Treatment Issues, Vol 11, No 3; March 1997
Dave Gilden

ACTG 320: The Skeletons in the Closet

In stopping ACTG 320 at the end of February, the AIDS Clinical Trials Group ended the group's largest ongoing effort. ACTG 320 was supposed to enroll 1,750 volunteers over nine months and follow them for a year. The volunteers had to be HIV-positive persons with CD4 counts under 200 and more than three months previous AZT therapy. They would be randomly assigned to receive either AZT/3TC or AZT/3TC/indinavir and monitored for the occurrence of AIDS-defining illness or death. (ACTG 320 was a clinical endpoint trial meant to confirm indinavir's FDA approval under the accelerated approval rules.)

When ACTG 320 was announced in 1995, it received widespread community criticism because it was felt to be a waste of resources. AZT/3TC plus indinavir surely would prove better than AZT/3TC by itself, so that the point under study was not terribly interesting from a scientific perspective. Further, potential participants would be hesitant to enroll in the trial because they did not want to be assigned to the AZT/3TC combination without indinavir. People who did enroll would check their viral loads and rapidly drop out if they were not receiving a treatment with acceptable potency. Finally, indinavir's manufacturer, Merck & Co., should be paying for indinavir's confirmatory trial, not the government-sponsored ACTG.

Enrollment began in January, 1996 and did indeed fall short. After more than a year, only 1,156 participants (17% women) had signed up. They were followed for a median of 39 weeks. About 20% of participants dropped out of the study, though most of these continued to be followed for disease progression. Another 9% changed nucleoside analogs within the context of the study. (To reduce the drop-out rate, study participants were allowed to modify the AZT/3TC part of the combination, substituting d4T for AZT in the event of drug intolerance or perceived disease progression short of one of the study endpoints.) In both cases, the alterations involved twice as many people on the double combination as on the triple.

The mounting differences in disease progression obviated any need to continue the trial as planned. Eighteen people died in the AZT/3TC arm and only eight in the AZT/3TC/indinavir arm. There were 45 other AIDS-defining events in those receiving only AZT/3TC versus 25 in those who also got indinavir. Overall, the risk of disease progression was calculated to have been cut in half by adding indinavir to AZT/3TC. An analysis of CD4 count and viral load trends has yet to be completed.

A simple-minded inference to draw from this trial is that three drugs are better than two -- period. Making such a broad statement is quite a stretch. The results were dominated by events in trial participants starting with CD4 counts less than 50. In the trial stratum having CD4 counts from 50 to 200, disease progression was low with both regimens, and the difference was not statistically significant. We also cannot draw any conclusions from this trial about long-term differences in outcome. If ACTG 320 had been extended to two or three years, the difference between the two treatment arms might vanish, depending on such issues as the emergence of drug resistant HIV and the limits to an HIV-damaged immune system's ability to defend the body for opportunistic infections. Long-term effectiveness is particularly important for people with higher CD4 counts who face a decision on what medications to take even though it may be some time before serious illness threatens them.

ACTG 320 cannot tell what is the best strategy for people with prior AZT exposure, just that adding 3TC and indinavir is better than adding 3TC alone. It could even be that the combination of 3TC/indinavir is just as good as AZT/3TC/indinavir in these people, at least over nine months. The trial also has nothing to say for the many people who already have an extensive history with both AZT and 3TC together. Probably just adding indinavir will do them little good.

One interesting point is that the ACTG 320 cohort on AZT/3TC is now eligible for a rollover trial, ACTG 368, in which participants will receive indinavir plus DMP 266 and/or 1592U89. These are two experimental reverse transcriptase inhibitors of unprecedented potency that require HIV to make several mutations before it can become resistant. It may well turn out in this trial that the right two drugs are every bit as good as the three-drug combination of AZT/3TC/indinavir. Indinavir plus either 266 or 1592 might even be active enough that it is not necessary to take the three together.

An enormous number of questions remain unanswered. The lessons of ACTG 320 are very limited. They merely confirm the results of Merck protocol 035, which looked at CD4 count and viral load trends in about 90 AZT-experienced volunteers taking AZT/3TC, indinavir or the three drugs together. ACTG 320 also repeats the results of a number of previous disease progression trials that added an additional agent onto simpler regimens and found disease progression significantly reduced.

To achieve this modest end, ten people had their lives cut short.

