September 20, 2007
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.
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 Cmin 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 studies16,17 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.
Antiretrovirals in development, I think, was the real story of ICAAC 2007. Can you discuss some of the highlights?
Sure. We saw new information about novel classes, as well as new drugs in familiar classes. Let's start with one of the big studies in the field, the study called DUET that evaluates the new non-nucleoside [NNRTI] called etravirine [also known as TMC125] in treatment-experienced patients. This study, DUET 1 and DUET 2, was combined here, and so we saw a combined analysis of roughly 1,200 people who participated in these two randomized studies.2
The design is a simple one: it's etravirine or a placebo, with a background regimen containing darunavir, optimized nucleosides, and the option to use enfuvirtide [brand name: Fuzeon; also known as T-20]. The key to this study, of course, is that etravirine is being developed for non-nucleoside resistant virus, and so patients had to have a history of, or, at that time of entry, evidence of, resistance to the non-nucleosides. Otherwise, patients were also eligible because they had at least three or more primary protease mutations, suggesting that this was a pretty heavily pretreated population.
In terms of demographics, this study involved mostly men, 90% males, about 70% of whom were white. Their viral loads were pretty high, 4.8 log, and their CD4s were pretty low, around 100 cells ... not surprising for a triple-class-experienced patient population with at least three protease mutations.
Of interest is that about half of the patients used enfuvirtide on this study, although only about a quarter started enfuvirtide for the first time while on this study. Also of note is that a fair number of patients had a regimen that was pretty compromised, meaning that when we look at the optimized background, about 16 to 17% had no other fully active antivirals in their background regimen, and that it was either etravirine or placebo with a compromised background for that small subset.
Nevertheless, despite these advanced patient populations, etravirine did exactly what it was designed to do. It improved the response rate by about 50%, meaning it was a 41% response rate without etravirine and 59% with it. So, 40 to about 60 means an improvement by about 50%.
Not surprisingly, the change in viral load out to week 24 was also considerably more, statistically more, by about .7 log on the etravirine versus the placebo arm.
Similarly, there was a CD4 benefit of around 20 cells -- a difference that became clinically significant, not just statistically significant, as we'll get into in a couple of moments.
The virologic suppression was actually kind of interesting, particularly with regards to the question around using enfuvirtide. In recent analyses of this study, what was noted was that etravirine clearly demonstrated activity in the patients who did not have fully active enfuvirtide. In the subset [of patients], for example, who either recycled enfuvirtide or didn't use it all, etravirine clearly improved the response rate. It went from about a third to just over a half of the patients who got their viral load suppressed to less than 50 at week 24.
But in the subset of people who used enfuvirtide for the first time, when the data were presented for the first time in the Sydney conference [the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007)], we saw similar numbers: about 65% on average in the two arms who had viral load suppression. And then we didn't see the additional benefit of etravirine, if enfuvirtide was used in the regimen. So the statisticians were asked to help us understand this, since [we were interested in finding out] where is the effect of etravirine. Just because enfuvirtide's there, this doesn't mean etravirine becomes inactive. What explains this?
It turns out that, by chance, there was an explanation, in that in those patients who got etravirine, they also had, just by chance, more compromised darunavir. Again, recall that everybody took darunavir in this study. By chance, more of the people who were assigned to get etravirine had higher phenotypic resistance to the darunavir. When that difference is adjusted for, what we again see is the statistical advantage for using etravirine versus the placebo, in that what we saw was about a 10% improvement, 11% improvement, in the response rate of etravirine, or no etravirine, in those patients who had enfuvirtide in their background regimen. This is consistent with what we've learned for, again, several years now -- which is, it's not just picking active drugs; it's picking active regimens.
Overall, what we saw is that the use of etravirine was clearly, dramatically important in the subset of people who had no fully active drugs -- active is, again, determined by phenotypic score, suggesting that the drug was not fully active. It's actually pretty impressive that, for the subset of people who had no fully active drugs and who received the placebo arm, only 8% got their viral load to less than 50. But for those on etravirine and that same compromised background regimen, 45% got their viral loads to less than 50 ... not something we would have expected from a non-nucleoside in a non-nucleoside resistant population, and a dramatic difference illustrating that this is not just the typical non-nucleoside with a fragility in a compromised background, but certainly a much more durable response.
Nevertheless, as we added additionally active drugs, we got a better response. We're up to a 60% [response] with one additional active drug, and we're up to 74% for people who have two or more active drugs.
This issue with, of course, new drugs in existing classes is that there can be resistance mutations that confer cross-resistance to new drugs, like etravirine. Etravirine's no exception. There are, in fact, 13 non-nucleoside resistance mutations that can confer resistance to etravirine. The impact of those was again reviewed in this presentation. In the subset of people who had none of these etravirine-associated mutations, 75% of them got their viral load to less than 50. In contrast, if somebody had three or more etravirine mutations, their response rate went down to 41%, or less. Again, consistent with what we understand, which is: This is a great drug for the right person, but, unfortunately, there are resistance mutations that can impact its response.
Thankfully, in the population, at least, that enrolled in DUET, only about 16% of the patients had three or more etravirine relevant resistance mutations, suggesting that these mutations are not common in the population.
Now, I mentioned earlier that the CD4 count was clinically significant, not just statistically significant. How we learned that was a pretty unique presentation that we don't see with most of these studies, but with 1,200 patients you can learn some additional findings.
One of the things that, of course, we're trying to do is to not just change numbers, but help people stay healthier. And in as little as 24 weeks, there was evidence that people were, in fact, healthier. In the overall population, there was a trend of reduced numbers of AIDS-defining illnesses or death in those who got etravirine versus no etravirine. When they looked at the subset of people who were in some ways the most in trouble -- the subset who either did not use enfuvirtide or had recycled enfuvirtide, the subset of people who were the most in trouble clinically -- then there were statistically fewer clinical events in the subset who got etravirine versus placebo. It was 3.8% on etravirine and 8.3% on the placebo arm who developed some clinical illness, even in as little as 24 weeks. It was a highly significant finding, not just for statistics, but for patients.
