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Understanding HCV Nonresponse a...

Understanding HCV Nonresponse and Identifying Candidates for Retreatment

Source: New Management Strategies for HCV Nonresponders and Relapsers

By: Mitchell L. Shiffman, MD

http://clinicaloptions.com/Hepatitis/Treatment Updates/HCV Nonresponders/Module/Shiffman.aspx

Introduction

Approximately 40% to 45% of patients with chronic hepatitis C virus (HCV) genotype 1 and 75% to 80% of those with genotypes 2 and 3 achieve a sustained virologic response (SVR) when treated with the combination of peginterferon alfa and ribavirin for 48 and 24 weeks, respectively.[1-3] The ability to achieve an SVR during peginterferon alfa and ribavirin treatment is based on 2 separate and independent steps. First, the patient must respond virologically and achieve undetectable HCV RNA (< 50 IU/mL). Patients who do not respond virologically cannot achieve an SVR by continuing the same treatment for a longer period of time. Virologic response is primarily dependent on the action of peginterferon alfa and, to a much smaller degree, ribavirin.[1,4] The second step in achieving an SVR is the prevention of relapse. This is primarily a function of the action of ribavirin and the maintenance of its dosing[1,3-6] but is also affected by how quickly the patient achieves undetectable HCV RNA after the initiation of treatment and how long the patient remains on treatment after achieving undetectable HCV RNA.[7-10]

Patients with HCV nonresponse can be classified into 3 patient groups:

1)     nonresponse,

2)     breakthrough, and

3)     relapse. Many patients with previous nonresponse can be retreated successfully and achieve an SVR. Identifying which HCV nonresponders are appropriate candidates for retreatment requires a complete understanding of the various virologic response patterns and the pitfalls associated with achieving and maintaining virologic response.

This module discusses the definitions and rates of virologic response, nonresponse, and relapse observed in HCV-infected patients treated with peginterferon alfa and ribavirin and explains how to identify those patients who would be good candidates for retreatment if they fail to achieve SVR during an initial course of interferon-based therapy. Many of the issues discussed in this module reflect data and concepts that have only recently emerged and may therefore differ somewhat from treatment algorithms developed several years ago by various medical societies [11,12] and those included in the National Institutes of Health Consensus Development conference.[13]

 

Defining the Patterns of Virologic Response and Nonresponse

Virologic response patterns can be divided into 3 groups (Table 1): 1) those that lead to virologic response where the patient achieves undetectable HCV RNA (Figure 1), 2) those associated with nonresponse where the patient does not achieve undetectable HCV RNA (Figure 2), and 3) those associated with an initial virologic response which is subsequently lost either during treatment (breakthrough) or after treatment has been discontinued (relapse) (Figure 3). It is important to realize that only those patients with a virologic response in which HCV RNA becomes and remains undetectable throughout treatment can achieve an SVR. Continuing treatment in patients with a virologic pattern of nonresponse or breakthrough will not lead to SVR. As a result, it is imperative that the patterns of virologic response and nonresponse be recognized. These patterns can only be accomplished by assessing HCV RNA at monthly intervals until the HCV RNA has become undetectable or a nonresponse pattern has been defined.

 

Rapid Virologic Response

Rapid virologic response (defined in Table 1) occurs in approximately 15% of patients with HCV genotype 1 and 66% of patients with HCV genotypes 2 or 3 treated with peginterferon alfa and ribavirin (Figure 4).[3,7] It is critically important to identify patients with RVR because these patients have up to a 90% SVR rate if they remain on treatment for 48 weeks for HCV genotype 1 infections[4] (and 24 weeks for HCV genotype 2 and 3 infections.[3] Furthermore, this very high SVR rate in patients with RVR is achieved regardless of the regimen these patients receive. This was shown in a retrospective analysis of a large, randomized, placebo-controlled trial in which patients who achieved RVR had an SVR rate of approximately 90% regardless of whether they received peginterferon alfa and ribavirin, standard interferon and ribavirin, or peginterferon alfa monotherapy.[7] In addition, the likelihood of SVR patients with genotype 1 infection who achieve an RVR does not appear to be affected by shortening the duration or reducing the dose of ribavirin. In one trial, patients with genotype 1 who achieved undetectable HCV RNA were randomized to stop or continue ribavirin at treatment Week 24. Patients with RVR had an SVR rate of approximately 90% whether they continued or stopped ribavirin.[14] A retrospective analysis in patients with genotype 1 demonstrated that reducing the dose of ribavirin in patients with RVR also did not impact the rate of SVR.[15]

