LINKS FOR THIS SECTION Viral Kinetics First Phase of Viral Decline Second Phase of Viral Decline Third Phase of Viral Decline Clinical Significance Print This Page Print Full-Color Figures from Monograph Print Entire Monograph

Viral Kinetics as a Predictor of Response to Therapy, and the Implications for Treatment Duration

The treatment of chronic HCV infection with interferon (IFN) has improved rates of sustained virologic response from 10% to more than 50% during the past 10 to 15 years. This increase occurred as a result of (1) prolonging therapy from 6 months to 12 months, (2) adding ribavirin to IFN therapy, and (3) pegylating IFN such that IFN blood levels are maintained at higher levels over a week of therapy. Another possible factor was the institution of weight-based dosing.

However, IFN treatment is associated with many significant side effects that are difficult to tolerate over 12 months of therapy, and upward of 10% of patients, even those in hepatitis C treatment centers, are unable to finish the entire 12-month course. Moreover, among genotype 1-infected patients, who account for 70% of infected patients in the United States, only 40% to 50% of highly selected study patients achieve a sustained virologic response with pegylated IFN (PEG-IFN) and ribavirin.^49 50

In patients with genotype 2 and 3 viral infection, sustained virologic response rates exceed 80% with 6 months of PEG-IFN alfa and ribavirin therapy.^49 50 However, such favorable rates are not seen in patients who are infected with genotype 1a or 1b virus. Over the past decade, we have come to recognize that a number of viral and host factors may account for the diminished response to treatment in these patients. These factors include the size of the initial viral load, body mass index, and race.

Among patients with genotype 1 disease, those who have a high initial viral load do not respond to treatment as well as those with a lower viral load. Our understanding of viral dynamics and the effects that drugs have on them has dramatically improved since the introduction of mathematical models to study HCV, human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infections. The pioneering work of Perelson, Ho, Neumann, and others has had a significant impact on our understanding of the HIV life cycle and on means by which we can improve treatment response.

Working with Perelson and Neumann, clinicians at the University of Illinois at Chicago attempted to understand the life cycle of HCV—and how IFN-based therapy interferes with that cycle—by using a mathematical model that describes viral infection. Their initial observations^51 52 and research by Zeuzem et al⁵³ demonstrated that IFN alfa caused a rapid reduction in viral serum levels (0.5 to 2.0 log) within 24 hours of the administration of a single dose (Figure 4). This reduction proved to be dose-dependent.^51 52 After the initial decline, viral decay slowed (Figure 4) and became highly variable among patients, despite daily doses of IFN alfa-2b over a month of treatment.^51 52 This slower phase was referred to as the second phase of viral clearance, thus establishing the biphasic model of viral kinetics (Figure 5).

FIRST PHASE OF VIRAL DECLINE

The best explanation for the initial rapid decline in viral levels during the first 24 to 48 hours is that IFN inhibits either viral production, viral release, or both in a dose-dependent manner.⁵²To account for this rapid decline, the viral serum half-life must be short. Indeed, the calculated serum half-life of HCV averages 3 hours, which is eight-fold less than the calculated half-life of HBV. The symbol ε was adopted to represent the effectiveness of IFN in inhibiting viral production; it is expressed as a percentage. An effectiveness of 90% reflects a 1.0-log drop in viral levels within 24 hours; a 99% effectiveness represents a 2.0-log drop within 24 hours.

It is interesting that the mean effectiveness of IFN is more than 99.5% (>2.5-log decline) in patients with genotype 2 or 3 infection and 95% (1.5-log decline) in patients with genotype 1 infection—a log difference of greater than 1.0.⁵⁴ The combination of this finding and the more rapid rate of second-phase viral decline seen in genotype 2- and 3-infected patients represents a mathematical explanation for the greater rate of viral clearance in genotype 2- and 3-infected patients. The mathematical conclusion that IFN lowers HCV levels in part by inhibiting viral production and/or release has been substantiated in the subgenomic HCV culture model, in which viral production and/or release is inhibited by IFN in a dose-dependent manner.