What are the downsides to these drugs? What are the cautions? Well, really, the only one that was identified is [the incidence of] rash in about 8% of patients. There are no nervous system disorders, as we see with other drugs like efavirenz. There were certainly no abnormal dreams reported in any difference versus placebo, and no difference in hepatic adverse events, as we see with other non-nucleosides, like nevirapine [brand name: Viramune; also known as NVP]. The rash is worth some attention, since it happened at a rate of 8% greater on drug versus placebo. As was true with most of these drugs, the rash typically happens in week 2, and typically lasts for about two weeks. Thankfully, the rashes were grades 1, 2 and 3. There were no grade 4 rashes, meaning no Stevens-Johnson. Two percent of patients did discontinue permanently, but most of the other patients could treat through their rash.
Of interest is that the rash incidence occurred at a rate that was higher in women, but the severity or discontinuations are similar by gender. For whatever reason, it's just more common to have a rash in women than in men. The rash was not associated with CD4 counts or other characteristics of our patients, nor was there evidence that it was a higher rate in people who had a history of non-nucleoside rash.
So, etravirine looks like a very important drug. While it's not yet approved, it is available in expanded access protocols. And clearly, the use of etravirine certainly improved the response rates and, depending on the activity of the regimen, what we can see is consistent relevant activity with etravirine, of course, realizing that there are, unfortunately, some percentage of patients who will have too many resistance mutations to take advantage of this drug. Thankfully, the majority of patients -- as I mentioned, 86% -- have less than three mutations conferring resistance. So this drug looks like it will be an important drug for people with a history of non-nucleoside resistance.
When is it expected for this drug to be approved?
As we understand it, it will be sometime -- obviously the FDA [U.S. Food and Drug Administration] has to review the data, but if the data continue to be as good as the data shown here, it would have to be sometime next year, since certainly the FDA has not had a committee meeting about this drug. So, odds are good it's going to be sometime in 2008.
We will now focus on the integrase inhibitor data for treatment-experienced patients, if for no other reason than we certainly are seeing a lot of enthusiasm for this class, based on the results of Merck's BENCHMRK trial, illustrating just how interesting these integrase inhibitors can be in the treatment-experienced populations.3,4
But the interest in these drugs actually started about a year ago at ICAAC, at ICAAC 2006 [the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy], when we saw the first 24-week results of raltegravir [also known as MK-0518] in a highly treatment-experienced population from a study called Protocol 005.5 Here at this meeting, we saw the 48-week results of that population.6
The results were essentially the standard dose finding result in a phase 2 design. It was randomized and double blind. Patients got either placebo or one of three doses of raltegravir with an optimized background regimen. To be in this study, people had to be, again, triple-class experienced and use an optimized background regimen in this study.
There was a 24-week, double-blind phase. Then afterwards, there was an open-label phase, in which patients could -- if they did well on raltegravir -- remain on an open label. There was also a crossover for people who were on the placebo arm if they had virologic failure -- or in the raltegravir arms, certainly had access to raltegravir, as well.
It's a phase 2 study, which means that there are about 43 to 45 people per arm. This was again a dose finding study. What we learned from it was consistent with what we saw in BENCHMRK. Those who enrolled into this study were, again, the typical patients who were triple-class experienced. Their CD4 is at 200. Their viral loads are around 4.6, 4.7 log -- around 50,000 [copies/mL]. These patients had a lot of resistance. For example, in terms of their phenotypic susceptibility score -- again, demonstrating a lack of complete activity -- about half of the patients had an optimized background regimen with no fully active drug in the regimen other than raltegravir, or the placebo, suggesting that most of these patients really had a lot of resistance to contend with.
Nevertheless, raltegravir did dramatically improve the response rates, certainly to less than 50. Somewhere around 50% to 60% of patients, even a year later, had viral loads less than 50, in contrast with the placebo arm, in which about 10% had their viral loads suppressed to less than 50. So, a dramatic illustration of this drug.
In order to also understand the durability of response, they presented a Kaplan-Meier. The Kaplan-Meier curves illustrate quite nicely that, if we look at who failed on raltegravir, most of the virologic failure seems to occur in the first 24 weeks. Meaning, if your viral load got to less than 50 by week 24, you typically seemed to stay there, although they certainly didn't break it down as precisely as we might, to answer that question of: How predictive is less than 50 at any given week?
Nevertheless, if there was virologic failure on raltegravir -- and there was in about 30% to 40% of the patients -- it seemed to happen usually in the first 24 weeks, after which failure was much less likely. Not surprisingly, the CD4 response was also much better on raltegravir, about a 100-cell bump, versus almost no change on the placebo arm.
If somebody didn't respond to raltegravir with virologic suppression, as about 30% didn't, there was raltegravir resistance. Indeed, of the 38 people who had virologic failure, almost all of them had integrase resistance. There's one of two pathways that will tell you where resistance has -- it's what's called the 155-pathway or the 148-pathway.
In fact, at the time the samples were analyzed, most patients had two or more resistance mutations, suggesting that this drug is either fully active in a good regimen, or can select for resistance in nonsuppressive regimens. Not surprisingly, the factors that predict resistance or suppression are: how active is your regimen -- the PSS [phenotypic susceptibility score]; did you use enfuvirtide or not, for example; and your viral load -- low viral load patients typically, once again, have a better chance of achieving [suppression] than do people with high viral loads in this and other studies.
The safety of the drug looks very good, however. There were very few patients who had increases in transaminases. There was one or two overall in the raltegravir arm, with very few other toxicities identified in the overall study. So the drug, certainly for 38 weeks in these patients, looked very well tolerated. Indeed, certainly as well tolerated as placebo for a lot of the toxicities that we look at, such as GI [gastrointestinal]-related, headache, fatigue, and so on. It looked pretty similar to what we see on placebo.
