Panels to develop standards for antiviral therapy, viral-load testing
Panels to develop standards for antiviral therapy, viral-load testing
AIDS treatment changing more than ever
Earlier this year, Gary Rose had two viral-load tests performed on himself. The first test detected no virus in his blood. The second test, taken about a month later, measured 40,000 copies per ml.
"What am I supposed to do with that? That doesn’t give me information, that gives me panic," says Rose, treatment and research coordinator for AIDS Action Council in Washington, DC.
The huge variance in the two tests appears to have been an anomaly. Rose’s second test was offered free as a promotional effort by Hoffmann-LaRoche shortly after its test was approved, and his sample may have sat in a lab several months, he says. The experience, however, illustrates just one of many perplexing questions that clinicians and patients face in the new era of HIV treatment.
Those questions may soon be answered when two government panels develop the first standard of care for antiviral therapy and viral-load testing with the government seal of approval. The first panel was established by the U.S. Public Health Service (PHS) in Bethesda, MD, and is chaired by Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases in Bethesda, and John Bartlett, MD, chief of the division of infectious diseases at Johns Hopkins University in Baltimore. This panel is responsible for promulgating the standards based on principles drawn up by a second panel, which was formed by the National Institutes of Health in Bethesda, MD, and is chaired by Charles Carpenter, MD, associate professor of Medicine at Brown University in Providence, RI.
The panels plan to publish their recommendations sometime this month in the CDC’s Morbidity and Mortality Weekly Report. Unlike previous ad hoc AIDS committees formed to set standards for AIDS treatment, the panels will meet on a regular basis over the next three years and update the guidelines as needed, says Bartlett.
Even though the principles of AIDS treatment have changed more in the past year than in any previous year, AIDS Action Council and other AIDS organizations say the guidelines are sorely needed — and soon.
"We can’t wait another six or nine months with everyone taking a best guess at what they need to do," Rose says. "We need a statement with a PHS stamp on it. We need it for funding, planning, and evaluation."
Bartlett agrees: "In this field we are always going to be operating in a certain element of unknown, so to put them off because we have to gather more information would be erroneous."
The first and only guidelines for protease inhibitor use and viral-load testing were issued by the San Francisco-based International AIDS Society - USA in June.1 The recommendations were based on four guiding principles: "maximum suppression of HIV replication should be the goal of therapy; suppression must be continuous to maximize the benefits of therapy; treatment regimens need to be changed in response to emergence of drug resistance; and antiretroviral therapy alone may not be sufficient for immune restoration, particularly in patients with advanced disease."
Modest’ changes to existing guidelines
While the society’s guidelines are not obsolete, they were formulated prior to the XI International Conference on AIDS in Vancouver last summer, where much of the clinical data on protease inhibitors were first presented. Since then, nevirapine has become the first non-nucleoside reverse transcriptase inhibitor to reach FDA approval, dual protease inhibitor combinations have been tested, and zidovudine and d4T have been shown to be a poor combination, Bartlett says. New studies since the conference also have underscored the importance of early viral suppression and viral-load monitoring.
"I think we’re looking at making modest changes," he says, "with the guiding principle based on the statement that we ought to kill the virus and do it for as long as we can."
"I would judge that most people are more aggressive in using protease inhibitors earlier now than they were six months ago, and in making every effort to keep viral load as low as possible for as long as possible," Carpenter tells AIDS Alert. "They also are relying more on plasma viral load as an indication for treatment and a guide for continued treatment and changing therapy."
Because protease inhibitors were approved in record time and without extensive clinical trials, there is "enormous variation" in how patients are being treated, Bartlett says. Some clinicians tell AIDS Alert that they are changing what they prescribe almost monthly as new information becomes available. Increasingly, they are seeing patients who have failed on one protease inhibitor, and they must decide whether to switch to another protease inhibitor or add a second one. They say guidelines are especially needed for the gray area between the extreme ends of the spectrum (low CD4 count/high viral load and high CD4 count/low viral load), which are easier to judge.
"I think the consensus is going to be that anybody who has a high viral burden needs to be treated, and treated with at least two and possibly three or four drugs," Bartlett says. "The question is what is too high — is it 500, 5,000, 10,000 or 30,000 [copies]? Everyone has a different way to define high viral burden, so there is some fine tuning that needs to be done."
CD4 takes back seat to viral load
The principles panel has had difficulty reaching consensus on the importance of CD4 count testing in the new treatment scheme, reflecting how much the treatment paradigm has shifted in the past year. While CD4 count is important to determining the extent of immune dysfunction prior to initiating treatment, it has taken second place to viral load as the gold standard of clinical efficacy.
"I think people agree you need viral-load testing before treatment, repeated in two to three weeks after initiation of treatment, and probably at three-month intervals afterward," Carpenter says. "But how helpful CD4 count will be after the initial test is still up in the air, and certainly not every three months."
While the "hit hard, hit early" philosophy of treatment is embraced by many panel members, Carpenter says other members feel strongly that clinicians should not feel compelled to treat patients who have undetectable viral load without treatment. "There are many people who would feel that in persons who are not ill and have a CD4 count of 400 and a viral load of 15,000 [copies], it might be preferable simply to monitor the viral load rather than to put them on a therapy such as two nucleosides, which would probably be less durable and would probably stimulate the development of resistant organisms."
Carpenter’s panel, which last met in mid-December, currently lacks evidence to make a recommendation about who would and would not benefit from combination therapy. Citing anecdotal reports of extremely sick patients responding well to protease inhibitors, Carpenter says many panel members don’t feel comfortable setting a threshold below which therapy should not be offered.
Neither panels are likely to address at which point treatment should stop. Although the Aaron Diamond Institute in New York City is taking the bold move of asking study patients who have had non-detectable viral loads for nearly two years to voluntarily stop treatment to see if they have been cured, Bartlett points out that those patients began treatment shortly after seroconversion.
"For most of us, 99% of patients are people who have been infected for some sustained period, and there we are not talking about when to stop," he explains. "We are talking about how aggressive to be and how long we can stick with one regimen."
Reference
1. Saag M, Holodniy M, Kuritzkes D. Viral load markers in clinical practice: recommendations of an International AIDS Society - USA panel. Insert. Improving The Management of HIV Disease 1996; 4:insert.
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