Figure 4. Frequency of virologic response and nonresponse patterns.[3,7] 

Several small studies have suggested that patients with HCV genotype 2 or 3 who achieve an RVR can be treated for a shorter duration (12-16 vs 24 weeks) without any significant decrease in the number of patients achieving SVR.[16-18] In addition, a single retrospective analysis has evaluated the impact of reducing the duration of therapy from 48 weeks to 24 weeks in patients with genotype 1 who achieved an RVR.[19] Unfortunately, in each of these studies, reducing the duration of therapy was associated with approximately a doubling in the relapse rate. In addition, a large, randomized controlled trial in patients with genotypes 2 and 3 demonstrated that SVR was significantly reduced in patients with RVR—from 90% to 82%—when the duration of therapy was shortened from 24 to 16 weeks.[3]

Based on these observations, it is apparent that patients who achieve an RVR are highly sensitive to the duration of interferon-based therapy. Taken together, these studies also suggest that patients with genotype 2/3 with RVR should be treated for 24 weeks and those with genotype 1/4 for 48 weeks and that doing so is associated with high rates of SVR. As a result, the management strategy for patients with RVR who develop adverse events should be to consider reduction of the doses of ribavirin and/or peginterferon alfa so that these patients have a better chance to complete the current standard-of-care duration of therapy.

 

Achieving Undetectable HCV RNA After Week 4 and Slow Virologic Response

Approximately 65% of genotype 1 patients and approximately 93% of genotype 2/3 patients achieve undetectable HCV RNA during the course of peginterferon alfa and ribavirin treatment. Most patients with genotype 1 who achieve undetectable HCV RNA do so after Week 4 of treatment. Previous studies have demonstrated that approximately 35% of genotype 1 patients achieve undetectable HCV RNA between Week 4 and 12 of treatment.[7] Recently, these patients have been termed as having a “complete” EVR. Another 15% of genotype 1 patients achieve undetectable HCV RNA between Week 12 and 24 of treatment and have been referred to as “slow to respond.” Virtually no patients will achieve undetectable HCV RNA levels after Week 24 if they have not done so already by that time point, regardless of genotype. Therefore, if a patient has not achieved undetectable HCV RNA by Week 24, treatment should be stopped.

It is critically important to recognize the point at which a patient achieves undetectable HCV RNA during treatment as this is directly related to the likelihood of achieving a SVR (Figure 5).[7] In other words, the later a patient achieves undetectable HCV RNA during treatment, the higher the likelihood that the patient will relapse after treatment is discontinued following the standard duration of therapy (24 weeks for genotypes 2/3 and 48 weeks for genotype 1).[7] Three recent studies have now demonstrated that relapse can be significantly reduced in slow-to-respond genotype 1 patients—those who achieve undetectable HCV RNA after Week 12—by extending the duration of treatment from 48 to 72 weeks.[8-10,20] In each of these studies, the relapse rate was reduced from more than 50% to less than 20%. Two of these studies suggest that this benefit may be less or nonexistent in patients with higher HCV RNA levels at baseline and at Week 12.[8,9] However, these observations will need to be confirmed in future studies before these patients are not considered for treatment extension. Therefore, for now it appears that prolonging the duration of therapy will increase SVR rates in patients who are slow to respond and should be routinely practiced. By contrast, it does not appear from these studies that extending the duration of therapy beyond 48 weeks in genotype 1 patients who achieve undetectable HCV RNA after Week 4 and before Week 12 will significantly reduce relapse rates. As a result, extending the duration of therapy for this subset of patients is not recommended at this time.

