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Gay Men's Health Crisis
Outdated yet Out-of-Reach: AIDS Society Treatment Guidelines at the International Conference
Gabriel Torres, M.D.
September 1, 1996
GMHC Treatment Issues 1996 Sep 1; 10(9): 3

A thirteen-member international panel of HIV experts convened by the International AIDS Society-USA (IAS) released new antiretroviral treatment guidelines amid a turbulent crowd of demonstrators, researchers, HIV clinicians, people with HIV and AIDS and other participants of the XI International AIDS Conference in Vancouver, Canada, on July 6, 1996. These guidelines are essentially an updated version of those drafted at a meeting in January and published in the July 10 issue of the Journal of the American Medical Association. The panel endeavored to address the most common HIV and AIDS treatment scenarios in clinical practice, using the latest information available at the time the guidelines were drafted. But discussions at the Conference indicated that the guidelines have significant shortcomings because they do not take into account either the rapid evolution in anti-HIV therapy or the real-world limitations and complications practitioners will encounter in following even these now outdated recommendations.

When to Initiate Therapy The panel agreed that treatment needs to be initiated before irreversible immunologic damage occurs based on an assessment of disease progression. For asymptomatic patients, treatment was recommended for those with any of the following conditions: CD4 count less than 500, a CD4 cell percentage below 25, CD4 count greater than 500 if viral loads are higher than 30 to 50 thousand or those with a rapidly declining CD4 count (loss of greater than 300 cells/mm3 over twelve to eighteen months). Some of the panel's experts would defer therapy in patients with stable CD4 counts between 350 to 500 and viral loads less than 5,000 or 10,000.

Those with CD4 counts greater than 500 who are considering initiating therapy should be aware that there are no available data to support treatment at this early stage of HIV disease. Difficulties concerning a patient's tolerance to and acceptance of a given treatment, the expense of the treatment, the potential for development of viral resistance to the treatment and other problems associated with long-term toxicity are all major considerations in starting therapy at this point.

The panel also felt that therapy for those with HIV levels greater than five to ten thousand should be considered, but some members suggested that all patients with viral loads greater than 5,000 definitely should be treated. In addition to these guidelines, it was strongly recommended that all symptomatic patients (including those with oral candidiasis, hairy leukoplakia and other symptoms of mild immunodeficiency) should be treated with antiretroviral drugs, regardless of CD4 count or HIV viral load.

The panel did not address the critical issue that many clinicians and patients still do not have access to HIV viral load testing, and thus the recommendations based on viral load are not applicable for a substantial number of people.

What Types of Drugs to Use for Initial Therapy The panel felt that the strongest data supported the use of AZT plus ddC, AZT plus ddI or AZT plus 3TC for initial therapy. ddI monotherapy was less favored. For patients with a high risk of progression (rapidly dropping CD4 count, presence of symptoms, or rising viral loads), the use of protease inhibitors in an initial treatment regimen may be warranted. If a protease inhibitor is to be added to any of these regimens, the panel felt that the choice should be based primarily on antiretroviral potency and then on safety, tolerability, durability of antiviral effects, drug resistance patterns, the potential for limiting future treatment options and cost. The panel came to this conclusion after discussing whether the most potent regimen, which is usually a triple regimen that includes a protease inhibitor, is appropriate during the initial stages of treatment or whether such therapy should be reserved for patients at higher risk of progression.

The panel omitted the role of nevirapine in initial or follow-up regimens or the use of two protease inhibitors together, data concerning which were released in Vancouver. The recommendations also ignored d4T monotherapy altogether even though it is one of the stronger monotherapies available and widely used.

None of the recommended regimens included more than three drugs, despite the fact that many in the community are starting to use four or five antiretroviral drugs together, often in conjunction with supportive agents such as interferon alpha, interleukin-2, hydroxyurea and many other alternative and complementary therapies. Furthermore, the panel did not rank its recommendations based on preference. Various options appeared to be given equal weight in the report though some were supported by large-scale trials measuring disease progression and others were not.

When to Change Therapy The first reason for changing therapy discussed by the panel was treatment failure -- a rebound to 0.3 to 0.5 log (one-half to two-thirds) of pretreatment viral load, a CD4 count decline after an initial rise or a return to the pretreatment value or new opportunistic infections. Other reasons mentioned for switching included a patient's inability to comply with a prescribed regimen due to toxicity or lifestyle factors or use of a suboptimal regimen such as AZT or ddC monotherapy.

Just how a patient's therapy should change would, of course, depend on the reasons for altering it. For example, if a patient's intolerance to a given drug is the primary reason for change, then finding drugs that the patient can tolerate is paramount. If the problem is treatment failure, then drugs with greater potency and different mechanisms of action are recommended, particularly those who do not exhibit cross-resistance. A change to the most potent regimen available, based on virologic, immunologic and clinical characteristics of the individual patient is recommended.

