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HCV, CMV viral load—treatment, testing, timing

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William Check, PhD

April 2013—Treatment for hepatitis C virus infection turned a corner in 2011 when direct-acting antiviral inhibitors were approved and combined with dual therapy—pegylated interferon and ribavirin. Cure rates shot up from about 45 percent to 70 to 75 percent. With antivirals that are even more potent in late-stage clinical trials now, “Use of oral antiviral therapy without interferon appears to be a real possibility for the near future,” said Mitchell L. Shiffman, MD, director of the Liver Institute of Virginia at Bon Secours Health System in Richmond and Newport News, in an Association for Molecular Pathology session at the 2012 annual meeting, where he spoke about viral load monitoring for HCV.

In the same session, Aneesh K. Mehta, MD, assistant professor of medicine and assistant director of transplant diseases at Emory University School of Medicine, addressed viral load monitoring for cytomegalovirus. Which viral load value predicts disease, how long to treat, and how often to test are the important questions clinicians and laboratorians face for both HCV and CMV.

Others weigh in too. “We have seen the development of [HCV] diagnostics, therapies, and monitoring tests,” says David Hillyard, MD, professor of pathology at the University of Utah School of Medicine and director of molecular infectious disease testing at ARUP Laboratories. “Now we have the development of very advanced therapeutics. For a disease that threatens various dire consequences for 4 million Americans, to potentially be able to diagnose them and cure those who are able to come into the health care system, even though these are expensive treatments, is an amazing clinical story.”

For CMV, “Introduction of molecular testing certainly improved things relative to culture,” Rodney C. Arcenas, PhD, D(ABMM), says. “We were waiting up to 48 hours for a culture result.” Turnaround time is far more rapid now. “There have been some instances where we have been able to diagnose neonatal CMV infection much more quickly than with culture,” Dr. Arcenas says. “We are trying to convert entirely to PCR and convince our clinicians not to ask for culture to decrease send-out costs.

“We do CMV viral load monitoring on our pediatric cardiac and adult stem-cell transplant patients,” says Dr. Arcenas, clinical scientist-microbiology/molecular pathology for Consultants of South Broward in the Memorial Healthcare System, Hollywood, Fla.

Early detection and treatment of HCV infection with one of the new direct-acting agents against the virus’ serine protease, telaprevir or boceprevir, along with PegIfn and ribavirin, produces sustained virological response, or SVR, rates of 70 percent to 75 percent (Jacobson IM, et al. N Engl J Med. 2011;364:2405–2416; Zeuzem S, et al. N Engl J Med. 2011;364:2417–2428; Poordad F, et al. N Engl J Med. 2011;364:1195–1206; Bacon B, et al. N Engl J Med. 2011;364:1207–1217). (SVR is defined as undetectable HCV RNA 24 weeks after cessation of therapy.)

Dr. Shiffman

Attaining a sustained virological response equates to cure—the five-year recurrence rate after SVR is less than one percent (Swain MG, et al. Gastroenterol. 2010;139:1593–1601). Patients who attained SVR had a 50 percent to 70 percent reduction in five-year mortality (Backus L, et al. Clin Gastroenterol Hepatol. 2011;9:509–516) and significant reductions in hepatocellular carcinoma and need for liver transplantation. Dr. Shiffman showed in his AMP presentation that even liver histology improves on followup biopsy.

Response-guided therapy relates duration of therapy to rate of reduction in viremia. For example, patients who achieve a rapid virologic response on telaprevir triple therapy—HCV RNA undetectable within four weeks of starting the oral antiviral agent—are treated for 24 weeks. Patients who become HCV RNA undetectable more than four weeks after initiating treatment with an oral antiviral agent plus peginterferon and ribavirin require 48 weeks of treatment. Similar criteria apply for boceprevir.

Hard stop rules are defined in the FDA-recommended algorithms. For telaprevir, treatment is terminated if HCV RNA is not less than 1,000 IU/mL at week four or week 12 or is not undetectable at week 24. For boceprevir, the criteria are less than 100 IU/mL at week 12 and undetectable at week 24. “If viral load is greater than those values at those times, we stop giving drugs,” Dr. Shiffman says.

Quantitative PCR assays for HCV RNA are central in these algorithms. “An HCV RNA assay that both quantifies and discriminates unquantifiable from undetectable is essential,” Dr. Shiffman says. “An assay that reports less than 25 IU/mL without qualifying if HCV RNA is detectable or undetectable should not be utilized. A value of less than 25 IU/mL detectable is not undetectable and the patient is not eligible for a shorter duration of treatment.”

