Treatment Round-up from the International AIDS Conference
New and improved drug information
by Jeff Berry
At this year’s International AIDS conference in Mexico City some useful, longer-term data was presented on FDA-approved antiretroviral drugs and strategies on how to use them, as well as research on drugs currently in the pipeline. While we’re not, at least for the near future, as likely to see as many new blockbuster treatments or novel classes of drugs come to market such as what we’ve seen over the past couple of years, there is still much research being done in both treatment naïve and experienced populations. Following are some of the highlights.
Visit www.kaisernetwork.org/aids2008 for webcasts, podcasts, and transcripts from the conference; view the abstracts at www.aids2008.org.
Treatment-naïve individuals
Sustiva vs. Kaletra
A 48-week non-inferiority study by Madero JS, et al. (abstract TUAB0104) looked at 189 HIV-positive individuals in Mexico with CD4+ cell counts less than 200 who were starting treatment for the first time. The NNRTI Sustiva (efavirenz) went head to head against the PI Kaletra (lopinavir/ritonavir), and once-daily Sustiva was found to be superior to twice-daily Kaletra. Both groups in the study also received Combivir (3TC/AZT), and the soft-gel formulation of Kaletra was used; study participants were allowed to substitute Ziagen for AZT (zidovudine). At week 48, 70.5% of those in the Sustiva group vs. 53.2% in the Kaletra group achieved a viral load of less than 50. CD4 counts increased in both groups, and those with more advanced disease tended to fare better in the Sustiva group. Incidence of grade 2-4 adverse events were comparable in both groups, as were increases in total cholesterol, HDL and LDL, but significantly higher triglycerides were seen in those taking Kaletra.
Two new non-nukes, RDEA806 and IDX899
In several small phase 1 studies in HIV-negative individuals (used in early research before medication is given to people with the virus), data was presented on two second-generation NNRTIs which have demonstrated a potential for high barrier to resistance in vitro. During an 8-day dose ranging of Ardea BioSciences’ RDEA806, a median reduction of viral load from -1.3 to -1.8 log was seen at day 8, and no serious grade 3-4 adverse events were reported. RDEA806 is currently enrolling a phase 2a dose-ranging monotherapy study in HIV-positive individuals using several different doses taken both once and twice daily. Idenix Pharmaceuticals conducted a 7-day dose ranging study of its NNTRI IDX899, with a mean reduction of baseline viral load of around 1.8 log observed. Mild adverse events were reported in those taking IDX899, similar to placebo. IDX899 was studied using once-daily doses ranging from 200–800 mg; planning for a phase 2b study is currently underway. Visit www.clinicaltrials.gov for more information.
PEARLS
A large, phase 4 study of 1,575 treatment-naïve HIV-positive individuals found a significantly greater risk of treatment failure in those taking 400 mg ddI (didanosine-EC, brand name Videx-EC) in combination with 200 mg Emtriva (emtricitabine) and 400 mg Reyataz (atazanavir), all once-daily, compared to those taking Combivir (zidovudine/lamivudine) twice-daily plus Sustiva (efavirenz) once-daily. The Videx-EC/Emtriva/Reyataz treatment group was discontinued due to inferiority back in May 2008 after a planned, interim analysis by its Data Safety Monitoring Board (DSMB). The study, known as ACTG 5175, or PEARLS (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings), also contained a third group receiving Sustiva plus Truvada (Emtriva/Viread), both once daily. The two Sustiva-containing arms of the study will continue, following a comparison of the two groups which was inconclusive.
Norvir film-coated vs. soft-gel
A small, single-dose PK study of 93 HIV-negative individuals compared the newer film-coated, heat-stable Norvir (ritonavir) tablet to the currently available soft-gel capsule and found both formulations to be generally well tolerated and no differences in adverse events, with both achieving similar blood concentrations, meeting the criteria of bio-equivalence.
Boosting 2.0—PK enhancers
Almost all protease inhibitors (PIs) are taken with a Norvir booster, especially in treatment-experienced individuals. The booster allows more of the PI into the bloodstream, resulting in smaller doses and fewer side effects. Many pharmaceutical companies are racing to become the next to bring a boosting compound, or “PK enhancer,” to market, but it is most likely still several years away. Only time will tell if these PK enhancers will be released first as a stand-alone booster to compete with Norvir, which is currently the only boosting compound available, or in a co-formulation with another compound(s) in an effort to compete with the appeal of Abbott’s Kaletra. One would hope that they would both occur simultaneously. Gilead’s GS9350, a PK enhancer currently in development, has no antiviral activity (unlike Norvir) which is good news (in that it should not have any potential for contributing to HIV resistance). Nor does it seem to have the dreaded gastrointestinal side effects of Norvir. All of this is ultimately good news as the next phase of HIV treatment unfolds. Advocates continue to push for companies to find ways to work together, such as with the groundbreaking partnership of Gilead and Bristol-Myers Squibb in the development of the blockbuster co-formulation of Truvada and Sustiva, found together in the once-a-day pill Atripla.
| All of this is ultimately good news as the next phase of HIV treatment unfolds. |
Rilpivirine (TMC278) at 96 weeks
A 96-week phase 2 dose-ranging study in antiretroviral-naïve individuals of the next-generation NNRTI rilpivirine (TMC278) found it to be effective and well tolerated. Rilpivirine (TMC278) taken once daily in combination with two NRTIs was associated with a high sustained response rate, comparable to Sustiva plus two NRTIs. More rash (21% vs. 9%), nervous system disorders (48% vs. 31%), and neuropsychiatric adverse events (21% vs. 16%) were seen in those taking Sustiva compared to rilpivirine, and fewer lipid abnormalities were seen with rilpivirine versus Sustiva. QTc interval (a measure of time in the heart’s electrical cycle) increased (or was prolonged) in all study arms (both rilpivirine and Sustiva) through week 48, and then plateaued. QTc prolongation was lowest with the 25 mg per day dose, and phase 3 trials of rilpivirine with the 25 mg once-daily dose are ongoing.
