HCV in 2011: Ebb Tide, or the Gathering Storm?

The current issue of Seminars is a snapshot of the hepatitis C virus (HCV) epidemic at a pivotal moment. This year, the first direct-acting antiviral drugs for hepatitis C were introduced into the clinic, and jaw-dropping data were presented at international meetings showing that interferon-free regimens can lead to sustained virologic responses in only 12 weeks. These are heady achievements! Global eradication of HCV glitters on the horizon—a fitting reward for the Herculean efforts that have made this moment possible. However, objects at the horizon are often farther away than they seem. In the past, many promising drugs have ended up in the pharmaceutical graveyard. The long history of late drug failures means that the push for new HCV drugs needs to continue at full force. There are other major problems that are unrelated to the high pharmaceutical dropout rate. Half or more of the HCV-positive patients in the United States are not aware of their infection and thousands need better access to care. Even patients fortunate to achieve a sustained virologic response often continue to suffer from liver-related morbidity, according to Innes et al.[1] With millions of patients progressing toward end-stage liver disease at an ever-increasing pace, it is no wonder that excitement about the new direct-acting antiviral drugs coexists with a sense of urgency and dread. This issue provides guideposts for addressing the difficult challenges that lie ahead.

In the first article, “What Is Killing People Who Are Infected with HCV?” Jason Grebely and Gregory Dore provide a revised and grim view of HCV natural history. Based on mortality statistics from cohorts around the world, they establish that end-stage liver disease is claiming an increasing percentage of patients with chronic HCV infection. The thousands of baby boomers who acquired HCV through injection drug use are reaching middle age (and beyond). As this happens, the percentage of drug-related deaths (overdose, suicide, and accidents) is falling and the fraction of liver-related deaths is increasing at an ominous rate. It now stands at ∼10 to 20%; however, according to a projection by Rein et al, unless effective antiviral treatment bends the survival curve, ∼35% of people with chronic HCV infection will die of liver-related causes.[2] These sobering data indicate that hepatitis C is more lethal than many once thought. They underscore the need for broader HCV screening and treatment, and the need to prepare for the tidal wave of patients with end-stage liver disease and hepatocellular carcinoma (HCC) that almost inevitably will be arriving in clinics in the decades ahead.

Current approaches for managing these patients are presented in the article by Jawad Ahmad and me, “HCV and HCC: Clinical Update and a Review of HCC-Associated Viral Mutations.” Approaches for HCC screening and treatment options are discussed. In addition, the article contains information about an interesting set of HCV mutations that are associated with HCC. These mutations have been studied intensively in Japan. They appear to enhance the oncogenic potential of the strains that harbor them, countering the prevailing view that HCV lacks oncogenic sequence variants or strains. To our surprise, my research group recently discovered that the HCC-associated mutations profoundly alter HCV gene expression, regulating the levels of a previously unknown family of HCV proteins (minicores). These novel viral proteins and their associated mutations offer a unique opportunity to investigate HCV pathogenesis at the molecular level.

Continuing with the theme of unexpected findings, this issue's Diagnostic Problems in Hepatology presents, “A Maxed-Out Liver: A Case of Acute-On-Chronic Liver Failure,” by Gene Im, Sofia Kazi, Swan Thung, and Ponni Perumalswami. Their report is a reminder that HCV patients often have multiple serious comorbidities and that they may be unusually susceptible to severe drug-induced liver injury. This case of acute-on-chronic liver failure occurred in a 51-year-old man with HCV-related cirrhosis, HIV infection, sickle cell trait, and a history of marginal zone B cell lymphoma. This man's end-stage liver disease was treated by replacing the failed organ with a liver transplant. The biopsy and repeated questioning of the patient revealed the etiology of liver failure. This catastrophe was precipitated by the use of MaxOne^®, a product advertised as promoting detoxification.

Although the burden of HCV-related end-stage liver disease and the number of patients awaiting liver transplantation is growing, a bright side of the HCV epidemic is the decrease in new infections that has occurred in many parts of the world. The factors responsible for changes in the incidence of HCV are discussed by Miriam Alter in her article, “HCV Routes of Transmission: What Goes Around Comes Around.” She ably demonstrates how a technological innovation—mass production of hypodermic syringes—acted as an accelerant in the spread of HCV, allowing it to establish a global presence with the help of health care providers and recreational drug users who made use of the inexpensive syringes. Fueled by high-risk sexual practices and recreational drug use, HCV has recently entered a new community. Infection is occurring at an increased frequency in HIV-positive men who have sex with men. Although the specifics change, key factors in HCV transmission continue to be lack of HCV awareness, poor infection control, and the insidious background level of hepatitis C, which lies ready to seed new infections whenever the opportunity arises. HCV's varied routes of transmission demonstrate the remarkable ability of this ancient and resilient virus to capitalize on both old and new human foibles.

HCV's survival strategies are as fascinating and varied as its routes of transmission. Patrizia Farci discusses some of its survival tactics in her article, “New Insights into the HCV Quasispecies and Compartmentalization.” As she explains, the adaptive immune system seems to ignore high-level HCV replication for the first 8 to 12 weeks of infection. During this lapse, HCV replicates without the constraints that would otherwise be imposed by the adaptive immune system, using its low-fidelity RNA polymerase and ability to accommodate sequence change to create a large and diverse viral population that poses an insurmountable challenge when the adaptive immune system finally mounts an attack. Sequence diversification undoubtedly contributes to HCV's peculiar ability to evade the immune system and establish persistent infection in up to 85% of infected individuals, most of whom are immunocompetent. However, despite the advances in our knowledge, Dr. Farci concludes that more research is needed to fully elucidate how HCV achieves persistent infection.