Figure 5. SVR rates in genotype 1 patients based on time to undetectable HCV RNA.[7]  

Approximately 25% of patients with genotypes 2 or 3 do not achieve an RVR but later achieve undetectable HCV RNA between Weeks 4 and 12. It is important to recognize that only 49% of patients with this response achieve an SVR when treated for 24 weeks.[3] It is therefore rational to assume that prolonging the duration of therapy from 24 to 48 weeks in these slow-to-respond genotype 2 and 3 patients may reduce relapse and enhance SVR rates, and a retrospective analysis supports this hypothesis.[21] Unfortunately, no prospective studies have yet addressed this important issue.

It is difficult for many patients to tolerate even the standard duration of peginterferon alfa and ribavirin therapy. Many studies have suggested that at least 20% of patients have adverse events that are severe enough to require either a reduction in the dose of peginterferon alfa and/or ribavirin, a temporary treatment interruption, or a permanent discontinuation of treatment.[22,23] Staying on full doses of these medications for another 24 weeks is often more than many patients can tolerate. One strategy to enable patients to remain on treatment longer is to reduce the doses of ribavirin and/or peginterferon alfa by small increments. This will frequently ease the adverse events of these medications and enable patients to remain on treatment longer. Several studies have now demonstrated that mild reductions in the doses of either peginterferon alfa and/or ribavirin will not adversely affect the chance of achieving SVR, especially if this strategy is employed after the patient achieves undetectable HCV RNA.[15,24] By contrast, interrupting treatment for more than 7 days because of adverse events leads to breakthrough and relapse.[24] Therefore, it is the recommendation of this author to reduce ribavirin stepwise by 200 mg every 2-4 weeks until adverse events either resolve or are tolerable. Peginterferon alfa-2a can be reduced from 180 to 135 µg/week and peginterferon alfa-2b from 1.5 to 1.0 µg/kg/week. Neither peginterferon alfa nor ribavirin dosing should be interrupted unless the adverse event is particularly severe and there is a concern for patient safety. Whenever the doses of peginterferon alfa and ribavirin are modified or temporarily interrupted, HCV RNA testing should be performed again to ensure that breakthrough has not occurred.

 

Early Virologic Response and Nonresponse Virologic Patterns

Early virologic response was the first HCV-related virologic response pattern to be recognized and described.[1,7] The definition includes any patient who achieves a ≥ 2 log10 IU/mL decline in HCV RNA from baseline (in addition to those with a complete EVR, as described in Table 1). Patients who do not achieve an EVR will not achieve undetectable HCV RNA with continued treatment and are referred to as having a null response. The lack of an EVR is therefore an excellent marker for nonresponse and has become a widely accepted indication for stopping treatment.

Unfortunately, EVR is not a good predictor of SVR. Although 80% of patients with HCV genotype 1 and 93% of patients with genotypes 2 and 3 achieve EVR, only 65% of these patients achieve SVR.[1] Approximately 15% of genotype 1 patients have a ≥ 2 log10 IU/mL reduction in HCV RNA and therefore have an EVR but never achieve undetectable HCV RNA.[7] These patients are referred to as having a partial virologic response. Since these patients do not achieve undetectable HCV RNA by Week 24, there is no possibility of SVR being achieved if the same therapy is continued. Treatment must either be discontinued or modified as soon as partial virologic response has been recognized. Partial virologic response can only be identified if HCV RNA is monitored on a regular basis through Week 24.

