GMHC Treatment Issues, Vol. 10, No. 2; February 1996
Theo Smart

In one study, Abbott's ritonavir (brand name Norvir) was found to dramatically prolong survival and slow disease progression in people with advanced AIDS. Other trials found that Merck's indinavir combined with several nucleoside analogs can hold HIV blood levels for many months below minimum detectable levels (less than 500 copies of HIV genes (RNA) per ml of plasma).

Findings from the Ritonavir Clinical Study

Abbott, which was running behind Merck and Hoffmann-La Roche in the race to develop protease inhibitors, is so far the first and only company to show that its drug extends survival and delays opportunistic infections (abstract LB6a). The company accomplished this feat by counting the clinical events that occurred in 1090 volunteers with advanced HIV disease -- CD4 cell counts of 100 or below -- randomized to take either ritonavir (600 mg) or placebo twice daily. The participants had a history of more than nine months of prior anti-HIV therapy and added ritonavir to their existing regimen of nucleoside analogs (most commonly AZT or d4T -- 3TC was not yet approved).

At baseline, the median CD4 cell count was 18 in the ritonavir arm and 22 in the placebo group. The median HIV plasma viral load was over 250,000 copies per milliliter. After completing four months on the study, trial participants who reached an AIDS-defining event were given open-label ritonavir.

When planning the study, Abbott researchers had calculated that it would take only 191 clinical events (the appearance of new opportunistic infections) or deaths to show definitively that ritonavir had an effect. That figure was reached within one month, although the trial continued while the company confirmed each event. When the results were analyzed, it became clear that the people on ritonavir were doing better than those on placebo within ten days. After one month, only 69 opportunistic infections or deaths had occurred in those receiving ritonavir as opposed to 149 in those on placebo, a statistically significant difference. Forty-four of these events were deaths -- seventeen on ritonavir, and 27 on placebo.

After a median of six months follow-up (see table), 26 people on ritonavir versus 46 people on placebo had died, a 43 percent reduction in mortality. New OIs or death occurred in 85 people on ritonavir and 181 on placebo.

Viral load response was analyzed in 159 patients from the trial. Levels of virus decreased by 96 percent in the ritonavir arm but over time returned back upwards toward baseline. The trial's rapporteur, John Leonard, M.D., of Abbott, argued that virologic responses might have been more sustained if trial participants had begun their concurrent therapies at the same time as they started ritonavir. CD4 and CD8 cell responses (followed in 215 participants) were also significantly better in those taking ritonavir (47 CD4 cells and more than 200 CD8 cells above baseline at week sixteen).

An Australian team led by David Cooper, M.D., performed a more in depth exploration of the immunologic effects of ritonavir in 21 patients from an earlier trial by analyzing the functional responses of the new CD4 and CD8 cells (abstract 232). The team determined that the new CD4s acquired during the first four weeks of therapy were primarily clones of existing memory cells (lymphocytes that respond to previously encountered pathogens), and that new "naive" cells (which might be able to mount an immune response to infections for which there is no pre-existing defense) were noted only after the first four week period.

CD8 cells increased here too (abstract 451). Andrew Carr, M.D., one of the Australian team, noted that ritonavir's ability to increase CD8 cell counts has no parallels in the CD8 responses observed for reverse transcriptase inhibitors, whether alone or in combination. In laboratory tests, the ability of some patient's cells to proliferate after exposure to certain foreign antigens improved, as did the ability of cells to secrete the immune stimulant IL-2. Improvements in a few clinical conditions, such as KS and oral hairy leukoplakia, were also noted and attributed to a restored immune response.

Surrogate Marker Data

Abbott: A group of French researchers addressed whether combinations of ritonavir with other antivirals can force the virus into submission in an open-label study of ritonavir plus AZT/ddC in 21 individuals (abstract 285). The baseline CD4 count was 156 and viral load was 69,780 copies per ml. Early data suggested that over time, viral loads dipped below the limit of detectability in a growing number of patients on the combination (see last October's Treatment Issues, pages 4-5).

The combination's antiviral effect, which really improved only slightly after the first month, may now be dwindling (see table). Viral load was undetectable in seven patients at month five, but only in five at month six. The actual change in median viral load between month five and six is very small, though, (median viral load merely went from 351 to 892) so it is not clear yet whether the increase is a random blip or reflects a gradual viral rebound.

