Necrolytic acral erythema

Dermatology Online Journal
Volume 16 Number 11
November 2010

Utpal Patel MD PhD, Aaron Loyd MD, Rishi Patel MD, Shane Meehan MD, Roopal Kundu MD
Dermatology Online Journal 16 (11): 15
Department of Dermatology, New York University, New York, New York

Abstract

Necrolytic acral erythema (NAE) is a recently recognized dermatosis almost exclusively associated with hepatitis C virus (HCV) infection and closely related to a group of necrolytic erythemas and metabolic syndromes. NAE is characterized by pruritic, symmetric, well-demarcated, hyperkeratotic, erythematous-to-violaceous, lichenified plaques with a rim of dusky erythema on the dorsal aspects of the feet and extending to the toes. Based on morphology and histopathologic features, NAE can be difficult to distinguish from certain groups of necrolytic erythemas, which include necrolytic migratory erythema, acrodermatitis enteropathica, biotin deficiency, niacin deficiency, and essential fatty acid deficiencies. The condition is particularly important for clinicians to diagnose because the majority of the patients present to dermatologists without a known history of HCV infection. Thus, NAE can serve as a cutaneous marker for underlying HCV infection. Resolution of NAE can be achieved by treatment of the underlying HCV infection and the use of oral zinc therapy.

History

Figure 1

Figure 2

A 53-year-old woman presented to the Charles C. Harris Skin and Cancer Pavilion with a scaly, lichenified, pruritic eruption over the dorsal aspects of the feet and ankles for approximately one year. A diagnosis of eczematous dermatitis initially was made, and she was treated with triamcinolone 0.1 percent ointment and urea cream. This treatment led to resolution of the pruritus; however, there was minimal improvement of the cutaneous lesions. A biopsy was performed, and patch tests to the North American Standard Series and shoe series were negative. Review of systems was not contributory.

Past medical history included dermatomyositis that was treated with intravenous immunoglobin, hepatitis C virus infection treated with ribavarin and INF-α, cataracts, and iron-deficiency anemia. The patient was treated with zinc sulfate 220 mg twice daily. There was partial resolution of the plaques over three months of treatment.

Physical examination

Symmetric, sharply-demarcated, hyperkeratotic, violaceous, hyperpigmented, lichenified plaques were present on the dorsal aspects of the feet and extended to the toes and over the Achilles tendons.

Laboratory data

A comprehensive metabolic profile, complete blood count, thyroid function tests, amylase, lipase, and zinc levels were normal. Hepatitis C virus RNA count was measured at 11.5 x 106 IU/mL, and the genotype was determined to be type IA. Ultrasound and a computed tomography scan of the abdomen showed no evidence of cirrhosis, portal hypertension, or hepatocellular carcinoma.

Histopathology

There is a superficial, perivascular inflammatory infiltrate comprised predominantly of lymphocytes. Some lymphocytes extend to a hyperplastic epidermis where there are spongiosis and foci of sharply demarcated parakeratosis. There is slight pallor of the superficial epidermis.

Comment

Necrolytic acral erythema (NAE) is a recently recognized dermatosis, which is almost exclusively associated with hepatitis C virus infection and is closely related to a group of necrolytic erythemas and metabolic syndromes. It was first described in 1996 in Egyptian patients with hepatitis C virus (HCV) infection [1]. NAE is characterized by pruritic, symmetric, well-demarcated, hyperkeratotic, erythematous-to-violaceous, lichenified plaques with a rim of dusky erythema on the dorsal aspects of the feet and extending to the toes. The average patient age is 40 years (range from 11 to 76 years) and there is no sex predilection [2]. Since the initial report, over 70 cases have been described worldwide, including Pakistan, India, United States, and Taiwan, but the vast majority of reports have come from Egypt [3-18]. The disproportionate regional distribution is likely due to several factors: 1. The worldwide prevalence of HCV infection is 3 percent, whereas in Egypt it is estimated to be 15 to 20 percent. 2. There are differences in the HCV genotype. 3. There is likely a lack of clinical awareness of the condition among physicians [12, 14, 19]. NAE is particularly important for clinicians to diagnose because the majority of patients present to dermatologists without a known history of HCV infection [12, 14] Thus, NAE can serve as a cutaneous marker for underlying HCV infection.

