Subject: State of The Antiviral Art Date: Feb 1993 (364 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Project Inform P E R S P E C T I V E &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Permission granted for non-commercial use. Survey: State of The Antiviral Art Behind the various headline grabbing stories from the International AIDS Conference in Amsterdam, there was a lot of information on the more mundane area of nucleoside analog antiretrovirals, both approved and in development. There was also some promising information on antivirals that work in other ways. On a practical level, these drugs, more than some of the ambitious high-tech treatments that get the publicity, will offer the real options for most people in the upcoming year. Understanding the new information available on AZT, ddI and ddC is key when considering new uses of these drugs, possibly in innovative combinations or at different doses. Various studies have come to light over the past few months which may help shed some light on shaping treatment strategies and reconsidering current courses of treatment. Early Intervention The debate on when to start antiviral therapy is ongoing. Some people believe that beginning AZT immediately, regardless of CD4 count, is the best treatment strategy. Others feel that waiting until the CD4 cell count falls below 500 is more beneficial. A recent report suggesting that the virus is never latent, or dormant, truly gives credence to the idea of beginning anti-HIV therapy earlier, perhaps when the body's immune system is still very healthy and functioning well. Fears around the development of AZT resistance, however, enter the debate and make the decision more complicated, although all studies to date have concluded that AZT resistance develops much more slowly in early disease. Whatever the outcome, the decision to initiate antiviral therapy must include weighing the pros and cons, considering the information available, and being aware of the potential risks and benefits. Regardless what the decision is, careful and ongoing monitoring of general health and laboratory tests is critical to making wise choices. Moreover, taking charge of your health, paying attention to nutrition, and considering options are all things that can be done right away, with very little risk and a whole lot of benefit. The center of this discussion typically falls to the question, "When should I start taking AZT?" It is important to remember that AZT is not the only option. More and more there is a growing consensus in the scientific community that combination antivirals are the way to go. There are no data, however, on the usefulness of combinations in very early stages of HIV-disease, although logically it makes sense that aggressive treatment early may alter the disease course. Because there are no clear data, the decision as to when to begin therapy, and what therapy to begin, falls mostly to personal choice and how you feel about it. In the April 1992 Perspective, we reported on preliminary information from a placebo-controlled, 1000-patient European/Australian study of AZT for early intervention. Study volunteers were asymptomatic with more than 400 CD4 cells, and two-thirds of the volunteers entered the study with between 500 and 750 CD4 cells. The earlier data showed that the placebo group was twice as likely to progress to symptoms or to significant CD4 cell decline (below 350) as the AZT group, and the side effects were indistinguishable in the two groups. In Amsterdam there was a final analysis of that study, which was stopped because it showed that, even leaving aside CD4 decline, people on placebo were progressing to symptoms twice as often as people on AZT. This lends weight to the idea of starting antivirals at counts above 500. The counterpart American study, ACTG 019, is following AZT and placebo groups who began the study with up to 800 CD4 cells. Thus far, there have been no definitive answers out of ACTG 019. AZT Versus ddI As noted in our July, 1992 Briefing Paper, ACTG 116B/117, a large study of AZT versus ddI in people who had at least four months of prior AZT use, showed a 33% advantage for ddI in preventing progression to new infections, and a modest advantage in CD4 counts. The advantage for ddI was the same no matter how long people had been on AZT, and it was most evident in people who started the study without a previous AIDS diagnosis. Subsequently, Bristol-Myers (maker of ddI) asked the FDA to widen the approved indications for ddI to include anyone with four months of prior AZT use, regardless of their immune status or how they were responding to AZT. In late September, 1992, the FDA approved an expanded labeling indication for ddI. Results of another large AZT-versus-ddI study (ACTG 116A), were