Merck: This company may be seeing more sustained results with a different combination. Roy Gulick, M.D., of New York University reported on a study comparing Merck's protease inhibitor indinavir plus AZT/3TC to AZT/3TC or indinavir monotherapy (abstract LB7). The study enrolled 97 people with at least six months of prior AZT therapy, CD4 cells between 50 to 400 and a viral load higher than 20,000 copies/ml. The median baseline viral load was 40,000 copies, and the median CD4 cell count was 142.

The three drug combination most reduced viral load (by more than 99 percent -- see table on page 2). The antiviral effect appears sustained in the combination arm, maybe dissipating slightly in the indinavir monotherapy arm, but is clearly on the way back to baseline in the AZT/3TC arm (only 75 percent below baseline). The results at week 24 are a little shaky, though, since only eight to ten patients in each arm have been on therapy for that long. Viral loads at week 24 were below detectable limits in six out of seven trial participants receiving the triple combination for that long. CD4 cell responses were greater in the indinavir containing arms.

Indinavir plus AZT/ddI may not sustain its antiviral effect as well (abstract 200), but this is a completed study and not merely an interim analysis. A 24-week study enrolled 78 antiretroviral naive patients. At study entry, the median CD4 count was 150 and median viral load was 100,000. Again, the antiviral effect of three drug combination was greater and more sustained than AZTddI or indinavir monotherapy (see table for details), although ten patients dropped out of the study because of ddI's gastrointestinal side effects.

Agouron: The company has now shown a dose effect with its protease inhibitor, nelfinavir, by raising the dose to 2,250 mg a day. During the conference, Agouron presented data on the combination of nelfinavir with d4T in a meeting with community representatives, doctors and stock analysts.

An ongoing trial is comparing d4T to d4T plus nelfinavir (two doses) in people with CD4 cell counts 200 or higher and viral loads above 15,000 copies per ml. The median baseline viral load in the different trial arms ranged from 50,000 to 70,000. The two drug combination achieved dramatic reductions in viral load (more than a 99 percent reduction day 45 -- see table on page 2) and increases in CD4 cell counts, but data are available for only seventeen people at day 28 and six to eight at day 45.

Duration of Effect

The Agouron study illustrates the chief problem with the information available on protease inhibitors -- the effect is profound, but given the development of resistance, will it last for more than a few months? Researchers suggest that the combination therapy approach will postpone resistance, but again for how long?

There is no way to say until studies longer than six months are conducted. Some researchers and doctors are pushing patients to use the combination therapies while they still have low viral loads and high CD4 cell counts because they reason that the effect will last longer and that resistance will take still longer to develop with early treatment. But, again, no one knows how much longer.

What scant long-term data there is comes from studies of indinavir. Data out to sixty weeks were presented from an open-label phase 1 trial of indinavir monotherapy in five volunteers (abstract 147). After 24 weeks, four of the five resumed taking their previous nucleoside analog therapy in addition to indinavir. Mean CD4 count for the five at week 60 remained 140 cells above baseline, and viral load was still 96 percent below baseline -- levels not significantly different from their peak responses. Weight also had increased an average of 3.5 kilograms and remained stable.

Another presentation (abstract 146) had a positive report on indinavir monotherapy. The dose-ranging study was in 70 infected people with a median baseline viral load of 126,000 and a median baseline CD4 count of 250. This baseline CD4 count is about 90 to 100 cells higher than in the combination studies above, and the viral load response seemed greater and more sustained. There was little difference between the study arms, but the dose now used in clinical studies (800 mg every eight hours) at week sixteen reduced plasma HIV levels by a median of 99.5 percent, and the effect was sustained out to week 24.

In a state of the art symposium on protease inhibitors, Emilio Emini, M.D., of Merck (abstract L1) briefly presented follow-up data from this study. The suppression of HIV continued unchanged through week 48 in fifteen people who had at least a 99 percent reduction in viral load at week 24. There clearly is not the rebound in viral load that was seen in Merck's earlier studies with lower doses.

The profound antiviral effect seen with indinavir may even be depleting the viral reservoirs in the lymph nodes. The lymph nodes trap large amounts of free virus which can survive for an unknown length of time and may infect cells passing through the nodes. Dr. Emini presented data of antiviral activity in the lymph nodes of five people who had lymph node biopsies after eight weeks on therapy. The people experienced a 99 percent reduction of infectious virus in the lymph nodes that matched a 99 percent reduction in plasma viral loads. Indinavir may also penetrate the brain, another reservoir for virus, at levels 40 to 50 percent of that achieved in the blood.

