Reports

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46th Interscience Conference on Antimicrobial Agents and Chemotherapy

San Francisco, California / September 27-30, 2006

The newly released 96-week data from the pivotal RESIST (Randomized Evaluation of Strategic Intervention in Multi-drug Resistant Patients with Tipranavir) trials have confirmed that HIV infection can be suppressed indefinitely even in highly treatment-experienced patients if they are initiated on an effective regimen. These data provide the proof of principle that the goal in treatment-experienced patients is to bring HIV levels below 50 HIV RNA copies/mL. Once that is achieved, the likelihood of a sustained response on effective therapy may approach that of patients who are treatment-naive.

Maintaining Viral Suppression Below 50 Copies/mL

“Most patients who achieved a viral load of <50 copies/mL at week 16 were able to maintain this level of virologic suppression for at least 96 weeks,” reported Dr. Charles F. Farthing, Chief of Medicine, AIDS Healthcare Foundation, Los Angeles, California. Overall, randomization to the protease inhibitor (PI) tipranavir (TPV) in the RESIST studies more than doubled the likelihood of achieving a viral load <50 HIV RNA copies/mL. However, initiating at least two compounds with predicted efficacy is important. According to Dr. Farthing, the likelihood of achieving a viral control <50 copies/mL was almost doubled again when TPV boosted with ritonavir (TPV/r) was combined with another drug active against resistant HIV. The data provide powerful evidence that the key to regaining control of HIV infection in treatment-experienced patients, like those who are treatment-naive, is initiation of an effective combination.

The RESIST data were drawn from two similar phase III studies that randomized a total of 1483 patients, producing one of the largest outcome studies ever conducted in a treatment-experienced population. In the RESIST trials, triple-class-experienced patients that had been exposed to at least two PI-based regimens were randomized to tipranavir 500 mg plus ritonavir 200 mg or a comparator boosted PI (CPI/r). The 48-week data, which were recently published (Hicks et al. Lancet 2006;368:466-75), demonstrated a highly significant advantage for TPV/r over CPI/r for every important outcome, including sustained treatment response (P<0.0001) and time to treatment failure (P<0.0001). The 96-week data demonstrate that these advantages have continued to persist through follow-up to date.

“Patients taking TPV/r were twice as likely to experience a treatment response at week 96 as those taking a CPI/r,” Dr. Farthing noted. Just as importantly, “TPV/r plus an optimized background regimen was significantly better than CPI/r plus an optimized background regimen in delaying treatment failure. In other words, the response to TPV/r was durable over at least 96 weeks.”

Initiation of Additional Active Agents

In the RESIST trials, the importance of initiating treatment with at least two agents with predicted efficacy was demonstrated when patients were stratified by those who did or did not receive enfuvirtide, an entry inhibitor administered by injection. Although TPV/r response was greater to CPI/r whether or not enfuvirtide was administered, starting TPV/r with enfuvirtide in those with no previous exposure to enfuvirtide increased the proportion achieving a viral load <50 copies/mL by more than 50%. A similar phenomenon was observed with the phase III enfuvirtide trials when patients were stratified according to previous exposure to lopinavir/ritonavir (LPV/r). It was also observed in the phase III POWER (Performance of TMC-114/r When Evaluated in Treatment-Experienced Patients With PI Resistance) studies with the new PI darunavir, which also stratified patients by exposure to enfuvirtide. In all cases, the likelihood of achieving a sustained viral load of <50 copies/mL was increased significantly when two active agents were started simultaneously.

“It is clear now from several studies that the potency and durability of novel agents is markedly enhanced if that agent is combined with additional active antiretroviral treatments,” Dr. Farthing observed. He indicated that this has important implications for determining when to consider newer agents. In particular, he added, it suggests that effective novel agents should not be withheld until there are no other options with which it can be paired.

Although the POWER studies with darunavir were conducted with only 255 patients, which is less than one-fifth the size of the RESIST trials, the similarity of results relative to the CPI/r arm, before and after stratification with enfuvirtide, reinforce the importance of active combinations.

Promising Interim Data

Fortunately, the opportunity for pairing novel agents may improve substantially due to progress with other new compounds. The most recent data has been generated by MK-0518, an integrase inhibitor. In interim 24-week data from a double-blind, dose-ranging, placebo-controlled trial in triple-class treatment-experienced patients, the compound was associated with impressive reductions in viral load and acceptable safety.

“The 24-week results were very similar to the 16-week results presented earlier this year, demonstrating that the viral load reductions have been sustained,” remarked Dr. Beatriz Grinsztejn, HIV/AIDS Clinical Trials Unit, Evandro Chagas Clinical Research Institute, Rio de Janeiro, Brazil. The three doses studied were 200, 400 and 600 mg. Each was combined with an optimized background regimen and compared to optimized background regimen alone. The proportion of patients achieving a viral load <50 copies/mL ranged from 57 to 67% vs. 16% for those taking the optimized background regimen alone.

As has been seen in other trials conducted in patients with advanced HIV, many adverse events, such as diarrhea, occurred less often on the study agent than on placebo, an advantage attributed to a reduction in HIV-related complications. However, no side effects occurred with significantly greater frequency on the integrase inhibitor, suggesting a “tolerability profile similar to placebo,” according to Dr. Grinsztejn. She reported that although the safety and efficacy of the three doses of MK-0518 were similar overall, upcoming clinical trials are expected to be conducted with the 400 mg dose.

Pharmacokinetics

Clinical results from MK-0518 are encouraging because this oral agent may be more acceptable than the injectable enfuvirtide for highly treatment-experienced patients seeking to regain a viral load of <50 copies/mL. It was shown to be compatible with TPV/r in a pharmacokinetics (PK) study that specifically evaluated the 400-mg dose. In this study, multiple dose administration of TPV/r and MK-0518 in healthy volunteers did not reveal any significant changes in area-under-the-curve (AUC), time to maximum concentration (Tmax) or maximum concentration (Cmax) PK values when the two agents were combined or administered separately. The combination was also found to be well tolerated with no laboratory adverse events reported.

The lack of change in liver function tests (LFTs) is consistent with new data from a RESIST analysis that focused on changes in LFTs, as presented by Dr. Mark Sulkowski, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Although TPV/r was associated with a higher incidence of grade 3 or 4 LFTs than CPI/r, serious hepatic events occurred in <1% of those randomized to TPV/r. More importantly, the vast majority of patients who developed grade 3 or 4 LFTs were able to remain on therapy. Of the 60 patients whom investigators selected to continue on therapy with or without a temporary interruption, LFTs resolved to a grade £2 in 51 (85%).

“While LFT elevations were observed in the RESIST studies, only 1.9% of patients who received TPV/r discontinued therapy due to an emergent grade 3 or 4 LFT, and among these serious hepatic adverse events were rare,” reported Dr. Sulkowski.

Summary

Due to the increasing number of clinical trials conducted in highly treatment-experienced patients, the characteristics of an optimal regimen are being increasingly better defined. Perhaps surprisingly, these characteristics appear to be exactly the same as those of an optimal regimen in patients who are treatment-naive. A large proportion of patients who simultaneously initiate a regimen with at least two active compounds that is sufficiently convenient and well tolerated to encourage adherence can expect to achieve a viral load <50 copies/mL with a high likelihood of sustained control. In 96-week data from the RESIST trials, the largest trial yet conducted in highly treatment-experienced patients, early control with TPV/r predicted sustained viral suppression.