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  2. Abstract

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There are multiple reasons that any individual patient might be considered difficult to treat with the current standard therapy of pegylated interferon α (PEG-IFN), ribavirin (RBV), and a protease inhibitor (PI). Overall, we can divide these patients into three broad categories: (1) a lack of efficacy, (2) an increased risk of side effects or drug-drug interactions, and (3) absolute contraindications.

The baseline and on-treatment predictors for a lack of efficacy in difficult-to-treat patients are well defined.1–6 Foremost among viral factors is the viral genotype, with a clear diminution in efficacy from genotypes 2 and 3 to genotype 1; less important is the viral load. More recently, it has been found that even within genotype 1, there is a further diminution in efficacy from subtype 1b to subtype 1a when a PI is being used. Host factors that affect the response include the interleukin-28b genotype, the patient's race, and the presence of cirrhosis (Table 1). Obesity, age, and sex, which previously were important predictors of treatment difficulty, have become less important with the recent use of direct-acting antiviral (DAA) agents. Using these predictors, we can predict a difficult-to-treat patient even before the initiation of interferon (IFN), and once the patient starts treatment, we can further define the likelihood of a response by viral kinetics. A lack of a response to PEG-IFN with a <1-log reduction in the first 4 weeks of treatment is associated with a reduced likelihood of a sustained virological response (SVR) for all genotypes.7 Also included in this poor efficacy group are patients who are coinfected with human immunodeficiency virus (HIV) and patients who are on immunosuppressive therapy after transplantation.8 In both groups, traditional PEG-IFN/RBV has impaired efficacy, but we are beginning to see improved SVR rates, particularly in the HIV group, with the addition of PIs to treatment.9 This entire subgroup with poor treatment efficacy is being modified by continuing improvements in the potency of DAAs. Newer DAAs in combination with PEG-IFN/RBV are able to produce SVR in up to 90% of naive patients with genotype 1 with only 12 weeks of therapy. Thus, this group of so-called difficult-to-treat patients will continue to be a target for novel therapies using more potent DAA/PEG-IFN combinations.

Table 1. Baseline and On-Treatment Predictors of SVR With PEG-IFN/RBV in Genotype 1 Patients
PredictorOdds Ratio95% Confidence IntervalP Value
  1. This table was adapted with permission from Gastroenterology.1

  2. Abbreviation: RVR, rapid virological response.

Interleukin-28B genotype: CC versus non-CC5.934.57-7.69<0.0001
HCV RNA: ≤600,000 versus >600,000 IU/mL3.12.3-4.1<0.0001
RVR versus non-RVR and non-CC genotype9.15.8-14.0<0.0001
Ethnicity: Caucasian versus African American2.771.96-3.92<0.0001
Ethnicity: Hispanic versus African American2.031.20-3.430.0041
Metavir: F0-F2 versus F3-F42.71.8-4.0<0.0001
Fasting blood sugar level: <5.6 versus > 5.6 mol/L1.71.3-2.3<0.0001

The second group is perhaps the most important group for which physicians need to really evaluate the risks and benefits, and it is the focus of many chapters in this series. These patients are at risk for significant side effects of treatment, and as a consequence, efficacy is reduced by an inability to use optimal doses and duration of PEG-IFN and RBV or by significant drug-drug interactions. These patients include those with a relative or increased risk of anemia secondary to RBV and (more recently) PIs.9 The average reduction in hemoglobin from hemolysis and bone marrow suppression is 3 g with PEG-IFN/RBV and another gram with the addition of a PI. Patients with a hemoglobinopathy such as sickle cell disease or thalassemia and even patients with low baseline hemoglobin levels fall into this group. Also, patients with impaired renal function and patients on dialysis are more prone to anemia because RBV is almost entirely renally excreted and is not cleared effectively by dialysis. None of these are absolute contraindications to treatment, but the clinician may need to either reduce the dose of RBV or use lower doses and also should be prepared to use erythrocyte-stimulating agents and even blood transfusions. Cardiac patients, who may not tolerate anemia, also fall into this category of hard-to-treat patients because of the risk of anemia complicating the underlying cardiac disease. Also included in the increased-risk-with-treatment group are those patients who have a relative contraindication to IFN; again, the risks and benefits need to be assessed. The primary members of this group are patients with autoimmune and neuropsychiatric diseases. Autoimmune diseases can be exacerbated or induced by IFN, and patient selection is very important. IFN is also associated with many neuropsychiatric side effects but can be used even in patients with moderate depression, manic-depressive disease, or posttraumatic stress disorder so long as a multidisciplinary and experienced management team is used. HIV/hepatitis C virus (HCV)–coinfected patients present special challenges, which are outlined by Sulkowski in his review.10

Finally, perhaps the most important group consists of patients with cirrhosis, who are at increased risk for side effects of treatment and hematological side effects (e.g., thrombocytopenia and anemia) and are also at risk for worsening liver function.11–16 Here the benefit is significant because SVR has been associated with improved clinical outcomes and a reduction (4- to 14-fold) in the risk of liver failure and liver cancer. In patients with compensated cirrhosis, the SVR rate is reduced with both the standard IFN/RBV therapy and the PIs currently in clinical use. There is an even worse response in patients with more advanced cirrhosis and portal hypertension and in pretransplant patients.11–16 In all of these patients, the issues are combinations of the inherently poor responsiveness of patients with cirrhosis to IFN-based therapy and the major increases seen in side effects and infections, which necessitate significant dose reductions and discontinuations. For these reasons, patients with cirrhosis who have poor hepatic function or features of decompensation (variceal hemorrhaging, hepatic encephalopathy, ascites, and jaundice) should be referred to a liver transplant center before consideration is given to antiviral treatment.

As this series on difficult-to-treat patients will show, the major roles of the clinician are the identification of patients suitable for treatment, the choice of the optimal approach for individual patients, and the utilization of an experienced, usually multidisciplinary team to ensure safe and effective patient outcomes.


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  2. Abstract
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