IT'S TIME TO CHANGE THE STANDARD OF CARE FOR PEOPLE WITH AIDS

ACTG 320 Proves that Indinavir and 3TC, when Added to AZT, Reduce AIDS and Death by Half when Compared with AZT and 3TC without Indinavir in HIV-Positive Individuals with Fewer than 200 CD4 Cells and Over Three Months of AZT Experience
by Mark Harrington

24 February 1997

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Results of AIDS Clinical Trials Group (ACTG) 320, one of the most important studies of triple-drug antiviral therapy in people with AIDS were released today by the National Institute of Allergy & Infectious Diseases (NIAID). The principal investigator was Scott Hammer, M.D., of Harvard Medical School.

• ACTG 320 was the first study to prove that the protease inhibitor indinavir (Crixivan^®), when added to two nucleoside analogues (AZT or d4T plus 3TC), prolongs AIDS-free time and extends survival in people with fewer than 200 CD4 T cells and over three months of AZT experience.

• The study is also the first to prove clinically that combination anti-HIV treatment strategies -- adding at least two new drugs when making a decision to switch therapy -- are more effective than adding single new drugs to antiretroviral treatment regimens.

• The study was also innovative and flexible in allowing participants to change underlying regimens based on toxicity -- those experiencing AZT toxicity were allowed to use d4T instead.

• Finally, the study may be the last of its kind, demonstrating as it does that AZT/3TC alone, which only last year proved its superiority to AZT monotherapy, is inadequate as a treatment for advanced HIV disease. Two-nucleoside combinations are no longer appropriate control arms in people with AIDS or fewer than 200 CD4 T cells.

• ACTG 320, combined with data from Abbott and Roche-sponsored studies demonstrating a survival benefit to the protease inhibitors ritonavir and saquinavir, respectively, when added to nucleoside analogues, further strengthens support for changing the standard of care for people with AIDS and under 200 CD4 T cells to triple-drug therapy including a potent protease inhibitor plus two nucleoside analogues, at least one of which is initiated when the protease inhibitor is begun.

Starting in January 1996, ACTG 320 enrolled 1,156 HIV-infected persons who had fewer than 200 CD4 T cells, over three months of AZT experience, less than seven days of 3TC experience and no protease inhibitor experience. They were randomly assigned to receive AZT/3TC or AZT/3TC/indinavir and followed for a mean of 38 weeks (maximum one year).

Persons intolerant to AZT at baseline were allowed to take d4T, and persons experiencing moderate, non-AIDS defining disease progression were allowed to switch underlying nucleoside analogue therapy to any combination of the nucleosides AZT, d4T, ddI, or 3TC. They were followed for an AIDS-defining illness or death.

Participants were stratified at baseline by CD4 above or below 50 (38% below, 62% above). 83% of participants were male and 17% female; 27% were black, 19% Hispanic, 3% had hemophilia and 16% had a history of injecting drug use. The mean CD4 count at baseline was 86, and mean age was 39. Virologic analyses are ongoing and virologic results are not yet available.

The dataset was closed on 27 January 1997. An independent Data & Safety Monitoring Board (DSMB) analyzed the data on 18 February 1997 and recommended that ACTG 320 be stopped early. Study participants will be unblinded (told which arm they were on) and offered a number of follow-up treatment options.

A letter to the AIDS Clinical Trials Unit (ACTU) sites and participants is going out now. Participants on the AZT/3TC arm of ACTG 320 will be offered the following options:

• Stop study drug and seek best available treatment from primary-care doctor or from another study;
• Receive open-label indinavir, as promised by the protocol, for up to four months, as promised by Merck, with the strong recommendation that one switch underlying nucleoside analogues, (e.g., to ddI/d4T) to prevent resistance to indinavir, which evolves rapidly when one adds it to an unchanging nucleoside regimen;
• Enroll in a new rollover study now being planned, and due to open within one to two months, which will randomize people to receive:
  Indinavir (1,000 milligrams every eight hours) plus the new non-nucleoside reverse transcriptase inhibitor DMP-266 (400 milligrams daily) plus the new nucleoside analogue 1592 (300 milligrams twice daily);
  or
  Indinavir (1,000 milligrams every eight hours) plus DMP-266 (400 milligrams daily) plus 1592 placebo

The primary endpoint of this study will be plasma HIV RNA levels at 16 weeks. Responders (those who've gone undetectable) will be continued on study drug and followed for 48 weeks. Unlike in ACTG 320, participants in this rollover study will receive real-time HIV RNA values.

