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Chronic HCV Infection and IL-7 Treatment Potential

Chronic infection by the hepatitis C virus (HCV) is a frequent and serious medical problem which affects more than 170 million people worldwide with marked geographical variations in prevalence. At least 250 000 deaths are attributable yearly to HCV infection. HCV is transmitted mainly through contacts with blood. With the availability of routine blood screening for HCV antibodies, transfusion related hepatitis C has almost disappeared and intravenous drug use has become the most common source of transmission. However, in many patients the origin of contamination remains uncertain.  After a initial infection which is frequently silent (often allowing people to live for decades with the virus before showing any symptoms), HCV persists in at least 80% of immuno-competent persons, marking the origin of liver disease, and inconsistently, of a variety of extra-hepatic manifestations.

The standard current treatment for HCV is a bi-therapy combining pegylated interferon-alpha and ribavirin, a combination which provides a mix of antiviral and immunomodulatory effects. If a patient is responsive to the treatment, efficacy is measured by the “Sustained Viral Response” – commonly referred to as SVR – and is usually achieved after a few weeks of therapy. However, depending upon the HCV genotype, 20 to 50% of patients do not respond to the treatment, leaving the patient and the clinician at a therapeutic dead end, with no other therapies currently available. The non-responsive cases are higher with genotype 1, the most common form of HCV in Western World and with HIV co-infected patients.

Moreover, the toxicity of pegylated interferon-alpha and ribavirin has proven relatively high, with frequent or serious adverse side effects, often severe enough for patients to stop treatment. There are reports that some patients who have undergone cancer chemotherapy have even commented that their cancer treatment was easier than their HVC treatment.

IL-7 as a Potential Treatment for Non-Responders to Bi-Therapy

It is assumed that IL-7, as a complement to the standard treatment of pegylated interferon-alpha and ribavirin, could provide a potential solution for the HCV non-responder patients through three main effects:

• the quantitative and functional impact of IL-7 on CD4+ and CD8+ T- cells
  
  
• the antifibrotic potential of IL-7 likely related to a decreased production of TGF-β
  
  
• the additive effect of IL-7 and interferon-alpha, recently explored ex-vivo.

The Disease

As mentioned above, after a primo-infection HCV persists in the untreated person leading ultimately to significant liver disease.

• The liver disease, related to destruction of infected hepatocytes and fibrosis progresses slowly and silently over a long period of time with most patients unaware they are infected. Cirrhosis marks the end stage consequence of fibrosis progression, occurring, in the absence of treatment, at a median-time of 30 years from initial infection, though with much variability among patients. Numerous factors are associated with the rate of fibrosis progression, notably age at contamination, male sex, alcohol consumption, being overweight, diabetes and the immune status of the patient. Strikingly, HIV co-infection and a low CD4+ count foster fibrosis progression. Life threatening or fatal complications are related to liver failure, portal hypertension or occurrence of a hepato-carcinoma (HCC), observed annually in 2-4% of patients who reach the cirrhotic stage.
  
  
• Extra-hepatic manifestations are quite frequent, observed in approximately 75% of the patients and can impair quality of life a long time before the occurrence of cirrhosis decompensation. Most frequent symptoms are non-specific, rheumatic (e.g. arthralgia, myalgia) or cutaneo-mucous (e.g. pruritus, Sicca syndrome and Raynaud phenomenon) which often combine with fatigue. Hypo-thyroidism of auto-immune origin is less usual. Glomerulo-nephritis and systemic vasculitis related to a mixed cryoglobulinemia are severe but rare complications affecting < 1% of patients. 

HCV Genotype

HCV, a highly heterogeneous RNA virus, is classified according to 6 genotypes with varied sensitivities to the current treatment:

• In Europe, the US and Japan, the most prevalent genotype, which is also less sensitive to therapy, is genotype 1, isolated in approximately 70% of patients. The remainder of HCV patients in Western countries and Japan are usually infected by genotypes 2 and 3;
  
  
• Genotypes 4, 5 and 6, rarely isolated in Europe and in the US are frequent in other world areas and, as with genotype 1, are poorly sensitive to the treatment.

Current Treatment

The current standard treatment, a bi-therapy combining pegylated interferon-alpha and ribavirin administered during 24 to 48 weeks, has been assessed in large trials and is the accepted form of treatment for HCV.  While the mechanism of action of this bi-therapy remains incompletely understood, it appears to be a mix of anti-viral and immunomodulatory effects.  Notably, viral efficacy is markedly reduced in patients who receive pegylated interferon alpha alone and virtually nil with ribavirin monotherapy. The toxicity of these two drugs is frequent and well known.

