The Take Home

The Take Home: CROI 2014

Meeting highlights and analysis from the Conference on Retroviruses and Opportunistic Infections.

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 management and treatment of hepatitis C virus was featured prominently at this year’s meeting, which was held March 3 to March 6 in Boston. Attendees participated in workshops focused on clinicians who are new to HCV management; listened to sessions on the latest epidemiology, biology and treatment options for patients with HCV; and digested breaking research that is sure to clinically affect the near future.

HCV Next Editorial Board members David L. Wyles, MD, associate professor of medicine at University of California, San Diego, School of Medicine; Susanna Naggie, MD, MHS, director of infectious diseases at Duke Clinical Research Institute; and Arthur Y. Kim, MD, director of the Viral Hepatitis Clinic at Massachusetts General Hospital, shared their experiences and take-home messages from CROI 2014.

David L. Wyles, MD

The first oral abstract session on hepatitis was the most important session, in my opinion, for several reasons. First, and most importantly, this session solidified the concept that patients coinfected with HIV/HCV do just as well as those monoinfected with HCV when treated with HCV regimens that contain a direct-acting antiviral (DAA), including interferon-free therapy. Data on sustained virologic response at 12 weeks (SVR12) from both the phase 3 C212 simeprevir (Olysio, Janssen Therapeutics) coinfection study (74% overall, including 79% in treatment-naive patients) and the phase 3 faldaprevir (Boehringer Ingelheim) STARTVerso4 coinfection study (72% overall, including 69% in treatment-naive patients) demonstrated cure rates nearly identical to those seen in phase 3 HCV-monoinfected studies.

In the PHOTON-1 study, presented by Naggie, our first robust data in coinfected patients with an interferon-free regimen, sofosbuvir (Sovaldi, Gilead) plus ribavirin again showed equivalent response in coinfected patients, with a 76% SVR12 rate for treatment-naive patients with HCV genotype 1 as well as 88% and 67% for treatment-naive patients with HCV genotypes 2 and 3, respectively. Treatment-experienced patients with genotypes 2 and 3 also did very well, with a 92% to 94% SVR rate after 24 weeks of treatment. Overall, these data led to an excellent comment from the audience questioning whether patients coinfected with HIV should still be considered a "special population" with regard to HCV therapeutic trials. While issues surrounding drug-drug interactions differentiate this group, other key aspects such as efficacy and tolerability appear no different from those with HCV alone.

David L. Wyles

Second, the collective awe of the audience could be heard during the SYNERGY study presentation demonstrating that only 6 weeks of HCV therapy with a potent combination of sofosbuvir and ledipasvir plus an NS3 protease inhibitor, GS-9451 (Gilead), resulted in a 100% SVR12 rate in 20 monoinfected patients with HCV genotype 1. It will be interesting to see just how short HCV treatment can get; the speaker said 4 weeks of treatment are now being investigated with this combination.

Besides these treatment studies, the HCV treatment cascade and real-world experience numbers presented in several oral and poster sessions stand in stark contrast to the encouraging treatment trials presented. Much work remains to be done on effective means of screening at-risk populations, obtaining linkage to care and, ultimately, treating some of these difficult-to-treat populations.

One final buzz-related topic was the resurgence of simple noninvasive testing as a means for staging fibrosis and predicting clinical outcomes in patients with HIV and HCV. Juan Berenguer, MD, and colleagues presented data from the GESIDA cohort, which assessed how well having a fibrosis stage ≥F3 on biopsy vs. a FIB-4 of ≥3.25 predicted both liver-related events and all-cause mortality. While both tests were predictive, the FIB-4 score was more accurate at predicting outcomes than liver biopsy.

At future meetings, I look forward to results from recently initiated phase 2 and 3 trials of potential interferon-free HCV DAA regimens in coinfected patients. Given the dramatically shortened treatment durations with new DAA-based regimens and the use of SVR12 as a primary endpoint, preliminary results from treatment trials are now available in a short time frame. I am expecting preliminary results from many of these phase 2 and 3 trials next year at CROI.

I believe that understanding the new HCV treatment regimens and how to manage drug-drug interactions will be key for any HCV primary care provider going forward. I see HIV treaters as a key component of those whom will be needed to treat HCV in the future. CROI provides a wonderful opportunity for practitioners to network and establish new research collaborations, as well as get up-to-date on the latest science in the fields of HIV and viral hepatitis.

