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February 1996

  1. Two studies establish efficacy of ritonavir
  2. Ritonavir prevents disease progression and prolongs life
  3. Potent, sustained antiviral activity of ZDV and 3TC combined with indinavir

Two studies establish efficacy of ritonavir

New protease inhibitor has prompt and potent antiretroviral activity

In two recently completed Phase II clinical trials, the protease inhibitor ritonavir has demonstrated antiviral activity superior to the effects achieved with nucleoside analog monotherapies and comparable to those achieved with zidovudine plus lamivudine. (Peak reductions in viral load, as measured by branched-chain DNA assay, were 1.18 log for ritonavir, versus 0.7 log for ZDV or ddI and 1.01 log for ZDV-3TC.) Indeed, on the basis of these short-term studies ritonavir appears to be the most potent antiretroviral agent ever developed. This new agent has side effects, particularly at higher doses, but severe adverse events have been rare and the drug is generally well tolerated.

Unlike saquinavir, another agent in its class, ritonavir -- formerly designated ABT-538 by its developer, Abbott Laboratories -- has unusually good oral availability, a prolonged absorption phase, and a half-life of three to four hours. As a result of these superior pharmacokinetics, adequate serum drug levels can be achieved with a twice-daily dosing schedule.

Investigators at 10 European and Australian centers enrolled 84 HIV-positive subjects with CD4 counts between 50 and 500 cells/mm3 in a double-blind, randomized, placebo-controlled Phase I and II study of the safety and effectiveness of ritonavir monotherapy. During the first phase, patients were randomly assigned to one of four ritonavir regimens (600, 800, 1000, or 1200 mg/day administered b.i.d.) or placebo. After four weeks, all patients on placebo were randomized to one of the four ritonavir dosages for the 28-week maintenance phase of the trial.

After 16 weeks of treatment, mean concentrations of viral RNA had returned to baseline in patients in the low-dose arms of the trial (600 and 800 mg/day). However, in patients receiving the highest dose of ritonavir (1200 mg/day) the mean reduction in plasma RNA was 0.81 log (bDNA) at 32 weeks. This group also had the largest and most sustained rise in CD4 counts after 32 weeks of therapy: a mean increase from baseline of 230 cells/mm3.

At two of the participating centers, viral load was assessed by a new and more sensitive quantitative PCR assay, developed by Roche Laboratories, that has a detection limit of a mere 400 copies of HIV-1 RNA per milliliter. Using this assay, investigators found that the mean maximal decrease in viral load, reached after eight weeks of treatment, was actually 1.94 log (Figure) -- indicating that the standard branched-chain DNA assay used elsewhere was underestimating the decreases in viral load achieved with ritonavir monotherapy.

Similar results -- and a similar correlation between increasing dosages and duration of response -- were achieved in a multicenter trial of ritonavir monotherapy conducted in the United States. This study also included a four-week, double-blind, placebo-controlled phase, during which the 62 subjects were randomized to one of four ritonavir regimens (600, 800, 900, or 1200 mg/day administered t.i.d. or q.i.d.) or placebo. At the end of this phase, all patients on placebo were randomly assigned to either of the t.i.d. or q.i.d. regimens for the remaining eight weeks of the trial. At the end of 12 weeks, a persistent reduction in viral load of 0.50 log was noted in one of the seven patients in the 600 mg arm, but in four of the five patients in the 900 mg arm, with the greatest reductions (1.7 log by bDNA) seen after two to three weeks of therapy. Moreover, ritonavir therapy resulted in a marked, and sustained, increase in CD4 counts. The median increase, after 12 weeks of therapy, was approximately 100 cells/mm3.

Although virtually all participants in both studies reported at least one adverse event -- with subjects most commonly citing diarrhea, nausea, headache, and weakness -- these side effects were generally minor and reversible. (There were 10 therapy-related withdrawals in the European-Australian trial, and three in the U.S. trial.) "Overall," the investigators concluded, "the durability of the antiviral effect of ritonavir appears to be similar to that of zidovudine and lamivudine combined."

Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995; 333: 1528-33.

Markowitz M, Saag, M, Powderly WG, Hurley AM, Hsu A, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333: 1534-9.

Dr. Michael S. Saag, author of "The Protease Inhibitors" (Vol. 1, No. 3, pages 42-45), member of the editorial advisory board of HIV Newsline, and a principal investigator of the U.S. ritonavir trial reported above, comments:

Although the clinical benefits of ritonavir therapy have yet to be established, the results of these two trials confirm that this agent has extremely potent antiretroviral and immunostimulatory effects, matching or exceeding those of any single agent or combination of agents studied to date. The antiviral effect of ritonavir does diminish over time in the majority of treated patients, but in a few of our patients impressive levels of antiviral activity have been sustained. In fact, in two of these patients it is impossible to detect HIV-1 RNA in plasma or to culture the virus from blood samples.

