When should a person with HIV infection start antiretroviral therapy?
Since the International AIDS Conference held in Vancouver in 1996, most everyone has agreed that aggressive therapy includes a combination of three potent drugs as soon as possible. Now, some are rethinking this strategy.
The question was debated at an ICAAC symposium chaired by Daniel Kuritzkes, M.D., in which a group of clinical investigators and research scientists agreed on one thing: The goal of therapy for treatment-naïve individuals is complete suppression of the virus.
Best Approach May Vary
Representing the "hit hard, hit early" side was Dr. Chip Schooley of the University of Colorado Health Science Center. According to Schooley, the best therapeutic approach may vary from individual to individual. He then defended the U.S.-based guidelines, emphasizing five points.
If viral replication is not fully suppressed, then drug resistance occurs, resulting in virologic failure. If resistance (the 103 mutation) occurs, then an individual can be cross-resistant to other drugs within that class, especially in the case of NNRTIs. Once a decision on a therapy is made, the goal should be complete viral suppression.
Complete viral suppression is defined as the lowest level possible (under 20 copies). He states that if you keep viral load down as low as possible, that the drug regimen will be more effective for a longer period of time (Kempf et al. Abbott Laboratories) (Abstract 2196).
Once a therapy has been selected and is proved effective, it needs to be maintained indefinitely. Schooley believes there is a delayed reaction between virologic failure and immunologic and clinical failure, and that disease progression is inevitable in people with any viral replication.
Merck studies consisting of treatment-naïve individuals (Merck 060) or 3TC and P.I.-naïve individuals (Merck 035 and Merck 039, respectively) were cited by Schooley. The arm of the study which had the best results received AZT, Epivir and Crixivan. Most notably, the results from Merck 060 showed that 80 percent to 90 percent of individuals had a viral load go from above 10,000 copies to below 500 copies. These individuals also had a mean baseline T-cell count of 600.
Schooley concluded his lecture by stating that even though some people will advocate for delaying therapy because of long-term, drug-related toxicities, too little is known about these toxicities. Clinicians should not withhold treatment for HIV infection.
Some of those challenging the "hit hard, hit early" theory also expressed their views.
Perhaps the most intriguing and inflammatory theory was set forth by Brian Gazzard of London, who proposed delaying therapy and using a less than fully suppressive regimen. Gazzard often delays therapy for his patients until their T-cell counts fall to 350, rather than 500 as the U.S. Guidelines suggest. He also waits until viral load counts are higher than 10,000 bDNA and 20,000 PCR.
This minority point of view, which some in the medical community may view as reckless, is being discussed more and more by physicians, activists and people infected with HIV.
Gazzard offers five points to support his claim.
In the DuPont 006 study, baseline viral load didn't seem to affect virologic results because participants, whose viral loads were greater than 100,000, responded well to the three drug combination of AZT, 3TC and Sustiva.
People with 350 T-cells or more rarely get AIDS-defining conditions
Since people aren't at risk for AIDS-related conditions, why expose them to years of toxicity from HIV drugs? On the average, it takes up to four years for a person to go from 500 T-cells to 350 T-cells
According to the Options Study at San Francisco General Hospital, drug adherence is high in the beginning of treatment, but goes down with time. Starting initial therapy early may lead to virologic failure sooner than expected but not just because there is a lack of potency. Pharmacokinetics and adherence to a regimen play a vital role. There are many factors which may reduce adherence: amount of pills, side effects, drug-to-drug interactions. Due to resistance, giving HIV medications to a patient who is not fully adherent may be more harmful to the patient than beneficial.
Except for people with advanced HIV disease, delaying therapy saves money.
While Gazzard's argument for delaying the start of therapy may appear to have some merit, he did not propose an alternative, or "soft," regimen.