 

Breakthrough and Relapse

Breakthrough and relapse both involve the recurrence of detectable HCV RNA after a patient achieves undetectable HCV RNA; however, the first definition occurs while the patient is receiving treatment and the latter after the patient maintained undetectable HCV RNA to the end of the treatment course. A recent study has strongly suggested that the major, if not the only, reason for breakthrough is missing doses of peginterferon alfa and/or ribavirin.[14] In this study, patients who achieved undetectable HCV RNA by Week 24 were randomized to either discontinue ribavirin and continue peginterferon alfa alone or to continue both drugs. Within weeks of stopping ribavirin, recurrence of HCV RNA in serum began to occur and the rate of recurrence increased stepwise over time to a maximum breakthrough rate of 12% by the end of the 48-week treatment period. In the control group, breakthrough was observed in 3% during this same time period, but in all instances, the patients had discontinued one or both of the agents.

Missed doses can result from various causes. In many cases, physicians will instruct patients to temporarily stop treatment because of significant treatment-related adverse events. However, patients also miss doses of their own accord, either intentionally to self-treat treatment–related adverse events or by accident. Once viral breakthrough has occurred, the patient cannot achieve SVR with their current regimen; treatment should therefore be discontinued as soon as breakthrough has been identified and an alternative treatment option should be considered. Consequently, it is imperative that HCV RNA be assessed periodically during treatment even after the patient has achieved undetectable HCV RNA to identify breakthrough as soon as possible.

In addition to missed doses and premature discontinuation of ribavirin, the other main reasons for relapse include treatment initiation with insufficient ribavirin dosage, and failure to continue treatment long enough in patients with a slow virologic response. Three randomized trials have demonstrated that patients who initiate treatment with a higher dose of ribavirin have a lower relapse rate.[4-6] In one of these studies, the routine use of epoetin alfa did not affect virologic response, relapse, or SVR rates, even though the frequency of ribavirin dose reduction was reduced.[24] As discussed earlier, 3 studies have demonstrated that relapse can be significantly reduced in genotype 1 patients with slow virologic response by prolonging the duration of treatment from 48 to 72 weeks.[8-10,20]

 

Identifying Candidates for Retreatment: Null Response

Patients fail to achieve SVR for several different reasons (Table 2). All but one of these factors―namely, null response―can potentially be overcome during retreatment. Therefore, when assessing a patient who did not achieve a SVR during the initial course of therapy, the reason for this failure must be determined. Only those patients who have a known and correctable reason for their previous treatment failure should be considered for retreatment.

Table 2.  Reasons Patients Fail to Achieve SVR

Null Response

Patients with a well-defined null response during previous treatment are poor candidates for retreatment. Such patients have no significant decline in HCV RNA during treatment and are essentially refractory to the effects of interferon. Studies have shown that retreatment of peginterferon and ribavirin null responders with another course of peginterferon and ribavirin is not beneficial and results in only a 3% to 10% SVR rate.[25,26] No studies to date have shown that patients with a null response can benefit from higher doses of peginterferon alfa and/or ribavirin. An alternative approach to intensification for null responders is to utilize high-dose daily consensus interferon (interferon alfacon). The large, registration DIRECT trial is currently evaluating the use of 9 µg/day or 15 µg/day interferon alfacon both with ribavirin as a treatment option in patients that had a null response during their treatment with peginterferon and ribavirin regimens. An interim analysis of 500 patients in this study who had a null response to peginterferon alfa was shown to achieve SVR in up to 15% of treated patients (Capsule Summary).[27] Of note, 77% of the patients in this study had advanced fibrosis, a particularly difficult-to-treat population. It remains to be seen if such patients will benefit from retreatment with peginterferon alfa and ribavirin in combination with 1 or more of the HCV protease or polymerase inhibitors that are currently in development.

