This is part one of a three-part article. For part two, Antiretrovirals in Development, click here. For part three, HIV/HAART Complications and HIV Drug Resistance, click here.

Table of Contents

• First-Line Therapy
• Footnotes

I'd like to welcome everyone to The Body PRO's coverage of ICAAC 2007 [the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy], which took place Sept. 17 through Sept. 20 in Chicago, Ill. I'm Bonnie Goldman, Editorial Director of The Body PRO, and I'm here with two of the top HIV clinician/researchers in the United States.

First up will be Dr. Cal Cohen, Research Director of Community Research Initiative of New England and Harvard Vanguard Medical Associates in Boston. He's also a clinical instructor at Harvard Medical School.

First-Line Therapy

Welcome, Dr. Cohen. What did you take away from ICAAC 2007 in terms of breaking research for first-line therapy?

Probably the single-most important study in terms of first-line regimens was a study called ARTEMIS. ARTEMIS was a large study; 689 people in fact were treatment-naive who entered this study, and the only eligibility was a viral load greater than 5,000.¹ The design was straight-forward: Everybody received the same two nucleosides, tenofovir [brand name: Viread; also known as TDF] and FTC [generic name: emtricitabine; brand name: Emtriva], and either lopinavir/ritonavir [brand name: Kaletra; also known as LPV/r] or darunavir [brand name: Prezista; also known as TMC114].

What makes this study novel and important is that darunavir was tested at a new, 800 mg, once-daily dose with 100 mg of ritonavir [brand name: Norvir; also known as RTV], both taken once a day. The lopinavir was typically given twice a day, although, as some of your listeners probably know, in some countries, including the U.S., lopinavir has been approved for use in treatment-naive patients given once a day. So, based on country regulations where the patient is living, lopinavir could be dosed once a day or twice a day. Similarly, the Meltrex tablet formulation happened while this study was ongoing, so approximately 83% of patients who started on capsule had the opportunity to switch to the Meltrex tablet of Kaletra during this study.

The endpoint was the typical one, the percentage whose viral load was less than 50 after a year, with the usual secondary endpoints that we see for other metrics of success, both safety and efficacy. The study population is pretty typical of many of our studies, although 30% were women, which is more than for all of the studies of darunavir. But otherwise it was pretty similar with regard to most of the other criteria: The viral load was around 70,000, CD4s were in the 220 range, and about 13% had coinfection with hep B or hep C.

Now, after a year, one of the findings was that actually very few patients overall discontinued the study during the year. Indeed, only about 12 to 14 to 16% discontinued during the year. There was a small difference favoring darunavir in terms of loss to follow-up or due to adverse event rates, in that 3% stopped this study for adverse events on darunavir and 7% stopped it on lopinavir. Otherwise, it was pretty similar in that about 1 to 2% discontinued for other reasons over the course of the study.

The big news was really virologic. What we saw after a year was that 84% of people on darunavir once a day had a viral load less than 50, in contrast to 78% on lopinavir. Now, lopinavir did quite well at 78%, but darunavir just did a little bit better. So, the statistics of that 6% difference were presented to us.

The point of the study, of course, was to demonstrate that darunavir once daily, 800/100, was not inferior to a standard dose of lopinavir. Indeed, it's clearly not inferior; it's, in fact, 6% better in this study. So the protocol statistics said that if we have shown noninferiority, then let's test for superiority, and that 5½% difference was tested. The P value for superiority was .06, so the study could not prove superiority. But it certainly did clearly suggest that darunavir was at least as good as lopinavir, based on virologic suppression.

It's really the subsets that I think clarified some of the more interesting findings, rather than the overall data. For example, most of the patients had viral loads below 100,000, although about 40% were above 5 log at baseline. For those who entered with viral loads below 100,000, the results were almost identical: 85 to 85% had a viral load less than 50 after a year. For those above 5 log, what we saw was 79% on darunavir versus 67% on lopinavir got their viral load below 50. This difference of 12% was actually statistically significantly different; the P value below .05 certainly suggests that in this particular subset, darunavir once a day could be a better option than lopinavir based on at least these results.

There was also a similar trend for suggesting that more advanced patients did better on darunavir. By CD4 counts, we saw about a 10% difference favoring darunavir for CD4 counts less than 200. Including the subsets less than 50, we saw again that 77% on darunavir versus 67% on lopinavir gained their viral load control. In contrast, above 200 cells, 87 and 84%[, respectively,] got their viral load controlled.

Now, as I mentioned, lopinavir could be used once or twice a day. Some people took once-a-day lopinavir throughout the course of the study; others took twice-a-day. A small number actually switched between once-a-day and twice-a-day, and they were excluded from a particular analysis that looked to explore how much the schedule of lopinavir influenced its results. Overall, while lopinavir had 78% [of its users achieve a viral load of] less than 50, what was interesting was that with lopinavir twice a day 81% had [a viral load of] less than 50, versus on lopinavir once a day on which 71% had viral loads less than 50.

