November 13, 2006
David Cooper is a professor of HIV medicine in Sydney, Australia, and an extremely experienced physician. He leads on many high-quality antiretroviral research projects. As such, he was well suited to provide a review of new treatment paradigms for treatment-experienced patients at Glasgow.1 Cooper touched on four major areas related to new treatments: guidelines, new antiretroviral options, maintaining a failing regimen, and designing clinical trials as new agents become available.
Guidelines for treatment-experienced patients should carefully define treatment failure. The aim of therapy is to achieve maximal viral suppression, and expert advice will be needed to construct new regimens.
New Antiretroviral Options
The TORO (T-20 vs. Optimized Regimen Only) studies of the injectable fusion inhibitor enfuvirtide (T-20, Fuzeon) pioneered the concept of using an optimized background regimen (OBR) as a comparator in clinical trials. Using enfuvirtide with an OBR produced an undetectable viral load (< 50 copies/mL) in 17% of patients at 96 weeks -- much greater than the 5% achieved in the OBR comparator arm. Although enfuvirtide has minimal systemic toxicity, it has the disadvantage of injection site reactions.
Tipranavir (TPV, Aptivus), a second-generation protease inhibitor (PI), is useful against drug-resistant HIV, especially if used with enfuvirtide in individuals who are enfuvirtide naive. Tipranavir has been shown to achieve undetectable HIV RNA in 34.7% of treatment-experienced patients at 46 weeks. However, tipranavir does have some disadvantages in that it can cause elevations in liver transaminases, triglycerides, and cholesterol. Experience with this agent has led to a detailed understanding of various tipranavir resistance mutations and the fold-change in drug susceptibility associated with these mutations. This means that clinicians can quite reasonably predict how well tipranavir will perform based on a patient's genotypic profile.
The newest PI to be approved in the United States is TMC114 (darunavir, Prezista). The pivotal POWER (Performance Of TMC114/r When Evaluated in triple-class-experienced patients with PI Resistance) studies examining the use of darunavir in treatment-experienced patients have yielded the most promising results for this group of patients so far: 46% of individuals achieved undetectable viral loads at 48 weeks if darunavir was used with enfuvirtide for the first time. As with tipranavir, genotypic resistance testing can also be used to predict HIV susceptibility to darunavir.
Given these two new PIs -- tipranavir and darunavir -- how does one choose between them? Both agents have overlapping resistance mutations (33F, 47V, 54M, 84V), but the pattern of mutations may help push the selection of one agent over the other. More data are needed on how best to sequence these two drugs based on their patterns of resistance.
Other new agents under investigation include maturation inhibitors, CCR5 entry inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase inhibitors. Of these, CCR5 inhibitors represent a promising class of agents with extracellular activity and some synergy within the class, at least in vitro.
In a pilot safety study of maraviroc (UK-427,857) in treatment-experienced patients, there was no difference in virologic efficacy between an OBR + placebo and an OBR + maraviroc given either once or twice daily. However, there was a good CD4+ cell count response in the maraviroc recipients, at the very least suggesting that this agent is not harmful to the immune system. Unfortunately, other CCR5 inhibitors have revealed potential unwanted toxicities. For example, aplaviroc (GW873140) has resulted in excess liver toxicity, and a vicriviroc (SCH 417690, SCH-D) study was prematurely halted when a number of malignancies were found in study participants. A causal link between CCR5 inhibitors and these adverse events has not been firmly established, but the findings suggest that caution will follow these drugs. Also of note, CCR5 inhibitors are the first HIV drugs that function by blocking a human cellular target, and the long-term effects of doing so remain to be seen.
After more than 15 years of hard, dedicated work that at times seemed futile, promising integrase inhibitors have finally arrived on the antiretroviral scene, giving cause to pay respect to the pharmaceutical companies involved. The MK-0518 integrase inhibitor from Merck & Co., Inc., has shown sustained responses in treatment-experienced patients, as has the GS 9137 product from Gilead Sciences, Inc. The Gilead integrase inhibitor requires boosting with ritonavir (RTV, Norvir). These agents may play a role in heavily treatment-experienced patients who cannot use enfuvirtide due to treatment-limiting injection site reactions, or they may replace CCR5 inhibitors in individuals with CXCR4-tropic virus.
Maintaining a Failing Regimen
Not all treatment-experienced patients will achieve the goal of an undetectable viral load, so what is the role for continuing treatment in this scenario? The PLATO collaboration investigated CD4+ cell count declines in a large cohort of patients experiencing triple-class virologic failure and found that CD4+ cell counts were maintained as long as patients' viral load did not exceed 10,000 copies/mL.
At least in individuals with a high CD4+ cell count, continuing lamivudine (3TC, Epivir) monotherapy while stopping all other drugs seems to slow immunological decline.
The risk of continuing failing therapy may be the accumulation of more resistance. Steve Deeks' data from the SCOPE (Study of the Consequences of the Protease Inhibitor Era) cohort suggest that HIV resistance evolves in the context of failing therapy, with 50% of individuals acquiring a new nucleoside reverse transcriptase inhibitor (NRTI) mutation and a quarter developing a new PI mutation over 24 weeks.
Clinical Trial Design for Treatment-Experienced Patients
As mentioned, the TORO studies were the first to introduce the concept of an OBR comparator arm, but this arm poses ethical difficulties of enrolling treatment-experienced patients in randomized studies of novel agents. If individuals assigned to the OBR + placebo arm have few active agents available, they may receive functional monotherapy, thus increasing the risk of resistance to an active agent and subsequent treatment failure.
As time progresses, more active drugs will potentially become available, and it may be possible for placebo recipients to receive at least two new active agents. The possibility of combining two new investigational agents together in the same study was discussed after Cooper's presentation, but it was felt that this is a very difficult, and perhaps impossible, solution.
It may be that future studies will only assign individuals to the OBR + placebo arm if they remain susceptible to at least two active agents, and drugs could then be made available in parallel access programs for the individuals who do not fulfill the entry criteria.
Overall, the outlook for treatment-experienced patients has never been better given the new drugs and new classes now available.
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