These are isolated cases, and we must resist drawing broad conclusions from anecdotal evidence, but the response to ritonavir monotherapy seen in these two patients does underscore the apparently unprecedented antiviral activity of this agent. In both of these studies, sharp decreases in viral load were associated with sharp increases in CD4 counts, even among patients with low baseline counts. (In the European-Australian Collaborative Ritonavir Study Group trial, 22 of 29 patients with initial CD4 counts below 100 cells/mm3 had maximal increases of more than 100 cells/mm3, and eight of these had increases of 200 cells/mm3 or more.) These data support the hypothesis that the loss of CD4 cells is a direct effect of infection, and they reaffirm the value of both CD4 counts and plasma HIV-1 RNA assays as markers of disease progression.

Ritonavir's powerful antiviral effect, combined with its good bioavailability, tolerability, and apparent lack of overlapping toxicity with agents currently approved to treat HIV infection, make it a logical candidate for use in combination with other agents.

Ritonavir prevents disease progression and prolongs life

First evidence of the clinical benefit of protease inhibition

When ritonavir, a potent, orally bioavailable protease inhibitor, is added to standard antiretroviral regimens, this investigational agent reduces rates of disease progression and death by more than half in patients with well advanced HIV disease. Interim data from a large, multicenter, randomized, placebo-controlled clinical trial involving more than 1,000 patients in Europe, Australia, and the United States indicate that the addition of ritonavir to a patient's antiviral regimen confers immediate and dramatic benefits. When investigators compared the incidence of new AIDS-related illnesses or death in the cohort of patients randomized to ritonavir (600 mg b.i.d.) plus their current antiviral regimen, versus the incidence in the cohort randomized to placebo plus their current regimen, they found that disease progression or death had occurred in 12.7% of ritonavir-treated patients and in 27.3% of those receiving placebo after a mean of six months of therapy.

One noteworthy aspect of this trial is that it was conducted in very sick patients. The trial was designed to gauge response to therapy in patients with baseline CD4 counts below 100 cells/mm3, and most participants had counts well below 100. (The median CD4 count in patients randomized to ritonavir therapy was 18 cells/mm3, versus 22 cells/mm3 in the placebo group, and fully one quarter of the study subjects had CD4 counts below 10 cells/mm3.) These patients were, on average, taking 11 other medications, either as antiretroviral therapy or as prophylaxis against opportunistic infections. Interestingly, roughly half of the participants were on antiviral monotherapy at entry, and all of them had been on therapy for at least nine months.

There were no statistically significant differences, at baseline, between the two study arms. All of the patients had high viral loads (5.41 logs in the treated cohort; 5.40 logs in the placebo cohort), and all were instructed to remain on their current antiretroviral therapy for at least the 16-week blinded phase of study. At the ended of the blinded phase, crossover to ritonavir was offered to all patients who had experienced an AIDS-related illness during the first 16 weeks of the study.

Response to therapy was prompt. Within two weeks of the initiation of ritonavir therapy, virus burden fell by more than 1.3 log in treated patients, and at the end of six months of follow-up, reductions of 0.5 log were sustained in most of these patients. A rise in CD4 counts of 40-50 cells/mm3 was seen in treated patients, and these increases were sustained throughout follow-up. Highly significant changes in CD8 counts were also seen in treated patients.

The drop-out rate in the treatment arm was roughly double that of the placebo arm (15% versus 7%), with nausea and other GI problems the most common complaints.

Although this trial was designed to test the safety and efficacy of adding ritonavir to whatever antiretroviral regimen a patient was already on, it should probably be regarded as a trial of ritonavir as sequential monotherapy, according to principal investigator John Leonard. In these patients, whose immune function is all but nil, ritonavir not only restores some lost function and delays disease progression, it reduces mortality by 43%. These results prompted Dr. William Paul, head of the Federal office of AIDS research, to declare that HIV-infected patients should be told that ritonavir is a promising new agent. "All signs are optimistic," he said, adding that in this instance "it is wrong not to be optimistic."

Leonard J, Cameron B, Heath-Chiozzi M, Kravcik S, Mills R, Potthoff A, Henry D. Prolongation oflife and prevention of AIDS in advanced HIV immune- deficiency with ritonavir. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D. C., January 28-February 1, 1996. Abstract LB6a.

Potent, sustained antiviral activity of ZDV and 3TC combined with indinavir

Most powerful drug combination yet studied

When the protease inhibitor indinavir is added to the combination of ZDV and 3TC, the antiviral potency of this already effective combination regimen is significantly enhanced. Data presented earlier this month at the third Conference on Retroviruses and Opportunistic Infections, which attracted more than 2,100 of the world's leading AIDS experts to Washington, D.C., establish that this triple-drug combination has greater antiviral efficacy than any single agent or combination of agents yet tested.

In this three-arm, placebo-controlled clinical trial, 97 patients with CD4 counts between 50 and 400 cells/mm3 were randomized to receive either ZDV (200 mg every 8 hours) plus 3TC (150 mg every 12 hours), indinavir alone (800 mg every 8 hours), or all three drugs at those doses. All participants in this trial had been previously treated with ZDV for no more than six months, and all had high viral loads (20,000 or more copies per mL). Potential participants were excluded from the study if they had previously been treated with 3TC or a protease inhibitor, or if they had demonstrated intolerance to ZDV.