Susanna Naggie, MD, MHS

The Tuesday morning oral abstract session on hepatitis was critical, with two real take-home points. One, patients coinfected with HIV/HCV have the same response rates to DAA-inclusive therapies as patients monoinfected with HCV, and this is true with interferon-free regimens. Two, combinations of DAAs resulted in highly potent and efficacious regimens for the treatment of HCV. The question is how quickly can a patient with HCV be cured — data presented suggested 6 weeks or less — and will there be a one-size-fits-all or will more difficult-to-treat patients such as those with cirrhosis and nonresponders require longer courses of therapy?

The most exciting presentation was that of the SYNERGY trial, which investigated ribavirin-free triple DAA therapies. Although a pilot trial, results suggested that patients without cirrhosis can be cured in 6 weeks. This not only sets the stage for what is to come, but also reinvigorates the science to understand persistence and relapse. This is shorter than what most people imagined, and the investigators reported that they are also studying these same regimens for 4 weeks.

Susanna Naggie

There was a great deal of excitement at CROI about the all-oral interferon- and ribavirin-free regimens and excitement surrounding PHOTON-1, which is the first lead to the FDA approval of sofosbuvir in patients coinfected with HIV/HCV, making it the first DAA to be approved in this special population.

I look forward to seeing results of the combination DAA therapies in patients coinfected with HIV/HCV. Three phase 3 studies are currently enrolling these types of patients, so hopefully we will see some data at CROI 2015.

At next year’s meeting, one thing we might hear more about is the research that is presented in poster form. There were so many great posters this year investigating HCV screening and testing with linkage to care, HIV/HBV, cardiovascular disease outcomes in HIV/HCV and more.

Arthur Y. Kim, MD

What I took away from CROI 2014 was important information regarding the safety and efficacy of treatments for patients coinfected with HIV/HCV. We heard major findings reported for the first time.

The short answer of what was most important in my opinion is the SYNERGY study conducted at the National Institutes of Health. This study showed that with certain three-drug combination of DAA therapies for only 6 weeks, once achieved about 95% cure rates. The proof-of-concept that we could cure with only 6 weeks of therapy generated a bit of buzz.

Arthur Y. Kim

All-oral therapies are already here and will transform the treatment of HCV. After a patient management panel, during which Wyles, Naggie and Kenneth Sherman, MD, (professor of digestive diseases at University of Cincinnati College of Medicine) presented on how to care for patients with HCV, I overheard two groups basically saying that they didn’t need to refer to GI anymore — we should gear up to treat our own patients, presumably those who are HIV/HCV coinfected. The expansion of providers willing to treat HCV will be a critical issue in the future with these all-oral therapies.

It is clear to me that the treatment paradigms are changing rapidly. We look forward to clinical trials, especially in special populations — not only patients coinfected with HIV/HCV, but also substance-abusing persons and HIV-positive men who have sex with men — supplemented by reports from the so-called real-world experiences. Together, we can learn how to best take care of patients and what the future of HCV therapies will look like. I’d also expect by next year important data regarding the treatment of acute HCV infection.

HCV is becoming increasingly highlighted at CROI. It falls between the American Association for the Study of Liver Diseases’ (AASLD) The Liver Meeting and the European Association for the Study of the Liver (EASL) Annual Meeting, and it’s not surprising that investigators will choose to submit novel data regarding new treatment paradigms.

References:
Dieterich DT. Session O-1 Oral Abstracts. Faldaprevir plus pegylated interferon alfa-2a/ribavirin in HIV/HCV coinfection: STARTVerso4.
Dieterich DT. Session O-1 Oral Abstracts. Simeprevir (TMC435) plus pegIFN/ribavirin in HCV genotype-1/HIV-1 coinfection (Study C212).
Kohli A. Session O-1 Oral Abstracts. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: Final results of the SYNERGY trial.
Naggie S. Session O-1 Oral Abstracts. Sofosbuvir plus ribavirin for HCV genotype 1-3 infection in HIV coinfected patients (PHOTON-1). All presented at: CROI 2014; March 3-6, 2014; Boston.
Disclosures: Kim reports serving as a consultant/advisory board member for AbbVie and Gilead, and receiving research monies to his institution from Bristol-Myers Squibb and Gilead. Naggie reports receiving research grants or contracts that partially support her university salary from AbbVie, Achillion, Bristol-Myers Squibb, Gilead and Vertex; educational activities or lectures that generate revenue for her university from IAS-USA; and consulting/other non-CME services for AbbVie, Achillion, Bristol-Myers Squibb, Gilead and IDSA. Wyles reports receiving research grants for the conduct of clinical trials paid to UC Regents from AbbVie, Bristol-Myers Squibb, Gilead, Merck and Vertex, and serving as a paid consultant to AbbVie, Bristol-Myers Squibb, Gilead and Janssen.

