TREATMENT ISSUES: The Gay Men's Health Crisis Newsletter of Experimental AIDS Therapies - Volume 7, Number 6 -- July 1993
Derek Link

The Ninth International AIDS Conference in Berlin was one of the bleakest moments since the AIDS crisis began. Large, definitive studies prove that treatment with the nucleoside analogs (AZT, ddI and ddC), the cornerstone of current HIV treatment, is, at best, only marginally effective for a brief moment of time. Other large studies prove that early AZT use does not delay progression and prolong survival in asymptomatic patients for up to three years, and that combination AZT/ddC treatment is clearly no better, and perhaps even worse, than monotherapy. The belief that AIDS could somehow be transformed into a "chronic And Manageable" condition through the right mix of nucleoside treatments was shattered in Berlin.

In response, the National Institutes of Health (NIH) convened a panel of experts for a "State of the Art Conference on Antiretroviral Therapy for HIV-Infected patients" on June 25 in an attempt to make sense of the data and draft new treatment recommendations. After three days of intense scientific discussion, the panel made specific recommendations which address two critical themes in HIV clinical care: When should patients start AZT? How should ddI and ddC be used? Although these recommendations have not been finalized, it is unlikely they will change considerably since they have already been distributed nationwide. The final recommendations will be submitted to a peer reviewed journal later this summer.

In writing its draft recommendations, the panel was forced to deal in matters of belief and faith, not data. Virtually all the information upon which the recommendations are based is negative or conflicting. The panel had an extraordinarily difficult time reconciling studies which point in different directions, or demonstrate no benefit to the drugs. Dr. John Hamilton, an AIDS researcher at the Veterans Administration in North Carolina, summed up the meeting best when he commented that the data "extend the scope of our ignorance." In this article, we review the specific recommendations of the panel in regard to particular subgroups of patients. An overall analysis of the specific studies which support each recommendation reveals that the panel relied heavily on judgment calls and negative data in its deliberations.

RECOMMENDATIONS FOR INDIVIDUALS CONSIDERING AZT WHO HAVE NOT TAKEN ANY ANTIRETROVIRAL TREATMENT BEFORE

AZT vs. ddI vs. AZT/ddC

First and foremost, the panel reaffirmed that AZT is first-line therapy, based on data from two studies which agree with each other, ACTG 119 and 116A. ACTG 119 showed that AZT is superior to ddC for initial therapy; ACTG 116A showed AZT is superior to ddI for initial therapy. The panel recommends AZT monotherapy 500 to 600mg per day as initial therapy for all patients. Although combination therapy has been proposed as initial treatment, little data exist to support this theory. ACTG 106 demonstrated higher CD4 cell rises in combination AZT/ddC regimens. However ACTG 106 was very small (n=56) and did not collect clinical data. Data from studies designed to answer this question, most notably ACTG 175, will not be available until 1995. (However, one significant limitation of ACTG 175, in light of the Concorde study, is the trial's lack of a placebo arm. In other words, the trial only compares combination therapy to monotherapy, and not to "deferred" or no therapy).

Asymptomatic, Above 500 CD4 Cells

In patients with above 500 CD4 cells, the panel recommended monitoring, but not AZT. This decision is based on information from two studies. The Concorde study team analyzed 710 people who entered the study with greater than 500 CD4 cells. At three years, early AZT neither reduced disease progression nor improved survival. A European Australian study of early AZT in people with greater than 400 CD4 cells also showed no improvement in progression and survival at 93 weeks. Finally, the greater than 500 CD4 subgroup of ACTG 019 is still ongoing; the study will close this December. Data are expected in 1994.

Asymptomatic, 200 to 500 CD4 Cells

For asymptomatic patients with 200 to 500 CD4 cells, the panel recommended consideration of two options: AZT or continued monitoring. Two studies were presented which show that AZT does not improve disease progression and survival in this group up to three years: Concorde and the long-term follow-up of ACTG 019. Concorde evaluated immediate versus deferred AZT in 1749 patients followed for three years. Long-term follow up of ACTG 019 followed 1565 patients for an average of 2.6 years. Both studies proved that early AZT does not delay progression beyond one year or improve survival overall. [See Treatment Issues (May 1993) for a review of Concorde.] Furthermore, a European-Australian study of AZT in asymptomatic patients with 200 to 400 CD4 cells showed no difference in disease progression at two years. In short, it is hard to know what data the panel recommends front-line physicians consider when evaluating AZT treatment for this patient group.