Other viruses that establish persistent infection, such as HIV, HBV, HPV, and herpes viruses, use DNA for one or more steps in their replication cycles. In contrast to them, HCV relies solely on RNA, which is far less stable than DNA. Robert Ralston, Ira Jacobson, and Margaret Scull consider how HCV RNA avoids clearance in their thought-provoking article, “The Conundrum of Relapse in STAT-C Therapy: Does HCV Play the Red Queen or Rip van Winkle?” Their point of departure is the observation that patients often have undetectable HCV RNA during treatment, but later relapse. They review data from patients who relapsed following triple therapy with interferon, ribavirin, and boceprevir, an HCV protease inhibitor. Intriguingly, the virus in the relapsers was often wild-type. The surprising absence of resistance mutations could mean that HCV avoided clearance by suspending its replication cycle, thereby avoiding drug-selection pressure. This is a revolutionary idea. No RNA virus is known to enter such a latent phase. However, HCV has produced many surprises in the past, and a latent phase cannot be ruled out based on existing data. This possibility needs to be investigated further because a latent phase could give HCV an additional edge that antiviral drugs will need to overcome.

Whatever its elaborate natural defenses, it will be difficult for HCV to hold off the pharmaceutical armamentarium that is being amassed against it. In their article, “The Era of Direct-Acting Antivirals Has Begun: The Beginning of the End for HCV?” Marie-Louise Vachon and Douglas Dieterich review the many antiviral drugs in the pharmaceutical pipeline. It is impossible to read their piece and not be buoyed by a sense of optimism. The war on HCV is a grudge match for Dr. Dieterich, who acquired HCV through a needle stick while a medical student. For years, he has drawn on his own painful experiences to help patients deal with their disease. When they protest, “Doc, you don't know what I am going through!” He guffaws, “Au, contraire!” The article shows how his dedication, combined with the determination of many additional hepatologists and researchers, led to the development and testing of the first-generation drugs. These efforts are now leading to less toxic and more potent second-generation antivirals. Everyone who participated in this biomedical success story should take at least one night off to celebrate! Progress in antiviral drug development is hastening the day when HCV-related mortality will be on the wane. This cannot happen soon enough.

Just as new research methods are allowing the discovery and refinement of antiviral drugs, they are also providing insights into human susceptibility genes. A major breakthrough in this field came a few years ago with the discovery that single nucleotide polymorphisms (SNPs) in the region upstream of the IL28B coding sequence are associated with spontaneous clearance of HCV and with sustained virologic response rates. The IL28B gene is one of three genes reviewed with exceptional clarity in the article by Esperance Schaefer and Raymond Chung entitled, “The Impact of Human Gene Polymorphisms on HCV Infection and Disease Outcome.” If you have been wondering why TT is bad in the context of rs12978960, but good in the context of rs8099917, this article will help you out. I highly recommend it. Even though you cannot change the genes your patients were born with, knowledge of how to manage genetic risk factors will be increasingly important in optimizing medical care in the years ahead.

In addition to managing genetic risk, optimal care also depends on making sure patients' basic nutritional requirements are met. Recent data indicate that many HCV-positive patients are not getting as much vitamin D as they should, as discussed in the article by Julio Gutierrez, Neil Parikh, and me, “Classical and Emerging Roles of Vitamin D in Hepatitis C Infection.” To understand the importance of vitamin D, it is critical to realize that vitamin D is a steroid hormone. As such, vitamin D binds its nuclear receptor and regulates the expression of hundreds of cellular genes. Given this mechanism of action, it is not surprising that vitamin D deficiency (defined as a 25-hydroxyvitamin D level below 20 ng/mL) has adverse effects on multiple organ systems. Vitamin D deficiency is extremely common in HCV-positive patients and likely increases the risk of bone fracture, especially in liver transplant patients. Several studies show that sustained virologic response rates are negatively impacted by vitamin D deficiency, although these results remain controversial. Cell culture and animal studies reveal that vitamin D can synergize with interferon to reduce HCV replication and demonstrate that it can mitigate fibrosis progression. Vitamin D supplements improve longevity in the general population and should be considered for patients who are deficient. The article concludes with an algorithm for determining the appropriate vitamin D dose in HCV-positive patients.

In closing, I greatly enjoyed working on this issue and want to thank the authors and Editor Berk for their valuable contributions and for their commitment to improving the health of patients with hepatitis C and other liver diseases through research. I also want to thank Jag Khalsa (NIDA), Edward Doo and Jay Hoofnagle (NIDDK), Betsy Read-Connole (NCI), and Rajen Koshy (NIAID) for their enormous efforts on behalf of the HCV research community.

REFERENCES

• 1 Innes H A, Hutchinson S J, Allen S on behalf of the Hepatitis C Clinical Database Monitoring Committee et al. Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care.  Hepatology. 2011;  54 (5) 1547-1558
• 2 Rein D B, Wittenborn J S, Weinbaum C M, Sabin M, Smith B D, Lesesne S B. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States.  Dig Liver Dis. 2011;  43 (1) 66-72