Because kidney stones can develop in up to 3% of patients receiving the investigational drug indinavir, study participants were carefully monitored for changes in laboratory values. Hyperbilirubinemia did develop in 7 patients treated with indinavir and in 10 patients on triple-therapy, but no treated patient developed stones. Indeed, there was only one serious adverse event during the 24 weeks of this trial, and it was not thought to be related to drug therapy. In general, the drugs were well tolerated, and drug-drug interactions were not clinically significant.

Responses to therapy were highly dependent on baseline values, but all three treatment arms experienced highly significant reductions in virus burden. In the ZDV-3TC cohort, median viral load fell 1.4 log during the the first few weeks of therapy and remained 0.6 log below baseline at 24 weeks. Patients treated with indinavir alone did even better, with a median reduction of 1.6 log at Week 2 and 1.3 log at Week 24. However, the best results were obtained in patients who received the triple-combination: their median reduction in virus burden was 2.0 logs at Week 2, and that reduction was sustained over the 24 weeks of the study.

Percent of treated patients with
undetectable levels of virus
Regimen 12 wks 24 wks
ZDV + 3TC 8% 0%
Indinavir 41% 44%
Indinavir +
88% 86%
When investigators looked at the proportion of patients in each group who experienced reductions in viral load of 1.0 log or more, they found this effect in 40% to 50% of patients on ZDV-3TC, 60% of patients on indinavir, and a remarkable 90% of patients on triple-therapy. These researchers also looked at the percentage of patients in each study arm whose virus burden dropped to undetectably low levels with therapy -- that is, to levels so low they cannot be measured by the most sensitive assay. These percentages showed the same advantages for combination therapy with ZDV and 3TC plus indinavir (Table).

(These dramatic results were an improvement over those from another trial reported at the conference. That study, which compared the combination of ZDV, ddI, and indinavir, found that three-drug therapy reduced virus burden to undetectable levels, i.e, less than 500 copies per mt, in 59% of study subjects.)

A comparable benefit for triple-therapy with ZDV, 3TC, and indinavir was found when investigators considered the most widely used marker of disease progression, CD4 count. Patients who were treated with ZDV plus 3TC experienced a rise in CD4 counts of 30 to 40 cells/mm3, whereas those treated with indinavir alone or the three-drug combination exhibited increases of approximately 100 cells/mm3, sustained over the 24-week course of the trial.

Gulick R, Mellors J, Havlir D, Eron J, Gonzalez C, McMahon D, Richman D, Valentine F, Jonas L, Meibohm A, Chiou R, Deutsch P, Emini E, Chodakewitz J. Potent and sustained antiretroviral activity of indinavir (IDV) in combination with Zidovudine (ZDV) and lamivudine (3TC). 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-Fehruavy 1, 1996. Abstract LB7.

Dr. Catherine M. Wilfert, a member of the editorial advisory board of HIV Newsline, comments:

Although we must be cautious about interpreting the data from any 24-week study, these early results are certainly impressive -- and they are undoubtedly going to accelerate the shift from monotherapy to two-, three-, and even four-drug antiviral regimens (see "The Changing Face of Antiretroviral Therapy," Vol, 1, No. 6, pages 101-102). While there is now compelling evidence that most patients benefit from a change in antiviral monotherapies or a combination of antiretroviral agents, we must not lose sight of fact that some patients do well, for long periods of time, on monotherapies.

The data from the trial of ritonavir in late-stage HIV disease show clear and convincing clinical benefits to what was, in effect, a switch from nucleoside analog therapy to protease inhibitor therapy. Moreover, at least one patient who has been treated solely with indinavir for 112 weeks has experienced such complete suppression of viral replication that it has been impossible to detect virus in his blood for more than two years. This is, admittedly, an isolated case, but we are hearing about more and more of these cases -- like the two patients treated with ZDV, ddC, and ritonavir who have no detectable virus burden after 54 weeks of therapy. What these reports tell us is that it is possible to achieve profound and sustained reductions in viral load, sometimes with a single agent. Our hope -- and expectation -- is that these reductions will translate into a survival benefit for treated patients.

With the advent of assays that directly measure virus burden in HIV-infected individuals, it has become possible to gauge the efficacy of antiretroviral thera- pies in a matter of weeks. This tool should help us to individualize therapy for our patients, to know when it is time to switch patients to another agent or to add a drug to their current regimen, and to assess the impact of those changes.

Until such time as HIV-1 RNA assays become widely available, clinicians will be obliged to rely on CD4 counts as a measure of antiviral efficacy. The value of this secondary marker of disease progression should not be underestimated; the long-term follow-up data from the Delta trial, which show a survival benefit for ZDV-ddI over ZDV-ddC or ZDV alone, also show a strong correlation between CD4 counts and survival.

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