BETA March 1997.
by Ronald Baker, PhD
Preliminary results of a large, government-sponsored AIDS drug trial (ACTG 320) show that the triple combination of indinavir/AZT/3TC reduces the rate of deaths and new AIDS-related illnesses in people with advanced HIV disease by about 50%, compared to the double combination of AZT/3TC. Individuals in ACTG 320 who were intolerant to AZT used d4T instead, and experienced the same results, according to the ACTG 320 data. These results provide the first clinical data on the use of indinavir in combination with 2 nucleoside analog drugs.
ACTG 320 was halted after 38 weeks by a Data Safety and Monitoring Board (DSMB) when the reviewers found clinical evidence that the 3-drug therapy was superior to the 2-drug regimen for individuals in the study with fewer than 50 CD4 cells/mm3. There was a similar trend among study participants with 50-200 CD4 cells/mm3. The DSMB stopped the study because it would have been unethical not to offer the clearly superior 3-drug regimen to all study participants.
ACTG 320 was designed to compare the clinical effectiveness and safety of the 3-drug regimen of indinavir in combination with AZT (or d4T) plus 3TC versus the double nucleoside analog regimen of AZT (or d4T) plus 3TC in AZT-experienced individuals with fewer than 200 CD4 cells/mm3. One thousand one hundred fifty-six (1,156) individuals were randomized to the study over 1 year and were followed for a median of 38 weeks. There was a high rate of withdrawal in the double nucleoside analog arm (28%), compared to 11% in the indinavir-containing arm. The majority of the subjects in the double nucleoside arm withdrew because they wanted to take protease inhibitor therapy or because they experienced a high HIV viral load level, according to the study investigators.
The study demonstrates the clear superiority of indinavir/AZT (or d4T)/3TC over AZT (or d4T)/3TC in the populations studied. The overall rate of progression to AIDS or death was reduced from 11% to 6% among those taking the 3-drug combination, reflecting a 50% reduction in risk. This result was statistically significant, and led to the DSMBŐs recommendation to terminate the study early. The rate of disease progression in the arm with fewer than 50 CD4 cells/mm3 was also significantly reduced, from 20% to 11% among those taking the triple combination regimen. There was a similar trend seen in the 50-200 CD4 cell/mm3 arm, although the latter did not reach statistical significance (most likely because of the low number of cases of AIDS progression recorded).
Regarding time to death, the indinavir-containing 3-drug regimen also showed clinical superiority compared to the double nucleoside analog regimen. The overall death rate was 2.2%, with 18 deaths (3.1%) occurring in the AZT (or d4T)/3TC arm and 8 deaths (1.4%) occurring in the indinavir/AZT (or d4T)/3TC arm. The analyses of CD4 cell count and the plasma HIV RNA viral load responses of study participants will not be available for several months, according to the investigators.
The results of ACTG 320 show that an indinavir/nucleoside analog 3-drug regimen is clinically more effective than potent 2-drug combinations (e.g., AZT/3TC) in individuals with advanced HIV disease. Based on these results, physicians may feel confident about recommending 3-drug protease inhibitor-containing regimens as first-line treatment for their patients with more advanced disease.
Given the ACTG 320 results -- as well as the results of Abbott's trial 247 of ritonavir and Hoffmann-La Roche's trial NV14256 of saquinavir -- it is clear that protease inhibitor-containing 3-drug regimens offer increased benefits to individuals with advanced disease. However, these data do not address the critical issue of whether to start therapy with similar 3-drug regimens in individuals at earlier stages of HIV disease.
Over the past few months there have been increasing reports of reduced deaths and fewer hospitalizations among people with AIDS. Clearly, the use of new combination anti-HIV treatment regimens is in part responsible for the overall decrease in AIDS morbidity and deaths in the U.S. and elsewhere in 1996.
On February 27, 1997, the U.S. Centers for Disease Control and Prevention (CDC) announced an overall 12% decease in AIDS deaths in the U.S. in 1996. This represents the first annual decline in AIDS deaths in the history of the epidemic. The CDC report also noted a slowing trend in the number of Americans diagnosed with AIDS in 1996. The CDC data identified only a 2% decrease in AIDS deaths among African Americans and a 10% decrease among Hispanics, compared with a 21% decrease among Caucasians. In addition, although deaths from AIDS among males in 1996 decreased 15%, the death rate increased by 3% among women.
