Reports

Ten years after the introduction of highly active antiretroviral (ARV) therapy, the proportion of patients with HIV demonstrating multiple class resistance has been increasing. The progress in developing treatment options for highly experienced patients has been timely with the TORO (T-20 or Optimized Regimen Only) trials leading to the approval of the fusion inhibitor enfuvirtide in 2003. The RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) trials followed two years later and demonstrated that even orally available and well-tolerated agents from an existing ARV drug class can help patients regain undetectable HIV levels in those no longer responding to previous options.

Making Undetectability Possible

In RESIST, as indicated by Dr. Sharon Walmsley, Associate Professor of Medicine, University of Toronto, Ontario, “The primary end point was 1 log10 reduction in viral load [VL] because at the time that study was designed, reaching an undetectable level did not seem realistic.” While 22.8% of patients randomized to the protease inhibitor (PI) tipranavir arm achieved an undetectable VL, defined as <50 HIV RNA copies/mL (vs. 10.2% in the comparator arm; P<0.001), the proportion rose to 35.8% (vs. 14.4% in the comparator arm; P<0.001) among those who received another novel active agent, usually enfuvirtide. According to Dr. Walmsley, this rate of undetectability in highly treatment-experienced patients was “unprecedented” and “set a new goal for outcome” in a population for whom options had been exhausted.

In the two phase III RESIST trials, one of which was conducted in North America and Australia and the other in Europe and Latin America, 1483 patients were randomized to receive tipranavir 500 mg boosted with ritonavir 200 mg (TPV/r) or a comparator ritonavir-boosted PI (CPI/r). Both were combined with an optimized background regimen. At 48 weeks, treatment response was greater with TPV/r and for all secondary end points, including VL at <400 copies/mL and <50 copies/mL. The TPV/r degree of efficacy was similar when compared to each of the CPI/r regimens individually. Virological failure occurred in 10.9% of patients who received TPV/r vs. 40% of those randomized to a CPI/r.

Early Switch and PI Exposure

New data from RESIST presented here not only reinforce the main results but also emphasize the importance of switching early enough that patients still have at least one other agent with predicted efficacy. In data presented by Dr. Richard B. Pollard, Chief, Division of Infectious Diseases, University of California, Davis, patients were stratified by the number of PIs to which they were exposed in regimens previous to enrolment in the RESIST study. In all cases, TPV/r was more efficacious than CPI/r for treatment response (defined as >1 log10 reduction in VL), <400 copies/mL, and <50 copies/mL. The relative advantage for TPV/r improved with increasing exposure to PIs, but more patients reached undetectability if switched earlier. Specifically, in patients exposed to six PIs, 17.6% of TPV/r patients achieved an undetectable VL vs. 2.0% of patients randomized to a CPI/r. In patients exposed to two PIs, 35% of TPV/r patients vs. 24.3% of CPI/r patients became undetectable.

“At all levels of PI experience, TPV/r was more effective than CPI/r, but patients who started TPV/r with more limited PI experience had better treatment outcomes at week 48,” Dr. Pollard reported. He suggested that this could change the treatment paradigm for highly experienced patients, emphasizing the need to move to one of the growing number of novel compounds when experienced patients begin to show signs of failure in their current regimens. Dr. Walmsley concurred, suggesting that switching patients should now be considered earlier than it was when there were fewer options for patients who were highly treatment-resistant.

“All of the studies in treatment-experienced patients tell us that you really need a second drug to achieve a sustained VL reduction,” stated Dr. Walmsley, referring not only to RESIST but also to TORO and the POWER (Performance of TMC114/r When Evaluated in Triple-Class-Experienced Patients with PI Resistance) studies. Although TMC114/r, a novel PI which was the focus of the POWER study, is not yet available, the initial results suggested that efficacy of this agent, like tipranavir and enfuvirtide, is dependent on a combination that includes one other agent with predicted efficacy. According to Dr. Walmsley, the RESIST studies made undetectability a viable goal in the highly treatment-experienced patient and this requires switching patients “sooner rather than later if we are trying to regain viral control.”

PI Boosting and Resistance Mutations

The development pipeline is critical to make this strategy work. The advantage of newer PIs is that they remain active in the presence of multiple signature PI mutations. According to Dr. Carmen de Mendoza, Instituto de Salud Carlos III, Madrid, Spain, all boosted PIs are more effective than unboosted PIs for overcoming resistance mutations, but TPV/r is the only currently available boosted PI that remains highly active even in the presence of multiple PI mutations. In data she presented on 389 patients receiving boosted lopinavir (LPV/r), amprenavir (APV/r), atazanavir (ATV/r), saquinavir (SQV/r) and indinavir (IDV/r), response rates fell for all boosted PIs in the presence of HIV with an increasing number of PI mutations. However, even in patients with five or more PI mutations, the response rate was 64% with TPV/r vs. 47% for LPV/r, 46% for SQV/r, 33% for ATV/r, 25% for IDV/r and 16% for APV/r.

“The main determinant of potency when starting a new PI in treatment-experienced patients is the baseline number of PI mutations. Although boosting increases response rates in patients with multiple mutations, TPV/r demonstrated the greatest potency, particularly as the number of mutations climbed to five or more,” Dr. de Mendoza reported. However, even in the subgroup of patients with less than five mutations, TPV/r achieved a virologic response in 100% of patients vs. 75% for LPV/r, 77% for SQV/r, 93% for ATV/r, 89% for IDV/r and 60% for APV/r.

The initial development of enfuvirtide was a major step forward in improving options for highly treatment-experienced patients, but this agent requires injection, which is considered a hurdle for many patients, particularly because therapy must be continued indefinitely. One of the encouraging results of the RESIST studies was that TPV/r, which is taken orally, did not pose any unusual safety concerns relative to alternative boosted PIs. When calculated by adverse events (AEs) per 100 patient-years of exposure, the rate of AEs was actually slightly lower on TPV/r (23.9) than on CPI/r (27.8). Although rates of liver enzyme elevations (15.8% vs. 6%, respectively) were higher on TPV/r than CPI/r, discontinuation rates per 100 patient-years of exposure were similar (12.4 and 10.6, respectively).

Summary

New treatment options are providing an opportunity to reach undetectable status in a substantial proportion of highly treatment-experienced, HIV-infected patients. These options include new agents in novel classes of drugs, such as entry inhibitors, as well as new compounds in existing classes, such as boosted tipranavir. The clinical trials with the PI demonstrated that achieving undetectable status is a reasonable goal even in highly treatment-experienced patients, but benefits appear to be dependent on the initiation of two new agents simultaneously to which the infection is expected to be sensitive. Once virus is suppressed, long-term benefits in those who are treatment-experienced, like those who are treatment-naive, will depend on sustained safety and tolerability.