At the present time, patients with null response who are not retreated should be monitored at regular intervals. If these patients also have cirrhosis, screening for hepatocellular carcinoma should be performed at regular intervals.[28-30] It is currently unknown whether continuing peginterferon alfa long term as maintenance therapy could prevent fibrosis progression, hepatic decompensation, hepatocellular carcinoma, and the need for liver transplantation in patients with a null response. The only previous study of maintenance interferon therapy suggested that this treatment could be effective in patients with a partial response and at least a 2 log10 IU/mL decline in HCV RNA.[31] For the past 5 years, the HALT-C trial has investigated whether maintenance peginterferon alfa therapy could be of benefit in HCV nonresponders with advanced fibrosis or cirrhosis. The results from this trial will be available in November 2007. NO!!!

 

Identifying Candidates for Retreatment: Partial Virologic Response

Partial Virologic Response


Patients with partial virologic response are excellent candidates for retreatment. These patients elicited an initial response to interferon-based therapy and exhibited a 2 log10 IU/mL or greater decline in HCV RNA during the first 12 weeks of treatment. If these patients are treated with higher doses of interferon or peginterferon alfa, they can potentially achieve a greater decline in HCV RNA, perhaps achieving undetectable values and, in some cases, SVR (Capsule Summary).[32] Unfortunately, most retreatment studies have not characterized the previous virologic response pattern, and the relative percentage of null and partial responders is commonly unknown. However, in 2 studies, the previous response pattern was well characterized. In the first study, a population of patients with previous nonresponse to standard interferon were retreated with a higher dose of standard interferon and ribavirin. Only 13% of patients achieved an SVR. However, all of these responders had also achieved a partial response during their initial course of therapy; no previous null responders achieved SVR.[33] In the second study, patients with a previous nonresponse to standard interferon and ribavirin were retreated with peginterferon alfa and ribavirin.[34] Overall, 28% of patients in this study achieved an SVR. However, 75% of these patients had a partial virologic response during the initial course of treatment. In an interim report of another study, the REPEAT trial, patients with nonresponse to peginterferon alfa-2b and ribavirin were retreated with either standard-dose (180 µg/week) or high-dose (360 µg/week) peginterferon alfa-2a (Capsule Summary).[35] After 12 weeks of treatment, the percentage of patients who achieved undetectable HCV RNA was 17% greater with the higher dose of peginterferon alfa-2a compared with the standard dose. Final SVR results will be required to see if the advantage of high-dose peginterferon alfa treatment remains.

Based on these observations, it has been hypothesized that some patients with a partial treatment response can achieve undetectable HCV RNA if switched to a more intensive interferon regimen (Figure 6). The time at which to intensify the interferon regimen can be anywhere between 12 and 24 weeks. However, the patient must be able to tolerate the higher dose of peginterferon alfa and be motivated to continue with treatment. The major limitation to this strategy is firstly the accessibility of higher dose of peginterferon alfa to many patients, as it is unlikely to be approved by many insurance companies without more concrete data supporting this approach and, secondly, the increase in the discontinuation rates because of tolerability issues. In patients treated with a more intensive interferon regimen, HCV RNA should continue to be monitored at monthly intervals. If the patient does not achieve undetectable HCV RNA within 12 weeks of dose intensification, treatment should be discontinued. By contrast, if the patient does achieve undetectable HCV RNA, this treatment should be continued for an additional 48 weeks. This is the typical duration of extended treatment in patients with slow virologic response.

Figure 6. Intensification of interferon-based regimen at 12-24 weeks.

 

Identifying Candidates for Retreatment: Noncompliance, Medication Errors and Dose Reduction

Noncompliance and Medication Errors


When assessing patients who failed a previous course of treatment, it is important to determine their compliance to the previous treatment. It has been estimated that approximately 20% of treatment-naive patients purposely skip or take lower doses of peginterferon alfa and/or ribavirin to manage the adverse events of treatment without consulting their healthcare provider. In most cases, these patients are embarrassed to communicate this noncompliance. Other patients may be taking lower than prescribed doses of peginterferon alfa or ribavirin simply because they misunderstood the dosing directions. Some patients are noncompliant because they consume large amounts of alcohol or utilize illicit drugs during treatment, which interferes with dosing schedules.[31,36,37]