There were also no signals of problems of malignancies, as was seen in the BENCHMRK trials. Certainly sick patients can develop malignancies, but there was no evidence from this trial that there's any important rate of malignancies, and certainly nothing different than what you might expect from this patient population.
What we can easily conclude is that this is an important drug, and if used in combination with a good regimen, the majority of patients can achieve virologic suppression to less than 50. In this study, about half the patients did, but certainly that half was based on how compromised their regimens were. As we define more and more successful combinations, we will see more patients having virologic suppression.
That was the theme of the Gilead integrase. Their drug, called elvitegravir [also known as GS 9137], was presented to us for the first time at the retrovirus conference in early 2007 [the 14th Conference on retroviruses and Opportunistic Infections (CROI 2007)].7 They delved into the study data for us one more time to help us understand this drug, as well as the importance of a good background regimen.8
The design of this trial is very different; again, it's a dose finding study, with 60 to 70 people per arm. The design of this is very different. These are triple-class experienced patients who are randomized to either elvitegravir, one of three doses, or a comparative PI. There was no protease inhibitor used in the elvitegravir arms. In this case, the background regimen consisted of nucleosides with or without T-20; non-nucleosides weren't even allowed. This was an assessment of elvitegravir versus comparative PIs.
Interestingly, about half the patients chose darunavir, a quarter took tipranavir [brand name: Aptivus; also known as TPV], and the other quarter took other PIs that were available, such as lopinavir.
So what did we see in this study? What we saw in this study is exactly what we'd expect to see. The first finding, however, was unexpected, which is that the use of elvitegravir for the first 24 weeks was actually more successful than protease inhibitors. Indeed, the elvitegravir regimen got the viral load about a log lower than did the protease inhibitors. So, whether you looked at the viral load out to week 24 or to week 16, the overall results were -- particularly in the subset of people who had the use of T-20 during this study -- patients had virologic suppression that was a log better on elvitegravir versus a comparative PI. Again, not surprising: a new drug in a new class doing better than a new drug in an existing class.
Probably the single analysis that had the easiest way to summarize this data was an analysis by the background regimen. When we presented the analysis of the best dose, or at least the highest dose (the 125 mg dose), out to week 24, the percentage who got to less than 50 was clearly determined by how many active drugs were given with the raltegravir. For example, if raltegravir was given as essentially functional monotherapy -- no other active drugs -- 15% achieved less than 50 copies at week 16. If they had an active nucleoside, 30% achieved less than 50. Two or more nucleosides achieved up to 44%. If somebody got enfuvirtide for the first time -- a fully active enfuvirtide plus a fully active elvitegravir, with or without nucleosides -- we're up to 74% who achieved less than 50.
Interestingly, that 74% response rate shown here is remarkably similar to what was seen in the BENCHMRK trials,3,4 in which the combination of raltegravir and enfuvirtide certainly got the vast majority of patients to less than 400. Certainly, if we kind of subtracted the numbers that might be different between 400 and 50, we see remarkably consistent findings here in which the vast majority of patients can get to less than 50 copies with the use of two new drugs in two novel classes.
So I think what we've got now is evidence that we've got two active protease inhibitors, one of which has obviously completed its phase 3 studies, and the other of which a dose has been identified that could now be brought forward into phase 2/3 testing.
So we've got yet another class of drugs now to work with in our field: the CCR5 inhibitors, maraviroc [brand name: Selzentry; also known as MVC] being the first FDA-approved drug in this class. Now, at this meeting, we saw the 48-week results of one of the two pivotal studies for this drug, called MOTIVATE.9
MOTIVATE studied maraviroc or placebo in treatment-experienced patient populations. The design is typical for treatment-experienced studies; it's maraviroc (in this study, either once a day or twice a day was tested) versus placebo in a triple-class experienced population. Of note is that this study was also perhaps a bit hampered by the fact that darunavir was not used in this study because of how long ago this study was done versus the availability of darunavir, and tipranavir was used in only 10% of patients. So the background was perhaps not as active as it might be at the current time, given changes in background regimens.
We do, however, see evidence that maraviroc is clearly an important drug. Particularly the twice-a-day, which was FDA-approved. Even after week 48, there was an additional log suppression associated with the use of maraviroc versus placebo, and we've got two to three times as many people whose viral load is less than 50 with maraviroc than without. For example, at week 48, 16% on placebo had a viral load less than 50 while 47% (46.8 to be exact) on maraviroc had a viral load less than 50 copies. Again, supporting that this is an important drug, perhaps a two- to three-fold improvement in response rates, even with a relatively compromised background in terms of the protease inhibitors that were available in this study.
Again, not surprisingly, there's a good CD4 response: about a 70-cell difference favoring maraviroc at the twice-a-day regimen.
But of course the baseline viral loads do influence response. What they saw was for patients whose viral load baseline was below 100,000, 60% got to less than 50. In contrast, if somebody had a viral load over 100,000, only 30% did, once again illustrating how important the entire regimen is going to be for these very high viral load patients, and certainly the reason why it's so good that we have so many active drugs in our field at this point in time. For example, they illustrated this point by looking at the enfuvirtide data. When patients used enfuvirtide for the first time in this study, 60% to 64% of them got their viral loads to less than 50. In contrast, if someone didn't used enfuvirtide or recycled it, then only 30% got to less than 50, illustrating once again just how important it is to have an active regimen, not just single active drugs.
The great news for maraviroc continues to be not just how well it works, but how well it's tolerated. There doesn't seem to be all that much difference from placebo overall, in terms of adverse events, in terms of subjective toxicities. There [was a slightly larger percentage] of people who had some upper respiratory tract infections and a cough, but certainly not more than that, and [it was only a difference of a few percent]. There was no evidence of an increase of AIDS-related events, and certainly very little evidence of differences in LFT increases. There were a couple of grade 3 ALT [alanine transaminase] increases on maraviroc versus the control, although we were reassured by the presenter, Jay Lalezari, that in MOTIVATE 2, the companion trial, that the results were in fact the opposite, that there weren't increases in transaminases.
