A brighter future in the fight against hepatitis

Nature Medicine | Editorial

Nature Medicine 19, 791 (2013) doi:10.1038/nm.3269

Published online 08 July 2013

Public health and research efforts directed at managing and targeting viral hepatitis have borne fruit in recent decades. However, more work is necessary to meet the goals of preventing transmission and treating infection to eliminate the enormous burden of hepatitis worldwide.

In 2012, the World Health Organization (WHO) established a Global Hepatitis Program with the goal of fully preventing and treating viral hepatitis. This month, the WHO hopes to increase public awareness through the official World Hepatitis Day, on 28 July. In this issue, Nature Medicine features a series of Review and Perspective articles that discuss promising research and clinical efforts and continuing challenges in viral hepatitis.

Hepatitis B virus (HBV) and HCV are primarily responsible for the high global prevalence of hepatitis disease and for the morbidity and mortality associated with chronic infection. A key challenge for the management of hepatitis is its silent progression, as acute hepatic failure rarely occurs. Infection is often asymptomatic, causing liver scarring and damage decades later in up to 30% of people infected with HCV, and the proportion is even higher in those infected with HBV at birth or during early childhood. Inadequate recognition of infection and region-specific variation in prevalence and risk groups hinders diagnosis and precludes timely treatment. The lack of sufficiently widespread antibody screening to identify all exposed individuals and of follow up with RNA testing, a technique not yet available for routine medical use, to distinguish people with active virus, results in incorrect estimates of infection and increased transmission. In the case of hepatitis C, recent human studies showed that less than half of the infected people in the United States knew they carried the virus (Hepatology 55, 1652–1661, 2012), a number that may be higher in areas with limited disease-control tools. Moreover, the harsh side effects of pegylated interferon-α and ribavirin force many infected people to opt out of this standard therapy, contributing to viral persistence in the community and prevalence of chronic disease.

The advent of effective antivirals is changing the therapeutic landscape, and the goal for eradicating hepatitis viruses may not be as distant as it seemed five years ago, high treatment costs notwithstanding. Current antiviral therapies do not cure chronic hepatitis B, which affects about 210 million people worldwide. At the 2013 International Liver Congress, new approaches to eliminate the HBV replication template, which persists inside liver cells, by modulating host processes such as epigenetic mechanisms and hepatocyte regeneration showed promise and may offer the potential of a cure in the future. For HCV, which affects about 150 million individuals worldwide, there have been rapid advances in drugs. Two protease inhibitors approved in 2011 greatly improved responses in patients infected with the predominant genotype 1; however, host genetic variability affecting antiviral efficacy, evolving drug resistance and the lack of coverage to inhibit all existing HCV genotypes are major drawbacks. Also, these new drugs must be given with the standard therapy, which exacerbates side effects. Second-generation antivirals with different viral targets are under development, and combination strategies should improve efficacy and may even eradicate the virus. Although these therapies are promising, resistance may still develop, and monitoring the emergence of resistant variants will be necessary for guiding treatment choices.

An interferon-free therapy for hepatitis C may also soon exist. In April, a triple combination of direct-acting antivirals without interferon showed efficacy in treatment-naive individuals and in nonresponders to standard of care. And in May, four clinical trials tested an inhibitor of viral polymerase, sofosbuvir, in patients infected with HCV (N. Engl. J. Med. 368, 1867–1887, 2013). In combination with ribavirin, sofosbuvir showed increased efficacy against genotypes 2 and 3 compared to both standard of care and placebo, and adding pegylated interferon alpha-2a to the combination achieved broad genotype coverage. Patients with unacceptable side effects to standard therapy or who were unresponsive to previous therapies may therefore benefit from these new approaches. Research on host factors required for the HCV life cycle has also yielded targets that may overcome virus-acquired resistance and circumvent side effects. A recent example is the targeting of microRNA-122, which is liver specific and necessary for viral replication (N. Engl. J. Med. 368, 1685–1694, 2013) Although long-term studies are necessary to address their safety and toxicity in the long run, interferon-free strategies may become the future of hepatitis C therapy.

