Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Jon Hubert, DDS

Jon Hubert: How long have you been working with the ACTU? Ann Collier: I have been working with the ACTU since its beginning, and helped bring it into existence by writing a grant in 1985. We have been in existence now for almost seven years. The Spring of 1986 is when the unit formally started.

JH: So you were one of the founders.

AC: That is correct. Dr. Corey, Dr. Coombs and I (and others) wrote the initial grant to fund the ACTU at the University of Washington, and we are still all involved.

JH: My perception is that most of your work has been in antiretrovirals. AC: Well, the unit itself was initially funded only to do antiretroviral studies. That was a decision on our part because the initial grants for the ACTU were divided into two pieces, opportunistic infections (OIs) and antiretrovirals, and we did not feel that we had sufficient manpower to do both parts of the initial program as it was constructed years ago. It was a purposeful decision that we would do the thing that we were the best at. Subsequently in 1989, the national program made a decision that they were going to reorganize the structure of the program. Rather than have sites that did just antiretroviral studies, sites that did just OI studies or sites that did both, they reorchestrated the program so that everybody did everything. So since 1989, we have had an opportunistic infection program within the Seattle ACTU and have been an active participant in a number of different OI studies. My particular interest tends to weigh a little more towards antiretrovirals, but I have been involved in OI studies too.

JH: Who else besides yourself, Dr. Corey and Dr. Coombs is involved in the ACTU?

AC: We have several other faculty and a large staff. Dr. Mac Hooton spends a third of his time as the director of the opportunistic infection program of the ACTU. (He has another position at Harborview as director of the Madison clinic.) Other UW faculty include Drs. Kidd, Unadkat, Marra, and Raisis.

JH: So the Seattle unit is focused on antiretrovirals and OIs.

AC: Yes, althoug more recently we have also been attempting to expand our neurological HIV studies. There has been a group of University of Washington investigators both inside and out of the ACTU who have been interested in issues of neurology and HIV for years. There has been a natural history study of HIV and the central nervous system that Dr. Hunter Handsfield and I started several years ago, in conjunction with neurologists, neuroradiologists and neuropsychologists. Recently, Dr. Christina Marra has joined the faculty at the UW as a neurologist interested in HIV.

JH: How about on a national level?

AC: There is a fourth area of interest at the national ACTG, which is oncology. We (UW ACTU) have not been a participant in that area, primarily due to the lack of interest of university affiliated oncolgists here in HIV related treatment studies. The oncology divisions at the University and at Harborview have other research interests. There is a HIV oncologic program at the Fred Hutchinson Cancer Research Center studying bone marrow transplantation. Dr. Corey is a close collaborator with that group. However, it is not part of the ACTU program.

JH: Is there anything else going on locally?

AC: The other thing that has sprung from our unit is a pediatric unit. For several years, the adult unit ACTUally supported pediatric and perinatal trials. Then that program was successful in obtaining its own funding. So now there are basically two ACTU's in Seattle: an adult unit, and a pediatric/perinatal unit under the direction of Drs. Sandy Burchett and Heather Watts. There are also many other HIV/aids research projects in Seattle, but they are not focused on treatment.

JH: While we are discussing what is done where, there has been a lot of community interest in convergent therapy. The number of sites for one multicenter study was expanded from 10 to 15 in the interest of geographic diversity. Three sites are in California and none in Washington. What can you tell us about site selection?

AC: Convergent therapy refers to using a combination of antiviral treatments that work against the same step in the virus's life cycle. There are currently 28 different adult units which are part of the actg. The issue about which trials get done where is a very controversial and complicated one, especially for trials which are viewed as popular or high priority. The particular trial of convergent therapy, which is actg 241, is the first convergent trial within the actg. There was a request for sites that wanted to participate and we said yes we did. There was also a requirement for substantial laboratory work with this study. We had also made commitments to do several other studies that had heavy laboratory demands in terms of quantitative virology. (The other studies we had committed to include the first proteinase inhibitor study in the United States and two vaccine studies.) The proteinase study is also considered one of the very desirable studies, and was a major consideration at sites which were not chosen for the actg 241 study.

