Two sets of guidelines, one set of goals: No monotherapy, no resistance

New recommendations set standard of care with protease inhibitors

Two sets of guidelines for managing HIV infection in the era of combination therapy reflect the growing expectation that AIDS survival may soon be measured in decades instead of years. But reaching that quantum leap in prognosis requires specialized knowledge, a strong patient-provider relationship, a well-developed plan of attack, and a devout approach to maintaining difficult drug regimens, say the architects of the new guidelines.

The two documents, published within one week of each other, will provide a much-needed standard of care for HIV treatment, which has been transformed by new drugs and better understanding of HIV pathogenesis. The first document, Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, was issued by the U.S. Public Health Service and is published for comment in the Federal Register. The second document, Antiretroviral Therapy for HIV Infection in 1997, was issued by the International AIDS Society—USA (IAS), and published in the June 25 Journal of the American Medical Association.1

The two documents are remarkably similar, reflecting the fact that several AIDS experts sat on both panels. They underscore the consensus arising from accumulated data on the benefits of initiating aggressive therapy much earlier than previously recommended, and selecting the right regimen on the first try. They also lay out the framework by which physicians and patients should decide when to start therapy, when to switch a failing regimen, and how to choose alternative regimens that are most effective.

While HIV treatment has become more aggressive, it also has become more complex. The federal guidelines, some 90 pages long, emphasize the importance of clinicians becoming more sophisticated in their knowledge of HIV pathogenesis. The warning that effective HIV treatment requires specialized education and vigorous monitoring is a departure from federal pronouncements in the early 1990s that said HIV treatment belongs in the domain of primary care provi ders. (See related story on efforts to educate physicians about the new guidelines, p. 89.)

"As our understanding of HIV disease has improved and the number of available beneficial therapies has increased, clinical care of HIV-infected patients has become much more complex," the federal guidelines state. "Therapeutic success increasingly depends on a thorough understanding of the pathogenesis of HIV disease and on familiarity with when and how to use the more numerous and more effective drugs available to treat HIV infection."

Because the guidelines are a radical departure from treatment practices in the past — and because triple-combination regimens are so difficult to maintain — both documents highlight the importance of physicians and patients working closely together to assess whether patients are ready and able to commit to such a regimen. The guidelines emphasize that assessments should be made on an individual basis, and should not be based on membership in a specific group of people that may have a history of poor compliance.

"The guidelines do a better job than anything done before about discussing the absolutely necessary interaction between the physician and patient, such that the decision is a mutual one and no one has greater authority than the other," says Charles Carpenter, MD, professor of medicine at Brown University School of Medicine in Providence, RI, and chairman of the federal panel that laid out treatment principles. Carpenter attributes the emphasis on this interactive process to the fact that more community representatives sat on the PHS panel than on previous federal HIV guideline panels.

Update reflects new data on early therapy

The recommendations from the IAS panel update the organization’s guidelines for antiretroviral therapy published in 1996 — the first efforts to establish a protocol for testing patients for viral loads and treating them with combination therapy. The major change in the update is its recommendation to treat patients earlier and more aggressively.

The panel had previously recommended that therapy be given to patients with CD4 counts between 350 and 500 and with viral loads between 30,000 and 50,000 copies. Patients with viral loads greater than 5,000 to 10,000 copies were to be considered for treatment. The new guidelines recommend treatment for all patients with viral loads greater than 5,000 to 10,000 copies, regardless of their CD4 counts. Therapy also should be considered for all patients who have detectable viral loads, request treatment, and are committed to possible lifelong adherence.

While the panels for both guidelines were unanimous in stating the need for earlier treatment, they came up with different viral load cut-off points for initiating treatment. The federal guidelines recommend treatment for any patient with CD4 counts lower than 500 and viral loads greater than 10,000 copies, compared to 5,000 to 10,000 copies in the IAS guidelines.

These differences are not significant, Carpenter points out, because of the variability in assay sensitivity. "One set starts at 5,000 and the other at 10,000, but statistically that is not much different because the two assays [bDNA and PCR] overlap in variability by about threefold."

Until assay variability is reduced and more data are gathered in clinical trials, it will be difficult to assign an absolute value (as opposed to a range of values) for when to start treatment, he adds.

The federal guidelines call for all patients with AIDS or symptomatic HIV infection to receive antiretroviral therapy. The federal panel also recommends that physicians monitor all their HIV-infected patients for CD4 counts and HIV RNA or viral load. While viral-load testing has become a critical diagnostic tool in the past several years, not all physicians have offered it and not all insurers have covered it. With the guidelines’ recommendation for viral-load testing prior to and shortly after initial treatment and for follow-up testing every three months, routine monitoring of plasma virus will become as standardized as CD4 count testing, public health officials noted.

The federal panel notes there are no long-term data to show whether early aggressive treatment extends life. Still, it recommends that all asymptomatic patients with more intact immune systems and their providers weigh the continuous viral replication resulting from immunological decline against the side effects of triple combination therapy. Whether taking an aggressive or conservative approach, initiating therapy in patients with no prior treatment calls for a regimen of three drugs, with the goal of suppressing virus to undetectable levels. The 1996 IAS recommendations had centered on two-drug combinations, with a protease inhibitor as an option. The IAS panel now recommends that treatment start with a three-drug combination. It notes, however, that for asymptomatic patients the decision to start therapy should be discussed in detail with the clinician to assess the patient’s willingness to commit to "a complex, costly, and potentially toxic regimen."

Current triple-drug therapy involves a total of 12 to 20 pills each day. To avoid subdosing, the regimen requires rigid adherence to the three-times-a-day dosing schedule. Moreover, both guidelines recommend that all drugs should be started simultaneously (ideally, within one or two days of each other) rather than added sequentially. Staged introduction of drugs decreases the chance of complete suppression of the virus and increases the risk of drug resistance. In addition, the use of protease inhibitors requires that patients comply with a variety of dietary requirements.

"It is not inconsequential to start a patient on therapy; it will impact heavily on their lives," says John Bartlett, MD, a panel member and professor of medicine at Johns Hopkins University. "That is why some choose to observe asymptomatic patients and monitor any changes in the level of virus rather than begin treatment."

The guidelines state quite clearly, however, that should a physician and patient decide to start treatment, they should aggressively work to achieve maximum suppression of the virus. The panel’s preferred regimen is a combination of two nucleoside reverse transcriptase inhibitors and one protease inhibitor. The panel considers a two-drug regimen less than optimal and warns against the quick resistance problems associated with treating HIV with a single drug.

The only exception to this advice is in the case of pregnant women who don’t need antiretroviral therapy for their infection. The panel notes that in this case, treatment with zidovudine (AZT) during pregnancy and labor can reduce the risk of infecting the fetus. Pregnant women who need antiretroviral therapy should continue with combination therapy.

Reference

1. Carpenter C, Fischl M, Hammer S, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society — USA Panel. JAMA 1997; 277:1962-1969.