But the holy grail for eradicating and decreasing the burden of any infectious disease is a prophylactic vaccine. Prevention of infection with the effective HBV vaccines and with improved medical and lifestyle practices has reached impressive levels in developed countries, and continuing efforts to improve testing and implement mass vaccination programs in low-income countries should achieve similar results in these regions. A working vaccine for HCV, however, still remains elusive, in part because of the lack of experimental systems to study the virus and the lack of animal models to test vaccine candidates. Moreover, because this virus has developed mechanisms of persistence and has an enormous genetic diversity, vaccines will need to induce both neutralizing antibodies and T cell–mediated responses to achieve broad, lasting cross-protection. Unraveling how the host immune response clears the virus during the course of natural infection and prevents persistence will help us understand what constitutes protective immunity and provide a rationale to develop an effective pan-genotype vaccine.

The goals of preventing infection, slowing disease progression and curing chronic hepatitis will undoubtedly require continuing research and clinical efforts. Pharmaceutical companies should be encouraged to keep investigating future compounds to overcome the existing therapeutic barriers, and public awareness efforts should be intensified to underscore to funding and public health agencies that, although we are closer, we are still far from achieving the goals proposed to tackle these silent elusive killers.

Source

Poor treatment outcomes common among children with HIV/HCV coinfection

Provided by Healio

July 8, 2013

European children with HIV/HCV coinfection often have poor outcomes from HCV therapy, according to results presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In a retrospective case note review, researchers identified 10 patients collected from four of 10 evaluated cohorts containing one or more patients coinfected with hepatitis C and HIV aged younger than 25 years. All patients had perinatal or early childhood HIV acquisition and had received HCV therapy with either pegylated interferon alfa-2a or alfa-2b (n=5 each) with ribavirin for a median duration of 48 weeks.

“Little is known about anti-HCV therapy and its outcomes in HIV/HCV coinfected children,” the researchers wrote. “Our aim was to document use and effectiveness of HCV treatment in HIV/HCV coinfected children and young people in Europe.”

The cohort included six females and four males, with eight cases of HCV genotype 1, one genotype 4 and one with an unknown genotype. The patients (median age at treatment initiation, 17.1 years) had a median HCV infection duration of 13.4 years. Among seven cases with evaluable fibrosis, stage F2 was observed in two cases, F3 in three and F4 in two cases.

One participant experienced early response, defined as undetectable HCV RNA at 12 weeks, and later achieved sustained virological response. No other participants experienced early or sustained response to therapy. No patients discontinued treatment due to adverse events, though investigators noted two cases of decreased neutrophil counts during treatment. One patient, who required retreatment 2 years after the treatment included in this study, died after liver transplantation.

“There is a very limited experience of treating HCV in HIV/HCV coinfected children,” the researchers concluded. “Our results show poor treatment outcomes in these cases, most of whom had advanced fibrosis and [genotype 1].”

For more information:

Turkova A. WEPE484: HCV Treatment in Children and Young Adults with HIV/HCV Coinfection in Europe. Presented at: IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.

Source

Interferon-based therapy similarly effective with normal, elevated ALT in HCV/HIV coinfected patients

Provided by Healio

July 8, 2013

Treatment with pegylated interferon alfa-2a and ribavirin yielded similar response rates in patients with HIV and HCV coinfection with elevated and persistently normal ALT in a study presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In the prospective, multicenter CONTRA study, researchers administered 180 mcg peginterferon-alfa-2a weekly and 1,000 mg to 1,200 mg ribavirin daily for 48 weeks to 80 patients coinfected with HIV and HCV. The cohort included 42 patients with normal ALT levels as measured five or more times within the prior 2 years (case group) and 38 patients with elevated ALT (controls). The two groups were similar with regard to age, sex, BMI, HCV genotype prevalence and HCV viral load.

