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CROI 2015
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The annual Conference On Retroviruses and Opportunistic Infections, known by attendees as CROI, brings together experts from around the world in basic, translational and clinical research to share the latest studies, important developments and up-and-coming techniques in the ongoing battle against infectious diseases. The focus on the management and treatment of hepatitis C virus grew by more than 50 abstracts at this year’s meeting, which was held Feb. 23 to Feb. 26 in Seattle. Attendees also participated in workshops and symposia led by the leaders in the field.
HCV Next Editorial Board members Marion G. Peters, MD, John V. Carbone, MD, Endowed Chair Professor in Medicine and chief of hepatology research at the University of California, San Francisco, School of Medicine; Arthur Y. Kim, MD, director of the Viral Hepatitis Clinic in the Division of Infectious Diseases at Massachusetts General Hospital; and Susanna Naggie, MD, MHS, director of Infectious Diseases Research at Duke Clinical Research Institute, shared their experiences and take-home messages from CROI 2015.
Marion G. Peters, MD
There was a time when we pushed hard to treat acute HCV because the response was so much better than treating chronic HCV, but today, chronic HCV has a cure of more than 90% to 95%. So, it is not as critical to treat hepatitis C in the acute stage, except to stop transmission from one person to another. This issue was brought up by Arthur Y. Kim, MD, in one of the symposia at CROI 2015.
We should emphasize that it is important to recognize acute hepatitis C and to investigate other factors such as HIV, high-risk behaviors, pregnancy, and discuss with the patient the new drugs available. But you need explain to the patient that compliance and adherence to the medications is critical. Some data at CROI showed the importance of treating immediately to decrease the burden of disease among high-risk populations.
Marion G. Peters
The second message is that now there are three all-oral regimens approved: sofosbuvir/ledipasvir (Harvoni, Gilead Sciences); simeprevir (Olysio, Janssen) with sofosbuvir (Sovaldi, Gilead Sciences); and the “3D” regimen (Viekira Pak, AbbVie).
Patients now have options for treatment, but many insurance companies will determine what the patient can take. Because the drugs are so expensive, insurance companies, Medicare, state governments and Veterans Affairs have all negotiated with HCV treatment manufacturers to obtain price reductions for their patients.
It remains important to know the genotype and fibrosis stages of the patient. Whether they have genotype 1a or 1b determines whether they need ribavirin or not with the 3D regimen mentioned previously. Whether the patient has cirrhosis or not determines the duration of therapy, depending on the regimen, and also, potentially, whether ribavirin is used. Whether the patients is naive to therapy or treatment-experienced affects the overall treatment strategy.
These issues are important for both the patient and provider to choose the optimal regimen and the optimal duration of the regimen.
At this meeting, we saw that having coinfection does not adversely affect treatment outcome. Patients with HIV do not have worse outcomes, although no studies have actually compared HIV-positive patients directly to HIV-negative patients. This is exciting news.
However, there is an issue of drug-drug interactions that remains an important issue. Common medications like antacid therapy, proton pump inhibitors, some antidepressants and some hormonal therapy cannot be used with some all-oral HCV medications. So, it is absolutely critical that the provider carefully note all prescribed and over-the-counter medications that the patient is taking to determine whether the patient should stop those medications for the time they are on HCV therapy.
Lastly, it is important to diagnose cirrhosis not just to determine duration and type of therapy, but also because patients with cirrhosis need screening for hepatocellular carcinoma, as well as upper endoscopy, to screen for varices. If a patient has varices, they should be treated with nonselective beta blockers or undergo elective variceal band ligation to decrease the risk of variceal bleeding.
New drugs on the horizon are pan-genotypic. We do not yet have enough data to say that all the genotypes will be equally well treated. Ideally, in the future, a genotype may not be required if one regimen fits all. This would be a splendid outcome.
Those were the big messages from my point of view that came out of CROI.
Susanna Naggie, MD
Most people would agree that there was great representation of HCV research at this year’s CROI.
The highlights of the HCV data came during the exciting oral abstract session titled “Curing hepatitis C: mission accomplished.” One of the first abstracts from the CDC utilized laboratory data from Quest Diagnostics to assess the burden of liver disease in the patients having HCV testing from 2010 to 2013. Using a noninvasive marker of fibrosis (FIB-4), they calculated stage of liver fibrosis and reported that the majority of patients had fibrosis. Additionally, 81% of patients with severe fibrosis or cirrhosis were in the baby boomer “birth cohort,” highlighting the burden of liver disease in this patient population.
