A meeting was held in Toronto following the Salvage Therapy Workshop to discuss "The Challenges of Clinical Trial Design in Evaluating HIV Antiretroviral use in Heavily Pre-treated Patients". This workshop had a broad representation from the activist community, industry, academia and the government, including the Food and Drug Administration. A number of issues emerged from this highly productive two-day meeting.
Companies have been slow to test new agents in heavily experienced patients for a variety of reasons, even when the drug is targeted against drug resistant strains of HIV. Most current trials of "salvage" drugs currently require the patients to be experiencing their first protease inhibitor (PI) failure or to be non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve. This effectively excludes nearly half of the HIV treatment-experienced patients from access to novel antiretroviral drugs. There must be earlier evaluation of new drugs in treatment-experienced populations, and a mechanism needs to be developed that will allow companies with novel agents to evaluate combinations of these new drugs in heavily pre-treated individuals.
Combinations of antiretroviral drugs have become the standard of therapy. For treatment-experienced patients, this often involves a NNRTI combined with two protease inhibitors. Despite the common use of these agents in clinical practice and expanded access programs, there is essentially no pharmacokinetic (PK) data available to guide in the use of these drugs in combination. With the multiple effects of the current NNRTI and PI agents on P450, it is impossible to accurately gauge the impact of the agents in combination. There is an urgent need to obtain rapid PK data for the combinations of antiretroviral drugs that will be used in clinical practice prior to any widespread use in guiding clinical decisions. Developing the mechanism to obtain this data should be a high priority of the patients, the clinical community and industry in the near future.
It will be necessary to classify patients on study entry by susceptibility to drug classes or by clusters of genotypic drug resistance mutations for clinical trials in heavily pre-treated patients. Some drugs may need screening by resistance testing to exclude patients who would be expected to do poorly with the drug combinations under evaluation. To further this goal, drug combinations must be evaluated by rapid screening in small studies to determine which combinations should be advanced for expanded evaluation in larger groups of patients.
Predictors of early drug failure on HAART regimens remain very similar to those seen in monotherapy trials. These include: (1) high plasma HIV RNA, (2) low CD4 cells and low increases of CD4 cells on therapy, (3) duration of prior therapy, (4) duration on a "failing" regimen, (5) cumulative number of drug resistance mutations, (6) number of active drugs in the new regimen, (7) pharmacokinetic interactions, (8) adherence, especially related to number of pills and drug toxicities, and (9) potential impact of resistance mutations known to blunt subsequent treatment responses such as T215Y/F.
Heavily pre-treated patients generally have response rates of 20 to 40% for plasma virus of <500 copies/mL, indicating that the definitions of success and failure need to be revisited. Is the goal of therapy to reduce HIV RNA to <50 copies/mL? To <500 copies/mL? Is it CD4 stability? Or is it the former gold standard, lack of clinical progression? How does one determine clinical benefit with rapidly responsive markers such as HIV RNA being used to guide clinical management?
What is the role of mega-HAART versus drug therapy, targeted by clinical information and resistance data? When should patients and their providers consider a structured treatment interruption (STI, formerly called a drug holiday) to attempt reversion of the patient's virus back to wild type? What are the risks versus benefits of such a strategy?
What clearly emerged from the meeting was that clinical practice for heavily pre-treated patients has rapidly outstripped the data available from ongoing clinical trials. The gap between the information obtained from clinical trials and the information needed to treat heavily pre-treated patients is widening at this time. At the meeting, very few practitioners in the room actually followed the current treatment guidelines for salvage therapy. There is a critical need to re-assess the trials infrastructure for heavily pre-treated patients, the largest and most rapidly growing segment of our patient population, so that we can obtain the information needed to accurately determine the best clinical course for individual patients. I am certain that several clinical initiatives will emerge from this highly productive meeting.
