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47th Interscience Conference on Antimicrobial Agents and Chemotherapy

Chicago, Illinois / September 17-20, 2007

Like the nucleoside reverse transcriptase inhibitors (NRTIs) and the protease inhibitors (PIs), the new class of integrase inhibitors targets one of three viral enzymes that govern the life cycle of HIV. Phase III trials of the first agent in this new class, raltegravir, in both treatment-experienced and treatment-naïve patients are ongoing, but results from two pivotal phase III studies—the BENCHMRK (Blocking Integrase in Treatment Experienced Patients with a Novel Compound Against HIV: Merck)-1 study and BENCHMRK-2—were reviewed here by Dr. Eric Daar, Chief of HIV Medicine, Harbor-UCLA Medical Center, and Professor of Medicine, UCLA-David Geffen School of Medicine.

BENCHMRK Findings

Patients in both studies were resistant to one or more compounds from the PI, NRTI or non-NRTI drug classes and were highly treatment-experienced. Results from the intent-to-treat analysis showed that 77% of BENCHMRK-1 and -2 patients receiving raltegravir 400 mg b.i.d. plus optimized background therapy (OBT) had HIV RNA levels of <400 copies/mL at week 16 compared with 41% and 43% of patients, respectively, on OBT alone. The same analysis demonstrated that 61% and 62% of raltegravir patients in both studies achieved HIV RNA <50 copies/mL at week 16 compared with 33% and 36% of OBT controls. Mean increases in CD4+ cell counts for raltegravir patients were 83 to 86 cells/mm3 for the BENCHMRK studies vs. 31 and 40 cells/mm3 for placebo controls.

For the smaller number of patients who reached the 24-week assessment point, results were similar to 16-week data, Dr. Daar observed. Adverse events (AEs) in the raltegravir arms were comparable to those seen in the OBT group, with no increase in the incidence of laboratory abnormalities either. Some 76 patients in the BENCHMRK trials experienced virologic failure. Genotype analysis was made available for 41 patients who failed on raltegravir; of these, 32 had changes in the integrase gene that predominantly followed one of two pathways, characterized by the presence of either N155H or Q148K/R/H. In general, at least two mutations were present at the time of treatment failure, investigators reported. However, as noted by Dr. Daar, “It probably can be assumed that everybody who has not yet been on an integrase inhibitor will have a virus that is susceptible to it.”

A second integrase inhibitor, elvitegravir, is in phase II development for treatment-experienced patients. As pointed out by Dr. Daar, elvitegravir is metabolized by the CYP3A4 system and may have significant interactions with other antiretrovirals (ARVs). This is not the case with raltegravir, which is metabolized by glucuronidation.

Corroborative Results

In protocol 004, a phase II trial in treatment-naïve patients, approximately 80% of patients in both the raltegravir and the efavirenz arms achieved HIV RNA levels of <50 copies/mL at week 24, but the drop in viral load was more rapid with raltegravir: over half of patients in this treatment arm achieved undetectable levels by week 4. Similar rates of virologic suppression were also seen at week 48 in the same study. No dose-related toxicities have been identified to date for raltegravir.

Longer-term experience with the same agent in a double-blind, dose-ranging, phase II trial, again in experienced patients, confirmed that response to raltegravir is durable and that treatment is extremely well tolerated.

As presented by Dr. Jose Gatell, Head, Infectious Diseases and AIDS Units, and Professor of Medicine, University of Barcelona, Spain, patients with triple-class resistance and HIV RNA >5000 copies/mL were randomized to raltegravir 200, 400 or 600 mg b.i.d. plus OBT or OBT monotherapy for 24 weeks. The protocol was amended at week 24 when placebo patients received open-label raltegravir 400 mg b.i.d. for 24 weeks.