Within the ITT population, sustained virologic response occurred at similar rates between the case (38%) and control groups (42%) (P=.7). Complete response also was observed in a similar number of participants between groups at week 4 (32% of cases vs. 33% of controls) and week 12 (49% vs. 60%) (P=.56).

Seventy-one percent of cases and 84% of controls experienced adverse events. Treatment discontinuation was required in 10% and 5% of patients, respectively, and one incident of opportunistic infection was observed in the control group. Treatment modification was required in 41% of cases and 45% of controls.

“The treatment with peginterferon-alfa-2a and ribavirin in coinfected patients with persistently normal ALT levels has a similar efficacy to the one observed in patients with elevated ALT serum,” the researchers concluded. “Regarding toxicity, no significant differences were detected between both groups. The same treatment criteria should be used in both types of coinfected patients.”

For more information:

von Wichmann MA. WEPE486: PegIFN-alfa-2a and Ribavirin in HIV-HCV Coinfected Patients with Persistently Normal Aminotransferase Levels: Final Results of the CONTRA Study. Presented at: IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.

Source

Early Therapy May Lead to HIV Remission

Published: Jul 7, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• These preliminary results from a randomized trial demonstrated that early HIV therapy in patients with symptoms of primary infection or CD4 counts < 500/mm³ led to marked reduction in viral DNA.
• Be aware that the primary purpose of the trial -- to evaluate the feasibility of stopping therapy in select patients -- has yet to be reported.

KUALA LUMPUR -- Preliminary data from a French randomized trial suggest that early HIV treatment might be a step toward so-called post-treatment control, a researcher said here.

Post-treatment control is what investigators are calling the ability to stop HIV therapy -- after some time on treatment -- without having the virus resume replication within the body.

Some 14 patients -- known as the Visconti cohort and all treated within weeks of their infection -- have been shown to have such control, some for several years, according to Antoine Cheret, MD, of Sorbonne-Paris-Cite University in Paris.

At the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention here, Cheret presented early data from the first randomized trial aimed at duplicating the Visconti cohort.

The Optiprim study has enrolled 90 patients with early HIV infection and randomly assigned them to 24 months of a standard triple-drug regimen -- boosted darunavir (Prezista) plus tenofovir/emtricitabine (Truvada) -- or the same regimen plus raltegravir (Isentress) and maraviroc (Selzentry).

The primary endpoint of the study is what happens to the levels of HIV DNA -- regarded as the indicator of the reservoir if HIV needed to resume replication -- after the treatment period.

But at that time, Cheret reported, investigators plan to stop treatment for 6 months to see if either regimen leads to post-treatment control.

The "only problem with the presentation is they didn't have the results," commented Robert Murphy, MD, of Northwestern University Feinberg School of Medicine in Chicago.

Nonetheless, Murphy, who's involved in studies aimed at eradicating HIV reservoirs as a potential step to remission, said the data Cheret presented -- overall information about control of HIV and decline in HIV DNA -- is important.

"This will help in designing future trials," he said, even though it's preliminary.

At baseline, Cheret reported, the 90 patients were within a few weeks of infection, had a median plasma viral load of 5.4 log₁₀ copies of HIV RNAS per milliliter, and a median of 472 CD4-positive T cells per microliter of blood.

They also had a median of 3.65 log₁₀ copies of HIV DNA per million peripheral blood mononuclear cells (PBMCs).

As expected, viral loads declined during treatment with 92% of patients having undetectable levels after a year and CD4 cell counts rose by a median of 235 cells.

And HIV DNA fell by a median of 1.43 log₁₀ copies per million PBMCs, while one in four patients had a drop of at least 2.0 log₁₀ copies, Cheret reported.

While it would have been nice to see the data broken down by treatment group, "these are very important numbers," Murphy commented.

The study had support from Merck, Janssen, ViiV Healthcare, and Gilead.

Cheret made no disclosures.

Murphy reported financial links with Gilead.

Primary source: International AIDS Society
Source reference:
Cheret A, et al "Impact of 12 months HAART on cell-associated HIV-DNA in acute primary HIV-1 infection in the OPTIPRIM-ANRS 147 trial" IAS 2013; Abstract WEAB0101.

