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Two guidelines offer new insights on treatment of HIV
by ELENA PORTYANSKY-BEYZAROV, Pharm.D.
Two newly released sets of updated HIV treatment guidelines embrace several new therapeutic ideas, but they abandon, at least temporarily, the prospect of a cure.
"In the mid-90s, emerging clinical and basic science data supported a theoretical case for HIV eradication within two to three years through early and aggressive antiretroviral therapy that would completely suppress viral replication," said Paul Volberding, M.D., director of the University of California-San Francisco Positive Health Program at San Francisco General Hospital Medical Center. "Now we know that eradication with drug therapy alone is not a realistic goal at this time," he acknowledged. Instead, long-term survival appears to be the focus of HIV treatment these days. And now, health-care professionals have a pair of how-to guidelines to show them the way to attain this objective.
The first document—published in the Jan. 19 issue of the Journal of the American Medical Association—contains recommendations for HIV treatment in adults. These guidelines were prepared by a 17-member physician panel from the International AIDS Society (IAS). These guidelines are intended to extend to physicians who treat HIV patients in developing nations.
The second set of HIV guidelines, for adults and adolescents, represents a joint effort by the Department of Health & Human Services (HHS) and the Henry J. Kaiser Family Foundation. Released by the National Institutes of Health, this document focuses primarily on restoration and/or preservation of the patient's immunologic function, improving quality of life, and reduction of HIV-related illness and death. The HHS guidelines also delineate tools that may help to achieve these goals; they include:
Maximizing patient adherence to a regimen.
Selecting "user-friendly" regimens when possible.
Prescribing drugs in a rational sequence in order to preserve future treatment options.
Utilizing drug resistance assays when treatment fails.
So what are some differences and similarities between these two cookbooks? Tim Horn, executive editor of the Physicians Research Network Notebook, noted that both guidelines advocate starting therapy in HIV patients early—essentially before the immune system has incurred too much damage. The HHS guidelines, however, are slightly more aggressive—recommending that patients with CD4 cell counts below 500 or HIV RNA levels above 20,000 copies/ml be offered drug treatment. The IAS document generally recommends initiation of treatment in those with confirmed viral loads above 30,000 copies/ml, irrespective of CD4 counts, and for patients with CD4 counts below 350, irrespective of viral levels. IAS experts have taken into account certain issues—such as the emergence of long-term side effects from antiretroviral therapy—that suggest that deferral of therapy may sometimes be advantageous.
One of the major differences between the guidelines is reflected in the sections that discuss drugs for initial therapy, noted Horn, whose publication targets clinicians who treat HIV patients. While the IAS document does not make any recommendations regarding specific antiretroviral combinations, the HHS guidelines "actually list strongly recommended regimens, alternative regimens, and ones that are not recommended at all." The combination of the non-nucleoside reverse transcriptase inhibitor Sustiva (efavirenz) and two nucleoside analogs is now considered a strongly recommended regimen, since it has been shown to be at least as effective as a protease inhibitor plus two nucleoside analogs in suppressing plasma viremia and increasing CD4+ T cell counts.
Some experts would even argue that the former cocktail is the preferred initial regimen because it may spare the toxicities of protease inhibitors (PIs) for a considerable time. Regimens employing other non-nucleoside reverse transcriptase inhibitors with nucleoside analogs are not listed under the "strongly recommended" category because trials comparing them with PI-containing combos are still lacking.
Dual PI-containing combinations (recognized in both guidelines and listed under the strongly recommended category in the table on page 35) are increasingly being used because they offer pharmacologic and adherence benefits, as well as improved efficacy. According to the HHS guidelines, the combination of Norvir (ritonavir, Abbott) and saquinavir produces a 20-fold increase in saquinavir steady-state levels and significantly reduces the overall pill burden. Some data also support the use of ritonavir with Crixivan (indinavir, Merck) or Agenerase (amprenavir, Glaxo Wellcome/Vertex). "We're seeing that these dual-PI combinations can be taken twice daily or even once a day—as opposed to three times daily for each individual drug," disclosed Horn. It should be noted that ritonavir is considered as an alternative agent when used in regimens as the sole PI because of the difficulty many patients have tolerating standard doses of the drug and the many interactions associated with it. A similar rationale applies to saquinavir soft-gel, which is also difficult to tolerate and comes with a large pill burden.
One concept strongly emphasized in the HHS guidelines is resistance testing. This practice "can help explain the reasons for treatment failures and guide the rational selection of a new drug regimen," asserted John G. Bartlett, M.D., chief of the division of infectious diseases at Johns Hopkins University Medical Center and co-chair of the HHS guidelines panel.
"In the past, treatment decisions for patients who were beginning to fail their therapies were essentially based on their medication history and what we knew about the resistance profiles of the various antiretroviral drugs," said Horn. "Now we use genotyping—which shows us what the actual virus looks like and what kinds of mutations are present—and phenotyping—where drug sensitivity is established by measuring the ability of the patient's virus to grow in various concentrations of antiretrovirals." The practice has apparently taken much of the guesswork out of treatment decisions.
There are various other novel approaches to the management of HIV, which are not being advocated in the guidelines since they are still quite experimental. One rather risky practice, which Horn disclosed, is called structured therapy interruption, under which drug regimens are temporarily stopped so viral levels can increase just enough to spark the immune system to identify and perhaps destroy HIV. Another approach that's gaining popularity involves coupling antiretroviral agents with immune-based therapy in an attempt to retrain the immune system to gain better control of the virus.
Hydroxyurea has been used investigationally in combination with antiretroviral agents; however, its utility in this setting has not been established. This antineoplastic agent does not have direct antiretroviral activity on its own; rather, it is hypothesized to enhance the effects of Videx (didanosine, Bristol-Myers Squibb) and Zerit (stavudine, Bristol-Myers Squibb). The HHS guidelines urge clinicians who use hydroxyurea in a treatment regimen for HIV to be aware of the limited and conflicting nature of the data surrounding it and of the importance of monitoring patients closely for potentially serious toxicity such as cytopenias, hepatotoxicity, and possible neuropathy.
Recommended antiretroviral agents for
initial treatment of established HIV infection
Antiretroviral drug regimens are made up of
one choice each from columns A and B
Stavudine + Lamivudine
Stavudine + Didanosine
Zidovudine + Lamivudine
Ritonavir + Saquinavir
Zidovudine + Didanosine
Recommended as an alternative
Didanosine + Lamivudine
Zidovudine + Zalcitabine
Nelfinavir + Saquinavir
No recommendation; Insufficient data
Hydroxyurea in combination with other antiretroviral drugs
Ritonavir + Indinavir
Ritonavir + Nelfinavir
Not recommended; Should not be offered
(All monotherapies, whether from column A or B)
Stavudine + Zidovudine
Zalcitabine + Lamivudine
Zalcitabine + Stavudine
Zalcitabine + Didanosine
Adapted from the HHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents