Antiretroviral Therapy Roundup from CROI
Report on newer drugs in development and some already approved drugs
by Jeff Berry
Encouraging results were presented at this year’s 15th Conference on Retroviruses and Opportunistic Infections (CROI) on many of the newer drugs which have recently been approved in the last year or two, including drugs from new classes. Much of it confirms what we already know about these newer drugs, that they are much more potent, easier to take, with fewer side effects, and they offer hope for many individuals who have never been able to achieve undetectable viral load up until now.
Sharon Walmsley, M.D., Professor of Medicine from the University of Toronto, Canada, gave an excellent oral presentation on Wednesday morning entitled “Management of the Treatment Experienced Patient: The Second Wave of HAART.” In her opening remarks she pointed out that “we all know that 60 is the new 40; in HIV, what I hope to convince you of today is that the treatment-experienced patient is the new antiretroviral naïve patient.”
By looking at results from recent trials over the last few years, and subdividing the trials and comparing the treatment naïve individuals to those who were treatment-experienced, for those with two or three active drugs, the percentage achieving undetectable viral load was roughly the same.
“We treat the experienced patient now exactly the same way that we treat the naïve patient, and it’s funny that it took us this long to learn that.”
Vicriviroc, newest CCR5 inhibitor in development
Barry Zingman of Montefiori Medical Center in Bronx, New York presented data on the Phase 2 48-week trial of vicriviroc (VCV) in treatment-experienced adults. VCV is a small-molecule oral CCR5 receptor antagonist whose plasma levels are markedly increased by CYP3A4 inhibitors (requiring Norvir boosting), resulting in prolonged half-life, once-daily dosing without regard to food, and potent activity in ART (antiretroviral therapy)-experienced, CCR5-tropic patients. (See “Continued Challenges for CCR5 inhibitors” below.)
VICTORI-1 was a multinational trial with 37 sites in 12 countries. 116 individuals were randomized to receive either 20 or 30 mg of VCV or a placebo, plus optimized background therapy (OBT). Everyone received a ritonavir-boosted protease inhibitor (PI) in this study.
Key eligibility requirements for this study included R5 tropism at screening, triple-class experience with at least one NNRTI and one PI mutation, and viral load greater than 1,000. Individuals were stratified to greater than or less than 100,000 VL and T-20 (Fuzeon) use. This study was largely enrolled outside of the U.S. and Europe, in an advanced population with CD4 counts of around 200 and, a viral load of 4.5 log, with 30% having over 100,000 viral load. A minority of individuals in the study had some T-20 or Prezista use. Among the three groups, 23%, 25% and 14% were new to T-20, and 31%, 23% and 16% were new to Prezista in the 30 mg, 20 mg and placebo groups respectively. The majority (82-85%) had less than three active drugs in their OBT. Of 116 randomized participants, 114 received their first dose and are included in intent-to-treat (ITT) analyses. Most patients completed the study. Those who did not finish in the placebo group were mostly due to treatment failure.
There was a substantial reduction in viral load in both VCV 30 and 20 mg compared to placebo (1.77, 1.75 and 0.79 log respectively). In a subgroup that enrolled with viral load greater than 100,000 there was a trend towards improvement in the VCV groups, especially the 30 mg group. Substantially more (60-67%) achieved less than 400 viral load at 48 weeks in both VCV groups compared to placebo (26%), and similar results were seen in those achieving viral load less than 50 (53-56% of those on VCV vs. 14% on placebo) regardless of the number of active drugs in the OBT. As expected, greater CD4 increases were seen in those on vicriviroc (102 and 134 in the 30 and 20 mg groups respectively) than those on placebo (65). There was no significant difference seen in serious and other adverse events for those on vircriviroc or placebo, and no deaths in the study. The primary adverse events were gastrointestinal (GI) and respiratory symptoms (not including respiratory infections).
No seizures or malignancies were reported during the study. Patients were allowed to continue on an open-label continuation phase of VCV after 48 wks. Three months into the continuation phase, one patient developed Hodgkin’s lymphoma. It was noted that the patient’s CD4s never reached above 100 either during the study or afterwards in the continuation phase.
There were no Grade 3 or 4 elevated ALTs in the VCV groups. There were a few Grade 3 and 4 bilirubin events in the study, but all occurred in those also receiving Reyataz. An analysis of the emergence of dual-mixed/X4 virus during the study noted a few more in the 30 mg group and it was suggested that this be followed in larger studies. After the session during Q&A, Dan Kuritzkes, Associate Professor of Medicine and Microbiology at the University of Colorado Health Sciences Center, pointed out that in earlier studies of VCV there was actually more emergence of DM/X4 in those on lower doses of VCV, and cautioned against drawing any conclusions based on the small numbers in these studies. Schering is moving forward with the 30 mg dose in Phase 3 studies.