Based on a longitudinal study, NAE develops in three stages, with variable degrees of pruritus and/or burning [14]. The initial stage is characterized by scaly, dusky papules with an erythematous rim. The lesion then progresses to the fully-developed, erythematous-to-violaceous, lichenified, scaly plaque. In the third stage, the lesion progressively thins and exhibits increased hyperpigmentation. The most common sites of involvement are the dorsal aspects of the feet, over the Achilles tendons, malleoli, legs, and knees. Less frequent sites of involvement include the elbows, hands, buttocks, and genitalia. There is sparing of the palms, soles, face, and mucous membranes [12]. Histopathologic features include a non-specific psoriasiform pattern [5, 14, 17], acanthosis, papillomatosis, and hyper- and parakeratosis, with necrotic keratinocytes in the superficial epidermis. NAE can be difficult to distinguish from certain groups of necrolytic erythemas, which include necrolytic migratory erythema, acrodermatitis enteropathica, biotin deficiency, niacin deficiency, and essential fatty acid deficiencies. However, these entities can be distinguished based on clinical and laboratory evaluation [8].

Although a number of mechanisms have been proposed for NAE, there is insufficient evidence to support a precise pathogenesis. The most consistent finding associated with NAE is HCV infection. In fact, there are only four reported cases of NAE without associated HCV infection [3, 4, 8]. Furthermore, two of three studies have observed a correlation between the severity of HCV infection (based on liver enzymes) and the severity of NAE [1, 13, 14]. Additional support comes from cases in which treatment of HCV with ribavarin and INF-α has lead to resolution of NAE [1, 14, 16]. The mechanism by which HCV infection causes NAE is not clear. Attempts to demonstrate HCV viral particles in the involved skin with electron microscopy (for viral particles) or with real time polymerase chain reaction (for HCV RNA) have been unsuccessful [12]. NAE may arise secondary to HCV viral antigen-induced humoral and/or cell-mediated autoimmune responses to viral and/or endogenous cutaneous antigens. Yet another possibility is the development of metabolic abnormalities secondary to hepatocellular dysfunction from HCV infection, which leads to cutaneous manifestations [20, 21].

The next most consistent finding associated with NAE is zinc deficiency, which may result from HCV infection. There are a number of studies that demonstrate decreased zinc levels in patients with NAE [11, 13]. When patients with laboratory evidence of zinc deficiency are treated with zinc (at doses ranging from 60 mg to 440 mg per day), clinical improvement has been noted that ranges from mild to complete resolution [1, 7, 9, 11, 12, 13, 18]. The most consistent improvement is noted at the dose of 440 mg per day. Even in patients with normal serum zinc levels, zinc supplementation has lead to clinical improvement of NAE. It is thought that zinc deficiency may occur in the skin prior to the development of clinical zinc deficiency as assessed by serum zinc levels [22].

Other metabolic conditions that are less clearly associated with NAE are hypoalbuminemia, which is possibly due to the role of albumin as a carrier for essential nutrients that include zinc; hypoaminoacidemia, which is secondary to depletion of epidermal protein and which may increase susceptibility of keratinocytes to necrolysis; and elevated glucagon levels, which are thought to cause elevated levels of pro-inflammatory arachidonic acid and its metabolites [1, 13, 16, 18, 23, 24]. Some authors argue that NAE is a variant of necrolytic migratory erythema (NME) based on the similarity of the clinical and histopathologic features and the proposed pathologic mechanisms, such as hypoalbuminemia and zinc deficiency [13]. The main features that differentiate NAE from NME are the strong association of NAE with HCV infection and the typical localization of NAE to the dorsal aspects of the feet.

Treatment for NAE is not well defined. Because the majority of patients with NAE present without a prior diagnosis of HCV infection, it is imperative to determine HCV infection status in any patient suspected to have NAE. If an infection is identified, the HCV disease severity should be assessed and a treatment plan devised with a hepatologist. An evaluation should be carried out to identify and treat the underlying metabolic deficiency. Zinc therapy (440 mg per day) should be attempted, even in patients with normal serum zinc levels because the probability of benefit outweighs the minimal risk of therapy. There is a single case report that shows improvement with the use of tacrolimus ointment, which may be attempted [6].