The study team is also considering offering patients on the triple-therapy arm, some of whose viral load levels may be above the limit of detection, the option of a new rollover study, yet to be designed, which might include 1592, DMP-266 and/or nelfinavir.

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What ACTG 320 Tells Us About the Evolving Standard of Care for People with AIDS: Fourteen Points to Consider

1. The era of monotherapy with a single antiretroviral drug is over.

2. The era of double-drug therapy with two nucleosides is over, at least for people with AIDS and under 200 CD4 T cells. Possible future two-drug combinations may be as potent as what has now been seen with three-drug combinations, but currently-approved nucleosides, used alone or in combination only with each other, are suboptimal regimens for starting or switching antiretroviral therapy.

3. ACTG 320 confirms a survival benefit for protease inhibitor-containing combinations in people with AIDS. ACTG 320 is the third, and perhaps the most well-designed, study to demonstrate a survival benefit by adding a protease inhibitor to nucleoside analogues. Previously, in January 1996, Abbott showed that adding the protease inhibitor ritonavir, when added to underlying nucleoside analogues (AZT, ddI, ddC, or d4T), prolonged survival during six months of study in people with under 100 CD4 T cells. Later in 1996, Roche showed that its protease inhibitor, saquinavir, when added to the nucleoside analogue ddC, prolonged survival as compared with saquinavir or ddC alone. Like the Roche study and unlike the Abbott study, all ACTG 320 participants received at least one new drug, and those on triple therapy received two new drugs. Unlike the Roche study, however, whose control arms were ddC or saquinavir monotherapy, all ACTG 320 participants were on two nucleosides or two nucleosides plus indinavir. Hence, ACTG 320 more clearly defines a new standard of care than the two previous studies, but all three demonstrate that protease inhibitor regimens confer a survival benefit (a 50% reduction in death) in advanced, AZT-experienced people followed over six to twelve months.

4. ACTG 320 proves the benefit of changing more than one antiretroviral therapy at a time. ACTG 320 was the first controlled study to prove survival benefit not just for the protease inhibitors as a new class of drugs, but to prove the survival benefit of a new and revolutionary anti-HIV treatment strategy. In ACTG 320, all participants had received over three months of AZT, and all participants were given at least one new drug -- 3TC -- and half of the participants were given two new drugs -- 3TC and indinavir. This study proves what after Vancouver we only guessed and hoped -- that, when people with HIV make a decision to switch therapy, the best way is to add at least two new drugs, in order to reduce the chance that the virus can develop resistance to any one new drug. This means that the era of sequential monotherapy, as practiced since 1987, is over, and that the new treatment strategy, at least for people with AIDS, should attempt to administer potent antiviral combination therapy designed to reduce viral levels beneath the limit of detection. Particular praise goes to the study investigators who are planning a state-of-the-art salvage trial for the ACTG 320 participants now on AZT/3TC, rather than simply offering them open-label indinavir, as was done in the past. ACTG 320, like its predecessor protease studies, offers new hope for antiretroviral-experienced people with HIV.

5. ACTG 320 suggests that people taking therapy likely to cause maximal viral suppression have superior clinical outcomes. The results of ACTG 320 confirm earlier suggestions from surrogate marker trials (trials measuring viral load and CD4, but not clinical endpoints) Merck 035 and Merck 039, which showed that AZT-experienced persons adding 3TC and indinavir experience a high likelihood (65-85%) of having their plasma HIV levels go below the limit of detection (400 copies of HIV per milliliter of plasma). ACTG 320 suggests that this benefit -- of having virus go "undetectable" -- is associated with significant clinical benefit -- a 50% reduction in AIDS-defining events and death. However, virological analyses of ACTG 320 are incomplete.

6. AZT/3TC/Indinavir is just one of many combination therapy regimens which can drive viral load below detectable limits, and thus slow down progression to AIDS or death. There is nothing unique about the particular combination of AZT/3TC/indinavir. What is new is the clinical confirmation of the ability of maximally-suppressive antiviral combinations to extend health and prolong life. Other regimens which have demonstrated the ability to reduce HIV to levels beneath the limit of detection (in the blood at least) include AZT/ddI/indinavir, AZT/3TC/ritonavir AZT/ddC/ritonavir, AZT/3TC/nelfinavir, AZT/ddI/nevirapine and ritonavir/saquinavir. There is no reason to think that double-nucleoside combinations other than AZT/3TC, such as AZT/ddI, ddI/d4T or 3TC/d4T will not confer benefits equal to those seen with AZT/3TC when used along with a potent protease inhibitor.