JH: Can you summarize the major factors in site selection?

AC: ôThe powers that beö factor in access to the needed patient population, laboratory capability and what else a site is doing that is high priority and considered attractive. There is an attempt to spread the wealth of studies which are considered attractive and high priority. Part of our not being chosen for the convergent study had to do with already being a site for the actg proteinase inhibitor study.

JH: We had three of the studies that everyone else wanted, so why should we get the next high profile study too?

AC: Yes. The people making this decision know that this makes lots of people unhappy, at least the sites that are not chosen. The people who are involved in organizing such studies bear the brunt of that. (I got lots of unhappy phone calls from sites who were not chosen for the proteinase inhibitor study. That happens to be one I am head of so I got that kind of flack.)

JH: Is there a name of the committee for site selection?

AC: The Primary Infection Core Committee is the group of scientists and nih people that decides about the location of the primary infection studies, meaning the studies for the treatment of HIV. I am on that committee as is Dr. Corey, so it's not that we locally don't have a forum on that particular committee.

JH: Is there is community input at this level?

AC: The AIDS Clinical Trials Group nationwide has what is called the Community Constituency Group. This is a group of persons interested in HIV from a variety of communities. That is a formal committee within the actg. That committee has representation on the Primary Infection Core Committee. So there is a specific mechanism for community input into this national organization and national decision making. We actually have a representative who is head of the Community Constituency Group. Victor Rivera (from POCAAN) has been a member a couple of years and this past year was the head of that committee.

JH: How about local input?

AC: The other input into the University of Washington actu is what we call our Community Advisory Board (CAB). That is a group that we established four years ago. It is a very free-floating group. It is anybody who wants to give us input. There is wide open invitation. The group has monthly meetings and basically anybody who is interested can come. There is a core group who consistently attends and then a number of people who attend on an infrequent basis. STEP has a representative who attends faithfully, as do other organizations here in Seattle.

JH: Do you have an example of CAB input?

AC: One of our vaccine studies has a limited number of slots, I think it is 18 to 20 slots. Prior to the study, we had developed a number of lists of persons interested in the trial. There were more than 90 people on the lists. The dilemma we were faced with was how people should be chosen to participate. Which list should have priority or should we advertise and start a new list? We consulted an ethicist at the University who suggested we use a lottery. We discussed over several CAB meetings whether we should have a lottery. Was this fair? Should we start a new list? The group ended up giving us the advice that they thought a lottery was a reasonable thing. They also felt that we should advertise again in case someone hadn't heard about the study, and that these people should be added to the lottery.

JH: Did they have any other input into this study?

AC: They also gave us the advice that the demographics of the people chosen should not mimic Seattle's HIV demographics. They felt that using national demographics would include more people of color and women. This was the first example of a study where we actually were told it would be a good idea to have a quota and hold some slots for women and people of color. This did create all sorts of controversy, but that is an example of something we did in direct response to the CAB's.

JH: When does the CAB meet?

AC: It usually meets once per month on Thursdays (5:30 pm to 6:45 pm at POCAAN) and we advertise in advance.

JH: STEP publishes a list of the University of Washington ACTU trials. Could you discuss your largest trials?

AC: The two largest trials that we are part of are antiretroviral trials. One of them is a trial of combination therapy for people with CD4 counts between 200 and 500 that is looking at the question of which of four regimens is the best strategy for treatment: AZT versus ddI versus AZT plus ddI versus AZT plus ddC. We have 98 people enrolled. Nationwide there are about 2500. (By the way, the CAB advised us to enroll about a hundred rather that use up all of our budget on this one study.) This study will be going on for at least two to three years.

JH: What other larger trials are you doing?

AC: Another large trial we have been participating in now for 5 years is actg 019. Nationally this study has enrolled about 3000 people. We enrolled 148 people into this study. This is a trial of AZT versus placebo. This was a two part trial. The part that was for people who had CD4 counts under 500 was stopped in 1989 when it was found the AZT delayed the progression to advanced arc or aids. There were 50 people locally in this group. The remainder is the group of people who entered with CD4 counts above 500. They are still being followed. We have been following these people for over five years.