References

1. el Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol 1996; 35:252
2. Geria AN, et al. Necrolytic acral erythema: a review of the literature. Cutis 2009; 83:309
3. Nikam BP. Necrolytic acral erythema seronegative for hepatitis C virus - two cases from India treated with oral zinc. Int J Dermatol 2009; 48:1096
4. Wu YH, et al. Necrolytic acral erythema without hepatitis C infection. J Cutan Pathol 2009; 36:355
5. Bentley D, et al. Lack of classic histology should not prevent diagnosis of necrolytic acral erythema. J Am Acad Dermatol 2009; 60:504
6. Manzur A, Siddiqui AH. Necrolytic acral erythema: successful treatment with topical tacrolimus ointment. Int J Dermatol 2008; 47:1073
7. de Carvalho Fantini B, et al. Necrolytic acral erythema successfully treated with oral zinc. Int J Dermatol 2008; 47:872
8. Liu A, et al. Necrolytic acral erythema: a case not associated with hepatitis C infection. Dermatol Online J 2008; 14:10
9. Najarian DJ, et al. Hypozincemia and hyperzincuria associated with necrolytic acral erythema. Int J Dermatol 2008; 47:709
10. Fielder LM, et al. Necrolytic acral erythema: case report and review of the literature. Cutis 2008; 81:355
11. Najarian DJ, et al. Zinc deficiency associated with necrolytic acral erythema. J Am Acad Dermatol 2006; 55:S108
12. El-Ghandour TM, et al. Necrolytic acral erythema in Egyptian patients with hepatitis C virus infection. J Gastroenterol Hepatol 2006; 21:1200
13. Nofal, AA, et al. Necrolytic acral erythema: a variant of necrolytic migratory erythema or a distinct entity? Int J Dermatol 2005; 44:916
14. Abdallah MA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol 2005; 53:247
15. Abdallah MA, et al. Necrolytic acral erythema: a patient from the United States successfully treated with oral zinc. Arch Dermatol 2005; 141:85
16. Hivnor CM, et al. Necrolytic acral erythema: response to combination therapy with interferon and ribavirin. J Am Acad Dermatol 2004; 50:S12
17. Abdallah MA, et al. Histological study of necrolytic acral erythema. J Ark Med Soc 2004; 100:354
18. Khanna VJ, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol 2000; 136:755
19. Frank C, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000; 355:887
20. Mason AL, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999; 29:328
21. Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol 1998; 10:12
22. Delaporte E, et al. Necrolytic migratory erythema-like eruption in zinc deficiency associated with alcoholic liver disease. Br J Dermatol 1997; 137:1027
23. Jenkins DK, et al. Effects of albumin on fatty acid, protein, eicosanoid levels in rat mesenteric arterial bed perfusions. Can J Physiol Pharmacol. 1998; 66:679
24. Marinkovich MP, et al. Necrolytic migratory erythema without glucagonoma in patients with liver disease. J Am Acad Dermatol 1995; 32:604

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Infectious Curiosity

The Hepatitis C virus NS3 serine protease (in gray)

James Griffith, Vertex Pharmaceuticals

The Scientist
Volume 24 Issue 12 Page 24
Date: 2010-12-01
By Jessica Wapner

The course of virologist Charlie Rice's career changed with one phone call in 1989. Then at Washington University in St. Louis, Rice was the country's leading yellow fever expert. The voice on the other end of the line belonged to Stephen Feinstone, an FDA scientist asking about a vaccine for the disease that had just won agency approval. Yellow fever virus is a flavivirus. Feinstone wanted to know if Rice could help develop a vaccine to protect against another flavivirus: hepatitis C. “I can get interested in pretty much anything, I guess,” says Rice.

Today, more than 20 years after Rice took that call, hepatitis C virus (HCV) infects about 170 million people worldwide, but those statistics may soon take a downward turn. Two protease inhibitors that recently completed late-stage clinical trials—telaprevir and boceprevir—are curing significant numbers of patients who may otherwise have suffered a lifetime of liver problems. Published studies reported profound responses to treatment with either of these drugs when used in combination with pegylated interferon (PegIFN) and ribavirin—the current standard, but often ineffective, therapy (J.G. McHutchison et al., NEJM, 360:1827-38, 2009 and P.Y. Kwo et al., Lancet, 376:705-16, 2010).

After that pivotal call from Feinstone, Rice began studying the biology of hepatitis C, a task that attracted little interest in his laboratory at the time. Like a lone archaeologist mapping a forgotten city, Rice charted the structure and function of the virus's various components. His lab group, then at Washington University in St. Louis, found that the HCV polyprotein produced at least ten polypeptides upon cleavage. Rice also identified structural and nonstructural proteins at the polyprotein's N-terminus, several of which would eventually become drug-target candidates. Researchers had already noted the prominent role of serine proteases in flavivirus replication, so Rice and others identified the serine protease in HCV and began to characterize its functional requirements. They found that optimal protease activity depended upon binding to a small viral protein located immediately downstream in viral polypeptide (A. Grakoui et al., J Virol, 67:1385-95, 1993).

Rice was invited in 2000 to lead the newly established Center for the Study of Hepatitis C at Rockefeller University in New York City where he continued to elucidate the molecular biology of the viral serine protease. Because the HCV protease cleaves the polyprotein responsible for viral RNA synthesis at multiple sites, Rice reasoned that the virus probably couldn’t survive if the enzyme's function was blocked. Still, making the leap from the benchtop to an effective therapy required first knowing the exact structure of the protease molecule.

