard Bertz and Trevor Hawkins, wrestled with the question of what makes a pharmacokinetic (PK) enhancer good and, more specifically, whether Gilead's GS-9350 (cobicistat) has the goods to replace ritonavir as a booster of protease inhibitors (PIs) and other drugs metabolized via the CYP3A pathway.
Debating at the 11th International Workshop on Clinical Pharmacology and HIV Therapy, Bertz championed ritonavir as the gold standard of enhancing agents, while Hawkins maintained that ritonavir's well-documented disadvantages have left the door open for cobicistat.
Bertz, who works for Bristol-Myers Squibb but worked at Abbott during ritonavir's development, conceded straightaway that this PI is not a perfect booster. But "for those who are religious, nothing is perfect--and for those who aren't religious, nothing is perfect."
Everyone familiar with antiretroviral history knows that ritonavir got developed not as a boosting agent, but as a first-line PI. But some may not realize that Abbott, recognizing ritonavir's lock-down inhibition of CYP3A4, ran pilot studies of its boosting potential with saquinavir and indinavir even before ritonavir got licensed. When the high dose of ritonavir needed to suppress HIV proved too toxic for many people and indinavir, then nelfinavir became the first-choice antiretroviral, ritonavir's life as a low-dose PI booster began.
The main advantage of using ritonavir to hike exposure to other drugs, Bertz argued throughout his presentation, is "you know what you're getting." After nearly 14 years of clinical experience with ritonavir, its safety profile may fall far short of friendly, but it is well understood. Bertz cited data from a study of boosted and unboosted atazanavir to argue that low-dose ritonavir contributes little to lipid elevations [2]. Drug interactions with ritonavir are also well-characterized and, Bertz maintained, manageable. Combinations that rely on a ritonavir-boosted PI are well established.
Bertz allowed that low-dose ritonavir does pose a theoretical risk of resistance, but he argued that 100 or 200 mg of ritonavir daily yield concentrations "largely below" the reported 50% inhibitory concentration (IC50) of wild-type HIV. Jonathan Schapiro, one of the session's cochairs, noted that IC50 is not the appropriate threshold for selection of resistant virus. "When there's a chance of resistance, there usually is resistance," Schapiro advised. And that could be a problem because ritonavir selects the position 84 mutation, which darunavir and atazanavir "don't like." Still, Bertz insisted that "HIV activity theoretically leading to PI mutations and resistance at low doses seems unlikely."
The resistance risk may loom larger if ritonavir sees wider use boosting drugs other than PIs, such as Gilead's integrase inhibitor elvitegravir. In such cases, 100 to 200 mg of ritonavir may be the only PI a person takes. But Bertz said he knew of no case in which PI resistance mutations arose when ritonavir boosted a non-PI. Cobicistat has no anti-HIV activity so it cannot select antiretroviral-resistant virus.
Ritonavir's principal patent expires in 4 or 5 years, Bertz added. When that happens, companies will produce generic ritonavir that can be coformulated with other drugs. Bertz maintained that these new boosted generics will be cheaper than drugs coformulated with Gilead's booster, cobicistat, whose patent clock has just begun to tick. Workshop attendees noted that the patent for ritonavir as a booster is further from expiration, but Bertz proposed that the original "composition-of-matter" patent is the one that matters. (Thailand already has a generic tablet formulation of lopinavir/ritonavir at a dose of 100/25 mg.)
Bertz argued that ritonavir has not maintained its lock on antiretroviral boosting by default. Early on, the potent CYP3A4 inhibitor ketoconazole attracted interest as a boosting agent but fell by the wayside. Since then several companies--including Sequoia, Pfizer, Tibotec, Bioaval, and Gilead--have studied new boosting compounds. Of the candidates explored, Gilead's cobicistat has emerged as ritonavir's staunchest competitor, and Bertz's debating nemesis, Trevor Hawkins, advanced the cause for this novel compound.
Hawkins, a US clinician and researcher with an interest in HIV pharmacology, listed advisory work for Gilead in his workshop conflict-of-interest statement. He argued that ritonavir holds pride of place among boosters only because the competition--until now--has proved feeble. Hawkins criticized ritonavir for some of the drawbacks that Bertz dismissed: lipid elevations, glucose intolerance, gastrointestinal intolerance, perioral parasthesias, and the extra copay required when treating with any boosted PI because ritonavir is coformulated with no other PI but lopinavir.
"Mild" side effects of low-dose ritonavir cannot be ignored, Hawkins maintained. "My patients don't like grade 1 nausea; they don't like grade 1 diarrhea." Many of the people he treats with ritonavir boosting say they know every public bathroom in town. Citing evidence that even low-dose ritonavir raises levels of low-density lipoprotein cholesterol and triglycerides [3,4], Hawkins noted a recent D:A:D cohort study that found an independent 11% uptick in myocardial infarction incidence in HIV-infected people with every doubling of triglyceride levels [5].
Observing that cobicistat is highly soluble and easy to coformulate, Hawkins made light of Bertz's claim that ritonavir is perched to become a good coformulation partner. Because "ritonavir crystallizes as soon as you look at it," coformulation won't be easy, Hawkins alleged. Bertz countered that the new melt-extrusion formulation of ritonavir can be coformulated with tablet agents, but the speakers did not wade into the tricky technical currents of coformulation.
Ritonavir hits too many targets, Hawkins said. These "undesirable, off-target drug interactions" include inhibition and/or induction of CYP2D6, uridine diphosphoglucuronosyltranssferase, and P-glycoprotein. Gilead designed cobicistat to hit mainly CYP3A4, though it is a weak inhibitor of CYP2D6, which is involved in metabolism of nonnucleosides and other drugs.
Researchers will learn much more about cobicistat from three ongoing phase 3 trials. But the new booster did not emerge unscathed from phase 2 studies, in which serum creatinine rose more and average estimated glomerular filtration rate fell more with elvitegravir/cobicistat plus tenofovir/emtricitabine than with efavirenz plus tenofovir/emtricitabine [6]. Although Hawkins suggested that Gilead "has seriously bad renal karma," he repeated arguments made during the presentation of these phase 2 data to suggest that cobicistat's potential impact on the kidneys is equivalent to that of cimetidine, an over-the-counter stomach acid blocker (see link at reference 6 for details).
Hawkins concluded that ritonavir cannot be called the best pharmacokinetic booster. "Best implies excellence," he reasoned. But "ritonavir is essentially a prototype whose time is soon to be at an end."
1. Bertz R, Hawkins T. Is ritonavir the gold standard for pharmacokinetic enhancement. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Roundtable discussion.
2. Malan N, Krantz E, David N, et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naive HIV-1 infected subjects, both with and without ritonavir: 48-week results from AI424-089. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver. Abstract 107LB. http://www.retroconference.org/2006/Abstracts/27965.HTM
3. Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med. 2005;6:421-425. http://www.ncbi.nlm.nih.gov/pubmed/16268824
4. Malan N, Krantz E, David N, et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naive HIV-1 infected subjects, both with and without ritonavir: 96-week results from AI424089. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 22-25, 2007. Sydney. Abstract WEPEB024. http://i-base.info/htb/2230
5. Worm S, Kamara A, El-Sadr W, et al. Triglycerides and the risk of myocardial infarction in the D:A:D study.17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 127. http://www.natap.org/2010/CROI/croi_28.htm
6. Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 58LB. http://www.natap.org/2010/CROI/croi_14.htm