JH: This sounds like a fairly large commitment.

AC: Yes, but from the resource commitment standpoint, it is not the most intensive one. Our most intensive current study is the proteinase inhibitor study I mentioned before. This study will enroll only about 40 people. However, the financial, personnel and laboratory commitment is actually far and above greater than either of these other two larger studies combined. This study looks at proteinase inhibitor plus AZT compared to AZT plus ddC compared to all three together.

JH: How about OI studies?

AC: Yes, we are participating in some very important OI studies. One that has consumed the most energy is a PCP prevention study. This one asks the question: for people who have not had PCP, is trimethoprim-sulfa or aerosolized pentamidine or dapsone better PCP prophylaxis? This is the largest PCP prevention study that has ever been done. Locally we have almost 50 patients in this study. This one will end in July. This study will help us determine where dapsone fits in. We also have MAC and CMV prophylaxis studies which are going on now.

JH: What do you think of the calls for an AIDS czar or Manhattan style approach?

AC: I think there is no question that there are certain parts of our government that don't talk to each other well and aren't as organized as they might be. I do have some concerns about an AIDS czar. Would this person be powerful enough to make a difference? Would this add another layer of bureaucracy which would make things worse? I am on an advisory committee to the Division of AIDS at the NIAID that has had some very concrete example of lack of coordination brought before it and we have screamed about it. I would say that now, within nih, things go pretty well. I don't think that within that particular institution that there is a lot of duplication. However, there are numerous agencies besides nih who are involved with aids.

JH: If you were the AIDS czar what would you do?

AC: I don't really know enough about the national politics of the different organizations to know what we need to do.

JH: With AZT, ddI and ddC available what do you see as the most effective combination and sequence of these drugs? AC: My answer is based upon opinion, not fact, because there are insufficient data to answer that question. It just doesn't exist right now.

JH: We can put that caveat in bold type.

AC: There are clear data that AZT and ddI as a combination and AZT and ddC as a combination have better effects on CD4 cells and on viral load markers of HIV like p24 antigen, than AZT alone does. Either of those combinations is clearly better that AZT alone over the short term. One study (actg 155) has recently suggested that the effect of combination AZT/ddC versus AZT versus ddC in patients with advanced HIV who have taken prior AZT is related to CD4 cell counts. The combination of AZT/ddC delayed disease progression better than AZT in patients with CD4 counts 150-300 but was no better in patients with CD4 counts less than 15p/mm3. These two combinations (AZT/ddI and AZT/ddC) are being compared head to head in long term studies, but there are no results from those studies yet. ddI and ddC given alone have been compared head to head in only one small study with people with very advanced aids. This was the CPCRA 002 study. This showed ddI and ddC to be about equivalent for the patients, although there was slightly better survival in the patients treated with ddC.

JH: What is the theoretical basis of combination therapy?

AC: In theory, there is reason to think that combination treatment makes more sense than treatment with one antiretroviral. People are infected with a mixture of viruses (HIV). They may be partially resistant to something and partially sensitive to something. Given that none of these drugs are particularly potent, it seems to make sense theoretically that two less potent drugs may be better than one less potent drug. But, we also have to factor in the practical aspects of taking these drugs.

JH: What are those?

AC: Can people live an enjoyable life while trying to take these drugs? Some people get side effects. Some people find ddI very difficult to take. They are unable to chew the tablets, have to grind them, take them on an empty stomach and so on. Cost of treatment or the monitoring needed can be significant factors.

JH: What about dosages?

AC: The doses of AZT: 300 to 600 milligrams per day for an average size adult are effective doses. I think doses need to take into account how likely someone is to adhere to what they are supposed to be taking. Consequently if someone doesn't think they are going to be very reliable about taking all of the medicines every day, it may make sense to prescribe on the high end of that range knowing that if somebody skips some doses they are still in the 300 to 600 range. There is definite data that 150 milligrams of AZT is less effective than 300 or 600 milligrams daily.

JH: What about ddI?