This 10% difference has certainly been seen in at least one other study before, for the difference between twice a day and once a day, based on schedule. Here it is, corroborated a second time, and it is fair to point out that lopinavir twice a day did as well as darunavir once a day; 81 and 84%[, respectively,] getting their viral load to less than 50. Certainly one way to look at this is that darunavir once a day does about as well as lopinavir twice a day. And really, the main concern here was that -- both at high viral load strata as well as with lopinavir once a day -- you do see a difference favoring darunavir. We don't see a difference in terms of CD4 responses; they're essentially identical, as they typically are in studies in which almost everybody gets viral load suppression. The CD4 counts were not broken down further by high viral load strata or other differences I just mentioned.

There was also an analysis of the implications of not establishing virologic suppression, since, while most people did, there were some who did not. There were some cases of virologic failure. So the implications of virologic failure were presented to us. What we saw was that in those patients who had virologic failure, there were, as is typical, very few resistance mutations in these populations. Indeed, no one on darunavir and only one person on lopinavir developed protease resistance mutations; one person on darunavir and two on lopinavir developed nucleoside resistance -- once again suggesting that, as is typical of boosted PIs [protease inhibitors], not only is there minimal PI resistance, but there's also minimal regimen resistance.

I mentioned some of the dropouts due to adverse events at the beginning of the talk. In terms of overall adverse events, it's not surprising that one of the few that were observed was diarrhea, since lopinavir as a capsule was used in some patients during the course of the trial. The rates of grades 2 through 4 diarrhea were 10% for those on lopinavir and 4% for those on darunavir, certainly supporting that the once-a-day darunavir was generally pretty well tolerated. Now there's been a concern for rash on darunavir, because it is a sulfa drug. In fact, only 3% of patients on darunavir developed a rash of grade 2, 3 or 4; 1% on lopinavir did. It was also noted that there were no toxicities in terms of serious renal adverse events, no renal-related discontinuations and, indeed, the creatinine clearance was stable in the two arms for 48 weeks. That's important because obviously this was the use of tenofovir/FTC with the use of either boosted PI.

In terms of other laboratory toxicities, there were very few and they were similar in the arms, with 10% or fewer having a transaminase elevation. Pancreatic amylase and lipase were seen in a few patients, but, again, similar in the two arms. In terms of lipids, what we saw is a difference in terms of triglycerides: 11% on lopinavir versus 3% on darunavir having a grade 2 and above triglyceride elevation. But interestingly, the total cholesterol:HDL [high-density lipoprotein] ratio was essentially superimposable on these two drugs and certainly suggests that both once a day and twice a day on darunavir and lopinavir have similar lipid outcomes overall, except for the triglyceride fraction, which clearly favored darunavir. There was more of a triglyceride bump for those on lopinavir as we might expect from previous studies.

So why did darunavir once a day work so well? The last slide of the presentation was, in fact, that issue. The pharmacokinetics of once-a-day darunavir is sufficient, so that in the population who entered the study, there was a sample done of what's called "population PK," population pharmacokinetics. What was found is that the lowest sample of tame in this population during the course of the trial is still several fold above the C_min target concentration for this drug, suggesting that the dose of 800/100 is sufficient in essentially all of the patients to provide adequate exposure to see virus suppression at the high rates that we did.

Now, of course, that's also true for lopinavir twice a day, as I mentioned, but what we see here is data giving us confidence that this once-daily PI can do very well. It can in fact do as well as our gold standard lopinavir twice a day, and that in contrast, lopinavir once a day may not be quite as successful as we might have hoped from previous studies, although because that high viral load stratification is also there, we'll need additional information to sort out: Was it the high viral load issue? Was it the once-a-day issue? Which issue was it that had resulted in the differences of lopinavir? It's hard to know, [since the data] wasn't broken down further.

Nevertheless, I think what we've got here is great confidence that darunavir once a day is an important treatment option for the protease inhibitor class, even in treatment-naive patients -- certainly to supplement the broad portfolio of studies we've seen in treatment-experienced patients.

How are these results going to play out in the clinic?

Well, I think at this point, darunavir has been used nearly exclusively in treatment-experienced patients, if only because that's where the bulk of the data have been. The POWER studies^16,17 and then the TITAN¹⁴ studies have been in the either heavily PI pretreated or minimally-PI pretreated. Now we've got data in completely untreated patient populations, once again showing that darunavir does at least as well, if not perhaps sometimes better, than our standard-of-care alternatives.

I think that for clinicians who have a patient who's treatment naive, certainly we still have our non-nucleoside class. There's certainly nothing here that makes the protease inhibitors superior to our standard non-nucleoside approaches, but if somebody's looking at initiating a protease inhibitor, I think it's fair to say that twice-a-day lopinavir did well, as did once-daily darunavir. I think if patients are preferring once-daily regimens, we now have another one to choose from. Again, this doesn't discount possibilities still for atazanavir [brand name: Reyataz; also known as ATV] or even fosamprenavir [brand name: Lexiva, Telzir; also known as FPV, 908], but it's certainly in a very large study and gives us confidence that darunavir deserves to be in that conversation.

This is part one of a three-part article. For part two, Antiretrovirals in Development, click here. For part three, HIV/HAART Complications and HIV Drug Resistance, click here.