February 8, 2001
In a symposium on the final day of the conference, Diane Havlir gave a comprehensive summary of the many challenges facing providers and patients in their goal to optimize antiretroviral therapy. Incorporating appropriate quotations from literature and history, she covered a broad array of issues, including when to start, when to switch, and how to adjust treatment.
Beginning with the longstanding question of "When to start therapy," she outlined the potential benefits of doing so with high CD4 cell counts. Starting therapy with high CD4 counts, she noted, could prevent irreversible immune destruction, delay progression to AIDS and death, reduce the risk of transmission, and, at this juncture, also took advantage of the fact that most antiretroviral regimens work better when started in relatively immunocompetent patients. However, temporizing these benefits are several factors, including the realization that immune suppression is not irreversible, that delaying therapy delays drug toxicity, and that antiretroviral drug resistance only emerges under the selection pressure of treatment. Helpful data from cohort studies -- in particular several presented at this conference (abstracts 341, 342, 519, 520, and LB6) -- have pushed back the CD4 threshold for initiating treatment in asymptomatic individuals to 350 cells/mm3 in the latest DHHS Guidelines, although Havlir acknowledged that the optimal time to start remains an open question.
Since the major factor dominating treatment decisions in asymptomatic patients is minimizing drug toxicity, she outlined several reasons why this remains such a vexing problem. We certainly do not know the full spectrum of drug toxicity, and the mechanisms by which they occur are poorly understood. In addition, some (such as peripheral neuropathy or fat wasting) may be untreatable, and some do not always reverse even with cessation of the potentially offending agent or agents. Perhaps most disquieting is the uncertainty regarding the long-term consequences of drug toxicity, as it is sobering to remember that the era of widespread use of triple-combination therapy began only five years ago.
Offering some hope in this area, Havlir cited several novel approaches to reducing drug toxicity. These included measurement of drug levels to find the right "window" between effectiveness and side effects (correlation of efavirenz levels with CNS toxicity was cited), using genetic correlates to predict which patients will be at greatest risk for adverse events, and perhaps using treatment interruption as a way of diminishing drug exposure without compromising efficacy.
By way of historical perspective, she closed this section on "when to treat" by citing a quotation from Gerald Friedland from an editorial in the New England Journal of Medicine, where he describes uncertainty regarding finding "golden moment" to start treating HIV. That the editorial was published in 1990 -- an eternity ago in HIV care and research -- emphasized that despite our tremendous progress in treatment of patients with AIDS, the optimal approach to the large number of asymptomatic patients with HIV remains uncertain.
Once the decision is made to treat, however, there are tremendous opportunities -- and choices -- among the various treatments available. Listing a dozen or so potential combinations for initial therapy, Havlir emphasized the importance of individualizing treatment with each patient, and not relying on a "cookbook" or algorithmic approach. Further improvements in treatment, such as once-daily therapies, judicious use of directly-observed-therapy, co-formulation of currently approved drugs, and pharmacokinetic manipulations are all improvements in treatment both available now and under active investigation
She then moved onto the area of "when to switch," emphasizing that a distinction needs to be made between virologic failure and treatment failure, since the former generally greatly precedes the latter. Citing the tension between an early switch (which reduces accumulation of resistance mutations) and a watchful waiting approach (which preserves future options by avoiding exposure to new drugs and drug classes), she offered the following approach to first, second, and third (and beyond) regimen treatment failures:
|1st Failure||2nd Failure||3rd Failure|
|Goal||HIV RNA suppression||HIV RNA suppression and preservation of CD4 counts||Preservation of CD4 cell counts|
|Action||Modify treatment or switch||Wait if CD4 cell counts are at a safe level, or switch if they aren't||Wait if CD4s are at a safe level, or temporarily interrupt therapy, or switch|
To help choose new regimens when drugs are switched, Havlir summarized emerging data about cross-resistance within drug classes. Viral resistance to NNRTIs may develop with a single mutation and lead to broad resistance within the class, while protease inhibitors generally require multiple mutations, with each mutation conferring a variable amount of incremental resistance to individual agents. When resistance to one protease inhibitor initially appears, cross resistance is generally limited at first; under continuous selective pressure and accumulation of multiple mutations, however, resistance eventually becomes broad. And despite earlier data regarding limited cross-resistance within the nucleoside analogues, further clinical studies have shown resistance to be much more extensive within this class than previously believed. In choosing new regimens, finally, Havlir reminded us of the important findings of the HAVANNA study, which showed that optimum outcome was achieved using a combination of resistance testing (in this study genotype) and expert opinion (see abstract 434).
Overall, this lecture provided an excellent framework for clinicians and patients to focus decisions about the optimal treatment of HIV. It could also serve as a guide for researchers and industry in deciding future directions in antiretroviral research. As noted by several of the quotations chosen by Havlir during the talk, the best approach to HIV treatment right now is to look at the areas of uncertainty as an opportunity for the development of imaginative solutions.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|