Several common examples of clinical scenarios were presented for patients who have been on the following regimens and require a change in therapy: * AZT monotherapy: If the patient has stable disease, adding ddI, ddC or 3TC or switching to ddI monotherapy (less preferred) are all acceptable options. If the patient has advanced disease or extensive prior zidovudine history, adding 3TC or switching to another combination with or without a protease inhibitor were recommended.

* Combination therapy with two nucleosides or ddI monotherapy: Patients on these regimens should change to a two- or three-drug regimen containing at least two new drugs, one of which could be a protease inhibitor.

* Protease inhibitor regimens: For patients already using a protease inhibitor-containing regimen, the panel recommended a change to at least two new drugs, preferably including a protease inhibitor with a different pattern of resistance mutations in HIV.

This last switch alternatively could include addition of a non-nucleoside reverse transcriptase inhibitor (NNRTI) like nevirapine. Again, the panel did not consider NNRTIs when the guidelines were originally drafted, and the NNRTIs' precise role remained poorly defined in the eyes of many attending the IAS seminar.

When to Stop Antiretroviral Therapy The panel also addressed the question of when to stop antiretroviral therapy in selected patients. It concluded that stopping is only appropriate for patients with advanced HIV disease who have significant toxicity and declining quality of life associated with therapy. Consequences of increased viral replication after withdrawal of therapy, including the potential neurologic effects, should be considered prior to discontinuation of an antiretroviral regimen as well.

Three Special Cases * Acute or primary (new) infection: The panel recommended considering entering such patients in a clinical trial or treating with the most optimal combination of drugs (two or three) for at least six months. The panel did not address the treatment of persons with recent HIV infection (less than six months), even though there is evidence that such patients may receive similar benefit from therapy (see August's Treatment Issues, pages 3-4).

* Prophylaxis of high-risk exposures: For serious needle stick exposures, two nucleoside analogs (usually AZT plus 3TC) were recommended. A three-drug regimen (two nucleoside analogs and a protease inhibitor) was preferred if the exposure is likely to involve a drug-resistant HIV variant. No recommendation was issued for high-risk sexual exposures since no human studies have evaluated a "morning after" prophylaxis. Animal studies, however, do indicate that there may be a role in using antiretroviral agents to abort HIV infections.

* Vertical transmission: AZT monotherapy was recommended for HIV-positive pregnant women and for their newborns whether or not the mother receives treatment. The paucity of data on other regimens kept possible alternatives off the recommended list.

The absence of anything but AZT drew criticism from many obstetricians and gynecologists, who felt that such treatment is suboptimal. Limiting the recommendations to AZT failed to address those pregnant women with extensive prior experience with zidovudine or women who had been taking other antiretroviral drugs -- must they switch to AZT monotherapy two trimesters before giving birth? Some complained that no expert with experience treating HIV-positive pregnant women was included on the consensus panel.

Other important patient populations were not addressed by the panel. What treatment, if any, should be offered to long-term non-progressors or to patients with moderate viral loads of ten to twenty thousand? And finally, what should be done for those with markedly depleted immune systems (CD4 counts below 50), particularly those who have failed most if not all available treatments? Modifying the Guidelines The panel acknowledges that its recommendations leave out much new treatment information coming out of the very conference at which they were presented and anticipates revision in the next few months. As it is, the guidelines represent the perceived wisdom of first-rate HIV specialists earlier this year. But with the field in a state of rapid flux, guidelines can only be helpful if they advise on the state of the art on such topics as viral eradication and the optimal use of combination therapies as new agents become available.

------- SIDEBAR Did They Consult Darwin? One of the primary criticisms of the IAS guidelines was that they lacked an urgent call to hit HIV "early and hard" by using at least two nucleoside analogs and a protease inhibitor in persons with asymptomatic disease and relatively low viral loads. When changes in this initial regimen are necessitated by a rebounding viral load, the guidelines' critics argue that physicians should introduce three or more new drugs to which the patient's virus does not appear resistant. In a rare public display of outrage at one's scientific colleagues, Joep Lange, M.D., of the University of Amsterdam complained during an International Conference presentation on viral "eradication" (a commentary concluding session no. 436) that the IAS experts were giving "obsolete" advice. Dr. Lange commented that the IAS was not taking into account present knowledge concerning how readily drug-resistant HIV can evolve under conditions of partial viral suppression: "I am stupefied by the ignorance of biology exhibited by the IAS," he concluded.

But many physicians were not swayed by Dr. Lange's outburst. They felt that asymptomatic patients would not tolerate years of triple drug therapy and that three drugs may be unnecessary in any case. "I can bring the viral loads of many of my patients below undetectable levels with just two drugs, so why do they need three?" asked Steven Miles, M.D., of the University of Los Angeles after Dr. Lange's session was over.

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