Symptomatic, 200 to 500 CD4 Cells

For symptomatic patients with 200 to 500 CD4 cells, the panel recommended AZT. Two studies support AZT's ability to delay progression in this patient group. ACTG 016 and the VA Cooperative study both examined AZT in mildly symptomatic HIV-infected people with 200 to 500 CD4 cells. ACTG 016 enrolled 513 patients in this group and followed them for an average of eleven months. The VA study enrolled 338 patients in this group. AZT did not prolong survival in the VA study; survival information is not available from ACTG 016. Therefore, the panel recommended AZT treatment in this patient group despite data which show no survival advantage to the drug.

RECOMMENDATIONS FOR INDIVIDUALS WHO ARE TOLERATING AZT

Above 300 CD4 Cells

For patients who "appear stable" on AZT with CD4 counts above 300, the panel recommends continuing AZT. There are no data describing what to do in this specific group of patients. This recommendation was based on the clinical judgment of the panelists that "if it ain't broke, don't fix it" (again, this seems to rely on a presumption that therapy should be used, rather than the reverse).

Below 300 CD4 Cells

For patients with CD4 cells below 300, the panel recommends consideration of two options: continue AZT or switch to ddI. While there are no data which specifically address this question, there are several factors to consider. Advocates for a switch to ddI cite data from ACTG 116B/117, a study of AZT versus ddI in 913 patients who received, on average, thirteen months of prior AZT. In this study, ddI delayed progression of disease in asymptomatic and ARC patients, but not in people with AIDS. DdI did not improve survival in any study group. Those who support continued AZT emphasize their reluctance to place patients tolerating AZT on ddI, a drug with an entirely different set of serious toxicities.

RECOMMENDATIONS FOR INDIVIDUALS WHO ARE INTOLERANT TO OR HAVE FAILED AZT

AZT-intolerant, 50 to 500 CD4 Cells

For AZT-intolerant patients between 50 and 500 CD4 cells, the panel recommends switching to ddI monotherapy. This recommendation is based on CPCRA 002 which compared ddI with ddC in AZT-intolerant patients with under 200 CD4 cells. The median CD4 cell count of those who enrolled in the study was under 50. This study demonstrated that ddI and ddC are equivalent in this group. However, there may be a slight survival advantage to ddC in this group, based on the CPCRA study. No other data exist which define the optimal time to switch treatments.

AZT-intolerant, Below 50 CD4 Cells

For AZT-intolerant patients with under 50 CD4 cells, the panel recommends consideration of three options: ddI monotherapy, ddC monotherapy, or discontinuing antiretroviral treatment altogether. This group has few clearly defined treatment options. In fact, there is no proof that ddI or ddC is better than no treatment in this patient group. CPCRA 002, a study of ddI versus ddC in 467 AZT-intolerant or failed patients with under 50 CD4 cells, demonstrated a marginal survival benefit to ddC monotherapy. However, the difference in this study is so small that consideration must also be given to differential drug toxicities. Furthermore, the panel did not recommend combination in this group. Data from ACTG 155, the first definitive combination efficacy study, demonstrated that patients with under 50 CD4 cells may have had faster progression, lower survival, and more toxicities, when placed on combination AZT/ddC treatment. ACTG 155 included 991 patients who had received an average of eighteen months of prior AZT therapy. Furthermore, the ddC monotherapy arm had the fewest toxicities.

Failed AZT, 50 to 500 CD4 Cells

For patients with 50 to 500 CD4 who experience clinical progression while on AZT, the panel recommends switching to ddI monotherapy or combination treatment with either AZT/ddI or AZT/ddC. This recommendation is based entirely on speculation and hope. Although a switch to ddI monotherapy may be suggested by ACTG 116B/117, combination therapy is harder to understand. ACTG 155 demonstrated no delay in progression or improvement in survival in patients placed on AZT/ddC combination compared with those continued on AZT or switched to ddC alone. This recommendation rests on the hope that future combination therapy regimens will demonstrate clinical benefit, and a subgroup analysis from ACTG 155 which showed a possible benefit to combination AZT/ddC in patients with 150 to 300 CD4 cells.

Failed AZT, Below 50 CD4 Cells

For AZT failures with under 50 CD4 cells, the panel recommends switching to ddI or ddC monotherapy. This recommendation was based on reasoning similar to that for the recommendation to AZT-intolerant patients with under 50 CD4 cells.

CONCLUSION

Rapid changes in our understanding of nucleoside analog therapy occurred at the International AIDS Conference in Berlin. The treatment guidelines issued by the NIH-convened panel of experts are limited by lack of data supporting the efficacy of nucleoside therapy in virtually all patient groups. Also, the studies were designed to obtain approval of the drugs, not address questions in clinical care. The impact of the new data and treatment recommendations on clinical care, research, and drug approval will likely be enormous.

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