Isentress at 96 weeks
96-week data from a head-to-head study comparing the integrase inhibitor (INI) Isentress (raltegravir) to the NNRTI Sustiva (efavirenz), both in combination with OBT (optimized background therapy) in those taking therapy for the first time, showed those in the Isentress group had sustained viral suppression comparable to those in the Sustiva group. Adverse events were comparable between groups, with drug-related adverse events more common in the Sustiva group. Continued forthcoming data from treatment naïve studies of Isentress as well as other newer agents in combination will become even more important as they each battle for their positions in the strategy of first-line treatment of HIV. Ten years from now it may be an entirely different ballgame—instead of two nukes plus a boosted PI or NNRTI, we may be looking at an INI plus a PI or other possible nuke-sparing regimens for first-line treatment of HIV.
Treatment experienced
Prezista plus Intelence
A 48-week pooled, sub-analysis of DUET 1 & 2, which are two identical, parallel studies looking at boosted Prezista (darunavir/ritonavir) in combination with an optimized background regimen (OBT) plus either Intelence (etravirine) or placebo found that those in the Intelence group had a significantly higher rate of viral suppression than those in the placebo group (61% vs. 40%). The planned analysis of this 96-week study also demonstrated that virologic response was not significantly predicted by gender, race, or previous use of Viramune (nevirapine). However, the number of previous NNRTIs used did predict response to Intelence, with 67% of those on Intelence who had used one NNRTI reaching undetectable (viral load less than 50), compared to 58% of those who had used two or more NNRTIs.
Another DUET 1 & 2 sub-analysis found that those who had favorable combined resistance profiles for both Prezista and Intelence were predicted to have a higher virologic response rate at 24 weeks. These were multiclass-experienced patients receiving Intelence and Prezista/ritonavir plus optimized NRTIs who were not first-time users of Fuzeon. This sub-analysis used a weighted resistance score, which basically assigns a numeric value based on the resistance-associated mutation (RAM). While this is a more complicated method, it reduces the discrepancy between genotypic and phenotypic (two types of resistance test) scores.
Intelence in EAP; updated safety on Intelence
A sub-analysis of an open-label early access program (EAP) in the U.S. and other countries found that in the U.S.-based EAP, Intelence-containing regimens were associated with virologic response rates greater than 60% in treatment-experienced patients with limited treatment options at 24 weeks. When use of Intelence was combined with multiple agents, including Isentress and combinations of Prezista/ritonavir and Isentress, there were few discontinuations due to adverse events, and similar efficacy was observed across groups, including those receiving Prezista/ritonavir and/or Isentress.
Also in the DUET studies, rates of neuropsychiatric adverse events were similar in those taking Intelence compared to placebo, regardless of an individual’s previous psychiatric history, and no effects from Intelence were seen on the development of fetuses in rats and rabbits.
In related news, one case of hemarthrosis (bleeding into the knee) was recently reported by the U.S. Food and Drug Administration (FDA) in an individual using Intelence, as the agency began reporting of new drug safety evaluations this past summer. However, a drug’s inclusion in the report does not mean the FDA has concluded that there is a risk (see News Briefs).
Prezista/r + Intelence + Isentress
A phase 2 study (TRIO) of 103 HIV-positive treatment-experienced individuals with advanced HIV infection and multi-drug resistance found the combination of boosted Prezista (darunavir/ritonavir), Intelence (etravirine), and Isentress (raltegravir) to be highly active at 24 weeks (90% achieved viral load less than 50). There was a median CD4 increase of 99, and the regimen was generally well tolerated. There was an overall low rate of serious adverse events reported, although there were two possibly drug-related clinical grade 4 adverse events, one of which was rash/fever and led to discontinuation of treatment. Physicians continue to report seeing patients achieve undetectable viral loads for the first time ever when combining many of these recently approved newer agents.
Switching from Fuzeon to Isentress
In several studies of heavily treatment–experienced individuals on stable Fuzeon-based therapy who replaced Fuzeon with Isentress, 94-96% maintained undetectable viral load (less than 50) and immunologic control. Patients reported greater satisfaction in treatment, and there were few adverse events, with three case reports of hepatic cytolysis (breakdown of liver cells) after switching from Fuzeon to Isentress in men receiving Aptivus/r (tipranavir/ritonavir) plus Isentress.
| In several studies of heavily treatment–experienced individuals on stable Fuzeon-based therapy who replaced Fuzeon with Isentress, 94-96% maintained undetectable viral load (less than 50) and immunologic control. |
Selzentry entry inhibitor
In sub-analyses of MOTIVATE 1 & 2, two double-blind, phase 3 studies of 1,076 individuals using entry inhibitor Selzentry (maraviroc) plus OBT, superior outcomes were seen at 48 weeks compared to those using placebo plus OBT in patients with R5-tropic virus. In both TCR (triple-class resistant) and non-TCR subgroups, significantly better virologic and immunologic outcomes were seen in the Selzentry groups versus placebo, as well as early and greater increases in CD4+ cell and CD8+ cell counts.
Apricitabine
24-week data from a phase 2 study of apricitabine, a novel nucleoside (NRTI), showed it to be safe and very well tolerated in combination with other ART, and if approved should be a good second-line choice for treatment-experienced individuals.
Thanks to Dan Berger, M.D. for his review of this article.
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