Important note: Information in this article was accurate in January 2000. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, January 2000
David Gilden
Indinavir's standard dosing schedule is 800 mg every eight hours. Even if this schedule is strictly followed, the liver degrades indinavir so rapidly that blood levels subside by 98% before the next dose is taken. Taking indinavir along with the protease inhibitor ritonavir, which blocks the CYP3A liver enzyme that metabolizes indinavir, considerably reduces this extreme variation. Concurrent ritonavir also makes possible longer intervals between doses.
The amount of ritonavir necessary for such "pharmacokinetic (PK) enhancement" has not been pinned down. As may be recalled from our ICAAC report, there is an ongoing inter-company argument over whether more of Merck’s indinavir or more of Abbott’s ritonavir should go into the combination. The options range from a combination of 1200 mg indinavir plus 100 mg ritonavir once a day to 400 mg of each drug twice a day. The latter is Abbott’s favorite. The company’s scientists argue that the 400/400 combination provides more constant levels of indinavir between doses. Maximum levels are reduced while the inhibition of the liver increases the minimum levels.
This adjustment in the indinavir concentration curve could reduce the failure rate on indinavir (due to suboptimal interdose levels) while reducing indinavir side effects, which are related to high peak levels. (Major side effects include elevated, asymptomatic bilirubin levels and painful indinavir precipitation in the kidneys). A Dutch investigation1 reported at the 7th European Conference on Clinical Aspects and Treatment of HIV- Infection associated variations in indinavir’s toxicity and activity to the blood levels of the drug achieved in different individuals: Those with lower indinavir levels were more prone to HIV breakthrough over the course of a year while those with the highest indinavir concentrations showed more signs of kidney problems.
The Dutch study found wide variations in indinavir levels in different persons as well as in the same person over time. These variations probably result from small differences in liver metabolism. Use of concurrent ritonavir promises to moderate the interpersonal variation in addition to the intrapersonal one. Coadministration of ritonavir also allows indinavir to be taken with meals, which otherwise interfere with indinavir absorption.
Abbott is ahead of Merck in testing the ritonavir/indinavir combination. In two reports at the 7th European Conference, the 400/400 option proved quite active for as long a year. An uncontrolled German study2 followed 92 treatment-naïve volunteers who took 400 mg ritonavir and 400 mg indinavir twice daily plus two nucleoside analogs. Average baseline viral load was 401,000 copes/mL. Forty-eight weeks worth of data were available for 88 of the participants, including 24 dropouts. About 90% of the continuing trial participants, or 70% of the entire 88, had viral loads below 80 at this 48 week point. Similarly, Cassy Workman, M.D., of Sydney Australia followed 33 of her patients receiving an initial therapy of d4T /3TC / 400 mg ritonavir/400 mg indinavir, all taken twice daily.3 Twelve of the 14 patients now out to a year have viral loads below 50 copies/mL. Another 12 patients discontinued the dual protease combination. Blood lipids rose sharply in both studies. The Germans study recorded a mean 130% increase in triglycerides and a 40% rise in cholesterol. Seven of Dr. Workman’s patients had serious or life-threatening increases in these lipids. Ritonavir is usually most associated with lipid rises. These two studies lacked comparison treatment arms, though, so it is difficult to say how much responsibility each of the protease inhibitors bore for the lipid changes.
Indinavir’s specific side effects were uncommon in these studies, but ritonavir’s were a big issue. Both studies listed an inability to tolerate the foul-tasting liquid ritonavir formulation (since replaced by a new capsule) as a major reason for switching off ritonavir/indinavir. Other well-known ritonavir problems – nausea, diarrhea, numbness about the mouth and elevation of liver enzymes in the blood (a sign of liver damage) – also were common complaints.Ritonavir plus saquinavir, 400 mg of each twice daily, has been an accepted combination for the past several years. This combination, the most popular way in which saquinavir is administered, considerably reduces saquinavir consumption, saquinavir in the new, improved Fortovase formulation is taken alone as 1200 mg three times a day. That dosage requires swallowing six large, oily capsules each time. Hoffmann LaRoche, saquinavir’s manufacturer, has now weighed in with a new ritonavir/saquinavir combination, 1600 mg Fortovase plus 200 mg ritonavir taken once daily.
Seven Dutch patients described at the 7th European Conference4 were switched from the standard saquinavir/ritonavir regimen to this new one. An analysis performed 14 days after the switch found considerable interpersonal variation in blood levels. The critical minimum concentration between doses varied by eight-fold within the group. Four of the patients showed high saquinavir levels throughout the 24-hour period. The other three had markedly lower saquinavir levels. Their minimum concentration was below the targeted level, but only marginally so in two cases. Ritonavir levels were subtherapeutic for all seven. In addition, triglycerides in the blood decreased by an average 32% during the 14 days, a statistically significant reduction that may be due to the reduction in ritonavir intake.
These results are similar to a larger 14-day U.S. study5 conducted with 41 HIV- negative volunteers taking several once daily combinations of Fortovase and low-dose ritonavir. In that study, minimum blood levels of saquinavir in a 1600 mg/100 mg Fortovase/ritonavir once-a-day combination averaged 5.5 times higher than with the standard Fortovase alone regimen. Maximum saquinavir levels were about eight times higher. Major side effects (nausea and vomiting, diarrhea, flatulence, fatigue and sleepiness, headache, and irritability) occurred somewhat more frequently in the persons receiving ritonavir in addition to the Fortovase.
