GMHC Treatment Issues, 9(10) - October 1995
Theo Smart

Ritonavir: The combination of Abbott Laboratories' ritonavir, AZT and ddC rapidly achieves a CD4 count jump of more than 110 cells, and a greater than 99 percent reduction in viral load which is sustained for the duration of a twenty week study. Still more strikingly, there is an increasing proportion of participants whose HIV level becomes so low that it is below or at the limit of detection by the PCR assay used to detect viral load. Daniel Norbeck, M.D., of Abbott presented this very preliminary data from a French study, conducted by Jacques Liebowitz, M.D., in twenty-nine volunteers (not all of whom have completed twenty weeks of treatment). After two months, five of 27 participants had undetectable HIV levels. Seven out of twenty had undetectable HIV after five months, while four more experienced 99.9 percent of the maximum detectable reduction in viral load.

Dr. Norbeck suggests that "the reservoirs of virus are emptying," in the treated population. By reservoir, he means that the longer-lived infected cells, such as macrophages and monocytes, which continue to produce virus for weeks (unlike an actively infected CD4 cell, which dies in two days). Many researchers believe that since present drugs do not kill infected cells, their use can only eliminate all of the virus from the body if they can keep suppressing HIV replication, even in the face of mutations that confer partial drug resistance, for a period longer than these cells' lifetimes. It is debatable whether Dr. Norbeck can claim such success on the basis of one small study.

Abbott appears even more excited about the promise of combination therapy with ritonavir and Hoffmann-La Roche's protease inhibitor saquinavir (abstract LB-7). Although cross-resistance between protease inhibitors is a concern, the initial resistance mutations arising with ritonavir and saquinavir therapy are distinct, and the hope is that two- protease combination therapy could suppress viral replication enough to delay the emergence of resistance indefinitely. Saquinavir's antiviral effect, however, is limited by the low blood levels of saquinavir achieved with the current dose and formulation. People are not getting enough saquinavir, because the little that is absorbed is rapidly broken down in the liver.

Abbott may have a solution: ritonavir shuts off the metabolic pathway in the liver that breaks down saquinavir as well as ritonavir. In rats, co-administration of the two drugs led to an eighteen-fold increase in peak levels of saquinavir in the blood (from a single dosing) and extended the drug's half- life fifteen-fold. (The cumulative increase in drug levels from multiple dosing could be much higher.) Dr. Norbeck concluded that ritonavir and saquinavir may have a "two- dimensional synergy."

Follow-up studies must be done immediately to see whether the interaction occurs in people. Although no dose-limiting toxicities have been encountered yet with saquinavir, no one knows about higher blood levels, and an effect of this magnitude may be extremely dangerous. As GMHC's David Barr remarked, "people may want to trade in their livers after using this combination," if this interaction is indeed seen in people.

It may not be. The antifungal medication ketoconazole also slows down the same liver pathway. According to Noel Roberts of Roche Laboratories in Great Britain, co-administration of ketoconazole and saquinavir also dramatically boosted saquinavir levels in rodents, but the increase was much less impressive in humans. Still, just a three- or four-fold rise in blood levels could be helpful, particularly in those people receiving low doses of saquinavir in the current phase III trials and expanded access program.

[As Treatment Issues went to press, Miklos Salgo, M.D., Roche's director of clinical research notified us that Abbott and Roche have reached an agreement to start drug interaction studies in both dogs and people before the end of the year.]

Indinavir sulfate (Crixivan): Higher doses of this Merck protease inhibitor have a much more profound and sustained effect in naive patients than lower doses, reported John Mellors of the University of Pittsburgh (abstract I172). The findings come from a study comparing indinavir to AZT, discussed previously in Treatment Issues (January, 1995, pages 1-2). In this study, the dose of indinavir was increased to 600 mg four times a day after Merck found that HIV quickly becomes resistant to lower doses. Increasing the dose had little effect in the patients who had initiated therapy at lower doses, but researchers suspected that the CD4 and viral load responses would be better in patients who begin therapy at a higher dose.

This proved to be the case in the sixteen trial participants who had been randomized to AZT and were crossed over (at week 24) to the protease inhibitor at the 600 mg four times a day dose. These patients began indinavir therapy with median CD4 cell counts of 110. After six months of treatment, the majority of these patients had sustained reductions in viral load, although there was a trend back toward baseline. At week eight, half of the patients had more than a 1.98 log (almost 99 percent) suppression in viral load. At week 24, half maintained at least a 90 percent reduction in virus, and a third still had 99 percent less virus than when they started therapy. Median CD4 counts remained more than 100 cells above baseline.

