Hepatitis C Virus Detection Using HCV RNA Qualitative (TMA) Testing in the HALT-C Trial

HCV viral load testing is routinely used to guide decisions about whether to initiate hepatitis C therapy. However, the precise role of HCV RNA tests with increased sensitivity has not yet been defined.

In the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) trial, 1,145 prior nonresponders to interferon therapy with advanced fibrosis were retreated with pegylated interferon alfa-2a (Pegasys) plus ribavirin.

Patients who were HCV RNA-negative using a polymerase chain reaction (PCR)-based assay (Roche COBAS Amplicor HCV Test, v. 2.0; lower limit of detection 100 IU/mL) at week 20 received treatment for 48 weeks.

Stored specimens were tested using the more sensitive Bayer Versant HCV RNA Qualitative (TMA) Assay (lower limit of detection 9.6 IU/mL), and results were compared to PCR results for the ability to predict sustained virological response (SVR; undetectable HCV RNA by PCR at week 72).

Results

• Nearly all PCR-positive samples (1006/1007, 99.9%) were also positive as assessed by TMA.
• Among 1,294 PCR-negative samples, 22% were TMA-positive.
• Negative TMA results were more predictive of SVR than were negative PCR results at week 12 (82% vs. 64%, P < .001) and at week 20 (66% vs. 52%, P = 0.001).
• The earlier TMA became negative during treatment, the greater the likelihood of achieving SVR (82% at week 12, 44% at week 20, 20% at week 24).
• Among 45 patients who were TMA-positive but PCR-negative at week 20 and week 24, none achieved SVR.
• Approximately 10% of patients with a single positive TMA result at the end of treatment still achieved SVR.

Conclusion

Based on these results, the authors concluded, “Negative TMA results at or after week 12 were superior to negative PCR results for predicting SVR. In patients with negative PCR results during treatment, a single positive TMA test did not exclude SVR, although persistently positive tests did.”

Table 1. Comparison of HCV RNA Test Results According to PCR (Roche Amplicor) and TMA (Bayer Versant) by Visit

Table 2. Comparison of PCR (Roche Amplicor) and TMA (Bayer Versant) In Predicting SVR

Discussion

In their discussion, the researchers noted that these results agree with the findings of earlier studies showing that TMA testing may be able to detect patients at the end of treatment who will relapse after pegylated interferon therapy is discontinued. Detection of HCV RNA by TMA in samples that were PCR-negative suggests the presence of low levels of circulating virus, between 5 and 100 IU/mL.

Two of 19 patients who had undetectable viral load by PCR but positive HIV RNA by TMA at week 48 still achieved SVR. However, repeated TMA-positive but PCR-negative results during therapy clearly identified patients who would relapse when treatment was halted, “indicating the presence of a low-level, but clinically relevant, amount of HIV RNA.” Whether relapse could have been prevented with longer treatment remains to be determined.

Between 89% and 91% of patients who tested HCV RNA-positive by TMA but HCV RNA-negative by PCR were virological non-responders through 48 weeks, the researchers reported. Yet 9%-11% of patients with such responses still achieved SVR and had apparent long-term eradication of HCV.

“One possibility is that these patients may undergo delayed relapse, as has been described for a minority of patients years after achieving apparent SVR,” they wrote. “Alternatively, these results suggest that some patients clear HCV RNA late, even after discontinuation of therapy (i.e., those patients with SVR who were HCV RNA-positive by TMA at the end of therapy).”

Finally, they added, these results may be false positives or “indicate the detection of low levels of noninfectious virus particles of little clinical significance.”

8/11/06

Reference

C Morishima, T R Morgan, J E Everhart, and others. HCV RNA detection by TMA during the hepatitis C antiviral long-term treatment against cirrhosis (Halt-C) trial. Hepatology 44(2):360-367. August 2006