PROTEASE INHIBITOR PROGRESSION
									by James Leggett, M.D.
			The use of highly active antiretroviral therapy (HAART) since the mid-1990s has markedly improved the treatment of HIV infection, and raised our expectations for prolonging and improving the quality of life for people with HIV disease. Unfortunately, we continue to struggle with how to manage patients who have exhausted current therapies.
								What is failure? Eradication of HIV from the body is not currently feasible. Prolonging life and promoting quality of life by suppressing viral replication and/or enhancing immune function are the goals of therapy. Current treatment approaches are based on suppressing HIV activity as much as possible and for as long as possible using combinations of antiretroviral medications. Failure of antiretroviral therapy can be defined in a number of ways, usually termed clinical failure (disease progression), immunologic failure (CD4 decline), or virologic failure (HIV RNA rebound). Other factors associated with virologic failure include a persons HIV disease status, use of prior anti-HIV therapy, pre-existing HIV drug-resistant mutations, or inadequate drug exposure due to many factors, not the least of which is a lack of adherence in taking the medications. However, drug resistance appears to be the final common pathway in treatment failure at the present time. Virologic failure has been further defined in one of four ways: Not achieving a 1/2 - 2/3 log (meaning 3 to 5 fold) drop in HIV RNA level after four weeks of therapy Continued detection of blood levels of HIV RNA after 4-6 months of treatment Reappearance of detectable virus after an initial suppression, or A 3-fold or greater increase in HIV RNA. Up to one-half of patients will meet one of these four criteria for virologic failure, even after taking HAART.
		What are the different "salvage" therapy strategies? No agreement currently exists on how best to manage patients who have failed an antiretroviral regimen. Current Department of Health & Human Services guidelines recommend changing an HIV drug regimen early in order to avoid high level drug resistance, using at least two drugs to which the patient is naïve (meaning never taken), and using a medication strategy that combines two nucleoside analogs (NRTI) with either two protease inhibitors (PI) or a protease inhibitor and a non-nucleoside analog (NNRTI). Several studies of a single or double protease inhibitor substitution (e.g. ACTG 359, EuroSIDA, C-BIG, among others) have shown initial success. Unfortunately, by 12 months fifty per cent or more of patients have failed such second-line or third-line regimens. Predictors of successful response have included a high CD4 count, the use of a nucleoside analog not previously taken, the addition of NNRTIs, a low HIV blood level at the time of switch in therapy, or an undetectable viral load at some time on the prior regimen. In general, rates of HIV disease progression have been low despite a high rate of virologic failure. Distinction must be made between patients failing their first protease inhibitor regimen and those heavily pretreated ("experienced") patients who have received multiple, sequential regimens. In this latter group, several investigators in North America and Europe have attempted "mega-HAART" regimens using up to 6-9 drugs at the same time (many of them "recycled"), including up to 4 nucleoside analogs, 2 NNRTIs, and another drug, hydroxyurea. As expected, adverse events are common and adherence may be more difficult. While some investigators have reported viral suppression to less than 400-500 copies/ml for up to a year in this highly motivated subset of patients, others have reported less favorable results. It is unlikely that these "kitchen sink" regimens will provide a long-term solution for most patients, due to toxicity, adherence problems, durability of response to therapy, drug interactions, and medication cost issues. What about HIV resistance testing? Resistance testing is increasingly available for use in the clinic, and it may assist in monitoring and managing treatment failure. Phenotypic and genotypic antiretroviral resistance testing (PART and GART) each has its advantages and disadvantages. Genotypic testing may detect resistance earlier, while phenotyping actually cultures the virus in the presence of HIV drugs. Neither assay is yet able to detect quasi-species until they comprise 20% or more of the viral sample. In other words, resistance assays may miss information critical to proper drug selection for salvage therapy. A companion to resistance testing is therapeutic drug monitoring, since it is just as important to have adequate drug levels as to have a sensitive virus. The levels at which many antiretrovirals are tolerable are extremely close to the levels required to adequately suppress the virus. Since more and more data show that HIV drug kinetics vary widely among patients, therapeutic drug monitoring should become more widely used in identifying patients at risk of treatment failure. Should treatment be interrupted? A "drug holiday" involves stopping therapy in patients failing their current regimen, and allows for return of wild-type virus and/or an improved host immunological response. Small numbers of patients are currently being studied, suggesting that those who revert to wild-type virus tend to respond for up to 24 weeks. Unfortunately, interrupting therapy is not benign, since the wild-type reverters showed higher increases in viral load and deeper drops in CD4 cell counts off HIV therapy.
				For more information on C P C R A Study 057 (P I P): "A Randomized Study of the Virologic Efficacy of Different antiretroviral (AR) Treatment Strategies in HIV-Infected Individuals With Detectable Plasma HIV RNA Measurements After At Least 16 Weeks on their Initial Protease Inhibitor-Containing AR Regimens," please contact a Nurse Investigator with The Research & Education Group at (503) 229-8428 or toll free at (800) 875-8428.	What's the best strategy to minimize HIV progression despite aggressive protease inhibitor use? The Research & Education Group, as part of the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), is collaborating in two nationwide trials in order to answer these questions. One trial (CPCRA 057 or PIP) investigates two general questions about the choice of antiretroviral strategies in patients who have detectable HIV RNA after at least four months on their initial protease inhibitor-containing regimens. This protease inhibitor progression (PIP) protocol will address whether immediate or deferred use of an NNRTI is preferable, as well as whether a single or double PI regimen will be better. GART results obtained at entry will be provided to patients and their providers. Four separate randomized trials have been designed within this protocol, two for each research question. The PIP protocol will allow the patient and provider to choose between one of two strategies of drug class combinations. Another trial planned for early 2000 looks at the best way to treat multiple drug resistance by HIV in treatment experienced patients.