Merck Protocol 028: A Dirty, but not Quick, Trial in Brazil

The most meaningful part of ACTG 320 may turn out to be the viral load data it eventually yields. This data probably will show such a strong parallel between reduction of HIV levels and reduction of disease events that one-year clinical endpoints trials like ACTG 320 will be deemed unnecessary in the future. But even if that holds true, the ACTG 320 viral load information was anticipated a year ago by data from Merck protocols 035 and the much larger 028. Protocol 028, which was terminated in March for reasons similar to ACTG 320, also was a disease progression trial. Its initial viral load and CD4 count data were released along with those of 035 at the FDA advisory committee hearing that led to indinavir's approval (see Treatment Issues New Data from Protease Inhibitor Trials, March, 1996, pages 2-3). Protocol 028 was designed for people with CD4 counts under 250 without any prior anti-HIV therapy. The 996 trial participants (28% female) received either AZT alone, indinavir alone or the AZT/indinavir combination. Last summer, people taking the AZT-containing regimens were offered 3TC in addition, based on the data from 035. Participants' short period on 3TC is not considered to have affected the results.

The purpose of looking at this treatment-naive population with advanced HIV was to obtain rapid disease progression data uncontaminated by issues of resistance to AZT. Even without AZT resistance, it would have been highly surprising if the AZT monotherapy arm had done as well as either of the arms that included indinavir. The trial took place in Brazil because that is where a large number of untreated people with low CD4 counts could be found.

Many Brazilians were not impressed by Merck's largess. Since the trial's inception in April, 1995, community groups have protested it as unethical. The monotherapy arms are considered substandard therapy likely to trigger HIV drug resistance that would limit patients' future options, especially in regards to protease inhibitors. Furthermore, Brazilians were unhappy that no changes in therapy were allowed until a defined clinical endpoint occurred. Trial participants would have to suffer through a series of minor ailments and falling CD4 counts until a major AIDS-defining ailment transpired. Individual viral load test results were not given to participants, and such tests were not available in Brazil outside the trial.

Coincidentally or not, 028 was halted a day after a major article on the subject appeared in the Miami Herald. The viral load and CD4 count data at a median of 58 weeks reflected the pattern of a year ago: For the AZT monotherapy cohort, viral load was down an average of .25 log (44%) and CD4 count was up an average of 21 cells/mm3. For indinavir alone, the corresponding figures were viral load down .76 log (83%) and CD4 count up 103, and for the AZT/indinavir combination, viral load decreased 1.03 log (91%) and CD4 count climbed 112. As in past comparative trials, AZT did little, either alone or as part of the double combination, and this insignificant role was reflected in the clinical data -- 6% on the double combination experienced an AIDS-defining condition compared to 7.8% on indinavir alone and 18% on AZT alone. The difference between the first two arms is not considered statistically significant.

There were about 40 extra deaths or serious illnesses on the AZT monotherapy arm to prove a point that had become obvious. All survivors in the trial will now receive indinavir for life, compliments of Merck. The company hopes the state health system will supply the AZT/3TC or other drugs that patients should take in combination with its protease inhibitor, but the public health plan has supplied AZT/3TC irregularly so far. If the Brazilians in the trial now obtain all three drugs, many will face the problem that first they received AZT then AZT/3TC and then finally had indinavir added on. In the U.S., such an incremental sequence is considered highly undesirable because it allows HIV to become resistant to each medication, one at a time.

ACTG 333: Moving on, Quickly

A major issue in the controversy surrounding the Brazilian trial was the threat of drug resistance arising from incomplete HIV suppression. Even the best viral load reduction in that trial (1.03 logs from indinavir plus AZT, with only 42% below 500 copies/ml, the limit of detection) was not enough to shut down HIV's evolution. The magnitude of this threat was underscored by data from ACTG 333, which was "interrupted" in March.

ACTG 333 was a test of the consequences of long-term use of the current "hard capsule" formulation of saquinavir (brand name: Invirase). In this form, saquinavir is very poorly absorbed by the digestive system, and the effect on HIV is extremely modest (see Treatment Issues article Protease Inhibitor New Math, May, 1996, pages 3-4).

Participants in ACTG 333 had been on the saquinavir hard capsule for at least 48 weeks, and the median time on saquinavir was 112 weeks. They were assigned to receive their current nucleoside analogs plus either indinavir or the new saquinavir formulation in a soft gelatin capsule. This new formulation is much more absorbable. At the recommended dose (1,200 mg three times a day), it attains blood levels of saquinavir that are six to eight times greater than the previous saquinavir regimen (the hard capsule at 600 mg thrice daily). A third, comparison group was supposed to take the old hard capsule version of saquinavir for another eight weeks and then were to switch to open-label indinavir.