The last point, which was the focus of not just one presentation, but in fact two, is that an important concern for this class is not just response rates, but what are the implications of not responding.
First of all, if you're using an R5 inhibitor, what is going to happen in patients who don't respond? We've learned for some time now that what we're going to see typically are viruses that are dual/mixed or X4 tropic.10,11 Indeed, in this study in the maraviroc twice-a-day arm, about two thirds of the patients who rebounded did so with a dual/mixed-tropic virus population.12 Again, recall that everybody in this study had to have CCR5-tropic virus to be eligible at baseline, but at the time of failure, two thirds of the patients emerged with dual/mixed virus. We understand this to be essentially because at baseline people have dual/mixed virus. Even in patients who are screened, they may have some small amount of dual/mixed virus that is hidden among their viral population. If you use an R5 inhibitor and it's not fully suppressant, it's the dual/mixed virus that has the advantage.
Then the question is, so what, does it matter? The good news so far is that at least at the time of failure, people who rebound with R5 populations seem to have a pretty good CD4 response as a result of their participation in the study. In one analysis, they have about a 100-cell bump on maraviroc, even at the time of virologic failure. If somebody emerged with dual/mixed virus, they still have a pretty good CD4 response, though the CD4 response in that case was not different from placebo. Nevertheless they certainly didn't have any evidence of harm as a result of rebounding with a dual/mixed population. It was just no better than the placebo group, in that particular case.
That's been a concern for a while: If we unmask the dual/mixed virus, will we then cause some destruction of CD4s? So far, the news is reassuring in that we don't; we may not get the benefit of R5s, but we certainly don't seem to be creating harm, at least in the short-term of these studies.
So what we've learned so far is that maraviroc looks like an important drug. In these treatment-experienced populations, it provides substantial activity in an R5-screened population. Once again, we have another opportunity to take a pretty easy drug to work with and create a good regimen around it.
So we're getting reassuring news of some of the drugs that are in phase 2/3, and some good news that there continues to be a pipeline behind these drugs.
I'm here now with Dr. Eric Daar, Chief of HIV Medicine at Harbor-UCLA Medical Center in Los Angeles, Calif., and a professor of medicine at the University of California-Los Angeles' David Geffen School of Medicine.
Welcome, Dr. Daar. Could you talk a little about some of the more interesting presentations on HIV drug resistance at ICAAC 2007?
Yes. I think there were a couple of presentations of particular interest, related to drugs that are currently available. In particular, there was an additional analysis from the TITAN trial.13 Many remember, this was a study that was published over the summer in Lancet14 and presented for the first time at the International AIDS Society meeting15 in Sydney. This was a randomized, controlled trial with treatment-experienced patients who were lopinavir/ritonavir [brand name: Kaletra; also known as LPV/r] naive, who were then randomly assigned to a regimen that either included lopinavir/ritonavir or darunavir [brand name: Prezista; also known as TMC114]/ritonavir [brand name: Norvir; also known as RTV] at the standard, twice-a-day dose that's currently approved.
This was an opportunity to look at how these two ritonavir-boosted PIs [protease inhibitors] compared directly, head-to-head, as opposed to in the original POWER16,17 trials with darunavir/ritonavir, which just compared it to a comparator PI that was selected by the investigator. They attempted in the study to pick out a group of people who were likely to be susceptible to both drugs by making them lopinavir/ritonavir naive.
As you may recall, the results of this study were that they were able to demonstrate the noninferiority of darunavir/ritonavir to lopinavir/ritonavir. In fact, in that secondary analysis, they showed that darunavir/ritonavir was actually superior, for the primary endpoint, to lopinavir/ritonavir.
The difficulties in interpreting the study were that there was a little bit of an imbalance at baseline, in that there were more people who had resistance in the lopinavir/ritonavir arm to the assigned PI than in the other arm. And certainly, this could have influenced the results and is a limitation of the study, because, in general, in clinical practice, we would have resistance data. We wouldn't use a drug in which there's resistance if we had alternatives.
So there was this modest difference. What they looked at in this particular follow-up analysis was to further define the amount of resistance that emerged in the people who experience virologic failure. They looked at baseline resistance patterns, and then looked at it over time. What they showed was that there was more new resistance to both nucleosides and the protease inhibitor class in those who receive lopinavir/ritonavir than in those who receive darunavir/ritonavir.
Now, part of this, one might argue, is related to the fact that there was more baseline resistance in the lopinavir/ritonavir group. They attempted to adjust for that by narrowing the analysis to those who had less than 10-fold resistance to lopinavir/ritonavir -- a population of people that, based on the phenotype, we would consider using that drug in during the clinical trial or in clinical practice. They found, even in this group, that there was still a difference in the number of new mutations that occurred in the patients who were on lopinavir/ritonavir rather than on darunavir/ritonavir.
There are limitations to the analysis, as far as the ability to look at specific mutations, but at least it does suggest that, within the one group, there's less new resistance than in the other. How ultimately we use this in clinical practice, I think, is that we'll still rely very heavily on genotypic and phenotypic data to pick which protease inhibitor to include in the optimized regimen, recognizing that, in this particular study, both arms did very, very well, despite some imbalances.