The findings were similar in a 24 week study comparing indinavir sulfate (600 mg four times a day), AZT, and indinavir and AZT combined (abstract LB-6). This study enrolled 73 volunteers with CD4 cell counts below 500 (median 221) and viral load levels greater than 20,000 copies per ml, (median of approximately 80,000 copies per ml).

At the point of maximum antiviral effect, AZT monotherapy produced around a 75 percent reduction in viral load (0.6 log), while indinavir monotherapy and combination therapy reduced viral load by medians of 99.5 and 99.75 percent, respectively (2.3 and 2.6 logs). At week 24, viral load was only slightly (0.2 log) below baseline for AZT monotherapy. The viral load was still significantly below baseline for indinavir monotherapy and combination therapy, 1.5 log and 2.5 log, respectively. Although the difference between the combination arm and indinavir monotherapy arm was not statistically significant, there was a clear trend toward a rebound in viral load on monotherapy compared to a more sustained suppression of HIV on combination therapy. CD4 cell analysis was not complete for this study, yet there already is a clear benefit in favor of the arms containing indinavir.

In a meeting with activists several weeks before ICAAC, Dr. Jeffrey Chodakewitz of Merck reported data from a dose- ranging indinavir monotherapy study in more than 70 people. For the 800 mg thrice daily dose (the dose now used in Merck's trials), median viral load reductions were slightly greater than 99 percent at maximum, with a slight trend back to baseline by week twenty. CD4 counts increased by an average of more than 100 cells.

Activists asked Merck whether the company plans to run any studies of indinavir in perinatal transmission. Merck has expressed an interest in such studies, but the increase in bilirubin levels that indinavir induces are a more serious problem in infants than adults. Bilirubin can pass through the immature blood/brain barrier and cause severe disability.

AG1343 (VIRACEPT): Graham Moyle, M.D., reported on the British low-dose study, (abstract LB-3) previously reported in Treatment Issues (June, 1995, page 4). Six out of 22 patients had a greater than 90 percent reduction in viral load at day 28. This response was sustained for the duration of treatment (three to four months), and participants gained an average of 100 CD4 cells. Diarrhea was the most common side effect, occurring in eight out of ten of the people on the highest dose tested.

Marty Markowitz, M.D., of the Aaron Diamond AIDS Research Center in New York, announced the results of a dose-ranging study (that went higher than the British study) in people with CD4 cell counts greater than or equal to 200, and viral load levels greater than or equal to 20,000 copies per ml (abstract LB-4). The study evaluated three doses -- 500 mg, 600 mg and 750 mg -- all twice daily in 30 subjects. At day 28, CD4 counts had increased by more than 100 cells; the greatest response was seen in the patients on the highest dose. Several HIV-related conditions such as lymphadenopathy, hairy leukoplakia and candida resolved or improved in a number of patients.

The average maximum decrease in viral load ranged from 90 to 94 percent, and in some patients viral load dipped below the level of detection. There was no difference in anti-HIV effect by dose, although the viral load on the low dose did appear to begin to rebound toward baseline levels. However, Dr. Markowitz noted that individuals with higher drug levels in their plasma had more profound responses -- but higher doses did not always achieve higher blood levels of drug.

Overall, 21 participants had a greater than one log reduction needed to continue on VIRACEPT after the initial 28 day trial period. This criterion for study continuation caused consternation with AIDS activists on the West Coast, who noted that some participants who were dropped had desired to continue on therapy, largely because of improvements in CD4 cell counts. Dr. Markowitz countered that in patients who were not seeing at least a one log reduction, long-term therapy might induce cross resistance to other protease inhibitors, so treatment discontinuation was in their best interest. The activists felt that this decision should rest with the individual and their primary care provider.

Another area of concern to activists is VIRACEPT's shaky position as fourth protease inhibitor in a race for approval, where pivotal studies for the three competing drugs have already begun. Hoffmann-La Roche has already filed for approval of Saquinavir, and Merck and Abbott both plan to file for approval in the first quarter of the coming year. Agouron's pivotal clinical endpoint study in people with less than 50 CD4 cells is not slated to begin until the end of the year. The competing drugs almost certainly will be approved before this study is completed. It is unlikely that people with less than 50 CD4 cells will be compliant to the protocol when comparable drugs become available. Agouron's best chance of salvaging its phase III program would be to dramatically increase the size of this trial. This would decrease the time it would take to reach a conclusion, since increasing the number of participants will increase the number of endpoints that can be counted. Otherwise, the study may not find statistically significant evidence of the clinical benefit of the drug, and the company may have to start all over again, in a world where the other protease inhibitors are standard of care.

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