Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1–infected patients

Abstract

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1–infected patients represents one possible strategy. Four hundred thirty-three patients were randomly assigned to receive either 1.5 μg/kg peginterferon alfa-2b weekly plus 800-1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18-48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription-mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009.)

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma and has become the most common indication for liver transplantation.1-4

The primary aim of interferon-based antiviral therapy is a sustained virologic response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of therapy by way of a sensitive molecular assay. Side effects and the high cost of antiviral treatment5–7 point toward a need for a shorter course of therapy.8 Several ongoing studies in patients with HCV infection have been concerned with the evaluation of the optimal dose and duration of pegylated interferon and ribavirin. Although most investigations have focused on designing treatment algorithms for discontinuations of therapy in patients with little or no chance for achieving an SVR, recent clinical trials have used early HCV RNA decline data at week 4 to identify those patients with rapid virologic response and low viral baseline load who may benefit from a shorter treatment duration.8–10

Following this rationale, the primary aim of the present randomized, controlled multicenter study was to determine whether individually tailored treatment duration on the basis of early viral kinetics in HCV type 1–infected patients results in an equivalent treatment efficacy when compared with the established fixed duration of 48 weeks. This study also allowed us to compare two HCV RNA assays with different sensitivity (the quantitative branched DNA [bDNA] and qualitative transcription-mediated amplification [TMA] tests) with respect to their practicability to tailored treatment strategies and to predict long-term therapy outcome.

bDNA, branched DNA; HCV, hepatitis C virus; INDIV II study; follow up study of individual treatment strategy according to early viral kinetics in hepatitis C virus type 1–infected patients; ITT, intention to treat; SVR, sustained virologic response; TMA, transcription-mediated amplification.

Patients and Methods

Patients.

Patients of both sexes aged 18-70 years with compensated HCV type 1 infection who never had previous therapy with any type of interferon-α and/or ribavirin were eligible for enrollment and had to fulfill the following entry criteria: positive test for anti-HCV (third-generation enzyme immunoassay); HCV-RNA > 1,000 IU/mL by quantitative reverse transcription polymerase chain reaction (Roche AMPLICOR HCV Monitor version 2.0; Roche Diagnostics, Basel, Switzerland); increased serum alanine aminotransferase levels at screening; liver biopsy performed within the preceding 24 months of study enrollment confirming chronic hepatitis; neutrophil and platelet counts of at least 1,500/μL and 80,000/μL, respectively; hemoglobin values of at least 12 g/dL for females and 13 g/dL for males; and creatinine levels <1.5 mg/dL. Exclusion criteria were as follows: patients with HCV type other than type 1 infection; decompensated liver disease; hepatitis B virus or human immunodeficiency virus coinfection or other causes of liver disease; autoimmune disorders; concomitant immunosuppressive medication; clinically significant bleeding disorders; clinically significant cardiac or cardiovascular abnormalities; organ grafts; systemic infections; preexisting severe psychiatric conditions; evidence of malignant neoplastic diseases; excessive daily intake of alcohol (≥40 g/day in women and ≥60 g/day in men); drug abuse within the past year; or unwillingness to practice contraception.

Study Design.