At week 48, 64% to 71% of patients on raltegravir achieved HIV RNA <400 copies/mL, and 46% to 64% of them had undetectable levels. At week 48, mean increases in CD4+ cell counts from baseline ranged from 64 to 110 cells/mm3. There were also remarkably few discontinuations due to AEs, Dr. Gatell added, noting that patients in this study were a “very advanced HIV population” with a median of 10 years on ARV therapy, some 30% of whom had baseline viral loads in excess of 100,000 copies/mL. “These responses were very consistent with those seen at 24 weeks,” Dr. Gatell affirmed, “and reinforce the drug’s potential as the first in a promising new class of ARV agents.”

Further Research

The most mature data for a second new class of ARV agents, the entry inhibitors, are available for maraviroc. It is a CCR5 antagonist which works by blocking viral binding to the CCR5 coreceptor but not to its CXCR4 counterpart.

Thus, it becomes important to determine whether a patient has CCR5 virus only, noted Dr. David Kuritzkes, Professor of Medicine, Harvard Medical School, Boston, Massachusetts. Otherwise, virus that binds with the CXCR4 coreceptor (X4 virus) or viruses that use both receptors (dual/mixed or D/M) will not respond to CCR5 antagonists. According to a variety of studies, anywhere from 22% to 48% of treatment-experienced patients have either X4 or D/M virus and are not candidates for CCR5 antagonist therapy.

However, in treatment-experienced patients with pure CCR5 virus, maraviroc appears to be very potent. In updated data presented by Dr. Jacob Lalezari, Director, Quest Clinical Research, San Francisco, 50.9% of once-daily maraviroc patients in the MOTIVATE 1 and 2 (Maraviroc Plus Optimized Background Therapy in Viremic, ART-experienced Patients) trials were still <400 copies/mL at week 48, as were 57.5% of the twice-daily group compared with 22% of placebo controls. Corresponding percentages for those who were undetectable were 42%, 47% and 16% for the once-daily, twice-daily and placebo control groups, respectively. Mean increases in CD4+ cell counts were also significantly higher in the maraviroc treatment arms at 113 and 122 cells/mm3 for the once-daily and twice-daily arms, respectively, vs. a mean increase of 54 cells/mm3 in the OBT arm alone. Discontinuation rates due to AEs were comparable across all three treatment arms at £6% and there was no evidence of either hepatotoxicity or an excess of malignancies among patients receiving maraviroc. Some 60% of patients who failed on the maraviroc regimen had D/M or X4 virus, Dr. Lalezari noted.

Updated data from ACTG 5211 on vicriviroc, another CCR5 antagonist, showed sustained viral suppression through two years of therapy in advanced treatment-experienced HIV patients. After 12 months of therapy, 37% of patients on 10 mg and 27% of patients on 15 mg achieved HIV-RNA <50 copies/mL compared with placebo at 11%. Fewer patients in the active-treatment groups experienced virologic failure at between 27% and 33% compared to those treated with placebo at 86% at the same assessment point.

In another presentation, pooled 24-week data from the DUET 1 and 2 trials of the second-generation NNRTI, TMC125 (etravirine) plus OBT vs. OBT monotherapy again demonstrated consistent and significant superiority for TMC125 for all end points, including percentage of patients with HIV RNA <50 copies/mL (59% vs. 41%); HIV RNA <400 copies/mL (74% vs. 53%) and mean CD4+ cell increases (86 vs. 67 cells/mm3). Both the AE profile and laboratory values were essentially similar between the two groups, although rash was seen early on with TMC125. Discontinuation rates due to drug-related toxicity were very low.

Investigators concluded that even in the absence of a fully active background regimen, 45% of TMC125 patients were able to achieve undetectable viral loads, a clear sign etravirine is another active option in patients resistant to other NNRTIs.

Summary

The selection of a highly active ARV regimen is not without its challenges in treatment-experienced patients with mutations to multiple ARV drug classes. Nevertheless, the availability of new treatment options such as the integrase and entry inhibitors now make it possible to develop potent, safe and well-tolerated regimens for the great majority of HIV-infected patients, regardless of prior ARV exposure. Together with other agents already in development, these new options will allow physicians to meet patients’ needs today and hopefully long into the future.