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The Body Covers: The 37th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Double Protease Inhibitor Combinations

September 28-October 1, 1997

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Wednesday featured a lively session devoted to treatment with two protease inhibitors, with a number of provocative papers which left many questions posed but unanswered. They fell in to two categories: studies of protease naïve patients who had very good results on combinations which included ritonavir and saquinavir, and patients who had been previously treated with protease inhibitors, in whom the results were generally disappointing.

Abstract I-202. Safety and efficacy of a combination of ritonavir and saquinavir added to AZT + 3TC in HIV-infected patients. ANRS 069

This was a French pilot study of ritonavir/saquinavir added to AZT and 3TC in patients already on AZT/3TC for at least 3 months, who had viral loads of at least 20,000 copies/mL. Despite heavy pretreatment and failing AZT/3TC, nucleosides were not routinely changed. To date, 24 week results are available for 16 patients. Ten (had viral loads below 200 copies and 5 of 16 were below 20 copies. Elevations in liver enzymes were more common in patients with hepatitis C infection, a problem noted in the Abbott dual protease study. Although small, this study tends to support the findings of that study for protease naive patients. Since all patients had been on AZT/3TC, this study didn't help anwer the question of what other drugs should be used with ritonavir/saquinavir.

Abstract I-203. A pilot study of saquinavir in combination with ritonavir and d4T in patients with advanced HIV disease

A Swiss open label study reported triple combination therapy of two protease inhibitors and one nucleoside -- ritonavir, saquinavir, and d4T. The group had fairly advanced disease with a median CD4 count of 84 and almost 100,000 copies of RNA (4.9 log). Patients could have taken other nucleosides but were naïve to d4T and protease inhibitors. Results were available for 56 patients, although 64 have been enrolled. After 9 weeks of treatment, 67% were below 200 copies. Of those still taking drug, 79% were undetectable. Maximal suppression appears to be reached in most studies somewhere between week 12 and 18, depending on how high the initial viral load was, so final results for this study could be even a little better. However, 16% had moderate to severe side effects, usually nausea, vomiting and diarrhea. This may have been because all patients were encouraged to try to take 600 mg of ritonavir, but the dose was reduced for side effects.

I-207. The antiviral effects of ritonavir and saquinavir among HIV-infected adults: preliminary results from a community-based study

A community based study in British Columbia was presented by Julio Montaner which reported on patients treated with ritonavir, saquinavir, and whatever other drugs the doctor and patient felt were appropriate. Of those who had never taken protease inhibitors, 82% were below 500 copies at 7-24 weeks. However, of those who had taken protease inhibitors before, only 41% were below detection. In the analysis, previous use of proteases was the strongest predictor of failure. It was not clear that the choice of nucleosides made difference, although this type of study is not well suited to look at that. These provide more support for the activity of ritonavir/saquinavir in protease naive patients. Now for the bad news...

I-201. Usefulness of ritonavir and saquinavir combination therapy in HIV advanced patients failing on indinavir

Spanish investigators reported a series of 11 patients failing indinavir who were switched to ritonavir/saquinavir, and if possible changed at least on nucleoside RTI. There was a reasonable initial response with a 1.3 log drop in RNA at 24 weeks, although this is less than usually seen with protease inhibitor naive patients. However, 3 patients had no response whatsoever.

I-205. Virologic effect of ritonavir plus saquinavir in subjects who have failed indinavir

Steve Deeks reported on 19 patients from San Francisco General Hospital (SFGH) who had failed indinavir, but had never taken saquinavir. A median of 2.1 months after failing indinvavir, ritonavir/saquinavir was added and the nucleoside RTIs were changed if possible. There was an initial response with a 1.6 log drop in RNA, but by 24 weeks, only 2 of 15 patients were below 500 copies by bDNA assay. Interestingly, both of these patients had had undetectable viral loads, and changed after 2 viral loads had risen to over 1000. This suggests that intervening early after the virus starts to rebound may offer a better chance. Resistance studies showed that after failing ritonavir/saquinavir, almost all had mutations associated with saquinavir resistance, and most also had changes associated with ritonavir and indinavir resistance.

I-206. Efficacy of ritonavir and saquinavir in combination in protease inhibitor experienced patients

A French study reached similar conclusions to the SFGH study. Twenty four patients treated with indinavir (18) or ritonavir (6) were switched to ritonavir/saquinavir plus either d4T/3TC or AZT/3TC. Again, there was a reasonable initial response of 1.0 log, but it didn't last. At 4 months, the average response was less than a half log, and only 2 of 19 (10%) were below 500.

I-204. Experience with ritonavir/saquinavir based regimens for the treatment of HIV infection in subjects developing increased viral loads while receiving nelfinavir

But what about nelfinavir failures? Agouron has suggested that the unique initial mutation (D30N) may make it possible to successfully treat patients who fail nelfinavir with other protease therapy. Keith Henry from Minneapolis (at what was once known as St. Paul Ramsey Medical Center before the ravages of the market hit) reported preliminary data which does not yet answer this question. Patients who had participated in 3 trials of nelfinavir and had failed were changed to ritonavir/saquinavir. Those who had been on trial 506 had been on d4T and nelfinavir also added 3TC, those who had been on AZT/3TC and nelfinavir switched to AZT/3TC and ritonavir/saquinavir. A smaller group of patients with very advanced disease had been on trial 525. After 16 weeks, 12 of 12 patients who had been on trial 506 and 511 had viral loads below 500 and 6 of 7 were below 20 copies. Among those with advanced disease 3 of 7 were below 500. While this is encouraging, what matters is how long a salvage regimen lasts, and as Dr. Henry emphasized, 16 weeks and 12 patients is not nearly enough to know whether this response is "durable." In response to a question from the audience, Dr. Henry challenged the pharmaceutical companies to put an emphasis on funding studies for drug experienced patients who are failing protease inhibitors. The audience applauded.

Another fascinating tidbit came from a study of blood levels of the protease inhibitors. Two of the patients who did not respond well had much lower levels of saquinavir than expected. This points out person to person variability in drug levels of protease inhibitors. This author feels strongly that need to be able to measure drug levels to individualize drug dosing to improve our success rate.

State-of-the-Art Minilecture

John Mellors gave a summary presentation entitled "Dual Protease inhibitor therapy -- when and how should it be used" His first slide, said it all and read: "I don't know." He then went on to give a thoughtful and thought provoking overview. The logic behind studying dual protease regimens is well known. He proposed a check list against which to measure the regimens. Does the regimen: improve pharmacokinetics; decrease frequency of doses; lower the pill count; improve antiviral effect; delay resistance; and lower side effects. Prelimary data is beginning to come out on ritonavir and soft gel saquinavir, ritonavir and indinavir, ritonavir and nelfinavir, indinavir and nefinavir, and nelfinavir and saquinavir. Results should be available at the February Retrovirus meeting in Chicago (this is the meeting that used to be in Washington. February in Chicago was chosen to test the dedication of the researchers...)

The question left hanging over the end of the ICAAC was how to treat patients who have failed or will fail protease containing regimen. Combinations of two protease inhibitors with potent NNRTIs (like Dupont's DMP-266 aka efavirenz) and new nucleosides and nucleotides (like Glaxo's 1592 aka abacavir, and Gillead's adefovir) need to be carefully evaluated in clinical trials, rather than in series of anecdotes and case series. The last line of Mellors' last slide was sobering and important, although not eloquent: "Try to avoid protease resistance (salvage is difficult)"

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

See Also
More Third Line/Rescue HIV Treatment Research

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