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13th Conference on Retroviruses and Opportunistic Infections

Denver, Colorado / February 5-8, 2006

Need for New Therapies in Treatment-experienced Patients

Based on the emergence of promising new therapies, there is substantial hope for the growing number of patients who have cycled through all of the existing antiretroviral agents and now have multiple resistance mutations. One of these therapies, the protease inhibitor (PI) tipranavir, was newly approved in the US based on phase III data demonstrating significant HIV control in highly treatment-experienced patients. Other therapies earlier in clinical testing are also showing promise. These include a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that has proven efficacious even in patients with resistance to current NNRTIs and a novel drug from a new class of agents called integrase inhibitors.

According to Dr. John Mellors, University of Pittsburgh, Pennsylvania, “The biggest need that we have [in HIV medicine] is for more effective therapies to use in treatment-experienced patients who are running out of options. I think the data we have seen at this meeting suggest that we are making a lot of progress in this direction.”

Potent Therapeutic Option

Data from two phase III multinational trials of tipranavir boosted by ritonavir (TPV/r) doubled the proportion of highly treatment-experienced patients who achieved a viral load below the limit of detection after 48 weeks of follow-up. When combined with an optimized background regimen selected on the basis of treatment history and resistance testing, the advantage of the study combination was consistent over every comparator PI boosted with ritonavir (CPI/r) employed. The advantage was also consistent regardless of baseline CD4+ cell counts or baseline viral load.

“These studies demonstrate that TPV/r is a potent therapeutic option for treatment-experienced patients. It offers virological and immunological benefit in this patient group and enables them to achieve virological suppression,” reported Dr. Christine Katlama, Hôpital Pitié-Salpétrière, Paris, France.

RESIST Trials

The RESIST I and II (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) trials randomized 1483 patients. For entry, patients were required to be experienced with at least three antiretroviral classes and to have been treated with at least two PI-based regimens and have at least one primary PI mutation but less than three mutations at codons 33, 82, 84 and 90. The optimized background regimen and the CPI/r were selected before patients were randomized to receive TPV/r or enter the control group. The comparator ritonavir-boosted PIs were lopinavir, saquinavir, amprenavir and indinavir. Ritonavir-boosted lopinavir (LPV/r) was selected in about half of the patients with the remaining patients divided primarily between saquinavir and amprenavir. Ritonavir-boosted indinavir was selected in about 3% of patients.

The advantage of TPV/r was consistent against all CPI/r-based regimen. For example, TPV/r achieved a viral load of <50 copies/mL in 23.9% vs. 11.5% when compared to LPV/r and in 22.4% vs. 6.4% when compared to saquinavir/ritonavir (SQV/r). The therapeutic advantage of TPV/r further increased in patients who received another agent predicted to have efficacy, such as enfuvirtide, and in patients with higher CD4+ cell counts and lower baseline viral load at entry. Overall, the risk of treatment failure was 34% lower (P<0.001) in those who received the study combination.

“Most important was that these responses were durable. The 48-week results are consistent with the 24-week results, and demonstrate sustained control of infection in responders,” Dr. Katlama told delegates.

Minimum Inhibitor Concentrations: Analysis of RESIST Data

An analysis of the RESIST I and II data from regulatory investigators corroborated efficacy results when it demonstrated that patients who received adequate minimum inhibitor concentrations (Cmin) produced better response rates even if they had three to four baseline PI mutations. Although response rates remained at about 30% regardless of the Cmin when patients had five or more baseline PI mutations, response rates climbed from 39% to 64% among patients with three to four PI mutations if they had Cmin values of at least 34 µg/mL.

“Overall, response rates in the RESIST trials increased as plasma concentrations increased,” stated Lisa Naeger, PhD, U.S. Food and Drug Administration, Silver Spring, Maryland. She suggested that this was best reflected by computing the genotypic IQ (GIQ), which is derived as a ratio of the Cmin divided by the number of baseline PI mutations. Noting that the response rate climbed to 62% for those with a GIQ of at least 7.8 vs. 34% for a lower GIQ, she recommended studies to determine whether GIQ might be a useful clinical tool.

Emerging Options

In preliminary development, the NNRTI TMC125 also showed significant promise in highly treatment-experienced patients, including those with primary NNRTI mutations. Data from 79 patients treated with TMC125 were presented. Most were triple class-experienced, including 100% who had used a PI, 94% who had used a NNRTI and 30% who had used enfuvirtide. The median baseline number of PI mutations was four and the median NNRTI mutations were two. More than 80% of patients had no phenotypic susceptibility to any PI at baseline. After receiving 800 mg TMC125 b.i.d., there were substantial virologic responses in all patients stratified by number of baseline NNRTI mutations.

Remarked Dr. Johan Vingerhoets, Mechelen, Belgium, “The main result is that TMC125 retains activity in the presence of multiple NNRTI mutations where current NNRTI would not have been expected to be effective.” Although response rates decreased with an increasing number of NNRTI mutations, those with three or more mutations still achieved significant viral load reductions.

Specifically, after 24 weeks of therapy with TMC125 plus an optimized background regimen, the viral load reduction was 1.82 log10 in those with no NNRTI mutation, 1.65 log10 in those with one mutation, 1.0 log10 in those with two mutations, and 0.66 log10 in those with three mutations on an intent-to-treat analysis. It was well tolerated with no discontinuations due to adverse events. Based on these data, phase III trials with TMC125 in an 800 mg b.i.d. dose are being planned.

Data presented here on the integrase inhibitor MK-0518 demonstrated encouraging results for a new class of antiretroviral therapy in highly treatment-experienced patients. In a study that enrolled 132 patients, mean baseline viral load was approximately 4.8 log10. While all patients were treatment-experienced, approximately 30% had no antiretroviral agents with predicted efficacy when an optimized background regimen was selected for combination with the integrase inhibitor. There were four study agent groups at 200 mg, 400 mg or 600 mg b.i.d. and placebo.

“All of the doses of MK-0518 were active. At week 16, the proportion of patients achieving a viral load <50 copies/mL ranged from 57% to 72%, while only 19% achieved this level of response in the placebo group,” reported Dr. Beatriz Grinsztejn, Evandro Chagas Clinical Research Institute, Rio de Janeiro, Brazil. “The drug was very well tolerated with no adverse events that occurred significantly more frequently on the study drug relative to placebo.”

Based on this study, a phase III trial with the 400 mg b.i.d. dose is being initiated. According to Dr. Mellors, “the results with this integrase inhibitor are about as impressive as I have seen. These drugs have the potential to make a big impact on sustained HIV control.”

Summary

Substantial progress is being made in the development of therapies that can restore HIV control in highly treatment-experienced patients. The RESIST trials demonstrated that the ritonavir-boosted PI TPV can double the proportion of highly treatment-experienced patients, including those with multiple PI resistance mutations, who achieve an undetectable viral load. The NNRTI TMC125, although much earlier in development, has been associated with a high degree of activity even in patients with two or more NNRTI mutations. New drug classes, such as the integrase inhibitors, will also provide an opportunity to regain HIV control if they continue to show promise in ongoing clinical trials.