Another Schering CCR5 inhibitor in Phase 1
Data was presented on a Phase 1 study of a new CCR5 antagonist, SCH532706 (706). Twelve HIV-1-infected individuals received 10 days of 706 (60 mg) twice daily plus Norvir (100 mg) once a day. After 10 days there was a washout period, where they received no antiretroviral therapy for another 14 days, then started on combination therapy.
The mean reduction of viral load at day 10 was -1.3 log. Interestingly the drug had a post-antibiotic effect—a further reduction in viral load from baseline was seen after individuals stopped taking the drug.
The most common adverse event reported was GI upset in about two-thirds of patients, which could have been related to the Norvir in some of those individuals. One serious adverse event— pericarditis (inflammation of tissue surrounding the heart)—was reported and possibly related, occurring around two weeks after the individual had received the study drug and resolving after four days. No emergence of X4 virus was detected during the study.
The drug’s half-life when given with ritonavir is 40 hours, and it has a very slow disassociation from the CCR5 receptor, meaning it may be possible to give this drug once daily.
Once-daily boosted Reyataz more than matches up to Kaletra twice daily in treatment-naive
The CASTLE study is the first large-scale head-to-head study comparing boosted Reyataz to boosted lopinavir (Kaletra) in previously untreated patients. This is an open-label, international, multicenter, randomized 96-week study with 883 participants. Study entry criteria included those with a viral load greater than 5,000 with no CD4 restrictions. One group received 300 mg once-daily Reyataz boosted with 100 mg Norvir (ritonavir), and the other received Kaletra twice daily; both in combination with Truvada once daily.
| “I think the take-home message is that Kaletra, once felt to be the best, is not as effective in patients with advanced disease compared now with these newer protease inhibitors—Reyataz or Prezista.” |
The study’s primary endpoint was met, showing once-daily boosted Reyataz to be non-inferior to twice-daily Kaletra. Similar efficacy was seen in both groups, with 78% in the boosted Reyataz group and 76% in the Kaletra group having an undetectable viral load at 48 weeks.
Similar CD4 increases were also seen between both groups—203 in the boosted Reyataz group vs. 219 in the Kaletra group. To address the issue of response rates in those with advanced disease and low CD4 counts, a post hoc analysis was performed to assess response rates according to baseline CD4 count. The analysis showed that those receiving boosted Reyataz had similar response rates across four pre-specified baseline CD4 categories, while a trend towards reduced response rates in those with a lower CD4 count at baseline was seen in the Kaletra group. Also, of the patients who had viral loads greater than 100,000, there was a larger disparity between the two agents, with Reyataz performing better and Kaletra’s effect not holding as well for patients with high viral loads, (as with lower CD4 count). “This phenomenon was also seen when Kaletra was studied in a similar population in both the ARTEMIS and TITAN trials, where Kaletra’s potency again was not matched by Prezista,” commented Dan Berger, M.D., of Northstar Healthcare in Chicago. “I think the take-home message is that Kaletra, once felt to be the best, is not as effective in patients with advanced disease compared now with these newer protease inhibitors—Reyataz or Prezista.”
Interestingly only 2% of those on boosted Reyataz and 3% on Kaletra discontinued due to adverse events by week 48, the lowest discontinuation rate of any Kaletra study thus far according to presenter Jean-Michel Molina. 26% and 30% experienced some type of Grade 2-4 adverse events in the Reyataz and Kaletra groups respectively, with jaundice the most common AE in the Reyataz group (4%); nausea (8%) and diarrhea (11%) was the most common AE in the Kaletra group. More individuals had elevations in cholesterol and triglyecerides in the Kaletra group as expected, while elevated levels of bilirubin were seen in those on Reyataz. Of note, the capsule formulation of Kaletra (which is associated with a greater number of side effects) was used in the first 48 weeks of this study, and patients were allowed to switch to the newer formulation at 48 weeks.
Kaletra once daily vs. twice daily
Abbott presented 48 week results of study 703 which showed similar efficacy for Kaletra once daily vs. Kaletra twice daily in combination with Truvada in those new to antiretroviral treatment. Similar virologic suppression was seen regardless of an individual’s viral load or baseline CD4 count, with 77% of those on Kaletra once daily and 76% of those on twice daily achieving undetectable (less than 50 copies) at 48 weeks. No protease inhibitor (PI) or Viread-associated mutations were observed in either treatment group.
Isentress at 48 weeks
48-week data from BENCHMRK-1 and BENCHMRK-2, two identical Phase 3 studies of Isentress (raltegravir) in treatment-experienced individuals, were consistent with 24-week data upon which accelerated approval was granted last October. The ongoing studies compare Merck’s Isentress 400 mg twice daily in combination with optimized background therapy (OBT) vs. placebo twice daily plus OBT.
“The results show that after 48 weeks, Isentress in combination with other anti-HIV medicines continued to provide significantly greater antiretroviral activity and increases in CD4 cells compared to placebo with other antiretroviral medicines,” said David Cooper, M.D., D.Sc., professor of medicine and director of the National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia.
