The most exciting news to come out of the 14th Retrovirus Conference held in Los Angeles during February related to new drugs currently in development, including two integrase inhibitors, an entry inhibitor, and a second-generation non-nucleoside. Dr. John Mellors of the University of Pittsburgh introduced the late breaker session on Tuesday evening, remarking, “I don’t think it’s an understatement to say that this session marks a milestone in the treatment of HIV in resistant patients.”

Raltegravir

In the late breaker session on Tuesday, David Cooper, MD of the University of New South Wales in Sydney, Australia presented 16 and 24-week data from Phase 3 studies of Merck’s integrase inhibitor raltegravir (formerly known as MK-0518). Integrase inhibitors belong to a new class of drugs that target HIV at a different point in the HIV lifecycle. BENCHMRK-1 & BENCHMRK-2 are two identical studies under investigation in different countries, with approximately 350 patients in each study. The randomized, double-blind, placebo-controlled studies looked at raltegravir 400 mg twice-daily in combination with optimized background therapy (OBT). Patients were generally heavily treatment-experienced, with resistance to at least one drug in each of three classes (NNRTI + NRTI + PI) upon entering the study. Participants had the following characteristics: an average age in the mid-forties, 150 T-cells, a viral load of 4.5 logs, and 10–11 years on therapy. Most had tried an average of 12 different HIV medications. The drug was generally well tolerated with a safety profile comparable to that of OBT plus placebo. Few adverse experiences led to discontinuation of the drug.

Approximately twice as many patients on raltegravir achieved undetectable viral loads compared to those on placebo (77% less than 400 copies/mL and 61% less than 50 copies/mL). In both studies, 61% of those resistant to all other drugs in their background therapy still achieved a viral load less than 400 copies/mL at 16 weeks, an impressive result. In a combined analysis of the two studies, when raltegravir was given with Prezista and/or Fuzeon, more than 90% of patients achieved a viral load less than 400 copies/mL. CD4 cell counts increased between 83–86 cells/mm3 in both groups, more than 2–3 times those in the placebo group.

In a subgroup analysis looking at the percentage of patients with HIV RNA viral loads less than 400 copies/mL at week 16 by baseline viral load and CD4 cell count, 63% of patients with less than 50 T-cells, and 86% of those with more than 200 T-cells at baseline achieved less than 400 copies/ml. In this same analysis 88% of those with a baseline viral load of less than 100,000 copies/mL achieved undetectable viral levels vs. 55% on placebo; 64% of those with more than 100,000 copies/mL achieved less than 400 copies/mL compared to 19% of those on placebo.

(For more about raltegravir and other new drugs see One-on-One with Joseph J. Eron, MD).

Maraviroc

Also at Tuesday’s late breaker session, Howard Mayer, MD of Pfizer presented 24-week data on their oral CCR5 antagonist maraviroc, which belongs to an entirely new class of drug that blocks HIV at the point of entry into the CD4 cell. MOTIVATE 1 & 2 are two identical Phase 2b/3 trials ongoing in different countries, with 601 and 475 patients respectively. Patients were randomized 2:1:1 to receive optimized background therapy (OBT) plus 150 mg maraviroc once or twice daily. To be eligible for the study participants had to have CCR5 (R5) tropic virus, a viral load of at least 5,000 copies/mL, be on a stable antiretroviral (ARV) regimen or no ARVs for at least four weeks, and have resistance to and/or a minimum of six months experience with at least one ARV from three classes (at least two for PIs).

In MOTIVATE-1, which is being conducted in the U.S. and Canada, at baseline the mean age across all groups (OBT plus placebo, once-daily or twice-daily maraviroc) was 46 years; the majority were Caucasian (at least 90%) and male (81-84%). The mean reduction in HIV-RNA viral load from baseline was 1.82 log for the maraviroc once-daily group and 1.95 logs in the twice-daily group, versus 1.03 logs in the placebo group; the mean increase from baseline CD4 at week 24 was 107 cells/mm3 in the once-daily group and 111 cells/mm3 in the twice-daily group, versus an increase of 52 cells/mm3 in the placebo group.

In a combined analysis of the two studies, the most pronounced differences in viral load reduction between those on drug and those on placebo were seen in those with one to two active drugs in their OBT: for those with one active drug in their OBT, 43% reached a viral load less than 50 copies/mL in both the once-daily and twice-daily groups vs. 9% in the placebo group; for those with two active drugs in their OBT, 52% of those on maraviroc once-daily and 53% of the twice-daily group achieved a viral load less than 50 copies/mL vs. 19% for the placebo group.