Enter Vertex Pharmaceuticals. After the mid 1990s, when protease inhibitors revolutionized HIV treatment, the company was eager to investigate employing a similar strategy to thwart HCV. Vertex had been keeping tabs on Rice’s HCV work and invited him to collaborate on determining the crystal structure of the protease to aid in drug development.

Rice and Vertex quickly achieved several milestones: development of a biochemical assay, determination of the protease cleavage site specificity, and identification of the residues in the downstream protease cofactor required for optimal activity. Using X-ray crystallography, they determined the crystal structure of the serine protease/cofactor complex. For cell-based studies, Rice built on a landmark study from Ralf Bartenschlager's lab, then at the University of Mainz, Germany, to create highly efficient HCV “replicon” cell culture systems to study the effect of drug candidates on protease activity. “As a result of the development of HCV replicons, scientists now had the ability to screen vast numbers of molecules to test their ability to inhibit HCV replication,” says Ira Jacobson of Weill Cornell Medical College, in New York City.

But knowing the protease’s structure presented a thorny problem—it turned out that the enzyme contained a flat active site. Designing a structure-based drug was going to be like rock-climbing a smooth mountain face. Prepared for this obstacle by some preliminary images, Vertex and Rice were confident that some nook or cranny could be found.

Scientists at Vertex spent months combing the crystal structure for any shred of texture and finally managed to find a few small footholds within the protease’s active site. Vertex’s protease inhibitor, VX-950 (now known as telaprevir), has emerged as a leading agent for the treatment of HCV patients with the genotype-1 strain of the disease. A second compound, boceprevir, developed by Schering-Plough, proved equally effective in those patients. Doctors and HCV patients alike are anxiously awaiting FDA approval of these drugs, expected in 2011.

Still, more work is needed. Although the genotype-1 variant is the most common HCV strain in the United States, other genotypes prevail across Europe, Asia, and Africa. In addition, clinicians are hoping to phase out the use of PegIFN and ribavirin, both of which have toxic side effects. As second-generation HCV protease inhibitors are being developed, and research on the optimal combination regimen continues, Rice’s discoveries remain integral to the future of HCV research and treatment. “There can always be surprises when you’re dealing with a virus in 100 to 200 million people and generating [new] variants every day,” says Rice. “The game is not over at all.”

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Sticking Fast To Foil Hepatitis C

Avila Therapeutics

Hanging Tough A covalent inhibitor (blue) binds irreversibly to a cysteine in the substrate-binding site of hepatitis C protease (green). The active site serine is shown in red.

December 1, 2010
Biochemistry: Aiming beyond the active site of a virus's key protease yields selective blockers
Carmen Drahl
 
By targeting a noncatalytic cysteine, researchers have designed selective irreversible blockers of a protease enzyme essential for hepatitis C virus replication (Nat. Chem. Biol., DOI: 10.1038/nchembio.492).
 
The work is the first demonstration that steering clear of the active site is a viable design strategy for drugs that react to form a covalent bond to proteases, a broad class of proteins that includes many drug targets. This strategy has already proven useful for blocking other proteins such as kinases.

A team from the biotechnology company Avila Therapeutics developed the new protease blockers, which covalently bind to a cysteine in hepatitis C protease's substrate-binding site. In contrast, most other hepatitis C protease inhibitors in development reversibly bind to a catalytic amino acid common to proteases in human hosts as well as in viruses. Avila's published inhibitor structures are prototypes, but the company hopes to begin human clinical trials with optimized compounds in 2011. The team says its comprehensive structural analysis of hundreds of proteases suggests this strategy can be applied broadly.

However, it's not clear how applicable the team's strategy will be to all proteases, says Matthew S. Bogyo of Stanford University, who develops chemical tools to study the roles of proteases in disease. Nevertheless, "covalent inhibitors benefit from a long duration of action, and when used for clearing pathogens such as hepatitis C virus, they may make more sense than classical reversible inhibitors," Bogyo says. Covalent inhibitors can also make several aspects of drug development more straightforward because it's easier to monitor their target selectivity and distribution throughout the body compared with reversible inhibitors, he adds.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2010 American Chemical Society

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Also See: First-ever covalent irreversible inhibition of a protease central to hepatitis C infection

On the Eve of World Aids Day, Yee Recommits to Sterile Syringe Boll

Office of Senator Leland Yee

SACRAMENTO – On the eve of World AIDS Day, Senator Leland Yee (D-San Francisco) is hoping Governor-elect Jerry Brown (D-Oakland) will heed the advice of doctors, pharmacists, and AIDS prevention advocates, by signing legislation to allow pharmacies to sell sterile syringes to an adult without a prescription.

