Sep. 21, 1998 Treatment with antiviral drugs for HIV infection that begins too early can work against the patient's natural immune system and do more harm than good, says a pioneer AIDS researcher at the University of California San Francisco.
In a "viewpoint" piece in the September 19 issue of Lancet, Jay A. Levy, MD, a UCSF professor of medicine and one of the first to discover HIV, outlines his concerns about the current strategy advocated by the clinical community for prescribing combination drug therapy, often called the AIDS drug cocktail. His article is titled, "Caution: Should We Be Treating HIV Infection Early"
Levy's research has focused on natural immune response against the AIDS virus. The accepted treatment guideline, Levy says, is to begin therapy "as soon as possible and with as large an armamentarium as is available." He emphasizes that his concern is not about the treatment itself but is about the stage at which it is initiated.
"Physicians should carefully consider the time when drug therapy is begun for infected individuals who are past the acute infection phase," he writes. "Until we have a good surrogate marker presaging irreversible damage to the immune system or a means of inducing an anti-HIV immune response, a delay in initiating therapy should be considered."
In his view, he writes, "treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime of the person."
He adds, "Any decision to stop the drugs could only be made if one had assurances that all infected cells had been eliminated--now an unlikely event--or the immune system has recovered sufficiently to control HIV."
Levy supports therapy during acute or primary infection, noting that "within days after the virus enters the body, a major benefit to the newly infected individual can be provided by lowering the viral load dramatically and perhaps even arresting the establishment of HIV infection."
His great concern, he notes, is administration of drugs to persons who have been infected for several months or years. Many people may be without symptoms and in good health, but as soon as an HIV-positive diagnosis is made, they are usually placed on therapy immediately, he explains.
In Levy's view, current drug regimens should be prescribed only for patients who show symptoms of HIV infection or whose CD-4 cell counts have dropped substantially. CD-4 cells, also called T helper cells, coordinate the overall action of the human immune system. They are the primary target of HIV and when they succumb to infection, the stage is set for the opportunistic infections that cause AIDS.
He suggests starting treatment only after the CD-4 cell count falls below 400 and the viral load is above a level of 30,000 copies of viral genetic material per milliliter of blood on two separate tests. "Administering drugs at this selected time seems the best strategy because the virus can be controlled and the immune system can recover...," he writes.
He adds that instead of subjecting infected people to antiviral therapy early--when it is not needed because the immune system is functioning, when therapy requires strict adherence or drug resistance will take place, and when drugs can be harmful--a delay can provide an interval of several years in which immune cells can control the virus and selection of resistant mutants can be avoided.
In presenting his case, Levy notes that the current three-drug treatment for HIV may soon be extended to a four- or five-drug regimen, similar to the approach used for cancer patients. And he asks, "Have we really succeeded going in this direction with malignancies." He also notes that unlike the commitment for HIV therapy, no cancer patient takes three or four chemotherapy drugs for a lifetime.
Current assumptions in clinical strategy that concern Levy include:
* If virus replication takes place, mutations might develop that could lead to a drug-resistant strain of virus. -- He notes that mutations occurring at a steady rate during HIV replication are random and would not select for viruses resistant to current drugs. Instead, he adds, it is the drugs themselves that encourage these types of resistant viruses.
* Any replication of HIV will lead to irreversible destruction of the immune system. -- What is overlooked by this assumption, Levy says, is that these drugs can be toxic and can be directly detrimental to a natural immune response to HIV, which is present in most individuals even when they show no symptoms. This effective antiviral immune response is characteristic of long-term survivors who have been infected for more than 20 years, have no symptoms, have not been on therapy, and show strong activity by CD-8 cells to suppress virus replication while not killing off CD-4 cells. He says his studies have shown that people on triple therapy have a decrease in this CD-8 cell antiviral response.
Levy reports that recent research by his team and others has shown that persons who chose to stop therapy--even after three years--experienced a resumption of virus production, with the viral load often higher than the level at the onset of therapy. This finding suggests the function of the immune system against HIV has been compromised.
He suggests that the most valuable treatment in the future might be one that includes antiviral drugs, immune restorative treatment, and appropriate immunizations. This approach could induce an effective response to HIV and all the other pathogens that attack HIV patients, thereby overcoming the downfall of current therapies that leave patients "in a naive immune state, like an uninfected individual, rather than someone prepared to control HIV," he says.
If the virus cannot be eliminated, the ultimate objective is to return all HIV-infected people to the state of long-term survivors who do not need treatment even after 20 years of infection, Levy concludes.
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