Another study of interest related to non-nucleoside resistance sort of deals with the issue of how to stop people on therapy that includes NNRTIs [non-nucleoside reverse transcriptase inhibitors].18 Now, the problem here is that we have generally told people in the past that if they are going to stop therapy, they should stop all the drugs at the same time. But we have come to appreciate that NNRTIs, both efavirenz [brand name: Sustiva, Stocrin; also known as EFV] and nevirapine [brand name: Viramune; also known as NVP], have very long half-lives and, in fact, can have levels, inhibitory levels, present in the blood for days, or even several weeks after stopping the drug. The concern is that if they stop a regimen of two nucleosides and an NNRTI all at the same time, after about 24 to 48 hours, the nucleoside levels are down, but the NNRTI levels persist. That could very quickly select for high-level resistance to NNRTIs. In fact, there's clinical data showing that this does happen in some people who stop all of their drugs simultaneously when one of those drugs is an NNRTI.19
Based on that, there's not a lot of clinical data to guide what investigators or clinicians should do in this setting. What's been proposed is that we switch people from the NNRTI in the regimen to a protease inhibitor, continue them on their nukes and protease inhibitor for several weeks or a month, and then stop all of them at the same time, so that the NNRTI is out of the system.
Another strategy is to somehow cover the extended levels of the NNRTI, while continuing the nucleosides. Some people have proposed that what we should do if we're going to stop therapy in a controlled way is to stop the NNRTI and continue the nucleosides for some period of time, and then stop them with the hope that by the time you stop the nucleosides, the non-nucleoside levels will have declined to below those that are clinically relevant.
But as I mentioned, there's not a lot of clinical data. So the TI [treatment interruption] group, who performed a CD4-guided treatment interruption study, went in retrospectively and analyzed the subset of patients who were on NNRTIs, either efavirenz or nevirapine, and who then stopped therapy because their CD4 cells were sufficiently high for the protocol, and then needed to restart. That allowed the investigators the opportunity to determine if there was indeed resistance to NNRTIs prior to restarting therapy, as well as whether they had adequate suppression. And in the protocol, in the absence of data, what they recommended was that people continue the nucleoside for seven to 10 days.
So one of the strategies that we have actually suggested might work was tested in this study. What they found was, there were 43 individuals who met that criteria of having stopped an NNRTI, with the continuation of the nucleosides, as outlined in their protocol, and then restarted. They found that none of these people had evidence of resistance at the time they were about to restart therapy, and 100% of the patients re-suppressed on a non-nucleoside-containing regimen.
Again, there are limitations to this study. There was no control group. We don't know that they wouldn't have all behaved the same way had they not had nucleosides for seven to 10 days, but at least it's some clinical data that suggests that this might be a viable strategy.
Could you talk a little bit about renal complications in HIV-infected patients? I know there were some presentations about this at ICAAC 2007.
Investigators continue to try to look at this very carefully, because there have been case reports and case series of tenofovir [brand name: Viread; also known as TDF]-associated renal disease. We are using this drug commonly now, and for long periods of time, so it's important to look at it very carefully. We also recognize that, at least in the clinical trials, they often systematically exclude people who are at high risk for renal disease, or particularly have underlying renal insufficiency.
There were two groups at this meeting that looked at cohorts that try to identify and select out people who were at that high risk. One of them was a group from the University of Maryland,20 where they have a high-risk population, largely African-American, who we know are at higher risk for many of the comorbid conditions associated with renal disease, like diabetes and hypertension, as well as HIV-associated nephropathy. And, indeed, some of these people did have diabetes and hypertension.
They looked at two populations: a population of about 150 people who received tenofovir-containing regimens; and 68 that received abacavir [brand name: Ziagen; also known as ABC]-containing regimens. Then they followed them over time. It turned out that at the baseline, there were some differences between the two groups. In particular, the people who received tenofovir tended to be a little bit younger, and they actually had somewhat higher glomerular filtration rates -- about 10% higher at baseline.
They followed them over time, and what they found was that there was about an 8 to 10% reduction in glomerular filtration rate amongst those who received tenofovir, compared to abacavir. Most of the reduction occurred very early, and there were very few. In fact, four out of 149, or 3%, of the patients in the tenofovir group actually discontinued therapy due to a decrease in glomerular filtration rate, versus none of the group of abacavir-treated patients.
I think this study, like others, shows that there probably is effect, and in fact, it's real. But it tends to be modest and probably is only clinically relevant in a very small proportion of people. The take-home message is that we continue to need to use this drug carefully and monitor our patients' renal function.
Now, Ben Young presented data from the HOPS cohort, also trying to identify a unique population of patients that were particularly high risk.21 Recognizing the limitations of previous studies, they looked towards the HOPS cohort, which is the HIV Outpatient Study, and they identified people who had low glomerular filtration rates or significant renal disease in the past, or presently. They found 19 people that fell into their criteria[: six of whom had past renal insufficiency, defined as having a creatinine of less than 1.5 or a creatinine clearance of over 50, and 13 of whom] had current renal disease, with a creatinine of greater than or equal to 1.5, and/or a creatinine clearance of less than 50. They followed these people over time, with a median follow-up of about 13 months.
They found in these patients -- again, in a group that had bad disease in the past, or presently, and who received tenofovir -- that most did not experience any significant worsening of their kidney function during the course of 13 months of follow-up. Now, obviously, 13 months isn't very long and they need more follow-up. But, again, it's a suggestion or a clue that this may not be a big problem, even in people with underlying renal disease ... at least as long as you monitor them closely.
Although there wasn't much at ICAAC 2007 focusing on HIV metabolic complications, there was one presentation by Pablo Tebas that was interesting. Could you talk a little bit about that?
Yes. Pablo presented data from ACTG 5102, which was a trial that took patients who were on stable antiretroviral therapy with complete suppression and good T cells.22 It was actually an interleukin-2 [generic name: aldesleukin; brand name: Proleukin] and treatment interruption study. Their focus was really on what effect treatment interruption had on factors that they thought might be relevant in the context of cardiovascular disease. The background for this is the identification in several other treatment interruption studies of increased cardiovascular events, perhaps the most notable being the SMART trial,23 where people were randomly assigned either to continued therapy, or to stop it until their CD4 counts got to less than 250. As people know, that study was stopped prematurely because of increased risks for progression and non-HIV-related events, including some cardiovascular disease. It's led people to speculate that having uncontrolled viremia may create a situation, either metabolically or from an inflammatory perspective, that would put people at risk.