Total deaths from AIDS in New York City declined by almost 30% in 1996, according to city health authorities (New York Times, January 25, 1997). The new 3-drug combinations containing a protease inhibitor could not be the sole cause of the dramatic drop in deaths in New York, but wider use of 2- and 3-drug regimens likely contributed to the improved survival rate. Increased access to AIDS care and to AIDS drugs also contributed to the drop in deaths. At the 4th Conference on Retroviruses and Opportunistic Infections held in Washington, DC (January 22-26, 1997), Ramon Torres, MD, reported a 27% decline in hospitalizations among AIDS patients at St. Vincent's Hospital in New York. Dr. Torres also noted a 24% decrease from 1995 to 1996 in the average monthly number of patients hospitalized due to HIV/AIDS. At the same time, Dr. Torres reported an increase in the number of people seeking outpatient care for HIV disease. The cost for anti-HIV therapy at St. Vincent's increased from approximately $28,500 in 1995 to $219,500 in 1996 (abstract #262).
Peter Ruane, MD, of Tower Infectious Disease Medical Associates in Los Angeles, reported at the Retrovirus Conference that the new 3-drug therapies "completely transformed" care for the approximately 500 HIV/AIDS patients in the practice. Compared to 1995, Dr. Ruane reported that the practice experienced a 87% decrease in deaths due to AIDS and a 28% decrease in home health care costs. The incidence and severity of opportunistic infections dropped dramatically. The percentage of patients taking 2- or 3-drug therapies including a protease inhibitor increased sharply in 1996, and was linked to significant improvement in those patients' overall health. Although total medication costs increased by 116% in 1996 compared to 1994, $2 were saved in other health-related costs for every $1 increase in drug costs (abstract # 262).
An analysis of the medical records of over 7,700 HIV/AIDS patients in France showed a 35% decrease in the number of AIDS-defining illnesses and AIDS-related hospital stays from 1995 to 1996, according to a late breaker presentation at the conference by Dr. Y. Mouton. Three medical centers which started prescribing 3-drug combination therapy early saved $250,000 monthly in hospitalization costs in 1996, according to Dr. Mouton (abstract # LB12).
The decline in AIDS deaths in 1996 is cause for renewed hope and cautious optimism that anti-HIV therapy has become significantly more effective. In the coming months, it will be important to mount a strong effort to provide broader access to the new treatment options for women and communities of color, whose morbidity and death rates are much higher than those of their white counterparts.
For more details on declines in HIV death rates and hospitalizations, see Declines in AIDS-Related Deaths and Hospitalizations, this issue.
Ronald Baker is Editor-in-Chief of BETA and Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation.
ACTG 320 Protocol Team. Executive Summary: ACTG 320. A randomized double-blind, Phase III study of indinavir sulfate with open-label zidovudine (ZDV) [AZT] or stavudine (d4T) and lamivudine (3TC) in subjects with HIV infection with CD4 cell counts less than or equal 200 cells/mm3 and greater than 3 months prior ZDV experience. February 21, 1997.
Mouton Y and others. Dramatic cut in AIDS defining events and hospitalization for patients under protease inhibitors and tritherapies (TTT) in 9 AIDS reference centers (ARC) and 7,391 patients. Fourth Conference on Retroviruses and Opportunistic Infections. January 22-26, 1997. Abstract #LB12.
Ruane P and others. Impact of newer antiretroviral therapies on inpatient and outpatient utilization of healthcare resources in patients with HIV. Fourth Conference on Retroviruses and Opportunistic Infections. January 22-26, 1997. Abstract #262.
Torres R and Barr M. Impact of potent new antiretroviral therapies on in-patient and out-patient hospital utilization by HIV-infected persons. Fourth Conference on Retroviruses and Opportunistic Infections. January 22-26, 1997. Abstract #264.
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