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INDINAVIR (CRIXIVAN™)
Emilio Emini, Ph.D. Merck Research Laboratories
Indinavir (Crixivan™ or MK-639) is a potent HIV protease inhibitor with an inhibitor constant (Ki) for HIV protease of 0.3 nM. It is synergistic with nucleoside analogues in cell cultures. Studies with indinavir monotherapy with a lower than recommended dose have demonstrated a > 1 log (>90%) decline in viral load as determined by the amount of HIV RNA in serum and 50 to 80 cell/mm3 increase in CD4 counts.
Results from Merck protocol 019 have provided important clinical demonstration of indinavir's anti-HIV activity. This was a Phase II, multi-center, double-blind study involving HIV-infected people, who have received no more than 2 weeks of prior AZT therapy, with CD4 counts less than 500 cells/mm3 and HIV RNA of greater than 20,000 copies/mL. Study participants were randomized to receive either indinavir monotherapy (600 mg capsule every 6 hours) or AZT monotherapy (200 mg three times a day) or indinavir plus AZT. There were 20 to 25 patients per treatment group. The study duration was 24 weeks.
At week 24, participants in the indinavir and AZT group had a median reduction of HIV RNA by 2.5 log as compared to 1.5 log for those in the indinavir monotherapy group and fewer than 0.5 log for those in the AZT monotherapy group. Few patients in the indinavir/AZT group had a l log drop in HIV RNA at week 24. Dr. Emini explained that the diminished level of viral suppression was due, in part, to the selection of indinavir-resistant HIV strains.
In contrast, there were also a few patients in the indinavir/AZT group who
had decreases in HIV RNA by as much as 4 log which were maintained at week
24. Study participants' baseline HIV RNA levels, however, were not
reported.
The proportion of patients with at least a 2 log (99%) decline in HIV RNA were 60% in the indinavir/AZT group and 40% in the indinavir alone group. The proportion of patients with HIV RNA below 200 copies/mL was also higher in the combination group (40-50%) compared to the monotherapy group (10-20%).
Median CD4 increases of 50 and 100 cells/mm3 were observed in the indinavir and indinavir/AZT group, respectively, as compared to a median CD4 decrease of 25 cell/mm3 in the AZT group. Dr. Emini commented that while data from protocol 019 showed favorable trend toward the positive effect of indinavir plus AZT as compared to indinavir alone on surrogate markers--viral load (HIV RNA) and CD4 counts--but were not statistically significant due to the small number of study participants. However, both indinavir monotherapy and the combination were statistically significantly more effective than AZT monotherapy.
Indinavir was generally well-tolerated in all study participants. Principal side effects were a dose-related hyper-bilirubinemia (or elevated bilirubin levels) occurring at an incidence of about 15% and nephrolithiasis (or formation of kidney stones, possibly due to crystallization of indinavir), occurring at an incidence of 2 to 3%. There were no unique toxicities associated with the use of indinavir in combination with AZT.
Laboratory analyses of blood samples taken from study participants were performed to determine the presence of HIV genetic changes associated with AZT-resistant strains. At week 24, AZT-resistant mutant strains were detected in 11 out of 16 patients from the AZT mono-therapy group, 1 out of 13 patients from the indinavir monotherapy group, and 1 out of 13 patients from the indinavir plus AZT group. Taken together, these findings suggested that use of indinavir in combination with AZT may delay the emergence of AZT-resistant mutant strains over the study duration (24 weeks).
Dose-ranging studies (Merck protocol 006 and 021), conducted earlier, have demonstrated that indinavir's maximum anti-HIV effect can be achieved at current recommended dose of 800 mg every 8 hours. Administration of the current dose was associated with both a median HIV RNA decline of 2.0 log and a median CD4 count increase of 100 cells/mm3 at 24 weeks. Importantly, results from dose-ranging studies have indicated that patients who have initiated therapy at lower doses of indinavir exhibit less of an anti-HIV effect and were less likely to demonstrate a persistent effect (see table 3 below).
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Dr. Emini also stated that "patients who have initiated therapy at sub-optimal doses were less likely to exhibit the expected antiviral effects upon increase in dose to optimal levels."
Based on resistance studies of indinavir, Dr. Emini concluded that:
· HIV resistance to indinavir is mediated by the expression of multiple and variable protease amino acid substitutions (mutations). · Resistance to the inhibitor can be attributed to changes at 11 amino acid residue positions. · In general, higher levels of resistance involve the expression of greater numbers of substitutions at these sites. · Continued virus replication results in the sequential accumulation of substitutions.
Dr. Emini also offered the following considerations for people who might soon initiate protease inhibitor therapy:
1. Therapy with a protease inhibitor should not proceed from lower to higher doses since this will promote the step-wise accumulation of resistance-associated mutations and will select for virus populations with reduced susceptibility for the higher (optimal) doses. 2. Initial therapy with any protease inhibitor should begin at the highest effective and safe dose. This will result in more profound antiviral effects in significantly more patients and the effects will be sustained for longer periods of time.
To address the issue of cross-resistance between indinavir and ritonavir (Abbott's protease inhibitor) or saquinavir (Roche's protease inhibitor), Merck has conducted cell culture experiments using both laboratory strains and clinical isolates of HIV. These studies have revealed that HIV strains that were resistant to indinavir were fully cross-resistant to ritonavir. Furthermore, ritonavir-resistant viruses, selected by ritonavir in cell culture, were cross-resistant to indinavir. The mutations selected by indinavir and ritonavir were largely overlapping.
On the other hand, cell culture experiments with indinavir and saquinavir demonstrated that two-thirds of indinavir-resistant strains were cross-resistant to saquinavir. However, saquinavir-resistant isolates, taken from saquinavir-treated patients, retained full susceptibility to indinavir in cell culture. Dr. Emini mentioned that the mutation pathway for saquinavir resistance partially overlaps that for indinavir resistance. He concluded that the clinical consequences of saquinavir resistance for subsequent treatment with indinavir are unknown.
Conclusions:
1. As a class, HIV protease inhibitors represent the most potent anti-HIV agents described to date. 2. Potency and duration of activity vary widely among the clinically evaluated inhibitors. 3. Long-term suppression of viral levels is possible in some patients treated with the more potent inhibitors. 4. Selection of virus resistant to high doses of these inhibitors is apparently difficult. 5. Varying patterns of cross-resistance are seen among many protease inhibitors. 6. For some inhibitors, CD4 cell count recoveries are not lost rapidly upon selection of resistant virus. 7. Initial therapy should be with the highest safe dose of the more potent inhibitors and, once started, therapy should be maintained. This will forestall resistant virus selection and enhance the probability of long term virus suppression. 8. The probability of profound and long-term suppression may be enhanced further by combination therapy with other antiretroviral agents.
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