The study was designed as a prospective, open-label, randomized and actively controlled trial conducted between December 2001 and July 2003 at 19 centers in Germany. Ethics committee approval had been received at each center according to the Declaration of Helsinki and the International Conference on Harmonization/Committee for Proprietary Medicinal Products “Good Clinical Practice” guidelines. All patients provided written informed consent. Patients who met the inclusion criteria were randomized by stratification for baseline viremia (≤800,000 versus >800,000 IU/mL) to receive either 1.5 μg/kg body weight peginterferon alfa-2b (Pegintron; Essex Pharma GmbH, Munich, Germany) per week plus 800-1,400 mg ribavirin (Rebetol; Essex Pharma GmbH) daily for 48 weeks (group A) or an individualized tailored treatment duration (group B). In the latter group, treatment duration was calculated by the time required to induce for the first time HCV RNA negativity as defined by way of bDNA assay (Versant 3.0; formerly Bayer Diagnostics, Leverkusen, Germany [now provided by Siemens]; detection limit, 615 IU/mL;) multiplied by the factor 6. Thus, HCV RNA levels <615 IU/mL at week 3, 4, 5, 6, 7, or 8 had to be related to a treatment period of 18, 24, 30, 36, 42, or 48 weeks (Fig. 1). HCV RNA levels were quantified at baseline and weekly until week 8 as well as at week 12, 24, and 48 by bDNA assay, while the more sensitive transcription-mediated amplification assay (TMA; Versant qualitative HCV RNA; formerly Bayer Diagnostics, Leverkusen, Germany; detection limit < 5.3 IU/mL; now provided by SIEMENS) was reserved only for those patients who had HCV RNA levels <1,000 IU/mL by the bDNA test. The cut-off of 1,000 IU/mL instead of 615 IU/mL was chosen to improve the specificity of the bDNA assay. Patients with HCV RNA levels between 615 and 1,000 IU/mL but being HCV RNA negative on TMA were considered bDNA-undetectable after confirmation by retesting.

Figure 1. Patients randomized in group B (n = 208) received an individualized tailored treatment duration ranging from 18 to 48 weeks. Treatment duration was calculated by the time required to become HCV RNA–undetectable for the first time as defined by bDNA assay (detection limit, 615 IU/mL) multiplied by factor 6. The total treatment duration (in weeks) is given alongside each column.

All patients were evaluated as outpatients for safety, tolerance, and efficacy. SVR was defined as a negative qualitative HCV RNA test 24 weeks after end of treatment. Patients with HCV RNA levels >1,000 IU/mL by bDNA assay after 24 weeks of treatment were regarded as nonresponders and were excluded from further study treatment. HCV genotyping was performed by way of reverse hybridization (Inno LiPA HCV; Innogenetics, Gent, Belgium). Histological results were classified by local pathologists according to internationally standardized criteria.11 For better comparison between the different local pathologists, the individual fibrosis stage was documented as ≥ stage 3 or < stage 3 (presence of cirrhosis/transition to cirrhosis or no cirrhosis).

Rationale for Selecting Multiplication Factor 6.

Time to HCV RNA–undetectable levels has become an important predictor for long-term treatment outcome (SVR). From clinical practice there is ample evidence that patients who become HCV RNA–undetectable within the first 24 weeks have a chance to achieve SVR when treated for 48 weeks. In patients with rapid virologic response at week 4, high SVR rates have been observed already after a treatment period of 24 or 48 weeks. We therefore hypothesized that the treatment time necessary to maintain the complete viral suppression follows exponential and not linear criteria. Based on this concept, it follows that the earlier complete HCV RNA suppression is achieved, the shorter the total treatment duration (and vice versa). This also means that one has to multiply the time to HCV negativity by a certain factor instead of adding a fixed additional treatment time (for example, 36 weeks, as previously proposed by Drusano and Preston12) irrespective of the time to HCV RNA negativity on treatment. We estimated that an optimal multiplication factor would be within the range of 2 and 12 based on the findings that on standard treatment duration of 48 weeks, only patients with a virologic response at least at week 24 had a chance of SVR. The additional 24 weeks of treatment in these patients will lead to a multiplication factor for the necessary additional treatment time of 2. In contrast, in rapid responders at week 4 and treated for 48 weeks, a multiplication factor of 12 describes the additional treatment time. We therefore decided to choose arbitrarily the factor 6 for the calculation of treatment time on a more individual basis (Fig. 1). To give an example, when virologic response occurred within 3 weeks, the minimum treatment duration was calculated to be just 18 weeks (3 weeks to become undetectable multiplied by factor 6). On the other hand, when the virologic response was retarded beyond week 8, the standard treatment period of 48 weeks had to be chosen (8 weeks to become undetectable multiplied by factor 6). This approach helps to shorten treatment duration, especially in patients with early virologic responses.

Primary Endpoint.