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 management and treatment of hepatitis C virus was featured prominently at this year’s meeting, which was held March 3 to March 6 in Boston. Attendees participated in workshops focused on clinicians who are new to HCV management; listened to sessions on the latest epidemiology, biology and treatment options for patients with HCV; and digested breaking research that is sure to clinically affect the near future.

HCV Next Editorial Board members David L. Wyles, MD, associate professor of medicine at University of California, San Diego, School of Medicine; Susanna Naggie, MD, MHS, director of infectious diseases at Duke Clinical Research Institute; and Arthur Y. Kim, MD, director of the Viral Hepatitis Clinic at Massachusetts General Hospital, shared their experiences and take-home messages from CROI 2014.

David L. Wyles, MD

The first oral abstract session on hepatitis was the most important session, in my opinion, for several reasons. First, and most importantly, this session solidified the concept that patients coinfected with HIV/HCV do just as well as those monoinfected with HCV when treated with HCV regimens that contain a direct-acting antiviral (DAA), including interferon-free therapy. Data on sustained virologic response at 12 weeks (SVR12) from both the phase 3 C212 simeprevir (Olysio, Janssen Therapeutics) coinfection study (74% overall, including 79% in treatment-naive patients) and the phase 3 faldaprevir (Boehringer Ingelheim) STARTVerso4 coinfection study (72% overall, including 69% in treatment-naive patients) demonstrated cure rates nearly identical to those seen in phase 3 HCV-monoinfected studies.

In the PHOTON-1 study, presented by Naggie, our first robust data in coinfected patients with an interferon-free regimen, sofosbuvir (Sovaldi, Gilead) plus ribavirin again showed equivalent response in coinfected patients, with a 76% SVR12 rate for treatment-naive patients with HCV genotype 1 as well as 88% and 67% for treatment-naive patients with HCV genotypes 2 and 3, respectively. Treatment-experienced patients with genotypes 2 and 3 also did very well, with a 92% to 94% SVR rate after 24 weeks of treatment. Overall, these data led to an excellent comment from the audience questioning whether patients coinfected with HIV should still be considered a "special population" with regard to HCV therapeutic trials. While issues surrounding drug-drug interactions differentiate this group, other key aspects such as efficacy and tolerability appear no different from those with HCV alone.

David L. Wyles

Second, the collective awe of the audience could be heard during the SYNERGY study presentation demonstrating that only 6 weeks of HCV therapy with a potent combination of sofosbuvir and ledipasvir plus an NS3 protease inhibitor, GS-9451 (Gilead), resulted in a 100% SVR12 rate in 20 monoinfected patients with HCV genotype 1. It will be interesting to see just how short HCV treatment can get; the speaker said 4 weeks of treatment are now being investigated with this combination.

Besides these treatment studies, the HCV treatment cascade and real-world experience numbers presented in several oral and poster sessions stand in stark contrast to the encouraging treatment trials presented. Much work remains to be done on effective means of screening at-risk populations, obtaining linkage to care and, ultimately, treating some of these difficult-to-treat populations.

One final buzz-related topic was the resurgence of simple noninvasive testing as a means for staging fibrosis and predicting clinical outcomes in patients with HIV and HCV. Juan Berenguer, MD, and colleagues presented data from the GESIDA cohort, which assessed how well having a fibrosis stage ≥F3 on biopsy vs. a FIB-4 of ≥3.25 predicted both liver-related events and all-cause mortality. While both tests were predictive, the FIB-4 score was more accurate at predicting outcomes than liver biopsy.

At future meetings, I look forward to results from recently initiated phase 2 and 3 trials of potential interferon-free HCV DAA regimens in coinfected patients. Given the dramatically shortened treatment durations with new DAA-based regimens and the use of SVR12 as a primary endpoint, preliminary results from treatment trials are now available in a short time frame. I am expecting preliminary results from many of these phase 2 and 3 trials next year at CROI.

I believe that understanding the new HCV treatment regimens and how to manage drug-drug interactions will be key for any HCV primary care provider going forward. I see HIV treaters as a key component of those whom will be needed to treat HCV in the future. CROI provides a wonderful opportunity for practitioners to network and establish new research collaborations, as well as get up-to-date on the latest science in the fields of HIV and viral hepatitis.