announced on 30 December, 1992. The study, which enrolled 617 volunteers with CD4 counts of less than 300, randomized study participants to receive either AZT (600 mg/day) or one of two doses of ddI (500 mg./day or 750 mg./day). It is worth noting that at the time of the study the powdered formulation of ddI was still in use and 500 mg./day of the powdered formulation of ddI is equivalent to 400 mg./day of the current tablet form. Volunteers were eligible to participate in the study if they had CD4 cell counts of 300 or less, and symptoms of HIV-disease upon entering the study, or if they had CD4 cell counts of 200 or less and no symptoms. Of the 617 study participants, 380 had no previous history of AZT use, 118 volunteers had 8 to 16 weeks of prior AZT therapy, and 119 people had less than 8 weeks of prior AZT use. Of the 380 people who entered the study with no prior history of AZT therapy, only 18% of those randomized to receive AZT progressed in disease or died within one year. In comparison,31% of persons on the 750 mg./day dose of ddI and 29% of people on the 500 mg./day dose progressed or died within one year. While there is still more careful analysis which must be conducted on these data, the immediate take home message may be that if you are considering initiating single-agent antiviral therapy, AZT is a reasonable option. For the 119 persons who entered the study with less than 8 weeks of prior AZT therapy, who were then randomized to either continue AZT or switched to receive one of the two doses of ddI, there were no significant differences between clinical outcome. For the 118 volunteers who had 8 to 16 weeks prior AZT therapy, however, there was a significant benefit for those people who were switched to receive ddI. Of these study participants, 33% of the volunteers who remained on AZT developed a new AIDS- defining condition or died within one year, whereas only 11% of people receiving 500 mg/day dose of ddI, and 17% of those switched to 750 mg/day did. In this study, people taking AZT were more likely to have low white blood cell counts (e.g. granulocytopenia) than those taking ddI. While there was a trend toward a higher incidence of peripheral neuropathy (pain, burning or tingling in the hands and feet) in the group of people who were randomized to receive the 750 mg/day dose of ddI, there were no significant differences in the incidence of peripheral neuropathy between the group receiving ddI versus those who received AZT. If there had been any doubt, it now seems clear that the lower dose of ddI (500 mg/day which is equal to 400 mg/day tablet form) seems to be equally beneficial as the higher dose and there is a trend toward less adverse reactions to the drug with the lower dose. The optimal dose of ddI may be lower still. Doses of ddI are typically determined on the basis of body weight. Results of this study add to the bulk of information available on AZT and ddI, and provide additional information by which to make treatment decisions. However, the best therapeutic strategy may be combination use of AZT and ddI, or combinations of other antivirals, including ddC or d4T. Potential pancreatitis has been a serious obstacle to wider ddI acceptance, since this life-threatening side effect was seen to a significant degree in the very sick people who first got the drug. But interim reports, presented in Amsterdam, from two ddI studies in healthier people (CD4 counts up to 500) indicated no incidences of life-threatening pancreatitis and a much lower incidence of elevated amylase levels (a possible marker for pancreatic abnormalities). Then, in the August 27 New England Journal of Medicine, the publication of the final data from ACTG 116B/117 showed no statistically significant difference in pancreatitis between the group receiving 500 mg. of ddI and the group receiving AZT. People in this study either had baseline CD4 counts under 300 and a diagnosis of AIDS or ARC, or less than 200 CD4 cells and no symptoms. People taking ddI who are sicker than the study group must be considered to be at increased risk for pancreatitis, but it begins to look as if ddI-related pancreatitis may follow the pattern of AZT-related anemia, in which the severe anemia seen in sick people became rare-to- nonexistent as the drug was used in healthier people. A few additional points can be made about pancreatitis. First: people on ddI did see more frequent unfractionated amylase elevations than people on AZT, but this did not translate into more frequent pancreatic disease. Doctors whose patients are doing well on ddI but showing elevated amylase should request fractionated amylase levels, which look separately at amylase levels in saliva and elsewhere. If the increase is purely in the salivary amylase, there is little or no reason