The primary endpoint was specified as sustained virologic response (SVR), as defined by undetectable HCV RNA 24 weeks after the end of antiviral treatment. HCV RNA negativity was verified using the highly sensitive qualitative TMA assay (detection limit, <5.3 IU/mL). Treatment failures were categorized as follows: breakthrough (reappearance of HCV viremia during antiviral treatment period), relapse (reappearance of HCV RNA during follow-up after stopping therapy in patients with an end-of-treatment virologic response), or nonresponse (patients testing HCV RNA–positive at any time point during the study). Patients were classified as unknown with respect to treatment response in the case of missing relevant data for exact and reliable categorization.

Secondary Endpoints.

Secondary study endpoints were specified as follows: (1) sustained biochemical response as defined by alanine aminotransferase normalization at the end of follow-up period; (2) on-treatment virologic response rates as determined by qualitative (TMA) and quantitative (bDNA) HCV RNA assays at week 4, 12, and 24 and at the end of treatment. In this study, we further evaluated the applicability of both TMA and bDNA assays for individualized, tailored treatment strategies and treatment outcome prediction and the importance of other predictive parameters (such as patient age, ethnicity, sex, body weight, body mass index, gamma glutamyl transpeptidase, alanine aminotransferase, glucose, platelet count, baseline and on-treatment HCV RNA serum concentrations, HCV subtype) as well as parameters of safety and tolerability.

Statistical Analysis.

Our original intention was to show noninferiority of the individualized, tailored treatment duration to standard therapy. For the primary analysis, an SVR rate of approximately 45% was estimated for the standard fixed duration of 48 weeks of antiviral therapy. We investigated whether a shortened (individualized, tailored) treatment duration is associated with equal response rates. A difference in SVR rates of up to 12.5% across both study arms was considered as still being equivalent. Under this assumption, 436 patients were required if a level of significance of α = 0.05, a minimal power of 80%, and a dropout rate of 10% are assumed.

Because we observed a significantly higher SVR rate in the standard therapy arm, we switched from noninferiority to superiority in accordance with the “Points to Consider on Switching Between Superiority and Noninferiority” of the Committee for Proprietary Medicinal Products.13

The descriptive analysis of all relevant dependent variables included the absolute and relative frequencies for categorical data and means, standard deviations, and ranges for continuous scaled data. Statistical comparisons between group A and group B were made using the chi-square test. Multiple logistic regression was used to analyze the influence of independent predictive factors on the occurrence of an SVR. All tests were two-sided, and a P value less than 0.05 was considered significant. Statistical analyses were performed using the statistical software package SPSS for windows 14.0.

Results

Patient Profile.

Between December 2001 and July 2003, a total of 438 patients were screened against all above-mentioned inclusion and exclusion criteria for study enrollment. Five patients were classified as screening failures. This finally led to a total of 433 study patients who underwent the randomization procedure (225 patients were allocated to arm A and 208 patients to arm B, respectively). Table 1 displays pretreatment characteristics of the included patients, demonstrating that both treatment groups were well matched and differed only slightly with respect to relevant variables by univariate between-group analyses. An overview of the trial profile is presented in Fig. 2. In group A, 66.7% of patients completed both therapy and follow-up assessments. This percentage was almost identical in group B (64.9% [P = 0.761]).

Table 1. Summary of Demographic, Biochemical, Serological, Molecular, and Histological Characteristics of Patients at Baseline

Patient Characteristics	Group A (n = 225)	Group B (n = 208)
Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; GGT, gamma glutamyl transpeptidase; HCV, hepatitis C virus; SD, standard deviation; ULN, upper normal limit.
Sex, n (%)
Male	128 (57)	113 (54.3)
Female	97 (43)	95 (45.7)
Age (years)
Mean ± SD	42.8 ± 0.8	42.7 ± 11.69
Range	18–73	19–66
BMI (kg/m^2)
Mean ± SD	25.5 ± 0.3	25.5 ± 0.29
Range	17.7–39.8	18–40
ALT levels × ULN (IU/L)
Mean ± SD	2.6 ± 0.2	2.6 ± 0.4
Range	0.5–28.8	0.4–16
GGT levels × ULN (IU/L)
Mean ± SD	1.8 ± 0.1	1.8 ± 0.17
Range	0.2–18.1	0.2–26.4
HCV RNA (log IU/mL)
Mean ± SD	5.7 ± 0.49	5.7 ± 0.45
Range	2.79–7.8	3–7.6
Fibrosis stage, n (%)
Stage 0–2	177 (87.0)	161 (85.1)
Stage 3–4	34 (13)	31 (14.9)

Figure 2. Trial profile diagram.