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Susanna Naggie, MD, MHS

The Tuesday morning oral abstract session on hepatitis was critical, with two real take-home points. One, patients coinfected with HIV/HCV have the same response rates to DAA-inclusive therapies as patients monoinfected with HCV, and this is true with interferon-free regimens. Two, combinations of DAAs resulted in highly potent and efficacious regimens for the treatment of HCV. The question is how quickly can a patient with HCV be cured — data presented suggested 6 weeks or less — and will there be a one-size-fits-all or will more difficult-to-treat patients such as those with cirrhosis and nonresponders require longer courses of therapy?

The most exciting presentation was that of the SYNERGY trial, which investigated ribavirin-free triple DAA therapies. Although a pilot trial, results suggested that patients without cirrhosis can be cured in 6 weeks. This not only sets the stage for what is to come, but also reinvigorates the science to understand persistence and relapse. This is shorter than what most people imagined, and the investigators reported that they are also studying these same regimens for 4 weeks.

Susanna Naggie

There was a great deal of excitement at CROI about the all-oral interferon- and ribavirin-free regimens and excitement surrounding PHOTON-1, which is the first lead to the FDA approval of sofosbuvir in patients coinfected with HIV/HCV, making it the first DAA to be approved in this special population.

I look forward to seeing results of the combination DAA therapies in patients coinfected with HIV/HCV. Three phase 3 studies are currently enrolling these types of patients, so hopefully we will see some data at CROI 2015.

At next year’s meeting, one thing we might hear more about is the research that is presented in poster form. There were so many great posters this year investigating HCV screening and testing with linkage to care, HIV/HBV, cardiovascular disease outcomes in HIV/HCV and more.

Arthur Y. Kim, MD

What I took away from CROI 2014 was important information regarding the safety and efficacy of treatments for patients coinfected with HIV/HCV. We heard major findings reported for the first time.

The short answer of what was most important in my opinion is the SYNERGY study conducted at the National Institutes of Health. This study showed that with certain three-drug combination of DAA therapies for only 6 weeks, once achieved about 95% cure rates. The proof-of-concept that we could cure with only 6 weeks of therapy generated a bit of buzz.

Arthur Y. Kim

All-oral therapies are already here and will transform the treatment of HCV. After a patient management panel, during which Wyles, Naggie and Kenneth Sherman, MD, (professor of digestive diseases at University of Cincinnati College of Medicine) presented on how to care for patients with HCV, I overheard two groups basically saying that they didn’t need to refer to GI anymore — we should gear up to treat our own patients, presumably those who are HIV/HCV coinfected. The expansion of providers willing to treat HCV will be a critical issue in the future with these all-oral therapies.

It is clear to me that the treatment paradigms are changing rapidly. We look forward to clinical trials, especially in special populations — not only patients coinfected with HIV/HCV, but also substance-abusing persons and HIV-positive men who have sex with men — supplemented by reports from the so-called real-world experiences. Together, we can learn how to best take care of patients and what the future of HCV therapies will look like. I’d also expect by next year important data regarding the treatment of acute HCV infection.

HCV is becoming increasingly highlighted at CROI. It falls between the American Association for the Study of Liver Diseases’ (AASLD) The Liver Meeting and the European Association for the Study of the Liver (EASL) Annual Meeting, and it’s not surprising that investigators will choose to submit novel data regarding new treatment paradigms.

References:
Dieterich DT. Session O-1 Oral Abstracts. Faldaprevir plus pegylated interferon alfa-2a/ribavirin in HIV/HCV coinfection: STARTVerso4.
Dieterich DT. Session O-1 Oral Abstracts. Simeprevir (TMC435) plus pegIFN/ribavirin in HCV genotype-1/HIV-1 coinfection (Study C212).
Kohli A. Session O-1 Oral Abstracts. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: Final results of the SYNERGY trial.
Naggie S. Session O-1 Oral Abstracts. Sofosbuvir plus ribavirin for HCV genotype 1-3 infection in HIV coinfected patients (PHOTON-1). All presented at: CROI 2014; March 3-6, 2014; Boston.
Disclosures: Kim reports serving as a consultant/advisory board member for AbbVie and Gilead, and receiving research monies to his institution from Bristol-Myers Squibb and Gilead. Naggie reports receiving research grants or contracts that partially support her university salary from AbbVie, Achillion, Bristol-Myers Squibb, Gilead and Vertex; educational activities or lectures that generate revenue for her university from IAS-USA; and consulting/other non-CME services for AbbVie, Achillion, Bristol-Myers Squibb, Gilead and IDSA. Wyles reports receiving research grants for the conduct of clinical trials paid to UC Regents from AbbVie, Bristol-Myers Squibb, Gilead, Merck and Vertex, and serving as a paid consultant to AbbVie, Bristol-Myers Squibb, Gilead and Janssen.