Source

2013 SVR Updates

Provided by HIV – HCV - TB Pipeline Report

SVR in HCV Genotype 1, Treatment-Naive: Interferon-Free Regimens

Study/Drug	Population/Size	Treatment Arms	SVR
			Overall	HCV Subtype: 1a vs. 1b	IL28B: CC vs. non-CC
AVIATOR ABT-450/r +/- ABT-267 +/- ABT-333 +/- RBV   Phase II AbbVie	Non-cirrhotic (N = 571)	8-week, 4-drug	SVR-24: 88%	Overall: 91% vs. 98%	Overall: 95% vs. 89%
		12-week, 3-drug (no ABT-267)	83%
		12-week, 3-drug (no ABT-333)	89%
		12-week, 3-drug (no RBV)	87%
		12-week, 4-drug	96%
		24-week, 4-drug	90%
AI444-040 daclatasvir + sofosbuvir +/- RBV   Phase II Bristol-Myers Squibb/Gilead	Non-cirrhotic (N = 126)	24-week, 2-drug (7-day sofosbuvir lead-in, no RBV)	SVR-24: 93%	No impact
		24-week, 2-drug (no RBV)	100%
		24-week, 3-drug	100%
		12-week, 2-drug (no RBV)	SVR-12: 100%
		12-week, 3-drug	SVR-12: 100%
AI443-014 daclatasvir + asunaprevir  + BMS-791325   Phase II Bristol-Myers Squibb	Non-cirrhotic (N = 32)	12-week	SVR-24: 94%	No impact
		24-week	SVR-24: 88%
ELECTRON sofosbuvir + RBV   Phase II Gilead	Non-cirrhotic (N = 25)	12-week	SVR-24: 84%	No impact
ELECTRON FDC: sofosbuvir/ledipasvir + RBV	Non-cirrhotic (N = 25)	12-week	SVR-12: 100%	No impact
ELECTRON sofosbuvir + GS-9669 + RBV	Non-cirrhotic (N = 25)	12-week	SVR-12: 92%	No impact
LONESTAR sofosbuvir + ledipasvir +/- RBV   Phase II Gilead	Non-cirrhotic (N = 60)	8-week, 2-drug (no RBV)	SVR-8: 95%	No impact
		8-week, 3-drug	SVR-8: 100%
		12-week, 2-drug (no RBV)	SVR-4: 100%
SPARE sofosbuvir + weight-based (WB) or low-dose (LD) RBV   Phase II National Institutes of Health/Gilead	Non-cirrhotic (N = 10)	24-week, WB RBV	SVR-24: 90%	No impact (most participants were HCV genotype 1a, non-CC IL28B, high baseline HCV RNA, and African American)
	All stages fibrosis (N = 50); advanced fibrosis/ compensated cirrhosis (13/50)	24-week, WB RBV	SVR-12: 68%
		24-week, LD RBV	SVR-12: 48%
QUANTUM sofosbuvir + RBV   Phase II Gilead	Non-cirrhotic (N = 50); 6% cirrhotic	12-week	SVR-12: 56%	No impact	100% vs. 42%
		24-week	52%		67% vs. 47%

Sources:

Everson GT, Simms KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free, 12-week regimen of daclatasvir  (DCV), asunaprevir (ASV) and BMS-791325 yielded SVR-4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection (Abstract LB-3). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 November 9–13; Boston, Massachusetts.

Everson GT, Simms KD, Rodriguez-Torres M, et al. Interim analysis of an interferon (IFN)- and ribavirin-(RBV) free regimen of daclatasvir (DCV), asunaprevir (ASV) and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients (Abstract 1423). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953.