Virologic Response Rates.

With respect to the primary study endpoint, an SVR was observed in 48.0% of patients in group A exposed to standardized treatment duration, and in 34.6% of group B patients with individually tailored treatment duration according to an intention to treat (ITT) analysis (P = 0.005) (Table 2). The SVR rates differed significantly due to higher relapse rates occurring in group B (32.7% versus 14.2% [P < 0.0005]). According to a per-protocol analysis, SVR rates were 57.2% in group A and 41.4% in the individualized therapy group (P = 0.003).

Table 2. Virologic Outcome After 48 Weeks (Group A) or an Individualized Treatment Duration (Group B) of Combination Therapy in Chronic Hepatitis C Type 1–Infected Patients

Virologic Outcome	Group A (n = 225)		Group B (n = 208)
	n (%)	95% Confidence Interval	n (%)	95% Confidence Interval
End-of-treatment response	146 (65)	58.3%–71.1%	133 (64)	57.0%–70.5%
Sustained virologic response	108 (48)	41.3%–54.7%	72 (35)	28.2%–41.5%
Nonresponse	41 (18)	13.4%–23.9%	41 (20)	14.5%–25.8%
Virologic relapse	32 (14)	9.9%–19.5%	68 (33)	26.4%–39.5%
Breakthrough	11 (5)	2.5%–8.6%	7 (3)	1.4%–6.8%
Dropout	33 (15)	10.3%–20.0%	20 (10)	6.0%–14.5%

Variables Associated with SVR.

Multivariate regression analysis revealed that treatment arm (group A versus group B), gamma glutamyl transpeptidase, platelet counts, and baseline viral load were significantly associated with SVR (Table 3).

Table 3. Independent Individual Baseline Factors that Were Predicitive for Sustained Virologic Response by Logistic Regression Analysis

Baseline Factors	SVR, Odds Ratio (95% Confidence Interval)	P Value
Odds ratios and the respective confidence regions are shown for the treatment group (group A versus group B), gamma glutamyl transpeptidase (GGT), thrombocytes, and HCV RNA.
Treatment group (group B)	0.450 (0.289–0.700)	<0.0005
logGGT	0.244 (0.127–0.467)	<0.0005
Thrombocytes (100 g/L)	2.336 (1.650–3.305)	<0.0005
logHCV RNA	0.441 (0.312–0.623)	<0.0005

SVR Rates According to On-Treatment Response Rates (Time to First Undetectable HCV RNA by bDNA) and Baseline Viremia.

SVR rates were given in patients of group A and group B according to the time required to become first HCV RNA–undetectable (<615 IU/mL) on bDNA assay. Figure 3 shows that there was a clear correlation between on-treatment response and SVR rates. However, regardless of time to <615 IU/mL on-treatment, nearly all subgroups benefitted from standard treatment duration by the ITT analysis.

Figure 3. (A) SVR rates in group A (fixe) and group B (indiv) according to time to HCV RNA <615 IU/mL by bDNA assay. SVR rates are shown as percentages, and the total number of patients in each subgroup is given at the bottom of each column. *P = 0.026, **P = 0.013 (chi-square test).1 Includes 6 patients with early dropout. (B) SVR rates in group A (fixe) and group B (indiv) according to time to HCV RNA <615 IU/mL by bDNA assay and level of baseline viremia in patients with rapid virologic response. SVR rates are shown as percentages, and the total number of patients in each subgroup is given at the bottom of each column. *P = 0.026, **P = 0.015 (chi-square test). HVL, high viral load (>800,000 IU/mL); LVL, low viral load (≤800,000 IU/mL).