The efficacy of the treatment is usually assessed by the “sustained viral response” (SVR), which corresponds to a normal ALT and the absence of detectable HCV RNA six months after treatment. Beyond six months, the risk of viral relapse becomes very low. Therefore, SVR enables the achievement of at least three therapeutic goals: 1) the prevention of cirrhosis or its complications; 2) the reduction of extra-hepatic complications; and, 3) the prevention of HCV dissemination to other people.

Interestingly, the probability of achieving a SVR can be monitored a few weeks after the initiation of the combined therapy:

• 4 weeks after the beginning of treatment, a very early (Rapid Viral Response or RVR) and substantial decline in HCV viral load is predictive of the early viral response as well as the sustained response, with acceptable positive and even more negative predictive values.
  
  
• 12 weeks after the beginning of treatment, an “early viral response” (EVR),  defined as a decrease from baseline values of at least 2 logs in HCV viral load is a well established predictor of SVR, with an excellent negative predictive value, at least in patients infected by genotype 1. In patients with less than a 2 log decrease in viral load, the probability of achieving a sustained response is low. The combined therapy can be stopped in these patients if there is no extensive fibrosis which justifies continuing with pegylated interferon-alpha due to its anti-fibrotic effect.

“Naïve” Patients Never Treated With Bi-therapy

In “naïve” patients, those never treated with interferon or ribavirin, SVR is achieved with the bi-therapy in less than 50% of the patients infected by HCV genotype 1 or 4 and in more than 80% of the patients infected by genotypes 2 and 3, these latter two genotypes being more responsive to standard therapy.

Results are poorer in HIV infected patients, the mean response rate being lower than 50% when all genotypes taken into account. Immunosuppression negatively impacts efficacy of the combined treatment and its tolerance, which remains especially disappointing in patients whose CD4+ T-cell count remains sub-normal after several months of highly active anti-retroviral therapy (HAART).

Besides genotype and immune status, numerous predictive factors of response have been identified which can be considered in deciding duration of treatment. However, pivotal studies have shown that all patients infected by genotype 1 who achieve an EVR at 12 weeks should receive a full 48 weeks of treatment in order to clear the virus.

Patients Previously Classified as “Non-Responders” to Standard Treatment

The treatment of patients with chronic HCV has improved over the past few years. Despite this, nearly half of the patients fail to achieve a sustained virological response (SVR) and it is this population of non-responders, and their conversion into responders to the standard treatment, that is the initial focus of the Cytheris clinical trials in HCV.

The decision to retreat a patient classified as a non-responder should take into consideration several factors, including data regarding the response to the previous therapy and the likelihood that a response can be achieved with retreatment. It is also important to distinguish the “false” non-responder, one who did not receive a full optimal treatment, and the “true” non-responder, who failed after receiving an optimal treatment.

In the first category, the management of the factors of non-response or improvement of tolerance to therapy may optimize retreatment with a chance of viral eradication. Conversely, in the “true” non-responder, the chance of viral eradication is limited. Recent data demonstrates that about 18% of all patients with a previous non-response to standard therapy (with or without ribavirin) will achieve an SVR when retreated with pegylated interferon-alpha and ribavirin and nearly 10% in genotype 1. However, no therapy has been shown to be effective for patients who failed treatment with pegylated interferon-alpha and ribavirin.

Bi-Therapy Failure and Unmet Medical Need

Virological failure of combination therapy remains an unmet medical need. No second line treatment is currently available and the benefit of new molecules currently being developed in this indication remains uncertain:

• New engineered type-1 interferons may enable the improvement of the efficacy-toxicity ratio of this molecule, but will likely need to be combined with other molecules, such as the current pegylated interferon-alpha.
  
  
• Small molecules inhibiting HCV polymerase or protease will improve the HCV eradication rate only if they are powerful enough to achieve a full inhibition of HCV replication and remain active for a sufficient period of time, without inducing viral resistance. The experience gathered with HIV treatment indicates that the emergence of resistance to anti-retroviral molecules sharing the same mechanism of action is frequent.
  
  
• Novel agents which induce endogenous IFN by stimulating the innate immune response (TLTR7 and TLTR9 agonist) have been shown in Phase II studies to induce a slight decrease in viral load, but these drugs could be most effective when given in combination with exogenous IFN. Further studies are required.

It is still unclear why roughly half of patients in genotype 1 do not respond to the current bi-therapy standard of care, but it is assumed their immune system is unable to clear the HCV-infected cells. Such immune system defects seem unlikely to be overcome using targeted anti-virals because these drugs only stop RNA replication, leaving the virus able to rebound.  Thus, the new molecules currently under development may need to be combined with a well tolerated immuno-modulating agent such as IL-7 which facilitates their effects while at the same time improving control of HCV infection by the immune system.