Gane EJ, Stedman CA, Hyland RH, Ding X, Pang PS, Symmonds WT. ELECTRON: 100% SVR rates for once-daily sofosbuvir plus ledipasvir plus ribavirin given for 12 weeks in treatment-naive and previously treated patients with HCV genotype 1 (Abstract 41 LB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI); 2013 March 3–6; Atlanta, Georgia. Abstract available from: http://www.retroconference.org/2013b/Abstracts/47869.htm. (Accessed on 2013 April 15)

Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV GT1 infection: the ELECTRON study (Abstract 14).  Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Gilead Sciences (Press Release). Gilead reports interim data from phase 2 LONESTAR study. 2013 May 2. Available from: http://www.gilead.com/news/press-releases/2013/5/gilead-reports-interim-data-from-phase-2-lonestar-study. (Accessed on May 2, 2013)

King M, Xie W, Larsen L, Cohen D, Podsadecki, T, Bernstein B.  Risk of virologic relapse in hepatitis C virus GT1-infected subjects after 8, 12, and 24 weeks of ABT-450/r+ABT-267+ABT-333+ribavirin: identifying optimal treatment duration (Abstract 39). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, Georgia. Abstract available from: http://www.retroconference.org/2013b/Abstracts/46833.htm. (Accessed on April 15, 2013)

Kowdley KV, Lawitz E, Poordad F, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR-12 rates of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection (Abstract LB-1). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9–13; Boston, Massachusetts.

Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV genotype 1: results from the AVAITOR study (Abstract 3). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Lalazeri JP, Nelson DR, Hyland RH, et al. Once-daily sofosbuvir plus ribavirin given for 12 or 24 weeks in treatment-naïve patients with HCV: the QUANTUM study (Abstract 845). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Osinusi A, Meissner EG, Bon D, et al.; NIAID SPARE Study Team. High efficacy of sofosbuvir in combination with weight-based ribavirin for 24 weeks in difficult to treat HCV infected genotype-1 patients (Abstract 157-LB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, Georgia. Available from: http://www.retroconference.org/AbstractSearch/default2.aspx?conf=22. (Accessed on 2013 May 2)

Sulkowski MS, Gardnier DF, Rodriguez-Torres M, et al; for the AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 (Abstract LB-2). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 November 9–13; Boston, Massachusetts.

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SVR in HCV Genotype 1, Treatment-Naive: Interferon-Sparing Regimens

Study/Drug	Population/Size	Treatment Arms	SVR
			Overall	HCV Subtype: 1a vs. 1b	IL28B: CC vs. non-CC
ATOMIC sofosbuvir + PEG-IFN/RBV   Phase II Gilead	Non-cirrhotic (N = 316)	12-week, 3-drug	SVR-24: 89%	Not reported; 10/11 relapsers had non-CC genotype
		24-week	SVR-24: 89%
		12-week, 3-drug + 12-week SOF or SOF/RBV	SVR-24: 87%
NEUTRINO sofosbuvir + PEG-IFN/RBV   Phase III Gilead	N = 291 17% cirrhotic	12-week	SVR-12: 100% Cirrhotic: 80% Non-cirrhotic: 92%	92% vs. 82%	98% vs. 87%

Sources:

Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013 Mar 14. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60247-0/fulltext. (Accessed on 2013 April 20)

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Apr 23. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1214853. (Accessed on 2013 May 2)

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SVR in HCV Genotype 1, Treatment-Experienced: Interferon-Free Regimens