Another study reported on the “real-world” cost of simeprevir and sofosbuvir, which is an FDA-approved regimen that was the first clinically available interferon-free, direct-acting antiviral combination therapy. Currently, this is the most expensive DAA combination regimen, but this study reported that it’s still cheaper than the older telaprevir- (Incivek, Vertex Pharmaceuticals) and boceprevir- (Victrelis, Merck Sharp & Dohme) containing regimens. This study showed interesting and important data regarding 12-week sustained virologic response in a real-world setting with an overall SVR of 88% in a relatively difficult-to-treat patient population. But the big take-home was that the biggest driver of cost-per-cure was the cost of the DAA themselves, and in order to decrease cost-per-cure, we will need to decrease the cost of DAA, which can be achieved with drug discount rates.
An intriguing modeling study came out of the Swiss HIV and HCV coinfection cohorts regarding the impact of deferring HCV therapy in patients coinfected with HIV/HCV. Due to the cost of DAAs, many payers are limiting access to those patients with severe fibrosis.
Susanna Naggie
This study assessed risk of developing liver disease outcomes in the setting of deferring curative HCV therapy until severe fibrosis has developed. The assumptions made for modeling included: decrease in liver fibrosis progression by 10-fold; decrease in progression to decompensation by 10-fold; and decrease in progression to HCC by 2.6-fold. This study showed that if you delay therapy until patients are stage F2, F3 or F4, the risk of liver-related death increases 1.5-fold to twofold and then to fourfold, respectively. This abstract suggests that by delaying treatment of HCV, we are asking patients to assume significant health risks and this gives us data to argue why deferring therapy is not appropriate in the HIV-infected population.
The last two presentations in the oral session were the first phase 3 trials of DAA combination therapy in HIV/HCV coinfection. The ALLY-2 and ION-4 trials both investigated the combination of sofosbuvir, a nucleotide polymerase inhibitor, with a NS5A inhibitor. In the ALLY-2 trial, the NS5A was daclatasvir (Bristol-Myers Squibb) and, in the ION-4 trial, the NS5A was ledipasvir. Daclatasvir remains an investigational agent, currently under review by the FDA, and ledipasvir/sofosbuvir is an FDA-approved regimen that comes as a single pill, fixed-dose combination.
The ALLY-2 enrolled 203 patients, with 12-week and 8-week arms, which might be the only 8-week trial in a population coinfected with HIV. The study included a broad population of patients across genotypes 1 through 6, including patients with cirrhosis and those on a broad range of antiretrovirals. Overall, cure rates were 96% in the 12-week arm of treatment-naive patients and that rate dropped to 76% in the 8-week treatment-naive cohort. We can see that 8 weeks doesn’t fly here, but there were only a couple of relapses in the 12-week arm, all in genotype 1a patients. Ultimately, across all groups receiving 12 weeks, we saw high cure rates and a safe regimen with few adverse events. There was no discontinuation due to adverse events.
ION-4 took the approach to focus on the primary regimen approved by the FDA, which is 12 weeks of ledipasvir/sofosbuvir without ribavirin. This single-arm study enrolled 335 patients, which is the largest phase 3 trial in coinfected patients reported to date. Patients were genotype 1 or 4, treatment-naive and -experienced, with and without cirrhosis. The overall SVR in this study was 96% with 100% of genotype 4 patients achieving SVR12. High SVR rates were seen across all patient subgroups, including 98% SVR in the most difficult-to-treat patient population, treatment-experienced cirrhotics. One unexpected finding was that all 10 relapses in the study were in patients of self-reported black race. In further analysis, 90% of black patients vs. 99% of nonblack patients achieved SVR in the intention-to-treat analysis. In fact, no nonblack patient experienced virologic failure.
This lower SVR in black patients was not observed in the 308 black patients in the HCV monoinfected ION program. In an attempt to explain this observation, we hypothesized that these relapses may have been related to lower ledipasvir levels, especially in light of the healthy volunteer data that reported approximately 34% decreased ledipasvir exposures in patients on efavirenz (Sustiva, Bristol-Myers Squibb). However, population pharmacokinetic levels of ledipasvir were the same when evaluated by antiretroviral regimen, black vs. nonblack race, and SVR vs. relapse.
We further pursued a candidate gene study of the CYP2B6 polymorphism, which has been previously reported to occur at greater frequency in black patients and was associated with greater efavirenz exposure. This study showed consistent prevalence in both black and white populations. Thus, at this time we have no explanation for the ION findings, and have genome-wide association and full-exome sequencing studies underway. I have concerns that prior studies have been underpowered to assess for differences in SVR by race with DAA combination therapies. If nothing else, this brings to the forefront the need to adequately enroll black patients in our North American trials.