7. People who are already taking AZT plus 3TC should not be encouraged to rush out and add indinavir to their regimen. Instead, they should be informed (as trial participants are) about the need to switch underlying nucleosides if they add indinavir or any other protease inhibitor, in order to prevent resistance. Many physicians aren't using protease inhibitors properly; they're just adding a new drug to an already failing regimen to which people have likely developed resistance. When protease therapy is begun, at least one underlying drug, and possibly both, should be switched at the same time.

8. ACTG 320 may (and probably should) be the last trial of its kind in people with AIDS. Although AZT/3TC only last year proved clinical benefit in PWAs (in the CAESAR study), and AZT/ddI only did so in 1995 (with ACTG 175), double nucleoside combinations with approved agents should no longer be the standard of care for PWAs. Triple therapy with two nucleosides [at least one of them new] and a potent protease inhibitor should be recommended as the standard-of-care for people with AIDS or fewer than 200 CD4 T cells. The Abbott and Roche studies plus ACTG 320 demonstrate significant benefit for the class of drugs plus nucleosides versus nucleosides alone.

9. ACTG 320, like the Abbott and Roche studies, does not prove clinical benefit for people with over 200 CD4 cells. We still don't know when is the best time to start antiretroviral therapy. Healthy asymptomatics may have additional treatment options if they wait to begin therapy; indinavir-resistant HIV may become cross-resistant to many or most other protease inhibitors.

10. Viral load must be a standard part of HIV care, and should be provided in real time to all people with HIV. Participants in ACTG 320 were not given real-time viral load data at the study sites. However, over half the drop-outs from the two-drug arm said that a poor viral load responses or a desire for protease inhibitor therapy was the reason why they left the study, as compared with only 7% on triple therapy. Thus, many participants in the study were getting viral load off study, indicating the importance of viral load in making treatment decisions.

11. We still don't know enough about the long-term, or rarer, side effects of indinavir and the other new protease inhibitors. Serious side effects were similar in the two arms of ACTG 320. Only four patients on two drugs and six on three drugs dropped out due to side effects, although 20% and 23% respectively had grade three or four signs or symptoms (serious toxicity) and 29% and 23% respectively had grade three or four laboratory values. The notable toxicity differences between the two treatment arms include an excess of neutropenia on two drugs (15% vs. 5.3%), an excess of hyperbilirubinemia and nephrolithiasis (kidney stones) on three drugs (1.5% and 0% on two drugs and 5.7% and 1.2% on three drugs, respectively).

12. We don't know enough about resistance and cross-resistance among protease inhibitors, and whether starting with indinavir first will make it harder to benefit from nelfinavir or saquinavir. People starting on triple-drug therapy need to consider how their first treatment strategy will affect future treatment options. Newer drugs coming on line later in 1997, either through FDA approval (delavirdine, nelfinavir) or expanded clinical trials (1592, DMP-266, GW-141) may provide additional options for novel treatment strategies. People who are healthy, asymptomatic, and have higher CD4 T cell levels (over 350-500) and relatively low viral load may benefit by waiting a few months to see which combinations are most potent, least toxic and most convenient.

13. Education of physicians and people with HIV about how best to use protease inhibitors and combination therapy is not keeping pace with recent developments. Current pharmaceutical advertising campaigns are not helpful; they are product-specific and not strategy-specific. New Public Health Service (PHS) guidelines about principles and practice guidelines for HIV therapy are being developed now and will be published later in the spring, however, people making treatment decisions need to know about new treatment strategies now.

14. All people with HIV should have access to state-of-the-art treatment, monitoring and information about optimal management of HIV disease. Pharmaceutical companies should be encouraged to reduce the prices of their drugs and provide access to indigent uninsured people with HIV. At the same time, advocates must insist that all third-party health-care payers, including Medicaid, Medicare, state AIDS Drug Assistance Programs (ADAPs), health maintenance organizations (HMOs) and private fee-for-service health insurance companies reimburse fully for state-of-the-art treatment and laboratory monitoring for all people with HIV.

John Bartlett, chief of infectious diseases at Johns Hopkins University in Baltimore, Maryland, recently compared the price of combination therapies to that of many other commonly-used preventive and treatment interventions. According to Bartlett, "The most appropriate way to deal with cost issues in medicine is to determine cost-effectiveness for a new strategy compared to others that have become commonly accepted in medicine. On the basis of these criteria, protease inhibitors are a fantastic deal."