New class of HIV drugs good tools in the battle

Recent advances fuel hope for future drugs

[Editor’s note: Constance Benson, MD, professor of medicine at the University of Colorado Health Sciences Center Division of Infectious Diseases in Denver, has led clinical trials on the new HIV antiretroviral drug ABT-378. Abbott Laboratories of Abbott Park, IL, has recently submitted a new drug application with the U.S. Food and Drug Administration to market ABT-378/r (lopinavir/ritonavir) and to receive accelerated approval. Benson also is the vice chair of the Adult AIDS Clinical Trials Group, the principal investigator of the Mountain Plains AIDS Education and Training Center, and an expert on treatments for HIV-infected patients and opportunistic complications of HIV-1 infection. AIDS Alert asked Benson a few questions about new antiretroviral regimens and what these might mean in the long-term treatment of HIV disease.]

AIDS Alert: How do new drugs like ABT-378 compare in tolerability, dosing requirements, and potency to the older generation of antiretroviral drugs?

Benson: ABT-378 is co-formulated with low-dose ritonavir, which enhances the pharmacokinetic profile of ABT-378, resulting in concentrations of drug approximately 30-fold greater than the 50% inhibitory concentration (IC50) for wild-type HIV-1, and prolonging the duration that the concentration of drug is maintained above the IC50. These result in a drug with enhanced potency that can be administered in a twice-daily regimen.

Clinical trials with ABT-378/r have shown that the drug is well-tolerated, with few patients discontinuing drug due to an adverse effect. In my own clinical experience, mild gastrointestinal upset and/or mild diarrhea have been the principal side effects, and these have occurred in only a small number of patients, making this a very well-tolerated drug.

In terms of how this agent compares to other antiretroviral drugs, no studies directly comparing their tolerability and potency have been completed to date. However, based on in vitro data, the ratio of peak concentration to IC50 for wild-type HIV-1 is substantially greater for ABT-378/r than for other currently available protease inhibitors when the latter are used as single agents, suggesting that ABT-378/r may be more potent than first-generation protease inhibitors as single agents.

In general, rates of side effects associated with ritonavir, indinavir, and nelfinavir are reported to be higher than with ABT-378/r, and this has been my clinical experience as well. Ritonavir, alone or when combined with saquinavir, and nelfinavir can be dosed twice daily, similar to ABT-378/r. Dosing requirements are primarily a problem with indinavir when it is used as a single agent, due to its dosing schedule of every eight hours, the need to administer the drug on an empty stomach, and the hydration requirements to prevent nephrolithiasis. However, the combination of indinavir with low doses of ritonavir alters the pharmacokinetic profile of indinavir in a similar fashion to that of ABT-378/r, allowing the combination to be used twice daily and with less regard to timing of administration with food.

AIDS Alert: When you began your research work, did you have a clear idea of what a perfect HIV drug might be?

Benson: The attributes of a "perfect HIV drug" are theoretical. In my opinion, a "perfect" drug would be one that is potent and effective, can be taken once or at the most twice daily without regard to food or hydration, has minimal to no side effects, and can be safely taken long-term. These attributes can be applied to any drug used for treatment of a chronic illness, and my opinion has not changed with research work in HIV. I have, however, developed a more realistic view of the difficulties that have been and continue to be encountered in the development of new drugs that meet these characteristics, and realize the development process is a long, difficult one in which incremental progress is more likely to be observed than a single blockbuster finding.

AIDS Alert: How have the long-term priorities of HIV treatment changed since protease inhibitors were first widely used about four or five years ago? How has this shifted research?

Benson: The long-term priorities for HIV treatment have evolved in an interesting fashion. The optimism experienced with the initial availability of protease inhibitor regimens and the attendant reductions in mortality and opportunistic infections continues as the beneficial effects of more potent regimens continue. However, this optimism has been tempered by the recognition that many of the newer drugs and regimens are associated with substantive toxicities, some of which are treatment-limiting. In addition, the difficulties with dosing schedules, adherence, and toxicities — and the accompanying emergence of drug resistance — have led to a re-evaluation of critical issues such as when to start therapy, how to best individualize therapy and preserve future treatment options, and how to use new technology such as ultrasensitive plasma HIV-1 RNA assays and genotypic and phenotypic resistance testing to optimize treatment. As patients will require treatment, in most instances, for life, research is now focused on strategies that will provide the most effective and durable therapies associated with the least toxicity over the long term and that preserves the broadest variety of future treatment options.

AIDS Alert: In your opinion, what are some of the most promising possibilities that are occurring as a result of the recent advances in HIV treatment?

Benson: Recent advances that I think provide promise for the future are the ongoing development of potent drugs in several classes of compounds that have the potential to be active against drug-resistant strains of HIV-1, such as ABT-378/r, BMS-232632, second-generation non-nucleoside reverse transcriptase inhibitors, and tenofovir, among others; the development of entirely new classes of drugs that do not have cross-resistance with currently available agents, such as integrase inhibitors, CCR5 inhibitors, and fusion inhibitors; the availability of genotypic and phenotypic resistance assays that can be employed in a number of settings to optimize treatment; and the development of potent, less complex, and/or better-tolerated regimens (once daily or twice daily without regard to food) that may improve/enhance adherence, and as a consequence, reduce the risk of emergence of drug resistance. All of these are on the horizon and will continue to improve our ability to treat HIV-1-infected patients. Additional work with immunomodulators or immunotherapeutic interventions may show promise, although results are not yet available to discern whether the latter approaches will add to or supplant antiretroviral therapies.

AIDS Alert: What advice do you have for clinicians designing HIV antiretroviral regimens for patients? What are the factors they need to consider, and how should they go about making these choices?

Benson: Treatment of HIV-1-infected individuals should be undertaken by health care providers experienced in their care and who have had and continue to have appropriate training and continuing medical education to acquire and maintain their expertise. Antiretroviral therapy should be individualized based on a number of factors, including — in no order of priority — CD4+ T-cell count; plasma HIV-1 RNA level; prior treatment history; presence or absence of drug susceptibility; tolerability and complexity of the regimen; ability of the patient to understand, accept, and adhere to the therapy; social support; fiscal resources; and other underlying conditions or use of concomitant medications with which antiretroviral therapies may interact.

There are a number of approaches to the initial therapy of antiretroviral-naive patients recommended in the U.S. Department of Health and Human Services and/or IAS-USA guidelines for treatment of HIV-1 infection, both of which are published and can be used as resources for clinicians. Perhaps the most important factor in making the best treatment choices for patients is the development of a trusting, caring, and collaborative relationship between the patient and the provider. Spending the time necessary to educate the patient about their choices, the risks and benefits of treatment, the appropriate manner in which the prescribed drugs should be taken, and assuring appropriate monitoring and follow-up to deal with subsequent issues are part of the trusting, caring, and collaborative therapeutic relationship.