AC: We don't have that kind of data for ddI. The dose range that has been studied and looks best is around 400 milligrams of the tablet, 500 milligrams of the sachet. That's the dose that probably has the best balance of toxicity and efficacy for an ôaverageö size adult.

JH: What doses in combination?

AC: The study that we've done (combination AZT and ddI) didn't show much difference in any of the dose combinations when we were studying AZT and ddI in a wide range of doses. So you can go at it from two ways. If the lower dose combinations seem to be as good as the higher doses, then maybe you should go with the lower. On the other hand, you could say these aren't very good drugs and if I want to maximize my chances of suppressing this virus, maybe we should go with the higher dose combination. Both of those are reasonable stratagies. The toxicities of these drugs are not so great that they should preclude taking the standard doses of both drugs simultaneously.

JH: So taking 300 to 600 milligrams daily of AZT with 400 milligrams daily of the ddI tablets would be a good combination.

AC: Yes, the potency is such that trying to maximize it is a good idea because they are just not very good drugs. These three drugs (AZT, ddI, and ddC) are the only thing we've got widely available right now but there clearly need to be better treatments.

JH: Since AZT, ddI and ddC are relatively poor drugs, what are your thoughts about proteinase and tat inhibitors?

AC: As I have said, the potency of reverse transcriptase inhibitors (eg AZT, ddI, ddC) in inhibiting HIV is not great. They have some inhibitory effects but they are clearly not 100 percent effective, and have limited clinical benefits. They are also only effective in cells that have newly become infected with HIV. People who have had infection for a while presumably have large numbers of cells that have HIV integrated into their DNA, and for which these agents wouldn't be effective. So we need drugs that inhibit HIV in these cells. In theory, tat and proteinase inhibitors are examples of such drugs. I'm clearly excited about the theory. Whether these drugs will measure up in safety and effectiveness is another issue.

JH: Where are we in the study of these drugs?

AC: The one proteinase inhibitor study in this country just started. There are three other small studies with that particular proteinase inhibitor that have been going on in Europe for several months. At the Berlin AIDS meeting, results from these three phase I studies (of Ro 31- 8959) were presented, and suggested this agent has anti-HIV activity in humans. There were few side effects. These data suggest the need for larger, longer-term studies. There are other proteinase inhibitors made by other companies. At the Berlin meeting, one agent (A-77003, made by Abbott) was reprted to show no anti-HIV activity, but unfortunately was toxic when given intravenously.

JH: How about the tat inhibitor?

AC: The tat inhibitor that Roche makes has very complicated pharmacokinetics. The amount of drug that gets absorbed and the amount that gets excreted is not proportional to how much someone takes. The pharmacokinetics change from the time that people first start taking it to when they have been taking it for several weeks. Those kinds of parameters make it incredibly difficult to design even safety studies. That is one reason that the tat inhibitor study that is currently being done by the ACTG took a while to develop and design. It is now fully accrued, and preliminary results were presented at Berlin. Unfortunately, this study did not show any anti-HIV activity at the first three doses tested.

JH: What is the time frame for these drugs?

AC: As I mentioned for proteinase inhibitor, we will know a little bit more this Spring. Those studies, however, are Phase I which tell us about toxicity and dose but not much about efficacy. The proteinase inhibitor study that we are doing probably won't be done until the end of the year. Then we will have a lot more information about use of this drug in combenation with AZT, and AZT and ddC. The tat inhibitor study that is being done is looking at tat inhibitor with and without AZT. We will hopefully have some information late Summer about higher doses of the tat inhibitor that will help determine if this drug is active, can people take it, and where it should go next.

JH: What are the next types of studies for these drugs?

AC: These would be large trials to determine clinical effectiveness. That is, do these drugs delay disease progression, and do they prolong life? These studies take much longer to complete than Phase I studies.

JH: It could be two to three years before we get these answers, assuming they pan out in the first set of trials.

AC: Yes, that probably is about right. However, we are in the planning stages for these larger trials. This is one of the risks in this work. We do a lot of planning which may not work out. Because of the urgency of needing to improve treatment, we do a lot of planning before we really know whether we are actually going to need to do the trials.

