Monotherapy with Nucleoside Analogues

Monotherapy with Nucleoside Analogues

Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Joel Gibson M.S

The results of ACTG 116a were presented by Margaret Fischl, MD. This study enrolled 617 people at 33 ACTG sites, all of whom either never had taken AZT or had taken and tolerated less than 16 weeks of prior AZT therapy. Asymptomatic people with less than 200 CD4 cells or those with AIDS or ARC with less than 300 CD4 cells were eligible. This trial sought to determine if staying on AZT or starting or switching to ddI was more advantagous in regard to disease progression or death. Three study arms (AZT naive, AZT with less than eight weeks prior therapy, and AZT with eight to 16 weeks of prior therapy) each contained three subsets of drug treatments: AZT 500 mg/day, ddI 500 mg/day, and ddI 750 mg/day. The sachet form of ddI was used, so a 500 mg dose equals the 400 mg dose in the tablet form. The duration of follow up was 84-86 weeks. In those who had never taken AZT previously (AZT naive), there was less disease progression and death in those taking AZT than in those starting with either of the two doses of ddI. However, in those people with eight to 16 weeks of prior AZT therapy, both doses of ddI showed significant benefit than if AZT was continued. In the group of people with less than eight weeks of prior AZT treatment, no difference was seen in any of the three treatment regimes. Those people on 750 mg/day of ddI had a more likely chance of developing pancreatitis within one year compared to those on the 500 mg/day dose or those on AZT. Also, no significant difference in the development of peripheral neuropathy was seen between the AZT and ddI recipients. So, AZT was a better choice to initiate therapy in this group of people if they had never had prior AZT. But, after eight to 16 weeks of prior AZT therapy, those who switched to ddI did better compared with those staying on AZT. {Of note: the results of ACTG 116B/117 which were published last year in the New England Journal confirmed the results of ACTG 116A. The only difference is that in 116B/117, people had more than 16 weeks of prior AZT therapy. And only the 500 mg/day dose of ddI (not the 750 mg dose) was superior to continuing with AZT.}

The results of ACTG 118, an efficacy study of ddI administered to AZT intolerant individuals, was presented. The same patient population as specified in 116A (above) were recruited, with 50% having an AIDS diagnosis and 4% were asymptomatic. The mean duration of treatment was 61 weeks. Three ddI treatment arms were included: 200 mg/day, 500 mg/day, and 750 mg/day. Significant discontinuation of study participants occurred in the highest treatment arm. Disease progression and survival were the same in all three treatment groups. Trends which were not statistically significant, showed slower disease progression at the higher dosages. The highest dosage also showed a higher risk of developing neuropathy or pancreatitis. The lowest dosage had the fewest numbers of individuals developing pancreatitis. Although 50% of the cases of pancreatitis did not show an increase in serum amylase, monitoring of this blood chemistry was recommended by the presenter since the elevation of serum amylase was highly predictive of the develpment of pancreatitis. Also, individuals who had a good response to the initiation of ddI, i.e. increases in CD4 counts, had better clinical outcome.

A joint European/Australian study looked at the same issue as ACTG 118, i.e. safety and efficacy with regard to disease progression and survival in individuals intolerant to AZT. This trial, called "Alpha," enrolled 1775 people with advanced disease: at entry, 61% had an AIDS diagnosis and 65% had CD4 counts less than 50. ddI was given in sachets at either 200 mg/day or 750 mg/day. No difference in survival or progression was seen between the two dosing groups. Increased toxicity was seen at the higher dose. Again, an increase in CD4 cells following initiation of therapy was predictive of a decrease in clinical progression and an increase in survival.