Side Effects and Drug Interactions

None of the three potent protease inhibitors have been directly compared to one another. In a few months, though, ritonavir and indinavir will be competing for market share, and nelfinavir may be available, too, by the end of the year. The antiviral activity reported for these drugs may sound very similar at this point, but their side effects and drug interactions are distinct.

Ritonavir appears to be the least well tolerated. In the French surrogate marker study mentioned above, which used the old liquid formulation, three-fourths of the study participants experienced nausea, more than half had diarrhea, and more than a quarter had episodes of vomiting. One-third dropped out. Likewise, 91 (seventeen percent) of those receiving ritonavir in the clinical endpoint study for advanced patients stopped taking the drug because of nausea, vomiting, weakness and diarrhea.

Few patients seem willing to quit indinavir due to side effects. The reported elevated levels of bilirubin do not appear to produce symptoms or discomfort. Nephrolithiasis (accumulation of drug residue in the kidneys similar to kidney stones) seems more serious as kidney stones can be extremely painful. In the studies reported at the conference, though, people with this side effect continued on drug without dose reduction. Some new side effects were reported in the indinavirAZT/ddI study: indinavir therapy caused more cases of dry skin, insomnia, rash, pharyngitis and flank pain.

Meanwhile, nelfinavir causes grade I/II diarrhea, characterized as two to six bowel movements per day in 70 to 100 percent of the patients on the three highest doses. The company claims that this diarrhea is mild, "just loose stools, really" and that only 40 percent of the patients choose to treat it with antidiarrhea medication.

Convenience of dosing is a factor that people take into consideration when deciding whether to take a drug. Here ritonavir wins out, with twice-a-day dosing, although people have to take six capsules each time. Nelfinavir has to be taken three times a day with a little food. Conversely, indinavir has to be taken three times a day on an empty stomach, difficult to do for patients struggling to keep their weight stable.

Finally, ritonavir has a powerful inhibitory effect on the liver's ability to metabolize many drugs, which therefore cannot be taken concurrently (see last December's Treatment Issues, page 8).

The Next Generation

Other companies hoping to cash in on the protease inhibitors will have to find some marketing advantage for their compounds -- such as lower price, better potency, or fewer burdens for its recipients. An important positive feature would be that the drug requires of HIV a unique genetic pattern to protect itself from that drug. HIV that develops resistance to other protease inhibitors to which it is exposed would then not be cross-resistant to the new one even before a patient starts taking it.

A number of drug developers have already dropped out because they could not get ahead of the competition. Bristol-Myers did so after discovering that its compounds were not adequately bioavailable. Since these drugs did not stand out from the other current protease inhibitors, the company chose to scrap the whole program rather than spend more funds on improving them. The reverse transcriptase inhibitor nevirapine (see page 9) has exhausted Boehringer Ingelheim's will to do any further AIDS research, so its protease inhibitors are trapped in the starting gate.

For others, the work on perfecting their protease inhibitors continues. Glaxo Wellcome's 141W94 compound, purchased from Vertex, has the advantage of already being in human trials. It also has the distinction of accumulating in the brain -- cerebrospinal fluid levels of 141W94 reach about 170 percent of the levels in the blood.

Upjohn continues preliminary testing of its protease inhibitors, with the first safety and metabolic trial of the discontinued U-103017 in HIV-negative humans reported on at this conference (abstract 153). Upjohn's compounds are known for the unique resistance pattern HIV develops in response to them. They do not suffer from cross-resistance with the more established protease inhibitors. Gilead Sciences has temporarily delayed clinical studies of a potent class of protease inhibitors because the company's chemists believe they can make a few modifications to the lead compound so as to eliminate cross-resistance.

Parke-Davis has a class of novel compounds (abstract 149) that are currently hampered by binding to blood plasma proteins. The Parke-Davis compounds are similar to Searle's second generation compounds, which were reported to have little cross-resistance. Parke-Davis is currently trying to ascertain whether its drugs are active against virus resistant to the Merck and Abbott drugs.

The only new compound entering clinical trails in the near future is Ciba-Geigy's lead compound CGP 61755. A dose- ranging study and a fourteen day viral load study will begin shortly in the Netherlands. CGP 61755 is potent in the test tube and synergistic with saquinavir (abstract 150). Animal studies suggest that it is safe and highly bioavailable. Plasma protein binding appears to have little effect on its antiviral activity. Unfortunately, there may be cross-resistance problems between CGP 61755, ritonavir and indinavir, which give rise to similar resistance patterns in HIV. CGP 61755's chief advantage is that it is easy to manufacture. That should translate into lower retail costs, one hopes.

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