Part II

On the day of the initial interview with Dr. Collier the Lancet published the preliminary results of the Concorde study. This study seem to show that AZT provided minimal or no benefit in survival or progression to disease for those taking compared to those taking a placebo. We agreed to meet again in one week after Dr. Collier had time to review this new data. We appreciate her willingness to help us analyze this important study.

JH: The Lancet article is a preliminary article and not the definitive analysis. Will a more detailed piece be published in a number of months? AC: Presumably yes. The authors think these findings are important enough to present preliminary information about them, which may be the case. On the other hand when only preliminary information is presented, it makes it very difficult for readers, even readers who are very knowledgeable about this topic, to have enough information to really understand the implications of the information.

JH: What are some of the important pieces of information which have been left out?

AC: For example, we don't know exactly what the CD4 cell counts were. There were changes in study design that occurred in the middle of the trial, that we have a little information about, but certainly not the complete picture. We know that almost 300 patients who were not supposed to be taking AZT were allowed to take AZT in the middle of the trial. I just don't know the implications of this right now.

JH: So you can't comment, one way or the other, on the implications of the changeover?

AC: We know that 300 out of their 1700 or so patients started taking AZT in the middle of the trial as the result of information from some other studies. That has the potential of making the groups have a more similar outcome than they might have if they were on different treatment (ie AZT or placebo).

JH: What are some other potential problems?

AC: Since they used a larger dose of AZT than is currently considered standard in the United States, it would be useful to know how many people went off drug intermittently because of toxicity. The reason that it would be useful to know this is because there are some data from other studies suggesting that the intermittent use of an antiretroviral is not as effective as the continuous use of the drug. If they dose reduced early for toxicity so that people stayed on drug, that would have a different implication than people going on and off drug. This is an example of things that are just not in this preliminary report, and are important in trying to interpret what this means.

JH: So there are some potentially significant flaws in this study?

AC: Not necessarily. None of these questions are meant to imply that this may not be a very valid, well done study. I think the authors are to be congratulated on doing a large, long-term follow-up study, but we need the full data, not just some of the data.

JH: At this point in time what is your interpretation of what this means?

AC: I don't really feel I have an understanding of what the data show, but at this point I have the same conclusions they did. At the Berlin AIDS Conference, several presentations were made about the Concorde study. Much more information was available than in the preliminary in the Lancet. However, what is clear is that the study data do support the reported conclusions. In asymptomatic patients, the outcome at three years of patients treated immediately with zidovudine compared to those who did not receive zidovudine until they developed symptoms was the same. The early trends in this study do suggest a transient delay in progression of HIV disease, but the effect is transient and does not translate into a survival benefit. The other noteworthy finding in the Concorde study was that the favorable trends in CD4 counts seen with immediate zidovudine therapy (compared with the delayed group) did not match the clinical outcomes (HIV disease progression and survival). However, it doesn't come as a surprise that a long-term trial, with a drug that has a modest effect (that is analyzed in an intent to treat way) shows no long-term benefit of AZT monotherapy.

JH: How does this admittedly preliminary information compare to other AZT studies?

AC: The thing that is a little surprising about the Concorde information, which didn't initially seem to jive with most of the other studies, including the European/Australian study of early AZT, is that they contended that there was not any delay in progression of HIV disease. At the moment, this is the only study which concludes that. There are a number of other studies that conclude that AZT DOES delay progression for a time-limited period (ie. transient but not sustained benefit) in asymptomatic patients. When you have one study that says one thing and four or five studies that say the opposite it's even more important to have all the details about the studies.

JH: On the basis of the Concorde study, would you change any of your treatment recommendations?

AC: It is a very important studyWith the information available in the spring, I wouldn't change my recommendations. However, as of July 1993, I think it is important to discuss the transient nature of AZT's benefit in patients considering treatment and to individualize treatment.

JH: Can you touch on some of the strengths of the other important AZT studies?