In another trial looking at people who are "failing" or are intolerant to AZT, CPCRA 002 (Community programs for Clinical Research on aids) enrolled 467 individuals at 16 sites. One third of the participants were considered AZT "failures," and two thirds were AZT intolerant (50% of which were hematologic). Of the participants, 230 people were given ddI at 500 mg/day in the sachet and 237 took ddC at 0.375 mg three times/day. Sixty-seven percent of the study participants had an AIDS diagnosis at study entry. Mean duration of study follow up was 15 months. Disease progression or death occurred in two thirds of individuals regardless of treatment arm with neither drug showing a significant advantage over the other in this patient population. However, there was a trend toward better survival in the ddC treated group. If additional statistical analysis was done to correct for slight inequalities in initial CD4 count, Karnofsky score, and number of AIDS cases at entry, then a significant advantage of ddC over ddI was seen in terms of survival. However, both the severity and likelihood of peripheral neuropathy was higher in those taking ddC as compared to ddI. The Concorde trial enrolling 1749 people from 73 sites in England, Ireland, and France, has generated an immense amount of controversy, deliberation, and confusion. The mean length of follow up in this large study was three to four years. Its purpose was to determine the optimal time for initiating antiretroviral therapy with AZT in asymptomatic individuals. That is, is it better to give AZT to people when their CD4 counts fall below 500 (as is the current recommendation in the USA) or is it better to wait until the individual develops symptoms? The dose of AZT used in this study was 1200 mg/day, at least twice the current recommended dosage in the USA. The trial lasted from 10/88 to 10/91 and is the largest and longest trial of AZT use in asymptomatic individuals. Subjects were randomized to receive AZT (immediate group) or placebo (deferred group). The original intent was that individuals in the placebo arm would receive AZT if symptoms developed. However, in the Fall of 1989 when the initial results of a portion of the ACTG 019 trial were released, a change was made in the protocol of Concorde. They now gave those in the placebo arm the option of receiving AZT when their CD4 count fell below 500. Of the 872 individuals in the placebo group, 282 (32%) chose to receive AZT at that time. However, due to the "intent-to-treat" analysis used by the Concorde researchers, these 282 individuals who began taking AZT were considered as belonging to the placebo group when the analysis was done. The interpetation of the data by the Concorde investigators was that there was no difference in disease progression or survival between the immediate and deferred groups. When CD4 counts instead of clinical end points were used to evaluate the results, the immediate group showed an advantage over the deferred group. The investigators go on to say that CD4 cell counts as a marker of clinical disease progression in asymptomatic individuals on AZT monotherapy is unreliable. Their caveat on CD4 counts is that they are probably valuable in natural history studies, but not so reliable in evaluating drug treatment trials, where markers of viral load would be more helpful. The investigators also stated that the results of their trial do not indicate that "early intervention" is bad or harmful, but suggest that they are not sure there is a benefit either. They go on to say that some individuals will benefit from early intervention and others will not. The difficult task is deciding which course any single individual will follow with regard to progression. There has been a large amount of discussion generated from this study. Although additional data was presented in Berlin, there are immunologic and virologic analyses still being performed. The entire study data will appear in publication at some future point. Most major HIV/aids treatment newsletters throughout the country have written on this topic including Treatment Issues, AIDS Treatment News, and others. Therefore the reader is invited to search out other commentaries on this issue. It was not the purpose of Concorde to ascertain the efficacy of AZT in symptomatic individuals. The benefit of AZT therapy in this group has clearly been previously established. Also, it was not the purview of Concorde to ascertain the efficacy of AZT in combination with other antivirals in any patient population with regard to disease progression or survival.

