Triple-drug therapy may mean lifelong commitment
Response rate must be measured for the individual
Recent studies conducted in the United States and France strongly suggest that antiretroviral therapy administered with a combination of three or more drugs may need to be continued indefinitely if levels of HIV RNA are to remain suppressed. Both studies used combinations of indinavir (Crixivan), zidovudine (AZT), and lamivudine (Epivir).
Triple-drug therapy requires patients to take five or more pills two or three times a day. Because it is such a challenging regimen for patients to follow, researchers were seeking an acceptable alternative using fewer drugs.
Led by Diane Havlir, MD, of the University of California in San Diego, the AIDS Clinical Trials Group Study 343 Team studied 316 HIV-infected adults with a CD4 count of at least 200 cells and an HIV RNA plasma level of at least 1,000 copies. During the induction phase of the study, all subjects received a triple-drug AIDS cocktail. During the study’s maintenance phase, only 4% of those who remained on the triple-drug regimen lost viral suppression (at a plasma level of a minimum of 200 copies two consecutive times) as compared to 23% of those who switched to dual therapy and 23% of those who changed to monotherapy.1
A similar work by the Trilege Study Team, headed by Gilles Pialoux, MD, of the Pasteur Institute in Paris, produced analogous results. In 279 antiretroviral-naive French patients, plasma HIV-1 RNA levels fell below 500 copies after three months of induction therapy with all three drugs. Only 9% of those who continued the triple-drug combination experienced a rise in virus levels. Viral load increased in 22% of those taking zidovudine and indinavir and 31% of those taking zidovudine and lamivudine.2
According to Jeffery Laurence, MD, director of the Laboratory for AIDS Research at New York Hospital, Cornell Medical College, the information that came out of these studies was incredibly clear-cut. Laurence says the U.S. government would like to run another trial treating people with three drugs for two years, but only people who’ve had absolutely zero virus in their blood for that period of time. "When they took all comers and put them in this regimen, it was very disappointing," he says.
HIV reaction different from cancer
For a significant percentage of people, Laurence says, "as soon as they switched to a smaller number of drugs, the virus came right back in full force, which basically tells you the virus doesn’t go away and you’re going to need to take the full-court regimen of three drugs for the foreseeable future. The idea that you can start with a higher number of drugs and then go on to a lower number of drugs as we do in cancer is not working for AIDS."
However, Stephen Wolinsky, MD, associate professor in the division of infectious diseases at Northwestern University School of Medicine in Chicago, says though triple-drug therapy suppresses viral replication below the level of detection for many individuals, for others it does not. Wolinsky, who works both with individual patients and in research, defines successful maintenance therapy as "a fine balancing act. You have to see how the response rate is for the individual. Some people respond quite nicely and they have horrible side effects, they can’t tolerate the regimen. Other people tolerate it quite well and yet they don’t achieve a virologic response. It’s very important that we don’t delude ourselves into thinking this is the end,’ but realize that this is just one step along the way."
Noncompliance worsens outside trials
No one seems to disagree with the effectiveness of the AIDS cocktail in lowering detectable viral load as demonstrated by the triple-drug trials. There are, however, some serious issues for many patients receiving treatment outside the monitoring and support provided by a formal study that mitigate the success of a three-drug combination.
Once a triple-drug treatment regimen is begun, patients may need to remain on it for the rest of their lives. The perceived parallel between treatment for cancer and treatment for AIDS falls apart quickly when you realize that cancer patients do not take three or four chemotherapeutics for a lifetime. After three years of a three-drug regimen, virus production has not only resumed in patients who have chosen to stop triple-drug therapy, but the amount of viremia experienced has often been higher than it was when these patients began therapy.3
Patients become noncompliant with any prescribed regimen within the community a lot more frequently than they do in the more controlled environment of formal studies. Factors contributing to noncompliance include drug toxicity and lack of a good support system. Some patients are (or become) homeless. Side effects can include heart disease and disfiguring lipid abnormalities.
The question of what percentage of the HIV-infected population these drugs are really helping also has become quite an issue in the past few months. "Basically," Laurence says, "only 50% of people put on these drugs out in the community are getting the full benefit of constant suppression of virus below the levels of detection, which is what people are aiming for."
The other 50% don’t share that success. "Whatever the reason, be it their failure to comply or some problem with the pharmacology of these drugs—that is, that particular person wasn’t getting adequate levels of the drug even though the person was taking the drug as prescribed—or because of some interaction with other drugs or food or because of a pre-existing resistant virus that your drugs weren’t good enough to take care of, basically it isn’t working well for about half the people. In our hospital, I would say that about 80% of people who adhere to a good drug regimen are getting a good response if they were naive to the drugs."
A rising chorus within medical ranks is questioning the strategy dictated by national groups advising on clinical care. The current recommendation is to administer triple-drug therapy when the HIV RNA level in blood is over 5,000 and the CD4 cell count is below 500.4
This "hit early, hit hard" approach is being challenged by researchers and clinicians who question the practicality of using all the pharmacological weapons on the first shot when what they’re really hoping to do is to buy time until something better comes along.
These guidelines examine the problem only from the laboratory point of view. Jay Levy, MD, of the University of California School of Medicine in San Francisco, wrote in the Sept. 19, 1998, issue of Lancet that "The clinical state [if the person is without symptoms] is not a major detriment; it is the numbers that appear to decide the therapeutic course. . . . A justification for early [triple-drug] treatment is that if any virus replication takes place, mutations might develop, eventually leading to a drug resistant virus. We should be aware that mutations occurring at a steady rate during HIV replication are random and would not select for viruses resistant to current drugs. Instead, it is the drugs themselves that encourage the emergence of these types of viruses. Under normal circumstances, no selective advantage against a non-resistant virus is introduced and it is more likely that a wild-type virus will dominate."
"What Levy and others are beginning to suggest," Laurence says, "is that maybe you should wait until your virus level gets a whole lot higher than that, maybe 30,000. Much before a viral count of 30,000, most people don’t get sick, and if they do get sick, they can take the drugs then. There’s very little evidence that if you wait until your viral load is 30,000 rather than five or 10 or even 20,000 that you’re going to harm yourself. And you could have bought yourself many years of side effect-free life by starting these drugs later."
If multiple-drug therapy seems called for, some people may be better off taking more than one of the same class of drugs. A more conservative approach would be to stick with two classes. "The bottom-line message," says Laurence, "seems to be not to use the protease inhibitor up front. I think that’s coming more and more into the dialogue we’re having with patients. The data recently has opened up a whole new kind of discussion we really weren’t having six months ago."
References
1. Havlir D, Marschner I, Hirsch M, et al. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med 1998; 339:1,261-1,268.
2. Pialoux G, Raffi F, Brun-Vezinet F, et al. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. N Engl J Med 1998; 339:1,269-1,276.
3. Levy JA. Caution: should we be treating HIV infection early? Lancet 1998; 352:982.
4. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998. JAMA 1998; 280:78-86.
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