Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

15th Conference on Retroviruses and Opportunistic Infections

Boston, Massachusetts / February 3-6, 2008

In the recent past, there was concern that control of multidrug-resistant HIV would soon be lost. While this remains possible, it has been pushed further into the distance not only due to promising results with novel compounds but also with effective new agents from traditional antiretroviral drug classes. “As a clinician looking forward, I think I will always be a little concerned that we may run out of effective therapies, but we seem to be staying ahead of the curve so far,” observed Dr. John Mellors, Chief, Infectious Diseases, University of Pittsburgh School of Medicine, Pennsylvania.

Reassured by the number of emerging agents, including those in novel classes, such as CCR5 inhibitors and integrase inhibitors, Dr. Mellors indicated that the ability to coax effective new compounds from traditional drug classes has provided a particularly strong basis for optimism.

For example, in a recent data analysis of darunavir, a protease inhibitor (PI) recently approved for use in treatment-resistant patients, the virologic failure (VF) rate was half of that of another potent PI in a head-to-head study. Moreover, of those who did develop VF, there was a lower risk of developing primary PI mutations. In 48-week data from phase III studies in a treatment-resistant population with the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC125), undetectable viremia was achieved in more than 60% of patients with a side-effect profile comparable to placebo. In early-stage development, the new NRTI apricitabine (ATC) has passed 24 weeks without generating any resistance mutations.

Updates: From TITAN to ARTEMIS

The 48-week data of the phase III TITAN (TMC114/r in Treatment-experienced Patients Naive to Lopinavir) trial were initially presented at the International AIDS Society (IAS) conference in Sydney, Australia, by Dr. José Valdez-Madruga, Centro de Referência e Treinamento DST/AIDS, São Paulo, Brazil. Findings demonstrated a variety of advantages for darunavir/ritonavir (DRV/r) over lopinavir/ritonavir (LPV/r), including a significantly greater rate of undetectable (<50 copies HIV RNA/mL) viremia (71% vs. 60%). It was the first controlled trial in which another PI was superior to LPV/r in a population that was LPV/r-naive. New data presented here at CROI build on the initial findings.

In a 48-week analysis of TITAN led by clinical researcher Dr. Sandra De Meyer, Mechelen, Belgium, and colleagues, the development of resistance in patients experiencing VFs was characterized. Specifically, in a randomized population of 595 patients (298 receiving DRV/r and 297 receiving LPV/r), the number of VFs was more than double in the LPV/r arm (22% vs. 10%). A primary PI mutation developed in six patients of the DRV/r arm vs. 20 in the LPV/r arm. Moreover, of the VFs, a higher proportion of LPV/r patients than DRV/r patients developed resistance to other PIs on either phenotypic or genotypic analyses. In addition, a resistance-associated mutation (RAM) for a NRTI developed in four DRV/r-treated patients vs. in 15 of LPV/r-treated patients. Of patients experiencing VFs, fewer on DRV/r developped a NRTI RAM than those on LPV/r.

While the new findings demonstrated that DRV/r is better in preventing resistance development due to a lower risk of cross-resistance than LPV/r, similar findings were found in updated data from the ARTEMIS (Antiretroviral Therapy with TMC114 Examined in Naive Subjects) study. In ARTEMIS, the patients were treatment-naive and randomized to regimens containing either DRV/r q.d., or LPV/r q.d. or b.i.d. Undetectable viremia rates were slightly higher at 48 weeks on DRV/r q.d. (84%) even against LPV/r b.i.d. (81%).

In the new pharmacokinetic/pharmacodynamic analysis, quartile stratifications for plasma levels demonstrated no differences in the rate of undetectable viremia for the lowest vs. the highest plasma levels, confirming q.d. dosing as a viable strategy. Moreover, while DRV/r was well tolerated, there was no relationship observed between plasma levels and those adverse events that did occur. The authors indicated that the greater efficacy of DRV/r q.d. therapy in treatment-naive adults might be best attributed to its greater potency relative to LPV/r even on a q.d. schedule.

DUET-1 and -2

In the newly released 48-week, phase III data on patients with documented NNRTI resistance, the addition of the new NNRTI etravirine to an optimized background regimen raised the proportion of patients achieving undetectable viremia by 50% when compared to placebo (60% vs. 40%; P<0.0001). All patients in both arms received an optimized background regimen including DRV/r. The 48-week results mirror those seen at 24 weeks. Perhaps most notable in the context of efficacy for a highly treatment-experienced population, etravirine was extremely well-tolerated.

“With the exception of rash, which was mild to moderate in most cases, the incidence and severity of adverse events with etravirine were similar to placebo,” reported Dr. Richard Haubrich, Division of Infectious Diseases, University of California, San Diego. “The data demonstrate that etravirine provides a new effective and well-tolerated treatment option for treatment-experienced patients.”

The phase III data with etravirine come from two randomized trials, called DUET-1 and -2, for which a pooled analysis was prespecified. Both will accrue data out to 96 weeks. In DUET-1, conducted primarily in South America, Australia, Thailand and Europe, 612 patients were randomized to etravirine or placebo on top of optimized therapy. In DUET-2, which included study centres in Canada and the US but also centres in Europe and Australia, 591 patients were randomized to the same regimens. The trials included a variety of efficacy and safety outcomes, but the primary outcome was viral load <50 HIV RNA copies/mL.

Results of the two studies were essentially identical for every major end point, including viral load of <50 copies/mL, <400 copies/mL, change in CD4+ cell count and adverse events. It is notable that several adverse events, such as diarrhea (14% vs. 24%) and psychiatric disorders (14% vs. 18%), were actually less frequent in those who received etravirine than those who received placebo. This was likely the result of greater protection from progressive HIV infection.

Dr. Margaret Johnson, Royal Free Hospital, London, UK, told delegates, “Tolerability is an important issue for treatment-experienced patients. Etravirine allows patients to achieve viral control with very little to pay in the way of side effects. Once they are on this drug, they can stay on this drug. Of patients who achieved a viral load less than 50 copies at 24 weeks, 94% still have a viral load this low at 48 weeks.”

Other Developments

The data on the new NRTI ATC are at an earlier stage, but they reinforce the theme that new agents from traditional classes can still be effective in highly treatment-resistant patients. In the phase IIb AVX-201 study, 51 treatment-experienced patients were randomized to ATC 600 mg b.i.d., ATC 800 mg b.i.d. or lamivudine (3TC) 150 mg b.i.d. on top of an optimized multidrug antiretroviral regimen. At week 24, approximately 70% of patients on either dose of ATC had a viral load <50 HIV RNA copies/mL vs. 50% of patients receiving 3TC. Five patients reported adverse events such as diarrhea or nausea; all were mild and no patient discontinued therapy. Reported Dr. Pedro Cahn, Director, Fundación Huésped, Buenos Aires, Argentina, “Most importantly, there was no evidence of development of resistance to ATC observed in any of these patients.” Based on these results, a phase III trial is planned.

Summary

There are a number of agents in development with novel mechanisms that may expand therapeutic options in treatment-experienced HIV patients, but data from CROI demonstrate that existing classes are still viable. The recent approval of DRV/r in Canada and elsewhere is a significant advance, not only because of the efficacy it has demonstrated but also for its relatively low propensity for producing cross-resistance. The favourable tolerability of this and other new agents is also an important attribute of agents that must be employed in chronic regimens.