An analysis of the week eight viral loads of the first 72 volunteers (the plan was to enroll 144) registered results still more paltry than Merck's 028 trial. Those who stayed on hard capsule saquinavir were unchanged, as expected. Those who were switched to the soft gelatin capsule saw their viral loads drop by a mere .23 log (42%) on average, accompanied by an average CD4 count rise of 37. For the volunteers who were switched to indinavir, viral loads dropped by .58 log (74%) while CD4 counts increased by 23 cells/mm3. These responses were not good enough for the investigators. ACTG 333's design required termination of any regimen that did not achieve at least a 0.7 log (80%) reduction in HIV. Trial enrollment is now halted, and those on the hard capsule will be shifted to indinavir while those on the soft gelatin saquinavir capsule will be offered the choice of taking indinavir instead. When switching, trial participants should consider changing their other anti-HIV medications at the same time as a further guarantee against inadequate viral suppression and the rise of drug resistance. Monitoring of CD4 counts and viral load will continue until July 14.

What happened? Nobody knows yet, but the widespread presumption is that the problem is one of evolving drug resistance. Certainly exposing HIV to a low level of a given drug and then later upping the virus' exposure is the classic way to encourage the evolution of resistance to that agent. Lab studies of drug resistance are based on this technique. It would not be surprising if saquinavir resistance developed. And if indinavir's activity was diminished, too, then that could well be because the mutations that cause reduced sensitivity to saquinavir also lead to reduced sensitivity to indinavir. To achieve sufficient HIV suppression, volunteers should have been advised to change their concomitant HIV drugs in the first place. The ACTG 333 investigators are now checking trial participants' HIV for drug resistance, using both test tube culture tests and probes for genetic mutations.

Comment: New Ways to Answer the Basic Questions

ACTG 333 could represent the future as far as testing anti-HIV drugs is concerned. Agents that do not show immediate and continuous viral suppression of sufficient magnitude would be quickly discarded. The Food and Drug Administration is planning a meeting this summer of its Antiviral Drugs Advisory Committee to enshrine this approach. Anti-HIV drugs would receive accelerated approval based on short-term, 16-week viral load data, and drugs would receive permanent, full approval when a longer term viral load response, out to a year, say, was documented. (This proposal reportedly comes from Glaxo Wellcome, which now has two HIV drugs under development, the nucleoside analog 1592U89 and the protease inhibitor 141W94.)

Trial participants would then be taken off study drugs if they failed to show a viral load reduction or their HIV levels started to rebound. There would be no need to prove what turns out to be a very limited point by letting them get sick, as happened in ACTG 320 or Merck 028. The problem is that you cannot optimize drug regimens just by looking at viral load response, even at one year. Viral load responses do not necessarily reveal the total duration of response or suggest drugs that could replace the current regimen should it start to fail. For this you need an analysis of the "genetic barrier" surrounding the virus, i.e., the number and position of gene mutations necessary to cause significant losses in sensitivity to a given combination.

Two drugs might be as good as three only for a short period if HIV needs just a couple of mutations to evade them. Cross-resistance is the other issue that analyzing the genetic basis of resistance helps resolve. Mutations at certain positions can negate the activity of several drugs at once, making certain drugs unworkable as second line replacements for certain other ones.

But even having a resistance analysis in hand does not provide complete power to predict a therapy's effect. Some mutations may hamper HIV replication while others may lead to increased virulence. Multiple resistance mutations may have a range of interactions, from disabling the virus to resensitizing it to certain drugs or even reinvigorating it. The drugs themselves may have positive or negative interactions, both in relation to the virus and the body's metabolism. AZT and d4T seem to compete with each other for activation (phosphorylation) within cells, for example, whereas ritonavir increases saquinavir levels by blocking its metabolism in the liver.

The situation is far too complex to individually evaluate each combination regimen. One way around this dilemma is to run large post-marketing strategy trials. Participants and their doctors would be given wide latitude about which particular regimens to start with or switch to, so long as they followed the stated strategies, such as attempting to reach specific viral load goals or interpreting mutation tests in a particular way. At planned timepoints, the status of participants' HIV infection would be assessed and correlations between healthy outcomes and treatment history would be used to create guidelines for optimum care.

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