Study/Drug	Population/Size	Treatment Arms	SVR
			Overall	HCV Subtype: 1a vs. 1b	IL28B: CC vs. non-CC
AVIATOR ABT-450/r + ABT-267 +/- ABT-333 + RBV   Phase II AbbVie	Non-cirrhotic, null responders (N = 133)	12-week, 3-drug (no ABT-333)	SVR-24: 89%	93% vs. 97%	94% vs. 100%
		12-week, 4-drug	93%
		24-week, 4-drug	95%
AI444-040 daclatasvir + sofosbuvir +/- RBV   Phase II Bristol-Myers Squibb/Gilead	Non-cirrhotic, prior boceprevir or telaprevir use (N = 41)	24-week, 2-drug (no RBV)	SVR-12: 100%	No impact
		24-week, 3-drug	100%
		24-week	SVR-24: 88%
COSMOS (Interim data) simeprevir + sofosbuvir +/- RBV   Phase II Janssen/Gilead	Non-cirrhotic, null responders (N = 80) 100% non-CC genotype	12-week, 2-drug	SVR-8: 92.9%	No impact		N/A
		12-week, 3-drug	96.3%
		24-week, 2-drug	100% (5/5)
		24-week, 3-drug	66.7% (4/6)
ELECTRON sofosbuvir + RBV   Phase II Gilead	Non-cirrhotic, null responders (N = 10)	12-week	SVR-24: 11%	No impact
ELECTRON FDC: sofosbuvir/ledipasvir + RBV	Non-cirrhotic, null responders (N = 10)	12-week	SVR-4: 100%	No impact
LONESTAR (Interim data) sofosbuvir + ledipasvir +/-RBV   Phase II Gilead	Non-cirrhotic, prior boceprevir or telaprevir use (N = 40)	12-week, 2-drug (no RBV)	SVR-4: 95%	No impact
		12-week, 3-drug	SVR-4: 95%
QUANTUM (Retreatment) sofosbuvir + RBV   Phase II Gilead	N = 105 10% cirrhotic in control or discontinued arms	24-week, 2-drug retreatment	SVR-12: 66%	71% vs. 48%	84% vs. 63%

Sources:

Gane EJ, Stedman CA, Hyland RH, et al.  Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34-44. doi:10.1056/NEJMoa1208953.

Gane EJ, Stedman CA, Hyland RH, Ding X, Pang PS, Symmonds WT. ELECTRON: 100% SVR rates for once-daily sofosbuvir plus ledipasvir plus ribavirin given for 12 weeks in treatment-naive and previously treated patients with HCV genotype 1 (Abstract 41 LB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, Georgia. Available from: http://www.retroconference.org/2013b/Abstracts/47869.htm. (Accessed on 2013 April 21)

Gane EJ, Stedman CA, Hyland RH, et al. ELECTRON: all-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV GT1 infection (Abstract 14). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Gilead Sciences (Press Release). Gilead reports interim data from phase 2 LONESTAR study. 2013 May 2. Available from: http://www.gilead.com/news/press-releases/2013/5/gilead-reports-interim-data-from-phase-2-lonestar-study. (Accessed on 2013 May 2)

Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV genotype 1: results from the AVIATOR study (Abstract 3). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment: results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT1 null repsonders (Abstract 155 LB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, Georgia. Available from: http://www.retroconference.org/2013b/Abstracts/47930.htm. (Accessed on 2013 April 18)

Lalazeri JP, Nelson DR, Hyland RH, et al. Once-daily sofosbuvir plus ribavirin given for 12 or 24 weeks in treatment-naïve patients with HCV: the QUANTUM study (Abstract 845). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC) (Abstract 1417). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

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SVR in HCV Genotypes 2 and 3