In the two identical studies BENCHMRK-1 & BENCHMRK-2, 74 and 71% of individuals reached viral load below 400 copies compared to 36 and 38% of those on placebo, and 65 and 60% achieved viral load below 50 copies compared with 31 and 34% of those on placebo, respectively. CD4 cell counts increased by 120 and 98 for those on Isentress compared to increases of 49 and 40 for those on placebo in the two studies.
Common adverse events in these highly-treatment experienced study groups remained relatively low, with diarrhea, nausea and headache the most common side effects reported at 24 weeks.
Intelence at 48 weeks
48-week data was presented on Intelence (etravirine), a new non-nucleoside reverse transcriptase inhibitor (NNRTI or non-nuke) from Tibotec Therapeutics which was approved in January of this year. The new data showed significantly more treatment-experienced adults with HIV-1 who had documented drug resistance to NNRTIs and protease inhibitors (PIs) reached undetectable viral load (less than 50) with Intelence plus optimized background therapy (OBT) compared to placebo plus OBT.
In the two ongoing Phase 3 studies, DUET-1 and DUET-2, 60 and 61% of those in the Intelence group were undetectable at 48 weeks compared with 39 and 41% in the placebo group, respectively. Mean CD4 increases were 103 and 94 in the Intelence groups, compared with increases of 74 and 72 in the placebo groups.
The most common reported side effects at 48 weeks were rash, diarrhea, and nausea. Rash was generally mild to moderate and usually resolved within 1-2 weeks on therapy; 2% discontinued taking the drug due to rash.
Long-acting TMC-278
Encouraging results were presented on a small Phase 1 study of TMC-278 LA, a long-acting injectable form of TMC-278 (rilpivarine), the second generation non-nuke currently in development from Tibotec. Single doses gave prolonged exposure to TMC-278 for several months, and were well tolerated. TMC-278 LA was injected both intramuscularly and subcutaneously; injection-site reactions were mild to moderate and more frequent in those receiving subcutaneous injections. No serious adverse events or rash were reported.
48-week results given last year from a Phase 2b study of oral TMC-278 showed a greater than 2.5 log reduction in viral load from baseline in treatment-naïve individuals, almost identical to the Sustiva comparator group. The oral TMC-278 program is ongoing, and Phase 3 studies start soon. Should further studies pan out from the nanoparticle formulation, once-monthly injections of TMC-278 LA could possibly achieve the same results as once-daily oral TMC-278.
New data on Pfizer investigational compounds
Data from Phase 1 studies on PF-232,798, a second generation CCR5 antagonist, suggest it is well tolerated in healthy volunteers with a potential for once-daily administration, and Phase 2 studies should start soon.
UK 453, 061 is a second generation NNRTI shown to be effective against virus resistant to first generation NNRTIs and is now moving into Phase 2 study.
Selzentry at CROI
A presentation was given on a sub-analysis from the 48-week results of the MERIT study, which was conducted in treatment-naïve individuals. It suggested that Selzentry (maraviroc), the first-in-class oral CCR5 inhibitor which was approved last year, may have minimal impact on lipids and is at least lipid neutral compared with Sustiva (efavirenz) in this population.
Continued challenges for CCR5 inhibitors
With Selzentry now approved, and vicriviroc and other CCR5 antagonists in development, there continues to be interest around this new class, especially with the immunological benefits seen with these drugs. However, there are still some stumbling blocks that are inherent with the science and not necessarily the drugs, says Dan Berger, MD, of Northstar Healthcare in Chicago.
HIV uses two different co-receptors to attach to a CD4 cell—CCR5 (R5) or CXCR4 (X4). Some people have HIV which uses R5, while some use X4, and others use both (dual/mixed). A tropism assay is required before starting a CCR5 inhibitor to identify which co-receptor(s) your virus uses. Your HIV must be R5-tropic or you will not benefit from taking the drug (around 50% of those with HIV are R5-tropic, and even less for those with more advanced HIV disease).
With the current tropism assay (the Trofile test by Monogram) some studies have shown that dual/mixed tropism later emerges in approximately 5-10% of those who initially test as R5-tropic. “Additionally,” says Berger, “clinicians sometimes consider switching their patients off of Fuzeon or other antivirals to a more patient-friendly medication. However, to consider a CCR5 inhibitor in a patient whose viral load is undetectable, physicians are not able to use the required Trofile since the test requires a viral load of greater than 1,000.” Add to that the high cost of the Trofile test, and the use of this drug class continues to remain limited.
Clinicians are awaiting the arrival of the Enhanced Sensitivity Trofile Assay (ESTA) by Monogram, which was reported on at the conference and should be commercially available sometime later this year. However the more sensitive test will probably still be expensive, and this fact coupled with the same viral load restrictions as the current Trofile test will most likely continue to limit the wide use of this drug class, at least for the immediate future.
Special thanks to Dan Berger, MD for his thoughtful review of this article.
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