Thus, group B patients treated for either 18, 24, 30, 36, 42, or 48 weeks (time to HCV RNA <615 IU/mL 1-3, 4, 5, 6-7, or ≥8 weeks) had SVR rates of 63%, 57%, 40%, 39%, or 33%, whereas in group A patients the corresponding SVR rates according to time to HCV <615 IU/mL were 83%, 42%, 69%, 73%, and 57% with the fixed treatment duration of 48 weeks (Fig. 3A). Because of the low numbers within the different response categories, there was some variability of the results; we also pooled data from weeks 6 and 7.

In addition, baseline viremia added further information to the model and had a significant influence on the likelihood of achieving an SVR (Fig. 3B). In particular, patients with a rapid virologic response (<615 IU/mL at week 4) having a high baseline viral load (>800,000 IU/mL) benefitted from standard treatment duration. In contrast, SVR rates were comparable in group A and group B patients having low baseline viremia and becoming HCV RNA <615 IU/mL within the first 4 weeks (Fig. 3B). Late responders (HCV RNA <615 IU/mL beyond week 8) had an overall low chance of achieving an SVR regardless of the treatment group (Fig. 3A).

SVR Rates According to On-Treatment Response Rates Defined by Highly Sensitive TMA Assay and Baseline Viremia.

In Fig. 4, SVR rates are shown when patients were stratified according to treatment group and time to HCV RNA <5.3 IU/mL as defined by way of qualitative TMA assay. Choosing this scenario, the time to undetectable levels did not reflect the actual treatment duration in the individualized treatment group, because this was calculated according to the bDNA results. However, because all patients with undetectable levels on TMA assay also had undetectable levels on bDNA assay, the week 1-3 response corresponds to total treatment duration of 18 weeks. However, some of the patients with TMA response at week 4 and beyond also received only 18 weeks of treatment, because bDNA might have become undetectable at week 3. Stratification according to TMA response was superior with respect to SVR prediction compared with the time to bDNA response (Fig. 4A). Group B rapid responders defined by low baseline viremia and time to TMA response within the first 4 weeks achieved SVR rates that were comparable to those of group A patients (Fig. 4B), although the overall SVR rates were again in favor of the fixed treatment schedule (group A). Thus, we could identify a subgroup of rapid responders in whom the 18-week treatment duration resulted in an SVR rate of 90.5% (19/21 [ITT]) and a relapse rate of 0% (0/21 [two dropouts]). SVR and relapse rates in the corresponding group A patients were 93% (28/30) and 0% (0/30 [two dropouts]), respectively (P = 1.0).

Figure 4. (A) SVR rates in group A (fixe) and group B (indiv) according to time to HCV RNA <5.3 IU/mL by TMA assay. SVR rates are shown as percentages, and the total number of patients in each subgroup is given at the bottom of each column. *P = 0.018 (chi-square test). (B) SVR rates in group A (fixe) and group B (indiv) according to time to HCV RNA <5.3 IU/mL by TMA assay and level of baseline viremia in patients with rapid virologic response. SVR rates are shown as percentages, and the total number of patients in each subgroup is given on the bottom of each column. HVL, high viral load (>800,000 IU/mL); LVL, low viral load (≤800,000 IU/mL).

Safety, Tolerability, and Treatment Modifications.

Our analyses revealed that the percentage of patients reporting adverse events was similar in the two treatment groups: Both type (quality) and severity of treatment side effects (those typical of inteferon-based treatment) were not statistically different between groups A and B (data not shown). As far as serious adverse events were concerned, the frequency was 6.6% in group A (fixed duration; anemia [n = 1], appendectomy [n = 1], sinusitis [n = 1], pneumonia [n = 2], psychiatric disorder [n = 7], subileus [n = 1], wound infection [n = 1]) and 2.6% in group B with individualized duration (ankle fracture [n = 1], retina ablation [n = 1], pneumonia [n = 2], psychiatric disorder [n = 1]) (P = 0.243).