Noncompliance leads to nonresponse, breakthrough, and relapse. However, such patients are excellent candidates for retreatment if the reason for the noncompliance can be corrected and prevented from occurring again. For these patients, improving education and awareness about the adverse effects of peginterferon alfa and ribavirin, ensuring they have a stronger commitment to therapy, or seeking care from a more experienced and/or attentive treatment provider may be useful. Some patients who consumed alcohol and/or utilized illicit drugs during previous therapy may achieve long-term abstinence and then become acceptable candidates for retreatment following proper counseling, support, and enough time.

Dose Reduction or Discontinuation of Peginterferon alfa and/or Ribavirin
When assessing patients for retreatment, it is important to determine if adverse events during the previous course of therapy were severe enough to warrant temporary or permanent premature discontinuation of either peginterferon alfa and/or ribavirin. Up to 25% of patients enrolled in large, registration trials required that the doses of one or both of these agents be modified during treatment.[1-3] This figure is likely to be higher in less controlled settings. Several years ago, it was felt that any dose reduction could potentially impair the ability to achieve SVR.[38] However, it is now recognized that small reductions in the dose of peginterferon alfa and/or ribavirin, particularly after patients achieve undetectable HCV RNA, are less likely to impact SVR as long as dosing is not interrupted.[15,23]

Anemia is a common adverse event during peginterferon alfa and ribavirin treatment.[1-3] A randomized, placebo-controlled trial demonstrated that epoetin alfa can correct anemia in this setting.[39] However, a more recent randomized study demonstrated that the routine use of epoetin alfa initiated in all patients at the start of therapy did not improve virologic response, relapse, or SVR.[24] Although the dose of ribavirin was reduced in 40% of patients in the control group compared with only 10% in patients taking epoetin alfa, the percentage of patients who received more than 80% of the cumulative ribavirin dose was comparable in the 2 groups. This is because the ribavirin dose was reduced in only 200-mg increments every 2-4 weeks, and most dose modifications were performed after patients had achieved undetectable HCV RNA.

Some patients develop adverse events with such rapid onset and severity that there is no choice but to temporarily interrupt treatment. The approach to such patients is not to restart therapy immediately but rather to allow the severe adverse event to resolve while therapy is withheld and then plan for retreatment with the tools necessary to prevent the particular adverse event from occurring again or being as severe and debilitating. In some cases, this will require that growth factors such as epoetin alfa or granulocyte colony-stimulating factor be approved and ready to utilize at the onset of therapy. In other cases of adverse events such as depression, the patient will be required to receive frequent ongoing psychiatric care or medications to address severe pain or severe migraine headaches. If the reason for the severe adverse event can be corrected or more effectively managed, then these patients are good candidates for retreatment.

 

Identifying Candidates for Retreatment: Failure to Recognize That Virologic Response Has Occurred

Recognizing that a virologic response has occurred requires that HCV RNA be monitored at frequent regular intervals throughout and after treatment. Unfortunately, previous treatment algorithms had recommended that HCV RNA be monitored only at baseline, Week 12 of treatment, and 24 weeks following the completion of treatment. Such infrequent monitoring of HCV RNA prevents nearly all virologic response patterns from being recognized. For example, following this schedule, a patient who achieved an EVR at Week 12 but had detectable HCV RNA at 24 weeks after treatment was discontinued may have had either a partial response and never achieved undetectable HCV RNA or had a slow virologic response followed by relapse. Such a patient would need to be retreated to properly define the virologic response pattern. Patients with RVR, those with complete EVR, and those who are slow to respond can only be differentiated from patients with a partial response if HCV RNA is monitored on a regular basis.