There were no significant adverse events in either study. There was some concern, however, about the potential development of lymphomas and other malignancies, which occurred during the study of a second CCR5 antagonist, vicriviroc, though no definite cause-effect relationship has been shown. The study of a third CCR5 antagonist, aplaviroc, was terminated because of damage to the liver.

In summary, the authors concluded that maraviroc once-daily and twice-daily plus OBT “demonstrated significantly greater virologic suppression compared to placebo plus OBT in this treatment experienced patient population.” They added that there were “no clinically relevant differences in the safety profile between maraviroc and placebo treatment groups.” Also, “fewer patients receiving maraviroc experienced treatment failure compared to those receiving placebo; however more patients on maraviroc had a change in tropism result to D/M [dual/mixed-tropic virus] or X4 [CXCR4-tropic virus] at time of failure.” However, it was also noted that in this category the mean CD4 increase of maraviroc patients “was greater than that seen in the total placebo group who failed therapy.”

“I don’t think it’s an understatement to say that this session marks a milestone in the treatment of HIV in resistant patients.”

Elvitegravir

Andrew Zolopa, MD of the Stanford University School of Medicine presented 24-week data on the Phase 2b study of Gilead’s integrase inhibitor elvitegravir, formerly known as GS-9137. Elvitegravir requires boosting with 100 mg Norvir (ritonavir) and is dosed once-daily. Studies are moving forward with the 75 mg dose. The study, initially designed as a non-inferiority study, looked at 278 highly treatment experienced patients with a viral load HIV RNA of at least 1,000 copies/mL and at least one protease mutation, with an optimized background therapy (OBT) containing two or more NRTIs but no NNRTIs, while nearly 20% were on Fuzeon (efuvirtide, T-20). There was a comparator boosted-PI group of which 49% were on Prezista (darunavir) and 27% taking Aptivus (tipranavir). Three doses of boosted elvitegravir were initially studied, 20, 50, and 125 mg. However, the 20 mg group was discontinued at week eight at the recommendation of the Data Safety Monitoring Board (DSMB) due to a high rate of failure, at which point patients were offered open-label elvitegravir 125 mg. The DSMB also recommended permitting the addition of Prezista or Aptivus to the elvitegravir arms due to lack of drug-drug interaction with elvitegravir. As a result of these changes, only 16 and 24-week data were given. At 16 weeks a viral load of less than 50 copies/mL was seen in 38% of those on 50 mg elvitegravir and 40% of those on 125 mg elvitegravir, versus 30% in the PI group. By week 24 this was reduced to 32%, 36% and 27 % respectively. At 16 weeks, increases in mean CD4 cell counts were 52, 61 and 28 cells/mm3 in those on 50 or 125 mg elvitegravir or a comparator PI, respectively. At 24 weeks increases in CD4 cell counts were similar in all groups. Phase 3 studies are now being planned with a 150 mg tablet which is bioequivalent to the 125 mg currently being studied.

In a related poster (627) by G. Jones, et. al., the authors identified two primary resistance patterns that cause reduced susceptibility to elvitegravir. This could possibly lead to cross resistance with Merck’s integrase inhibitor raltegravir, but not to other antiretroviral drugs currently available or in development, including NRTIs, NNRTIs and PIs.

There were no significant adverse events in either study.

TMC-278

Anton Pozniak, MD of Chelsea and Westminster Hospital in London, UK gave a late breaker presentation on TMC-278, Tibotec’s second generation non-nucleoside that is currently in a randomized, controlled Phase 2b dose-finding study in treatment-naïve patients. TMC-278 has a long half-life (45 hours) and has been shown to be highly active against wild-type and drug-resistant HIV in vitro. A total of 368 patients, 30% who were women, were randomized to receive a backbone of two nukes (Combivir or Truvada) plus Sustiva (efavirenz) 600 mg once-daily or TMC-278 25, 75 or 150 mg once-daily. All arms performed well in the study and there was no statistically significant difference in efficacy among any of the treatment arms. Of those on TMC-278, 77-81% achieved a viral load less than 50 copies/mL at 48 weeks. The mean change in viral load was approximately -2.6 logs in all four groups. Mean CD4 T-cell count increases were also similar across all four groups, between 125 and 145 cells/mm3. The most common adverse events were nausea (TMC-278 35% vs. Sustiva 29%) and headache (18% vs. 16%). Nervous system disorders and psychiatric events were lower with TMC-278 (28% and 13% respectively) compared with Sustiva (48% and 16% respectively). Rash was less frequent for TMC-278 (8%) vs. Sustiva (19%), and total cholesterol/triglycerides were lower with TMC-278 than with Sustiva. No significant differences in serious adverse events were seen among the four groups. Development is moving forward with the 75 mg dose once daily.

Special thanks to Ross Slotten, MD for his review of this article.