The most commonly observed causes of dose modifications of peginterferon alfa-2b and ribavirin were neutropenia and anemia, respectively. In both groups, the percentage of patients with dose reductions owing to adverse events or laboratory abnormalities was comparable (16% in group A versus 15% in group B).

Discussion

The currently recommended therapy for chronic hepatitis C is the combination of pegylated interferon plus ribavirin for 48 weeks.14 However, not all patients with HCV genotype 1 are alike in their responsiveness to antiviral therapy, and especially those patients with low baseline viremia who achieved viral clearance by week 4 have been shown to have high SVR rates even when treatment duration is limited to 24 weeks.8, 10, 15–17 Thus, in view of the rather dynamic reactivity involved in the biological response to HCV infection, a fixed treatment duration of 24 or 48 weeks does not cover individual needs.

The present multicenter, randomized controlled study evaluated whether an individualized, adapted variable treatment time may still allow SVR rates similar to rates obtained by the standard treatment time of 48 weeks. The goal of the study was to reduce the length of therapy to a minimum of 18 weeks in patients with a rapid on-treatment response as determined on bDNA assay (detection limit <615 IU/mL) and to a maximum of 48 weeks. An extension of treatment period beyond 48 weeks was not included in the study design because no data were available at this time dealing with prolongation up to 72 weeks in patients with slow response.

Based upon the concept that the earlier the virus is rendered undetectable in serum, the shorter the treatment time to virologic response, we introduced a multiplication factor estimating that the optimal multiplication factor must be in the range of 2-12 defined by the time to achieve HCV RNA negativity. We chose factor 6 because it would help us calculate the optimal time for treatment duration (for the rationale, see Patients and Methods). This individually based treatment concept allowed varying treatment periods of 18, 24, 30, 36, and 48 weeks.

Our findings support the concept that patients with rapid virologic HCV RNA clearance have the highest likelihood to be cured by therapy.

In the standard treatment course of 48 weeks, SVR rates of more than 80% were observed in patients whose serum HCV RNA became undetectable (<615 IU/mL) within weeks 1-3. In those patients who cleared the virus within the first 4 to 7 weeks, SVR reached around 70%. In patients becoming HCV RNA–undetectable at week 12 or even later (<615 IU/mL) the chance for SVR was very low (around 25%). Thus, the relationship between time to HCV RNA <615 IU/mL and SVR rate was as follows: 83% at week 3, 42% at week 4, 69% at week 5, 73% at week 6 and 7, and 57% at week 8. The low SVR rate of 42% in patients becoming undetectable at week 4 is probably due to the low number of patients within this special subgroup as well as the fact that five of the 19 patients dropped out.

Patients in whom treatment duration was calculated on an individual basis using factor 6 (group B patients) showed the same good correlation between on-treatment and sustained response as the group A patients receiving standard treatment. Again, patients with an 18-week treatment duration attained SVR rates of 63%, while those with treatment durations of 24, 30, 36-42, or 48 weeks had SVR rates of 57%, 40%, 39%, and 33%-39%, respectively.

Although the individual treatment schedule was inferior to the standard treatment, it still became evident that a significant proportion of patients achieved SVR even when treatment duration was shortened.

We were aware in designing the study that shortening treatment duration to a minimum of 18 weeks in HCV type 1–infected patients based only on an on-treatment viral load quantification by way of bDNA assay bears a significant risk of higher relapse rates. We therefore further evaluated prospectively the applicability of a more sensitive HCV RNA assay (TMA; sensitivity limit <5.3 IU/mL) for individualized tailored treatment strategies as well as the importance of other predictive parameters (such as baseline viremia). We included these factors in the hopes of defining a subgroup of patients who may benefit from shortened treatment duration.