A few years ago SNPs were discovered that affect triple therapy by modulating the impact of PegIfn. Patients who have the CC haplotype of the IL28B SNP have a high rate of rapid response, 80 percent, while those with the TT version have a very low rate, 30 to 50 percent. Tests are available to assess the IL28B haplotype, one of which Dr. Shiffman’s program uses. “If the patient has an unfavorable allele, we counsel them that the chance for a rapid response is much lower. If the patient has several poor prognostic factors such as previous failure to respond to peginterferon and ribavirin, cirrhosis, and an unfavorable IL28B allele, we probably will not offer that patient retreatment. The risk for complications is not worth the risk and we offer them the option of liver transplantation.”

Dr. Shiffman showed a list of 16 anti-HCV drugs now in phase two or three trials that target the protease, polymerase, or other viral proteins. Early data from some of these drugs used in combination with ribavirin and each other but without PegIfn are impressive. Not only are cure rates above 90 percent, but resistance would be expected to be greatly diminished, since dual viral proteins are being targeted, as with HAART for HIV. “In two or three years,” he said, “some of these direct-acting agents will end clinical trials and we will then know whether they can truly produce high cure rates when used without PegIfn.” Eliminating PegIfn is a goal, he says, because of its many side effects and how difficult it can be for patients to take it over an extended period.

In a session Dr. Hillyard presented at last year’s AACC annual meeting, he focused on molecular testing in the HCV management process. “Diagnosis of HCV has always been based on serological screening,” he said. “However, serologies need to be confirmed.” For some time confirmation has relied on RIBA, when signal/cutoff in the serological assay was low, or PCR, if it was high. Since the supply of reagents for RIBA has been unreliable, and may now have ceased, Dr. Hillyard says, “The confirmatory test going forward will be PCR.” In addition to confirming serological results, quantitative PCR tests provide a baseline viral load for therapeutic monitoring. Although qualitative HCV tests are still available, “it is difficult to see a good clinical role for them at this time,” he says.

Dr. Hillyard

Viral load measurement is integral to all HCV treatment and “one of the best examples of how laboratory testing can both improve patient care and help manage total health care costs,” he says. HCV quantitative testing is the major determinant of length of therapy using established rules that prescribe extension or abandonment of therapy. With the approval of protease inhibitors telaprevir and boceprevir in May 2011, controversies arose regarding sensitivity and cutoffs for different viral load tests. “Clinical trials for these drugs had been conducted using a test with manual extraction that was not in widespread use in clinical laboratories,” Dr. Hillyard says. Although its quantitative performance at cutoffs of 100 and 1,000 IU per mL is equivalent to that of other tests, he says, its cutoff for limit of quantification (LOQ) of 25 IU/mL is different from that of other assays used to perform most clinical testing. Sometimes lost in the discussion, he says, is that commonly used tests have very similar limits of detection (LOD) for HCV genotype 1 virus (about 7 IU/mL). Therapeutic guidelines for these drugs include decision points based on whether virus is detected or not at this level of sensitivity.

“An important concept for clinicians and laboratorians to understand,” he says, “is that a report of less than a given limit of quantification is not equivalent to a report of virus undetected.” This situation was further complicated by the fact that some labs using tests in which LOD does not equal LOQ were not reporting detection status for samples below LOQ. “This experience has been an education to many about the small but significant intrinsic variability of molecular results, especially at levels approaching the statistical limits of detection,” Dr. Hillyard says.

Genotyping HCV infections has always been critical. “And with the advent of telaprevir and boceprevir therapies, which are approved only to treat HCV type 1, there is the new indication of genotyping as a qualifier for therapy,” he says. The importance of viral subtyping is a continuing controversy. “Type 1a infections are somewhat more difficult to treat, and new data with the protease inhibitors also reveals an easier pathway to resistance for type 1a virus.” The significance of this for managing patients remains to be elucidated, although accumulating data from clinical trials with newer direct-acting antivirals also reveal differences in treatment outcome between these two subtypes.

As Dr. Shiffman demonstrated, IL28B genotype is a robust pretreatment predictor of outcome. Dr. Hillyard noted that when the test first became available, there were mixed opinions about its role in patient care. The 2011 American Association for the Study of Liver Diseases guidelines concluded that data were lacking to justify use of IL28B to determine choice or length of treatment. At this time, Dr. Hillyard points out, “whether a patient has a favorable or unfavorable allele, their candidacy [for drug treatment] would be the same.”

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