AC: A European/Australian study of ôearlyö HIV, which studied about 800 people followed for over two years, suggested that disease progression to mild symptoms was delayed. I think the strengths of that study included that it was a multicenter study, a randomized study, and it enrolled a significant number of patients. The authors had very careful definitions and external review of what they considered disease progression. This made sure that what they called disease progression really was disease progression. However a decrease in CD4 count was one of the main outcome measures, which favored AZT so the recent questions raised about this marker may limet this study's conclusions.

JH: How about the actg 019 study?

AC: It has strength in that it was a quite large study, with about 3000 patients. One arm of that study, for patients with less than 500 CD4 cells per mm3, is partly what led to the standard of care for patients with less that 500 CD4 cells per mm3 in the United States. Information about the longer term follow-up of these pateints was presented in Berlin, and supports the idea that AZT has a transient benefit in delaying progression of HIV disease but that it is time-limited. Their data suggests the benefit lasts longer (average 24 months) in persons with CD4 counts 300-500 and is shorted in patients with lower CD4 counts. There is another part of that study that has been going on for six years. This part is patients who started the study with CD4 counts greater than 500. They have now been followed, on average, for more than three years and some up to six years. That study is due to be terminated by the end of this year. This will hopefully shed more light on the question of whether AZT affects disease progression and survival in people who start the drug early.

JH: What are the doses of AZT in that arm?

AC: Either AZT 500 or 1500 milligrams daily or placebo. So we should get some more information on the dosing issue, as well as about disease progression. The placebo group in this study gets AZT (500 mg) when CD4 cells drop below 500 per mm3.

JH: At this point in time, what would you say about progression?

AC: At this time, I would say that AZT does delay progression to more advanced disease temporarily. It prolongs life in people with advanced HIV (aids), but not in patients who start therapy earlier (asymptomatic with CD4 counts less than 500). In a sense though AZT monotherapy may be sort of a moot issue, because we now have other choices. Today, for people who have access to state of the art care, we would not expect people to be on AZT monotherapy forever.

JH: With that thought in mind, how long do you think AZT monotherapy is effective?

AC: The more advanced the disease, the shorter the effective time. There are many factors for an individual that alter the time span that AZT may be of benefit.

JH: Individuals do have to make decisions. For example, if someone has been on AZT for a year and the CD4 count is stable at 500, should that person switch?

AC: My current answer to that is if someone has been on AZT for a year and their symptom profile hasn't changed and their CD4 counts are stable, I would stay with AZT for a while. On the other hand, if there was marked, CD4 loss, change in symptoms, or beta two microglobulin levels going way up, then I would definitely say do something different.

JH: How about at lower CD4 levels?

AC: Two studies have addressed that and compared AZT to ddI in persons with none to prolonged amounts of prior AZT. One of which was actg 117. This had people who had been on AZT an average of 14 months at entry. The group of people that switched to ddI clearly did better. A companion study, actg 116a, suggested that people who had been on AZT for at least eight weeks benefited from a switch to ddI. What this is probably telling us is that the time, eight weeks, six months, or one year is not really the right determinant. There are probably factors like viral load, virus type or resistance factors that are the things that we would like to be able to measure to make decisions about treatment.

JH: How far in the future are such studies?

AC: They are being developed now. I would say that it will be at least a couple of years before these tests are available on a wide spread basis.

JH: For a person with 300 CD4 cells per mm3 just starting therapy what is your current thinking?

AC: If they are going to be on a single agent, AZT is probably the best one to start with. On the other hand, there are at least theoretical reasons to say they would be better to start with combination therapy. It is really a judgement issue and I discuss both options with the people I take care of. As I have said, there are the toxicity and convenience problems in taking two drugs, and sometimes financial issues to name a few factors. The reason I would lean towards combination therapy with lowered CD4 counts is that I think these people have less "margin" to work with.

JH: It seems that the message here is the patient has to be very well informed. They will have to make some important decisions and can't rely on their doctor to give exact guidance.

AC: Yes, it is an excellent idea to be well informed. I think even the best informed doctor doesn't know the answer because the answer is not there to be known yet. I am an advocate of having the patients be the final decision makers because they are the ones who have to take the medicines.
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