Figure 4 shows that prediction of treatment outcome was significantly improved in both study arms when based on TMA response instead of bDNA response. Thus to ascertain complete virologic response by sensitive HCV RNA assays is mandatory as also outlined by Morishima and coworkers.18–20

The determination of the baseline viral load has turned out to be of high importance to predict SVR.10, 21–23 We therefore analyzed whether the distinction of high and low viral load defined according to the study protocol as above or below 800,000 IU/mL may also help to better predict treatment response. We found in our study that this parameter is useful, especially in patients selected to be treated individually. Thus, in these patients with low viral load and treatment duration limited to only 18 weeks, SVR rates of 74% were attained; this is in contrast to low viral load patients receiving standard treatment duration and time to response of 1-3 weeks, who showed SVR rates of 83% (Fig. 3B).

Based on these two criteria (low baseline viral load and complete HCV RNA response as defined by TMA), it was possible to determine a subgroup of patients who had SVR rates after a short treatment duration of 18-24 weeks that were comparable to standard therapy (85%-100% versus 91%-95% [ITT analysis]) (Fig. 4B). Data are in accordance with recent findings by Ferenci et al. and Yu et al. showing that shortened treatment duration in HCV type 1 was only comparably effective in the presence of both low baseline viremia and rapid virologic response.16, 17 These findings may open new avenues in further prospective studies designed to evaluate new response-guided treatment strategies. They also could help guide the future application of direct antiviral drugs as the protease or polymerase inhibitors. It may also be of interest to explore the rational basis of the application of the defined factor 6 as a new strategy to calculate the appropriate treatment time.

Finally, we show in this study that patients becoming HCV RNA–undetectable (<615 IU/mL) beyond weeks 8-12 have a limited chance of attaining SVR even when receiving optimal standard treatment duration. Several studies have shown that slow responder patients (defined by a 2-log decline at week 12, but still HCV RNA–positive and becoming HCV RNA undetectable as late as week 24) will profit from an extended 72-week regimen.20, 24–26 However, our data also indicate that patients who are already HCV RNA–negative at week 12 (on TMA or bDNA assay) may show reduced SVR rates and may need to be treated for longer periods. Patients with high initial baseline viral load may especially profit (data not shown). Our data are in accordance with the findings described in a study by Mangia and colleagues in which patients were treated for either 24, 48, or 72 weeks depending upon the time (4, 8, or 12 weeks) of becoming HCV RNA–negative.27 Patients who were still HCV RNA–positive at week 8 and becoming negative at week 12 did profit from the prolongation of treatment time up to 72 weeks (38% versus 63.5% [standard versus variable group]).

In conclusion, the individualized treatment strategy based only according to time to bDNA negativity failed to provide comparable efficacy as compared to the standard of care. However, the inferiority of the individualized protocol may have been due to the use of a less sensitive HCV RNA and also by the underestimation of the importance of baseline viremia. Including these two important factors in further studies would help to improve response-guided treatment strategies. Some studies have been initiated (INDIV II study) to test the validity of our concept.

Acknowledgements

The authors thank David Hendricks, Ph.D. (formerly of Bayer Diagnostics, Emeryville, CA), as well as Gerald Warnat (Siemens Healthcare Diagnostics) for their advice and support. Thanks also go to Ullrike Dirla and Barbara Malik for technical assistance. In addition to the authors, members of the study group who participated included: C. Gelbmann, R. Wiest, Universitätsklinik Regensburg, Regensburg, Germany; S. Mauss, Gastroenterologische Schwerpunktpraxis Düsseldorf, Düsseldorf, Germany; I. Winter, Krankenhaus Barmherzige Brüder, Regensburg, Germany; T. Goeser, Universitätsklinik Köln, Köln, Germany; M. Loebermann, Universitätsklinik Rostock, Rostock, Germany; W. Schmidt, Universitätsklinik Bochum, Bochum, Germany; B. Kallinowski, Universitätsklinik Heidelberg, Heidelberg, Germany; U. Mihm, Universitätsklinik Frankfurt, Frankfurt, Germany; A. Bergk, F. van Bömmel, T. Müller, Universitätsklinikum Charité, Campus Virchow, Berlin, Germany; R. Somasundaram, Universitätsklinikum Charite, Campus Benjamin Franklin, Berlin, Germany; and A. Holstege, Klinikum Landshut, Landshut, Germany.