What they did in this study is, they looked very carefully at the time of the treatment interruption at changes in lipids, glucose, insulin levels, as well as immune activation.22 What they found was that as soon as therapy was stopped, very quickly there were no changes in glucose or insulin, but there were dramatic changes in total cholesterol. Total cholesterol went down and LDL [low-density lipoprotein] cholesterol went down. All of that would suggest something favorable from a cardiovascular perspective. However, HDL [high-density lipoprotein] cholesterol also went down. This has been seen in other studies.23 When you looked at the important total cholesterol/HDL ratio, it turned out that there was really no change, because of the balance in what happened with LDL versus HDL.22
They proposed, based on this observation, that most of the lipid abnormalities are driven directly by the drugs themselves, and that being off therapy would not create an increased atherogenic state, to try to explain what was observed in the SMART trial, and a few other studies like it.
When they looked at immune activation, they demonstrated what's also been shown before, in that there's a fairly quick increase in immune activation that correlates very closely with viral rebound in people who are fully suppressed and then stop therapy. They saw over a 30% increase in CD8 cell activation, using a CD38 as a marker, and tumor necrosis factor receptor. So, two markers of immune activation.
They proposed, although it by no means shows a direct link, that perhaps this increase in the activation state could be associated with proinflammatory mediators, which have been associated with cardiovascular disease. I think what the field needs now is some direct evidence that this kind of inflammation is actually linked to cardiovascular disease.
With the approval of maraviroc [brand name: Selzentry; also known as MVC], knowledge about tropism and tropism assays is suddenly in focus. Can you discuss some of the presentations that you noticed?
There were a couple of presentations that I think are going to be relevant as we move forward with clinical trials, and with the availability of a new CCR5 antagonist. One of them relates more about pathogenesis. And that's: What is the clinical relevance of these different viruses that use different coreceptors? The reason this is important is, as you know, the CCR5 antagonists block R5 viruses. They don't block viruses that use the CXCR4 receptor, and in the clinical trials, and in the population that we will be treating in the clinics, they are targeting those who are R5 only. One of the consequences that we have seen in these studies is the emergence of dual/mixed-tropic or X4 viruses, both of which use the CXCR4 receptor.
One of the concerns is that there are natural history studies that suggest that viruses that seem to be related to what we now refer to as CXCR4-utilizing viruses, the so-called syncytium-inducing viruses, in the past have been associated with CD4 decline and disease progression.24 There's now data using new assays, the ones we'll be using in the clinic to define tropism, showing that the same thing is true in natural history cohorts in people who have dual/mixed-tropic or X4 virus.
In fact, our group just published a paper in CID that showed that, in a hemophiliac cohort, people who had dual/mixed-tropic or X4 virus were at an almost four-fold increased risk of progression to clinical AIDS and death, even after adjusting for viral load and CD4 count.25
Another study here looked at a population of adults, and showed very similar results. Matt Goetz studied patients from CPCRA 060. They looked at a subset of people who were treatment naive and had over 350 T cells.26 They sent plasma samples in over 300 of these patients to Monogram Biosciences, where they performed the tropism assay that's currently being used and is licensed in clinical practice. They found that about 10% of the population of patients had evidence of dual/mixed-tropic or X4 virus, almost all dual/mixed tropic, with the remaining patients being R5 only. They demonstrated very convincingly that those who had dual/mixed-tropic or X4 virus were at increased risk for progression to this composite endpoint that they defined as having a CD4 count of less than 350, needing to start therapy -- which occurred at the discretion of their provider -- or death. They were able to adjust for baseline viral load and T-cell count and show that, even independent of that, there was about a two-fold increased risk of progression to this composite endpoint amongst those who had dual/mixed-tropic or X4 virus.
It's due to those kinds of natural history studies that we worry if dual/mixed-tropic virus has emerged. The good news is that, at least so far in the clinical trials, the people who have selected out this population of viruses do not seem to be experiencing any adverse consequences, such as CD4 decline. And as was discussed at this meeting with the 48-week data from the MOTIVATE trial,9 and now up to three years of follow-up in people who are receiving vicriviroc [also known as SCH 417690 and SCH-D],27 even though many of these people who failed, failed with dual/mixed-tropic and X4 virus, again, there doesn't appear to be any obvious adverse consequences.
In order to deal with the fact that some people are failing with this viral population, it is extremely important to make sure that our initial screening tests work. Because there is evidence that there is a low proportion of viruses that can be present below the limits of detection of the assay ... very similar to what we have dealt with in drug-resistance testing. What we don't see can be important. And from all of the studies that have been done so far, when you look at people who come in and get screened and are found to be R5 only, there's about another 5 or 10% who, between screening and entry, without the introduction of any therapy at all, due just to the passage of time, suddenly now have detectable dual/mixed or X4 virus. Presumably, these are viral populations that are just below the limits of detection.
There was also data presented here in follow-up from the MOTIVATE trials showing that those who fail early in therapy tend to be the ones failing with dual/mixed-tropic virus;12 along with other data that all support the fact that much of this is preselection of the viral population that existed before therapy was ever initiated. So there has been a lot of interest in trying to improve the quality of the assays, as well as perhaps come up with simpler assays.
The Monogram group, who developed the currently available and licensed assay for tropism, has been working on modifying it. They presented a poster here showing that they were able to, just by simply manipulating the assay they currently use, to perhaps increase the sensitivity to detect these low-level, dual/mixed-tropic or X4 virus that may have been missed with the standard assay currently being used, and was used in the clinical trials.28
I think the next best step after they have sort of refined this assay adequately is to go back and perhaps look at some of the baseline specimens in people in the large control trials, and try to get a sense as to how detection at low levels may have contributed to or predicted the risk of failure. That might be very helpful as we think about moving forward with a newer, perhaps more sensitive, assay in the future.