for concern because this bears no relation to pancreatic problems (though it may have some relation to dry mouth, another ddI side effect). Second: aerosolized pentamidine can also cause pancreatitis, or may contribute to it when used in combination with ddI. Although this potential side effect has long been reported, it has not been publicized or well understood, and some knowledgeable researchers suggest that the problem may be more widespread than most clinicians have realized. Although it has been common knowledge that pentamidine, when used intravenously, could cause pancreatitis, most physicians felt this was irrelevant with the aerosol, in the belief that the aerosolized drug never left the lung. This is apparently not true. Combinations of ddI and aerosol pentamidine should at least be watched carefully and avoided if possible, especially in people with a history of pancreatic disease. Finally: in June of this year, the American Journal of Gastroenterology published a study reporting a 43% pancreatitis rate in AIDS patients on ddI. This study is two years old, based on a small group in the early expanded-access program who received higher doses than are now used. There are various problems with this study's methods and conclusions, which called any elevated amylase levels "pancreatitis." The reported pancreatitis rate from the entire ddI expanded-access program and Phase I studies ranged from five to nine percent and, due to diagnostic inconsistencies, the actual rate may have been lower still. ddI Versus ddC Controversial results of a community-based study comparing ddI therapy to ddC in people who had failed or were intolerant to AZT were amlounced in late January 1993. The study (CPCRA 002) was an "open-label" study, which means that volunteers were aware which drug they were given. The study enrolled 467 people, two thirds of whom had an AIDS diagnosis. The mean CD4 cell count of study participants was 37. A first look at the study suggested that there was a slight, but insignificant, trend toward longer survival in the group of people taking ddC. A closer look at how the data were analyzed, however, reveals that this study is inconclusive at best The study was analyzed in such a way that the statisticians reviewing the data "corrected" for the fact there was a trend toward higher CD4 cell counts in the group of people who received ddI. This "correction" is misleading and in fact the actual numbers do not reflect a trend towards survival in people taking ddC While people who received ddI reported a higher incidence of stomach pain, diarrhea and symptoms of pancreatitis, people who took ddC reported a higher incidence of lesions in the mouth and symptoms of peripheral neuropathy. In both groups, however, there was an extremely high progression rate, nearly 66%, to a new AIDS defining illness or death within one year. What is most alarming about these results is they call into question the benefit of current antiviral options for people with more advanced stages of HIV disease. While it is clearly important to have adequate antiviral cover in later stages of HIV disease, this study seems to highlight first and foremost the need for more and better options, perhaps different therapeutic approaches incorporating new and innovative technologies, and a targeted research effort into therapeutic strategies for people with lower CD4 cell counts. Combination AZT and ddC On June 22, 1992, the FDA approved ddC for combination use with AZT, the first combination therapy approach to receive FDA approval. The approval was based on two small studies that showed superiority of combination therapy over monotherapy in both absolute CD4 increases and in duration of CD4 increases. Unfortunately, the wording of the approval was confusing, recommending the combination for some people under 300 CD4 cells with "significant clinical or immunologic deterioration", without defining the terms or indicating exactly who might best benefit from combination therapy, and leaving monotherapy as the standard of care. The first hope for clearing up this confusion may come from ACTG 155, a large study comparing AZT plus ddC to AZT alone Results from this study should be available soon In the meantime, with the buyers-club ddC gone and the approved ddC selling at a wholesale price of $1800 per year, some people are finding ddC less accessible than it was before it was approved. Combination AZT and ddI Not surprisingly, the combination of AZT and ddI appears to work at least as well as the combination of AZT and ddC. There were three studies presented at the International Conference in 1992, all fairly small, none very long-term, and all still in progress. Nonetheless, the evidence was generally comparable to the AZT plus ddC evidence and, in one