Governor Arnold Schwarzenegger (R-Los Angeles) recently vetoed Yee's Senate Bill 1029, which would have brought California in line with every other state in the nation (accept two) to no longer prohibit pharmacists from selling a syringe without a prescription.

Today, Senator Yee announced his intention to reintroduce the bill during the upcoming legislative session that begins next week.

Most states amended their laws in light of overwhelming evidence that criminalizing access to sterile syringes led drug users to share used ones, and that sharing syringes spread HIV, hepatitis B, hepatitis C and other blood-borne diseases that can live in a used syringe.

Under an existing pilot program, pharmacies in Los Angeles County, San Francisco, and some other parts of the state have been allowed to sell syringes. While he was mayor of Oakland, Brown's home county of Alameda authorized sterile syringe sales.

Yee's legislation would remove the existing sunset of the pilot program (2018) and would allow all pharmacists throughout the state with the discretion to sell sterile syringes without a prescription.

"AIDS and hepatitis do not recognize county borders and thus our current policy is not nearly as effective as it should be," said Yee. "This legislation will reduce health care costs to taxpayers and save lives. I am hopeful that under Governor Brown's leadership, we will get this bill signed into law."

The approach in Yee's bill has been evaluated extensively throughout the world and has been found to significantly reduce rates of HIV and hepatitis without contributing to any increase in drug use, drug injection, crime or unsafe discard of syringes. In fact, there is not one credible study that refutes these findings.

Alex Kral, an epidemiologist who has supervised several studies of HIV prevention, said, "In light of over 200 studies worldwide that establish improved syringe access means less disease with no downside, to continue a policy of making syringe sales illegal would amount to health policy malpractice."

The 200 studies Kral referred to were reviewed by the World Health Organization (WHO) in 2008. WHO concluded that the overwhelming scientific consensus showed improved syringe access reduced rates of HIV and hepatitis without contributing to drug use, crime or unsafe discard of syringes.

Among the numerous studies cited was one published in the American Journal of Public Health from 2001 that compared US cities that allowed pharmacists to sell syringes to adults without a prescription and those that did not. The study found that the rate of HIV among drug injectors was twice as high in cities that forbid sale without a prescription than those cities that allowed pharmacists greater flexibility to provide syringes.

"Based on a robust body of research, it is clear that Senator Yee's bill will save thousands of lives and hundreds of millions of taxpayer dollars by preventing HIV and hepatitis," said Laura Thomas, MPH, Dep. State Director, Drug Policy Alliance. "We thank Senator Yee for his leadership in promoting effective and affordable HIV and hepatitis prevention efforts."

Sharing of used syringes is the most common cause of new hepatitis C infections in California and the second most common cause of HIV infections. The state Department of Public Health estimates that approximately 3,000 California residents contract hepatitis C through syringe sharing every year and another 750 cases of HIV are caused by syringe sharing.

These diseases are costly and potentially deadly. Hospitalizations for hepatitis B and hepatitis C cost the state $2 billion in 2007, according to a report by the California Research Bureau. The lifetime cost of treating hepatitis C is approximately $100,000, unless a liver transplant is required, and then the cost exceeds $300,000 per surgery. The lifetime cost of treating HIV/AIDS is now estimated to exceed $600,000 per patient.

"Many studies prove that clean syringes can dramatically lower HIV transmission rates," said Courtney Mulhern-Pearson, Director of State & Local Affairs, San Francisco AIDS Foundation. "Sterile syringes not only protect injection drug users, they also protect their sexual partners. Providing broader access to clean syringes is the right thing to do for the health of entire communities across California."

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AASLD: Hepatitis C Vaccine Elicits Immune Response in Some Patients

By: DIANA MAHONEY, Internal Medicine News Digital Network
12/01/10

BOSTON – A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study’s treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

"There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant," he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%, he noted.

The vaccine strategy appears to be safe. "The most common associated adverse events were mild, transient injection-site reactions," said Dr. Pockros. Additionally, he stated, "the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms."

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, "mimicked what we saw with a virologic response," he said.

"Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response."

This finding is consistent with the hypothesis that the GI-5005 vaccine corrects a fundamental deficit in cellular immunity in IL28B T/T genotype patients, he said. Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted.

Because the immune response is similar to that observed in HCV-infected patients who are able to clear the virus without treatment, future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed financial relationships with GlobeImmune, Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, Johnson & Johnson, Achillon, Regulus, Debio, Zymogenetics, and Human Genome Sciences.

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