SECOND PHASE OF VIRAL DECLINE

The second phase of viral decline was initially theorized to be attributable in part to the immune eradication of virus-producing hepatocytes (mathematical symbol: δ). Thus, the rate of the second-phase viral decline was dependent on δ and the extent of IFN effectiveness. Recent studies that involved frequent ALT measurements early in treatment suggest that eradication of virus-producing cells by necrosis probably does not completely explain the second-phase viral decline.⁵⁵ A more likely explanation is that the second phase reflects the sterilization of virus-producing hepatocytes by immune system-related mechanisms (ie, cytokines). IFN has been shown to sterilize HBV-infected hepatocytes by inducing the T-cell cytokines that inhibit viral production.

Bergmann et al⁵⁶ and Herrmann et al⁵⁷ recently showed that there is a third phase of viral decline, which is seen in 30% to 60% of patients who are treated with IFN with or without ribavirin. Herrmann et al compared the viral kinetics in genotype 1-infected patients treated with PEG-IFN alfa-2b with or without 800 mg/d of ribavirin. They found that the first and second phases of viral decline, the calculation of effectiveness, and δ were similar in the two treated groups. However, they noted that a third phase of viral decline occurred in a substantial number of patients in both groups 7 to 28 days after the initiation of treatment. The rate of decline during this third phase was significantly faster in those patients who received ribavirin. The authors proposed a modified mathematical model and designated the letter M to represent enhanced infective-cell loss. As δ is a pretreatment calculation, the new model would indicate that δ could be modified during treatment. They hypothesized that the third phase reflected an upregulation of the immune system by ribavirin, which has been suggested by others.

In preliminary studies, Bergmann et al showed that 30% of patients treated with IFN experienced a third-phase viral decline.⁵⁶ They noted that the third phase was initiated when serum viral levels fell to a certain "set point," which suggested that the "paralyzed" immune system was activated when serum viral levels fell to a certain level. Such a finding has been seen in HBV-infected patients, in whom it has been shown that the T-cell system becomes activated as HBV levels decline.

CLINICAL SIGNIFICANCE

These early kinetic observations are clinically significant because some patients do not experience a significant decline in viral level until after 1 month of therapy with PEG-IFN and ribavirin. Whether this change in viral decline reflects an activation of the immune system or a change in IFN effectiveness needs to be assessed by careful kinetic analysis that accounts for changes in IFN blood levels over time.

Nonetheless, these observations may help explain the recent findings of Davis et al,⁵⁸ who examined early viral predictors of response with data from a large international treatment trial of PEG-IFN alfa-2b and ribavirin.⁴⁹ They found that 100% of patients who did not experience more than a 2.0-log decline in HCV RNA levels by 12 weeks failed to respond despite 9 additional months of therapy with PEG-IFN alfa-2b and ribavirin. Of those patients who did experience at least a 2.0-log decline at week 12, 72% went on to achieve a sustained response. The viral level and decline at 1 month was not an accurate predictor of failure to achieve a sustained response, a finding that might reflect the fact that some patients do not undergo a third-phase viral decline until after week 4. Davis et al proposed an algorithm for viral testing that involved measuring viral levels at baseline and at weeks 12 and 24 in genotype 1-infected patients. Based on the high rate of cure in genotype 2- and 3-infected patients, they suggested that viral levels need not be measured during therapy; instead, they recommended that they be measured 6 months after the completion of therapy.

In a large clinical trial of PEG-IFN alfa-2a plus ribavirin, Fried et al found that only 2 of 63 patients (3.2%) who did not experience more than a 2-log decline in viral levels at week 12 went on to achieve a sustained virologic response.⁵⁰

Finally, viral kinetics may also be relevant in understanding the lower response rate to treatment seen in African Americans, as well as ways to overcome it. One emerging theory is that the change in second-phase viral decline associated with ribavirin therapy might be explained by ribavirin-induced lethal mutagenesis, by which ribavirin is believed to inhibit the infectivity of uninfected cells. Such an effect would have greater impact in patients in whom IFN is less effective. This might explain why a 0% response rate to IFN monotherapy among African American patients increases to a 25% rate of sustained virologic response when ribavirin is added. Because ribavirin takes 3 to 4 weeks to reach plasma steady state, there may be a theoretical advantage to beginning ribavirin therapy 2 or 3 weeks before IFN is started. Further research on this theory is eagerly awaited.