major respect, better. The first study compared five different combination doses (ranging from 150 mg. AZT and 90 mg. ddI daily to 600 mg. AZT and 500 mg. ddI daily) to an AZT-only (600 mg.) arm. There were 69 volunteers, who began with CD4 counts under 400 (mean count: 259); half had less than four months prior treatment with AZT, half had none. At 24 weeks, all combination doses were significantly more effective than AZT alone (median CD4 increases: 166 on combinations, 77 on AZT alone), but there was little difference in response between the different combination dose levels. In all groups the peak CD4 increase was about twice as high in people who hadn't had previous AZT therapy, but combination therapy was still superior to monotherapy regardless of prior therapy. Decreases in viral burden were seen significantly more often in groups receiving combination therapy than monotherapy. The second study compared AZT plus ddI (one dose: 300 mg. AZT and 250 mg. ddI daily) to AZT (600 mg. per day) alternating with ddI (500 mg. per day) every three weeks. The 41 volunteers, some with AIDS and some without symptoms of HIV disease, began with CD4 levels below 350 and had less than three months prior AZT treatment. At week 54, the mean CD4 increase in the combination therapy group was 74, compared to a drop below baseline in the alternating therapy group. Of p24 antigen positive patients, twice as many reversed their positive status on the combination alm as on the altelnating arm. The third study compared three arms of AZT plus ddI (ranging from 150 mg. AZT and 134 mg. ddI daily to 600 mg. AZT and 500 mg. ddI daily) to a group receiving ddI alone (500 mg. daily). There were 116 asymptomatic patients with baseline CD4 counts between 200 and 500, with up to 13 months of prior AZT (but no ddI). At 24 weeks, across all the groups, the median CD4 increase was 64; there was no significant difference between the combination groups and the ddI-only group, and no significant difference between people who had previous AZT and people who had not. By 56 weeks, the numbers had changed somewhat but the basic conclusions hadn't. One interesting aspect of the third study is that thus far there is no apparent difference in benefit between the combination therapy arms and the ddI alone arm of the study. The study is still underway, however, and the advantage of a combination in healthier people might be more in how long it works than in how big the initial CD4 boost. An important finding of all these studies is the effectiveness of lower doses of AZT and ddI. Even at doses as low as 90 mg. ddI and 150 mg. AZT daily, the effect was as great as at full doses of each drug; whereas, in the comparable AZT- plus-ddC study, there were two low-dose arms that didn't show much promise at all. It may be that the synergy is stronger between AZT and ddI, or it may just be that ddI is a more effective drug than ddC. Time may change things, but it's reasonable to say, based on these three studies, that people planning to combine AZT and ddI might talk to health care professionals about using low doses of each drug: for example 300 mg. AZT and 250 mg. ddI daily (which is the sole dose used in the second study). This may provide a safety margin between the doses being used and the lowest doses that showed efficacy. People who have trouble tolerating even half doses of one or both drugs could experiment with cutting back to the lowest doses with the fair expectation of getting benefit. In effect, combining very low doses of AZT and ddI may provide an antiviral therapy for people who otherwise don't tolerate either drug alone. (Important note: all the ddI doses mentioned above refer to powdered ddI. Although the powder is still available, most people now take the tablet ddI, for which the doses are different. In tablets, the proper dose is four-fifths (or .8) of the powdered dose. So 500 mg. of powder equals 400 mg. of the tablets, 250 mg. of powder equals 200 mg. of tablets, and so on.) Dosing matters remain somewhat uncertain. AZT only comes in 100 mg. pills. ddI tablets and powder come in a variety of doses, as low as 25 mg., but at least two tablets need to be taken together, on an empty stomach, to provide the proper buffering, and a full powder packet should be used for the same reason. Some sources suggest that neither ddI nor AZT needs to be taken more than once a day, but this is unproven. In short, the case for combining AZT and ddI is strong. As a practical matter, how to pay for two drugs when insurance or government agencies may not cover both is a problem; but it helps that only half-doses of each are necessary. This potential for lower cost must be addressed in any discussion with insurers. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display