Some concerns that this author have are as follows. The "intent-to-treat" analysis skews the data in favor of no difference between the two groups: any potential benefit which the 282 individuals who received AZT were considered in the placebo group. The dosage of AZT used in this trial could possibly have a cytotoxic effect, thereby decreasing a perceived benefit. This point is further made in the following report on ACTG 019 when the effects of 500 mg/day of AZT is compared with 1500 mg/day. It is generally acknowledged that the benefit of AZT monotherapy is limited and decreases over time. Therefore, any benefit from treatment with AZT is going to be seen early on. As the length of time on treatment increases, either a change in monotherapy or the institution of combination therapy has suggested benefit and has been advocated by some for many years. Seen in this way, the results of Concorde are not all that surprising. Keeping individuals on a single nucleoside antiretroviral will no doubt lead to decreased effectiveness of that drug (no matter what it is) over a prolonged period of time such as three to four years. However, the conclusions drawn from the study investigators are in contrast to the five other studies of early AZT use in asymptomatic persons. Studies from Italy, EACG 020 (Europe/Australia), the MACS study in the USA, ACTG 019, and from John Hopkins have concluded that early treatment with AZT is advantagous in survival and/or disease progression. Recent accounts of the "non-latency" of the virus even during the asymptomatic stage, offer the rationale that intervention with drugs which inhibit the infection of new cells (like nucleoside analogues do) are going to be more effective at earlier stages of disease in contrast to later ones. The clinicians I speak with or have heard from, are not making any changes in their recommendations regarding treatment stategies based on Concorde.

In an ongoing follow up of disease progression in individuals previously enrolled in ACTG 019 with less than 500 CD4 cells, the duration of AZT's efficacy was studied. These are people who initially were randomized to one of three treatment arms: placebo, 500 mg/day AZT, 1500 mg/day AZT. The trial for this subset of participants lasted almost two years until it was stopped in 8/89 and those in the placebo group were offered AZT. Looking at disease progression for a subsequent follow up period of 2.6 years, 232 of 1556 people have progressed or died. When considering all 1556 individuals, decreased disease progression is seen in those initially randomized to receive 500 mg/day of AZT compared to 1500 mg/day AZT or placebo. This benefit has not been shown for survival. When these 1556 individuals are broken down into two groups with either more or less than 300 CD4 cells at entry, in those with less than 300 CD4 cells, no difference in progression among the three groups is discernable. However, in those with greater than 300 CD4 cells at entry, decreased progression was seen in the 500 mg/day group compared with the 1500 mg/day or the placebo groups. These results argue favorably for instituting antiretroviral therapy at earlier stages of infection rather than later. Dr. Paul Volberding, protocol chair and presenter of this study put forth two hypotheses: in patients with less than 300 CD4 cells, the benefit of AZT may be around 18 months; in patients with 300-500 CD4 cells, the benefit of AZT use could be greater than two years.

References

1. WS B24. IX International Conference on aids. Berlin, Germany. June 1993.

2. Kahn, J. et. al. 1992. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virua infection. The NIAID AIDS clinical trial group. New England Journal of Medicine 327(9): 581-587.

3. Aboulker JP, Swart AM. 1993. Preliminary analysis of the Concorde trial. Lancet 341(8849): 889-890.

4. Fischl, M.A. et. al. 1990. The Safety and Efficacy of Zidovudine (AZT) in the Treatment of Subjects with Mildly Symptomatic Human Immunodeficiency Virus Type I (HIV) Infection. Annals of Internal Medicine 112(10):727-737.

5. Volberding, P.A. et. al. 1990. Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection. New England Journal of Medicine 322(14):941-949.

6. Pantaleo, G. et. al. 1993. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355-358.

7. Vella, S. et. al. 1992. Survival of Zidovudine-Treated Patients With AIDS Compared With That of Contemporary Untreated Patients. Journal of the American Medical Association 267(9):1232-1236.

8. Moore, R.D. et. al. 1991. Zidovudine and the Natural History of the Acquired Immunodeficiency Syndrome. New England Journal of Medicine 324(20):1412-1416.

9. ME 13. IX International Conference on aids. Berlin, Germany. June 1993.

10. OP-01 (2). IX International Conference on aids. Berlin, German. June 1993.

11. Graham, N.M.H. et. al. 1992. The Effects On Survival Of Early Treatment of Human Immunodeficiency Virus Infection. New England Journal of Medicine 326(16):1037-1042.

12. Gold, David. 1993. The Concorde Study. Treatment Issues 7(4):1-7.

13. James, J.S. 1993. Berlin: Concorde Trial Questions Early AZT Use-Wider Implications. AIDS Treatment News 177:3-4
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Copyright © 1993 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102. Email: step100@aol.com STEP web page

This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1993. AEGIS.