Another important clinical issue that was addressed by ION-4 was the concern of increased tenofovir (Viread, Gilead Sciences) exposures and risk of renal toxicity. In healthy volunteer drug interaction studies of ledipasvir/sofosbuvir and antiretrovirals, an approximately 40% increase in tenofovir was noted in patients on non-nucleoside reverse transcriptase inhibitors. This increase was confirmed in ION-4 but was not different for the patients on raltegravir (Isentress, Merck Sharp & Dohme), efavirenz or rilpivirine (Edurant, Janssen). There was no clinically nor statistically significant increase in serum creatinine or decrease in creatinine clearance in this study. Only four patients met the study protocol definition of treatment-emergent, confirmed renal insufficiency. Two of these patients required changes in tenofovir dosing, one required a switch off of tenofovir and one required tenofovir dose reduction. Both patients had renal insufficiency at baseline and one of those at entry into the study had evidence of tubular injury with 4+ glycosuria and 2+ proteinuria. In patients with normal renal function, this increase in tenofovir exposure does not appear to increase risk of renal injury.
Overall, hepatitis C got a lot of press and a lot of space at CROI this year, and that was exciting for those of us who treat this infection. As we have increasing clinical access to these highly potent DAA combination therapies, I am hopeful that we will have the opportunity to show the benefit of HCV eradication on liver and non–liver-related clinical outcomes.
Arthur Y. Kim, MD
At the meeting, the most exciting data from a hepatitis standpoint was the presentation of both the ION-4 and ALLY-2 studies with verification of the ERADICATE data that the ledipasvir/sofosbuvir combination works well and achieves an excellent efficacy among HIV/HCV-coinfected individuals on the proper antiretrovirals; in this case, tenofovir and emtricitabine (Emtriva, Gilead Sciences) plus one of efavirenz, raltegravir or rilpivirine.
From the ION-4 trial, we also learned that although there’s a concern about elevated tenofovir levels while on ledipasvir/sofosbuvir, there was not a major signal in terms of renal toxicities. There were four patients that did suffer rises in creatinine, but for the most part, these were manageable.
There was another abstract presented by Polina German, PharmD, from Gilead Sciences that showed that the effect of ledipasvir/sofosbuvir on tenofovir levels was even higher with ritonavir-boosted protease inhibitors, so it’s important to note that we still lack actual data in HIV/HCV-coinfected patients on whether this latter combination is safe.
From the ALLY-2 study we learned the efficacy of daclatasvir and sofosbuvir for the coinfected population for multiple genotypes, and there we saw excellent SVR rates as well, and that was across genotypes 1 through 4, but with inferior SVR rates with 8 weeks vs. 12 weeks of therapy.
Daclatasvir is not yet approved in the United States but is approved in Europe, and they have been expanding indications there. The ALLY-2 trial had a limited number of patients with genotype 3, and while it displayed extremely high rates of success, in those without HIV, ALLY-3 showed lower levels of success in patients with genotype 3 and cirrhosis, so those with genotype 3 and more advanced disease were likely under-represented in the coinfection trial.
Overall, the data continue to support the idea that efficacy rates are similar in persons without HIV and with HIV, so we will continue to extrapolate data from the HIV-negative individuals who have been treated to the coinfected population, taking into account the drug-drug interactions.
The other major theme we saw was in abstracts suggesting the time to which patients become HCV negative does not impact results. They are typically measured at 2, 4, 6 and 8 weeks potentially, but the point at which a patient becomes undetectable for HCV RNA does not impact SVR rates.
Arthur Y. Kim
There was another major study in collaboration with CDC investigators and a large, national testing lab called Quest, which examined the putative burden of liver disease among hepatitis C-positive individuals and suggested there was more advanced fibrosis than previous studies showed.
The burden of liver disease as the population ages is another important public health message that emerged from the meeting.
One of the symposia discussed two issues of importance that are a little less appreciated: the concept that we may not be able to fully eliminate but reduce transmission by earlier treatment of hepatitis C among high-risk populations. Gregory Dore, MD, presented a nice talk on that.
Finally, Peters finished that session with a rousing overview of the cost issues involved and the various perspectives in what is going on in the real world. She remarked that many of us have become professional letter writers rather than doing what we were trained to do as medical providers and doctors.
It is clear that the field is rapidly changing with the introduction of multiple new medications and that it may be challenging for providers to stay up on the latest developments. The sessions reviewed the management of everything from the pathogenesis and evaluation of acute hepatitis C, managing chronic hepatitis C and early decompensated liver disease — topics that, particularly in the ID-trained audience, continue to require ongoing education.
It’s important for people to stay updated through continuing education as well as referring to up-to-date documents such as the HCV Guidelines.
This will be an ever-changing field for the time to come.
Disclosure: Kim reports financial relationships with AbbVie, Bristol-Myers Squibb and Gilead Sciences. Naggie reports financial relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck and Vertex. Peters reports financial relationships with Biotron.