Errors in measuring or reporting serum HCV RNA appear to occur in 1% to 2% of samples, regardless of the reference laboratory and/or assay utilized. Such errors include incorrect quantification (≥ 2 log10 units different from the actual level) and false-positive and false-negative results.[40] Measuring HCV RNA frequently during treatment may also allow such laboratory errors to be identified and will improve patient management compared with a single HCV RNA measurement obtained at Week 12 of therapy. Therefore, it is the recommendation of this author that HCV RNA be measured at monthly intervals until the patient either has undetectable HCV RNA or a nonresponse pattern has been defined and treatment is discontinued. Once undetectable, it is recommended that HCV RNA be monitored every 3 months until 24 weeks after treatment is discontinued. This will allow breakthrough to be recognized so that unnecessary treatment can be avoided. Patients whose previous treatment response was not well defined should be considered for retreatment.

 

Identifying Candidates for Retreatment: Insufficient Treatment Duration

Patients with a slow virologic response have a high rate of relapse. This is true both for patients with HCV genotype 1 who achieve undetectable HCV RNA more than 12 weeks after the onset of treatment[7] and patients with genotypes 2 or 3 who achieve undetectable HCV RNA after Week 4.[3] Genotype 1 patients with a slow virologic response during their initial course of therapy are excellent candidates for retreatment for a longer duration of 72 weeks. For patients with genotypes 2 or 3 who relapsed after their initial course of treatment, retreatment for a longer duration, from 24-48 weeks, is also a logical approach and supported by a retrospective analysis.[21] However, no prospective data are available to support this approach.

Conclusions

To understand why patients with chronic HCV infection do not respond to treatment, it is essential to first understand why patients do respond. It is also essential to recognize the various virologic patterns associated with response and nonresponse during interferon-based therapy. This requires that HCV RNA be monitored at frequent intervals during treatment. At least one half of all patients with nonresponse are good candidates for retreatment and could achieve SVR during retreatment. This includes patients, regardless of genotype, with breakthrough, relapse, partial response, and slow virologic response.

 

Summary of Clinical Implications

·                       A patient must respond virologically and achieve undetectable HCV RNA (< 50 IU/mL) to achieve an SVR.

·                       Patients who do not respond virologically cannot achieve an SVR by continuing the same treatment for a longer period of time.

·                       Patterns of virologic response and nonresponse be recognized by assessing HCV RNA at monthly intervals until the HCV RNA has become undetectable or a nonresponse pattern has been defined (Week 24).

·                       Up to 90% of patients with RVR achieve SVR if they remain on treatment for 48 weeks for HCV genotype 1 infections and 24 weeks for HCV genotype 2 and 3 infections.

·                       Rates of SVR in patients with genotype 1 infection who achieve an RVR do not appear to be affected by reduction of ribavirin dose.

·                       The initial management strategy for patients with RVR who develop adverse events should be to consider reduction of the doses of ribavirin and/or peginterferon alfa so that these patients can hopefully complete the recommended duration of therapy.

·                       It is important to continue to monitor HCV RNA through Week 24 even if the patient does not achieve undetectable HCV RNA during that time to allow for identification of partial virologic response. 

·                       It has been hypothesized that some patients with a partial treatment response may achieve undetectable HCV RNA if switched to or retreated with a more intensive peginterferon alfa regimen.

·                       Patients who do not achieve an EVR will not achieve undetectable HCV RNA with continued treatment and are defined as having a null response. This is an indication for stopping treatment.

·                       An important reason for viral breakthrough may be missing doses of peginterferon alfa and/or ribavirin.

·                       Patients fail to achieve SVR for several different reasons. All but one of these factors, null response, can potentially be overcome during retreatment.

·                       Only those patients who have a known and correctable reason for their previous treatment failure should be considered for retreatment.

·                       The outcomes of retreatment may be maximized by improving education and awareness about adverse effects of peginterferon alfa and ribavirin, having a stronger commitment to therapy, or seeking care from a more experienced and/or attentive treatment provider.

 

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