Study/Drugs	Population/Size	Genotype	Treatment Arms	SVR
AI444-040 daclatasvir + sofosbuvir +/−RBV   Phase II Bristol-Myers Squibb/Gilead	Treatment-naive, non-cirrhotic (N = 44)	Genotypes 2 and 3	24-week, 2-drug (7-day sofosbuvir lead-in, no RBV)	SVR-24: 88%
			24-week, 2-drug (no RBV)	SVR-24: 100%
			24-week, 3-drug	SVR-24: 93%
COMMAND GT 2/3 daclatasvir + PEG-IFN/RBV vs. placebo + PEG-IFN/RBV   Phase II Bristol-Myers Squibb	Treatment-naive, 20% cirrhotic (G3 only) (N = 151)	Genotype 2	12-week (N = 24)	SVR-24: 88%
			16-week (N = 23)	SVR-24: 83%
			placebo (N = 24)	SVR-24: 63%
		Genotype 3	12-week (N = 26)	SVR-24: 69%
			16-week (N = 27)	SVR-24: 70%
			placebo (N = 27)	SVR-24: 59%
ELECTRON sofosbuvir + RBV + 0, 4, 8, or 12 weeks of PEG-IFN vs. sofosbuvir monotherapy   Phase II Gilead	Treatment-naive, non-cirrhotic (N = 60)	Genotypes 2 and 3	8-week, 3-drug  (N = 10)	SVR-24: 100%
			12-week, with 4-week PEG-IFN (N = 9)	SVR-24: 100%
			12-week, with 8-week PEG-IFN (N = 10)	SVR-24: 100%
			12-week, 3-drug (N = 11)	SVR-24: 100%
			12-week, no PEG-IFN (N = 10)	SVR-24: 100%
			12-week, sofosbuvir only (N = 10)	SVR-24: 60%
FISSION sofosbuvir + RBV vs. PEG-IFN/RBV   Phase III Gilead	Treatment-naive, 20% cirrhotic (N = 499)	Genotype 2	12-week sofosbuvir + RBV	SVR-12: 97% Cirrhotic: 91% Non-cirrhotic: 98%
			24-week PEG-IFN/RBV	SVR-12: 78% Cirrhotic: 62% Non-cirrhotic: 82%
		Genotype 3	12-week sofosbuvir + RBV	SVR-12: 56% Cirrhotic: 34% Non-cirrhotic: 61%
			24-week PEG-IFN/RBV	SVR-12: 63% Cirrhotic: 30% Non-cirrhotic: 71%
FUSION sofosbuvir + RBV   Phase III Gilead	Treatment-experienced, 34% cirrhotic (N = 201)	Genotype 2	12-week	SVR-12: 86% Cirrhotic: 60% Non-cirrhotic: 96%
			16-week	SVR-12: 94% Cirrhotic: 78% Non-cirrhotic: 100%
		Genotype 3	12-week	SVR-12: 30% Cirrhotic: 19% Non-cirrhotic: 37%
			16-week	SVR-12: 62% Cirrhotic: 61% Non-cirrhotic: 63%
POSITRON sofosbuvir + RBV   Phase III Gilead	Treatment naive, interferon-ineligible, -intolerant, and -unwilling, 15% cirrhotic (N = 207)	Genotype 2	12-week	SVR-12: 93% Cirrhotic: 94% Non-cirrhotic: 92%
		Genotype 3	12-week	SVR-12: 61% Cirrhotic: 21% Non-cirrhotic: 68%
PROTON sofosbuvir + PEG-IFN/RBV   Phase II Gilead	Treatment-naive, non-cirrhotic (N = 25)	Genotypes 2 and 3	12-week	SVR-12: 92%

Sources:

Dore GJ, Lawitz E, Hézode C, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with hepatitis C virus genotype 2 or 3 infection: COMMAND GT 2/3 study (Abstract 1418). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24–28; Amsterdam, the Netherlands.

Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013 Apr 23. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1214854. (Accessed 2013 May 3)

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Apr 23. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1214853. (Accessed 2013 May 3)

Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013 May;13(5):401–8. doi: 10.1016/S1473-3099(13)70033-1

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SVR in HCV Genotype 4, 5, and 6, Treatment-Naive: Interferon-Sparing Regimens

Study/Drug	Population	HCV Genotype/Size	Duration	SVR
ATOMIC sofosbuvir + PEG-IFN/RBV   Phase II Gilead	Non-cirrhotic	Genotype 4 (N = 11)	24-week	SVR-24: 82%
		Genotype 5 (N = 6)		SVR-24: 82%
NEUTRINO sofosbuvir + PEG-IFN/RBV   Phase III Gilead	Liver histology not available	Genotype 4 (N = 28)	12-week	SVR-12: 96%
		Genotype 5 (N = 1)		SVR-12: 100%
		Genotype 6 (N = 6)		SVR-12: 100%

Sources:

Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013 Mar 14. Available from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60247-0/fulltext. (Accessed on 2013 April 20)

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Apr 23. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1214853. (Accessed on 2013 May 2)

Source