Abbott has one final argument for higher ritonavir levels. In lab tests, there seems to be a certain synergy between ritonavir and the other protease inhibitors.6 Combining ritonavir and another PI yields greater than additive HIV suppression. This would argue for including substantial, therapeutic amounts of ritonavir in addition to the other protease inhibitor.
The basis for such synergy is obscure. One possibility is that the various available protease inhibitors exhibit varying binding capacities to the protease enzymes present in different HIV virions. In particular, some HIV protease may contain mutations conferring resistance to some, but not all proteases. Two PIs would therefore cover more of the HIV in someone’s body. This synergy would be furthered in the body if the two drugs show differential penetration of different cell types.
Abbott’s claimed synergy is in any case minor except with saquinavir, and its benefit in humans has not been demonstrated. A Danish trial presented at the 7th European Conference,7 did find indications of a long-term difference in antiviral effect between combination regimens containing just indinavir or ritonavir and one with both ritonavir and saquinavir (each dosed at 400 mg twice daily).
The study included 318 volunteers, none of whom had received protease inhibitors before. All received two nucleoside analogs in addition to their protease inhibitors The proportion with viral loads below 20 copies/mL at 48 weeks was 42% for those on indinavir, 40% for those on ritonavir and 58% for those taking the saquinavir/ritonavir combination. This trend did not quite attain statistical significance.
The ritonavir/saquinavir certainly proved more bearable than ritonavir by itself. Notably, the ritonavir alone combination (dosed at 600 mg twice a day plus the two nucleoside analogs) had a very poor record for tolerability in this trial, two-thirds of the persons receiving this regimen dropped out. About a third of those in the other two treatment arms discontinued the study.
The twice daily ritonavir/saquinavir combination also was easier to take than the thrice daily indinavir regimen. The improved tolerance and convenience by themselves could account for much of the added antiviral benefit without resorting to the purported antiviral synergy between ritonavir and saquinavir. Fewer side effects and easier dosing would tend to increase trail participants’ adherence to dosing schedules, and adherence is a critical factor in an antiviral therapy’s success.
It will take a comparative trial of different doses of ritonavir plus a second protease inhibitor to definitively compare antiviral synergy, tolerance and other possible advantages of high- or low-dose ritonavir combinations.
ACTG 5055, a recently commenced American trial in 50 persons failing nelfinavir, saquinavir or amprenavir, proposes to do just that for indinavir/ritonavir. The trial will assign volunteers to take the two protease inhibitors twice daily at doses of either 400 mg each or 800 mg indinavir plus 200 mg ritonavir. (Everyone will also receive two nucleoside analogs, one of which must be new.)
The 800/200 indinavir/ritonavir regimen has achieved a certain popularity in HIV clinics because it seems better tolerated than the 400/400 combo while retaining activity as a second-line or salvage therapy. ACTG 5055’s central goal is to compare the pharmacokinetics (drug blood levels) and tolerability of these two regimens over 48 weeks. Antiviral response is included as a secondary endpoint.
Comment
ACTG 5055 will provide new information on the relationship between drug levels, effectiveness and side effects, but it will hardly have the last word. The subject of ritonavir-containing protease inhibitor combinations is fraught with commercial implications. Each company has a strong interest in boosting the intake of its own product at the expense of the competition. Whatever the outcome of ACTG 5055, reanalyses of the available data and further studies are sure to ensue as each company tries to advance its cause. In the end, the choice of doses may be an individual one, depending on each patient’s side effects and metabolism more than on theoretical anti- HIV efficacy.
1. Burger D et al. Indinavir Pharmacokinetics are Related to Efficacy and Toxicity. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. October 23- 27 1999; poster 826.
2. Rockstroh JK et al. Efficacy and Safety of BID Firstline Ritonavir+Indinavir plus Double Nucleoside Combination Therapy in HIV-Infected Individuals. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. October 23-27 1999; poster 452.
3. Workman C et al. Virologic & Immunologic Response to Combination Protease Inhibitor (PI) Therapy with Ritonavir (RTV) & Indinavir (IDV) in Antiretroviral Naïve HIV+ Patients. 7th European Conference on Clinical Aspects and Treatment of HIV- Infection. October 23-27 1999; poster 620.
4. van Heeswijk et al. The Steady-State Pharmacokinetics of Saquinavir in a Once Daily Dosing Regimen with a Low Dose of Ritonavir. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. October 23-27 1999; poster 830.
5. Saag MS et al. Saquinavir Systemic Exposure and Safety of Once Daily Administration of Fortovase (Saquinavir) Soft Gel Capsule (FTV) in Combination with Low-Dose Ritonavir (RTV). 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 26-291999; poster 330.
6. Moll A. et al. Synergistic Anti-HIV Activity of Ritonavir and Other Protease Inhibitors in the Presence of Human Serum. 12th World AIDS Conference. June 27-July 3 1998; poster 12315.
7. Lundgren JD et al. Comparable Virological Results among Patients Treated with Ritonavir, Indinavir or Ritonavir/Saquinavir in Combination with Two Nucleoside Analogues. Results from a Randomised Study. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. October 23-27 1999; poster 487.
000110
AM000102
Copyright © 2000 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2000. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.