The Body Covers: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy
ICAAC 2007: Key HIV Research on HIV/HAART Complications and HIV Drug Resistance
An Interview With Eric Daar, M.D.
September 20, 2007
Table of Contents
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-
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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