Then, finally, they also tried to determine whether an alternative strategy could be used to their tropism assay. Others are trying to work on assays pretty much like theirs, but also, trying to see if we can have a complementary genotypic assay. And we know that the viral envelope mediates tropism, and much of that is in the context of the V3 loop, the hypervariable loop of the envelope.
So they attempted to sequence that and see how that related to their phenotypic assessment.29 Their conclusions were that it's very difficult to sequence that area. That's been true when others have looked at it, as well, because there are a lot of insertions and deletions in variability in the V3 loop -- much different than in polymerase or protease genes. Also, they found that it was not terribly sensitive for detecting dual/mixed or X4 virus. Again, that's completely consistent with a lot of groups who have looked at this independently of them.
I think for now, genotype is not likely to be a strategy for the future, but perhaps enhanced phenotypic assays, both from Monogram and maybe other groups, may improve our ability to detect low levels of dual/mixed X4 virus, and may also result in better response rates with the CCR5 antagonists, which already look to be very promising.
Dr. Daar, can you talk a little bit about the pricing of this test, and how it's going to be afforded by all the clinics across the country?
I think that's a really important question, because it is an additional test. There's one thing that seems clear, in that if we're going to use a CCR5 antagonist, we really do need the results of this test. Upwards of 40 to 50% of people are highly treatment experienced. The population that we're going to be targeting with this drug have viruses that use CXCR4, and are not likely to be good candidates, in which case all we're doing is subjecting these people to the cost of the drug and toxicity.
So we need to use the test, but the test is going to be expensive, as these tests tend to be. We're going to need to see how that negotiation occurs between the company, Monogram Biosciences, or whoever else comes up with an assay like this, and the third-party payers. But it's going to be vital for both the patients and really to not inappropriately utilize this class of drugs.
Then the issue will come up: Okay, that's all fine and good when you do it at baseline. Do we then do it again, in people who experience virologic failure? Again, that's going to probably be driven by availability, because intuitively to me it makes sense that we would. If somebody experiences virologic failure on a regimen, we do resistance testing in follow-up to see what the next regimen should be. I think the same is probably going to need to be true with the tropism assay.
Almost everybody who fails on T-20 [generic name: enfuvirtide; brand name: Fuzeon] has evidence of resistance. We know from the MOTIVATE trials that, amongst the people who fail, while two thirds of them had dual/mixed virus, the third didn't.12 In the vicriviroc trials it was closer to 50 or 60% who didn't.27 So it may make sense to be able to look at that and decide whether this drug should be continued as part of the next regimen.
Could you now talk about the presentations focusing on non-AIDS-defining complications?
Over the last several years, I think there has been increased interest in this. We tended to focus on our clinical endpoints in trials and natural history studies as progression to AIDS and AIDS-defining illnesses and malignancies. But over the last several years, as we look more closely at people sometimes in earlier stages of disease, or off therapy, we have come to appreciate that there are other unique complications. They prove to be extremely important, as well, and may drive, in part, decisions about when to start therapy and when not to stop therapy.
There were two presentations that I thought were particularly relevant here. One was from the French group, where they looked at a population of patients that were enrolled between 1997 and 1999.30 There were 1,280 of them who were started on a protease inhibitor-containing regimen. So this is a group of over 1,000 individuals who thought that they needed to start on some antiretroviral therapy at the time. Then they were followed. There was a median follow-up in this analysis of 88 months, so it's quite a prolonged follow-up.
They looked for a variety of different events, including non-AIDS and non-antiretroviral-therapy-
related adverse events. They found that there were many. Most common were bacterial infections, about 23%. About 10% developed malignancies. Then there were about another 10% that had cardiovascular disease, and some psychiatric and neurologic events.
What they did was a multivariate analysis to try to tease out factors that were associated with an increased risk for these specific events. They found that, not too surprisingly, older age, based on the nature of these events, like malignancies and cardiovascular disease, was independently associated with increased risk. They found hep C positivity was [also associated with increased risk of these specific events], and this might be for a variety of reasons, including hepatitis C related liver disease.
But more importantly, in the CD4 count, they found that an important factor in the multivariate analysis was having a CD4 count of less than 100 -- and again, these are for non-AIDS or non-treatment-related events. Other studies have shown the same thing, that while we think about people being immune suppressed, being at risk for AIDS-defining illnesses, they may also be at increased risk for these other things. Perhaps the most interesting observation was that when you looked at plasma viral load, they found that having a viral load greater than 10,000 would significantly increase risk factor, independent of other factors, including baseline CD4s and current CD4s, for these various events.
Particularly, this was driven by the increased occurrence of bacterial infections. The authors conclude, I think appropriately, that in a group of patients who are on antiretroviral therapy, and have detectable viremia -- in this case, particularly above 10,000 -- regardless of what therapy they are on or their T-cell count, there's a risk factor for adverse consequences or outcomes ... and again, not necessarily AIDS related.
So, this argues strongly against treatment interruptions in a population of patients like this. It's a little bit more of a reach to suggest that this has implications for when to start therapy, because that's not the population they looked at. But I think it supports the idea that we do need to look at that closely when we think about the best time to start therapy, meaning, looking at non-AIDS-related issues.
Another poster looked at non-AIDS-related, or non-AIDS-defining, malignancies, which again, have come out in a variety of studies as being important, and associated with the level of immune function, as well. This was a study from the VA [U.S. Department of Veterans Affairs] where they looked at the VA electronic medical records system and looked at ICD9 codes.31 They were able to identify for this analysis 33,400 HIV-positive and 66,800 HIV-negative veterans, who were followed for a median of five to six-and-a-half years.
They looked at the incident rates of non-AIDS-related malignancies, and they showed that the incident rate ratio for these events in HIV-positives was 1.6, or 60% higher, than what was seen in the HIV-negatives.
