Rx CARE

SHARP TURN

A federal panel revises treatment guidelines for HIV-infected adults and adolescents

The "hit early, hit hard" approach toward HIV/AIDS treatment is suddenly changing course. The Department of Health & Human Services, in a joint effort with the Henry J. Kaiser Foundation, has released newly revised guidelines with a more conservative approach for treating asymptomatic HIV-infected adults and adolescents. The guidelines continue to recommend antiretroviral therapy for all patients with acute HIV syndrome, those within six months of HIV seroconversion, and all patients with symptoms attributed to HIV infection.

The new approach for when to initiate anti-HIV therapy comes in response to the growing concern that prolonged use of antiretroviral "drug cocktails" can cause potentially dangerous adverse effects and lead to drug resistance. But will these new guidelines prompt overreaction from both patients and physicians, causing patients to discontinue their medications and physicians to adopt a wait-and-see approach that may prove perilous? "I am very concerned that there might be an overreaction, saying that it's the right thing to delay [treatment]," said Charles Farthing, M.D., medical director of AIDS Healthcare Foundation, Los Angeles. "It isn't really [right to delay], it's just the practical thing to do in many cases and remains a complex issue."

The guidelines, which were constructed as a "living document" and are updated by the panel as new data emerge, include recommendations for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. The latest guidelines recommend starting antiretroviral therapy when an asymptomatic HIV-infected person's CD4 cell count falls below 350 (previously it was 500) or HIV RNA levels are above 30,000 copies/ml (previously it was above 20,000 copies/ml).

Risks and benefits of delayed initiation of therapy

Benefits of delayed therapy

Risks of delayed therapy

The conservative approach is based on the recognition that the restoration of immunologic function still occurs in most patients who start therapy with CD4 cell counts in the 200-350 range, and that toxicities and adherence challenges may outweigh the benefits at CD4 cell counts higher than 350. A major dilemma confronting patients and practitioners is that the available antiretroviral regimens with the greatest potency in terms of viral suppression and CD4 cell preservation are medically complex, are associated with several adverse effects and drug interactions, and pose a substantial challenge for adherence.

"What we have seen in the past five years is ever-increasing survival times in HIV patients, which is the good news. But it comes with the concern that we now need to balance long-term survival and long-term medication [use] with the possibility of long-term complications," said Benjamin Young, M.D., Ph.D., a specialist in HIV resistance with Rose Medical Center, University of Colorado Health Science Center, Denver.

Young noted that it becomes more important than ever to weigh the collective risks versus benefits and take a balanced, thoughtful approach toward treating each patient. As the recommendations evolve, patients who have begun highly active therapy at CD4 cell counts greater than 350 may wish to discontinue treatment. It should be noted that there are no clinical data addressing whether this should be done or can be accomplished safely, which highlights the need for an individualized approach to treatment. The table below summarizes some of the risks and benefits associated with delaying therapy.

The guidelines have also added an updated section on the expanding scope of antiretroviral drug toxicities. "Particularly alarming is the alteration of fat metabolism that can emerge during treatment," said Anthony S. Fauci, M.D., director of the National Institute of Allergy & Infectious Diseases and co-chair of the panel. "We are seeing an increasing number of patients with dangerously high levels of cholesterol and triglycerides.... We now must find ways to deal with unanticipated toxicities, including the potential for premature coronary disease," he said.

Clinical outcome data still support the use of a protease inhibitor (PI) in combination with two triple nucleoside analogs (NRTIs) for initial treatment, but also included in the revised guidelines are new drug-specific recommendations. Two new entries are included in the "strongly recommended" category of anti-HIV drug treatments. One of these is the recently approved PI Kaletra (Abbott), which is a coformulation of ritonavir and lopinavir.

The other new entry is a combination of ritonavir and indinavir. The use of ritonavir to increase plasma concentrations has rapidly evolved from an investigational concept to widespread use. Ritonavir is included in Kaletra only to inhibit the CYP3A isozyme metabolism of lopinavir to increase lopinavir's serum concentration and area under the curve; this gives more sustained drug levels and allows twice-daily dosages. While a considerable body of pharmacokinetic data supports the use of PI combinations, skimpy efficacy data are available for combinations other than ritonavir/saquinavir or ritonavir/ lopinavir. In addition, the long-term risks and toxicities of dual-PI combinations remain unknown.

Also in the revised guidelines is a section on the importance of adherence to therapy. Lack of adherence to complicated regimens can lead to increased drug resistance and treatment failure. One study has shown that when patients take only 90% of their antiretroviral medications on time, the rate of drug failure or resistance jumps to 50%. Data from this study indicated that a compliance rate of at least 95% is necessary to optimize treatment. Factors that impede compliance include number and timing of doses, number and size of pills, food restrictions, and adverse effects.

The guidelines include for the first time interventions associated with improving adherence. Topping the list is "pharmacist-based adherence encounters/clinics." Pharmacists are also mentioned in the section on strategies to improve adherence as part of the health-care team that can reinforce the need for compliance.

Tammy Chernin, R.Ph.

 

Tammy Chernin. A federal panel revises treatment guidelines for HIV. Drug Topics 2001;5:34.