PHS draft guidelines recommend triple drugs as initial therapy
Treating hard and early makes perfect sense to caregivers
Two expert panels are finalizing guidelines for HIV treatment that will provide the first government-sanctioned blueprint for HIV care in the era of protease inhibitors and viral-load testing. Preliminary tables from the guidelines indicate that triple-combination therapy is strongly recommended as initial therapy, and two nucleoside reverse transcriptase inhibitors plus one protease inhibitor is the preferred regimen.
One of the panels, established by the National Institute of Allergy and Infectious Diseases in Bethesda, MD, and co-chaired by John Bartlett, MD, chief of the division of infectious diseases at Johns Hopkins University in Baltimore, is developing the clinical practice guidelines. It is basing its recommendations on a set of principles drawn up by the other panel, which was established by the National Institutes of Health in Bethesda and is chaired by Charles Carpenter, MD, associate professor of medicine at Brown University in Providence, RI. The guidelines will replace the only existing Public Health Service guidelines for HIV treatment, which were issued in 1993 and recommended zidovudine (AZT) monotherapy.
At press time, the panels were reviewing final drafts of the recommendations. The clinical practice and principles guidelines will be presented as a single document and made available for public comment in mid- to late April, says Mark Feinberg, MD, medical officer at the NIH’s Office of AIDS Research. Following public comment and possible revisions, the document will be published several months later in the Morbidity and Mortality Weekly Report.
"Once it is available for public comment it becomes public information. Our hope is people will act upon them rather than waiting until they are published," he says, adding that the document is too long to be published in the Federal Register and probably will be posted on the Internet.
When they first met three months ago, panel members held divergent opinions on the best time to start therapy and the best regimens to use. The dependence on viral load monitoring and CD4 counts in treatment decisions also has been met with differing opinions. In the past month, however, as more data became available, the groups have reached a fairly strong consensus, Feinberg says.
"The information has congealed to make a clearer picture that would have been impossible even a few months ago," he tells AIDS Alert.
The guidelines will fill the confidence void created by the crumbling of old treatment paradigms based on monotherapy, CD4 counts, and the steady-state theory of HIV replication. They will provide clear and specific recommendations that will constitute the basis not only for clinical practice but for insurance coverage.
"To help clarify treatment issues for patients and health care practitioners, I hope this will make it very clear that there are certain basic things that need to be provided, and many of those are not now available," Feinberg explains. "People have to realize that a lot of the current practice is not only not maximally effective, but is actually potentially harmful for people. In my mind that is the most important aspect of this effort."
While reaching a consensus in the panels was not easy, Bartlett says the guidelines had to be fairly specific. "Third-party payers are probably going to reimburse on the basis of what national guidelines are out there, so for that reason you can’t hedge," he says.
While the rapid pace of drug development has made previous treatment guidelines obsolete within months, the basic principles behind the new guidelines should provide a stable foundation for the rationale behind the treatment decisions. The clinical practice panel is set up for at least three years and will add changes as new drugs are approved and proven effective. Its recommendations, however, name specific drugs it prefers and discourages, Bartlett adds.
Starting with three drugs
A first draft of the clinical practice tables obtained by AIDS Alert recommends that treatment should start when a patient’s CD4 count drops below 350. The draft had no corresponding viral load count for consideration in this scenario.
The recommendation for triple therapy at the 350 CD4-count level was given an A1 rating, meaning it is strongly recommended and is supported by randomized trials with clinical endpoints (in this case ACTG 175 and ACTG 320). The treatment should comprise three drugs two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor. This treatment also received an A1 rating. (See table on p. 51.)
Treatment also was recommended for patients with CD4 counts between 351 and 500, and whose viral load exceeded 10,000 copies. For patients with CD4 counts between 351 and 500 but with viral load less than 10,000, the panel made treatment optional. For patients with CD4 counts exceeding 500 treatment also was optional, regardless of whether viral load was less than 10,000 counts or greater than 30,000 counts. The strength of recommendations for these patients dropped to level III based only on expert opinion. However, the recommendation to treat them with three drugs remained an "A," except for patients with less than 10,000, which dropped to a "B."
While the panel chairmen were reluctant to go into details about the guidelines, Carpenter acknowledged that the panels still had not resolved differences in one critical area. Although he would not mention what that area was, he says the panel agreed that data were lacking on when to initiate treatment in asymptomatic patients.
"People [on the panels] agree on what data are valid," he says. "It’s just whether at one point to recommend or consider therapy. Whether the clinical practice guidelines fit with the principles on this one issue is the only debate right now."
As an example, he mentioned a patient with a CD4 count "that is not terribly low but below the usual recommended time of initiation, and a viral load that is not terribly high but slightly above the usual recommendations. It simply has to be explained that this is an area where we don’t have solid data. It doesn’t lend itself to a neat table without a lot of caveat."
Carpenter notes that the panels agreed that once a patient and physician have made a commitment to initiate therapy, the goal should be to reach low detectable limits of virus using current assays and to maintain that level for a lifetime.
What drugs to use
In choosing a drug regimen, the recommendation for two NRTIs and one protease inhibitor received an "AI" rating. For salvage therapy, the recommendation changed to two NRTIs and one non-nucleoside reverse transcriptase inhibitor, namely nevirapine. That recommendation received a "BII" rating.
For a category it termed "individual circumstances," the panel provided several options. Two protease inhibitors received a "CII" rating. Two-drug combinations AZT plus ddI, AZT plus ddC, d4T plus ddI, AZT plus 3TC, or d4T plus 3TC were optional but were not rated. The panel warned that regimens containing 3TC may cause long-term resistance. And it discouraged the use of AZT plus d4T.
The panel also noted that all monotherapies, except ddI, were not recommended.
AIDS experts contacted by AIDS Alert had not seen the draft recommendations and could not comment on them.
Michael Spence, MD, professor of obstetrics/ gynecology at Allegheny University in Philadelphia, has been treating asymptomatic, HIV-positive women with triple-combination therapy for more than six months. Based on available therapy and how clinicians treat other infectious diseases, the recommendations to treat hard and treat early make perfect sense, he says.
"As soon as I make a diagnosis for HIV, I initiate therapy," he says."There is no reason to give any disease I don’t care which one a running start, and I don’t think HIV should be an exception."
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