When they looked at which particular malignancies occurred more often, there was a 15-fold increased risk amongst the HIV-positives for anal cancer. There was a two-fold increased risk for lung cancer. If you think about it, some of this may be driven by other comorbid issues. Anal cancer almost certainly is related to HPV [human papillomavirus] infection; lung cancer is probably associated with increased smoking amongst this population, and they couldn't adjust for that. But there may be other issues. Melanoma occurred with increased frequency. Hodgkin's disease, which has been seen in a variety of trials, also occurred with an increased frequency amongst those with HIV. Liver cancer is probably related to hepatitis C and B coinfection. But overall, again, an increased risk and a relationship, in most of these cases, between the CD4 count, as well. People with HIV and these malignancies tended to have lower CD4 cells than those with HIV who didn't have the malignancies.
Finally, we're going to close with a discussion of HIV coinfections, notably hepatitis B and C. Anything that will change practice?
It's difficult to say, but I think that there have been some significant advances. One presentation related to entecavir's [brand name: Baraclude] effect on HIV and the selection for 184V has already changed practice.32 This was reported some time ago and has recently been published in The New England Journal of Medicine.33 It was the observation that entecavir actually has HIV activity.
Prior to this, it was thought that it did not, and it was recommended as one of the options for somebody who is coinfected, where you wanted to treat their hep B, but not their HIV. But what emerged from a few carefully studied cases is that you do, indeed, select for the 184V in a subset of patients.
There was further analysis performed here by this group to try to better understand molecularly why there may be differences in the proportion of people that select for it, and how it evolves. There may be some relationship between differences in the fitness effect of the 184V in the setting of entecavir with HIV.
But the bottom line is, right now, it clearly is a drug with HIV activity. The new guidelines suggest that it should not be used, except in somebody who is on antiretroviral therapy -- at least in HIV-infected individuals, of course. So I think that's already changed practice.
Another study that might influence what people do in the clinic looked at the possibility of re-treating people for hepatitis C with pegylated interferon [brand name: Pegasys, PEG-Intron] and weight-based ribavirin [brand name: Copegus, Rebetol], in particularly a group of people that may not have been adequately treated the first time.34
The question is, if I had somebody who I had treated with interferon monotherapy at a time when we did that, or pegylated interferon with ribavirin, but not weight-based ribavirin. Often studies and patient care was 800 mg, other than up to 1,000 or 1,200 mg. If somebody had failed those earlier regimens and they had been inadequate, what is the value of trying to re-treat them with what's now the current standard of care? They did that in a group of patients who did experience failure in the past. Some of these people, again, due to monotherapy. Some just not on the best dose of ribavirin. What they found was that there actually was a response rate. Overall, about 39% of patients had a sustained virologic response -- 27%, or a quarter, of those had genotype 1 and 4, and 70% had genotype 2 and 3.
The data set is small, and I don't think you can be sure that any given patient is going to able to respond. But it does provide some evidence to try to support revisiting treatment with patients who have failed previous therapy. And it's nice to be able to have at least something to go to the patient with, since you are proposing to subject them to considerable toxicity in the attempt to re-treat them.
Now, unfortunately, despite the fact that we have treatment for hepatitis C in both people with and without HIV, it's not always successful, and particularly with the genotype 1s in coinfected patients. A large portion of people don't respond to therapy, or don't tolerate therapy. And, as you know, one of the most common reasons why people need liver transplants is because of end stage hepatitis C disease.
There has been very slow movement over the years, although it's picked up some pace in studies, and even in practice -- the introduction of liver transplantation in patients with HIV -- particularly because of concerns that immunosuppressing people who are already immunosuppressed may have detrimental effects.
We have seen data emerge from various countries over the last several years showing that, overall, patients who are coinfected with hepatitis C with liver failure, who get liver transplants, seem to do fairly well.
There was another study presented here looking at the three-year survival of hep C/HIV-coinfected patients who had liver transplantation.35 They had 51 of these individuals, and they compared them to a control group of almost 1,200 HCV [hepatitis C virus]-monoinfected individuals. They followed them over time.
Now, these patients, very much like others in trials, tended to be people who either were on fully suppressive therapy, or it was felt that, because of their treatment history, they could be successfully treated. So it's a population of people who could be treated well for their HIV. Overall, the survival at three years was very good. For all of the patients in both groups, in terms of three-year survival, it was essentially the same -- 64 and 69% amongst those with HIV versus those who were hep C monoinfected. Hopefully, with this kind of data, liver transplantation will be more accessible to people who are coinfected and have liver failure and need it as their one option.
Finally, preliminary data was presented on novel drugs for hepatitis C. Certainly, there's a great need here, since current therapy with pegylated interferon and ribavirin is associated with considerable toxicity and relatively low response rates, particularly for the more common genotype 1s. There has been an active development program looking at new drugs, including hepatitis C virus protease inhibitors in clinical trials, and adding them on to standard of care peginterferon and ribavirin.
Mark Sulkowski presented preliminary data from the PROVE 1 study using this Vertex 950 compound.36 They had subjects that were followed longitudinally after starting on treatment in one of several different groups, with pegylated interferon and ribavirin and this new drug, at 750 mg, given every eight hours. Once everybody got to 12 weeks then they started to do an interim analysis. They found pretty extraordinary response rates, at least in this very preliminary look. At week 4, 79% of them had hep C viral loads that were below the limits of detection, compared to only 11% in the control group. At week 12, 70% continued to have undetectable levels, versus 39% of the control group.
So, very promising, as we move forward with new strategy and new novel therapeutics for hepatitis C with the hope that eventually we'll be able to successfully treat everybody, and prevent the consequences or sequelae of hep C infection and liver failure, and then the need for transplantation.
Thank you so much, Dr. Daar, for taking the time to speak with us, and for your incisive analysis.
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