Genotyping of Cytomegalovirus (or Herpes Simplex Virus) for Ganciclovir (Aciclovir) and Foscarnet Resistance (code 40514) Notice of Assessment
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1 Genotyping of Cytomegalovirus (or Herpes Simple Virus) for Ganciclovir (Aciclovir) and Foscarnet Resistance (code 40514) Notice of Assessment June 2013 DISCLAIMER: This document was originally drafted in French by the Institut national d'ecellence en santé et en services sociau (INESSS), and that version can be consulted at It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation. While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.
2 1 GENERAL INFORMATION 1.1 Requestor: CHUQ - Centre hospitalier de l Université Laval (CHUL). 1.2 Application Submitted: January 1, Notice Issued: April 12, Note: This notice is based on the scientific and commercial information (submitted by the requestor[s]) and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS. 2 TECHNOLOGY, COMPANY, AND LICENCE(S) 2.1 Name of the Technology Nucleic acid amplification test (NAAT) followed by amplified DNA sequencing. 2.2 Brief Description of the Technology The requestor has specified that the method used for DNA sequencing is the traditional Sanger sequencing procedure following nucleic acid amplification through polymerase chain reaction (PCR). This technique involves the following si stages: a) selection of a specific primer complementary to a single strand of an amplified DNA template (through PCR or RT-PCR); b) incubation of the template, the primer and the DNA polymerase in the presence of unlabelled deoynucleotides (dntps) and dideoynucleotides (ddntps) labelled with a single fluorophore; c) polymerization of the molecules continues until the integration of a ddntp stops the chain (random termination for each molecule); d) the sequence products that are different in size are purified based on their molecular weight through capillary electrophoresis; e) a laser scans the capillary and stimulates the fluorescent dye of the terminal ddntp of each size-separated fragment; f) the sequence of the fluorescent signals sent is analyzed, which in turn allows deduction of the nucleotide sequence. 1
3 Figure 1: Schematic Representation of Dideoy Sequencing Image courtesy of the National Forensic Science Technology Center, from NIJ s DNA analyst training program (figure from the NFSTC website, available at: This service is offered once a week at the requestor s laboratory. Results are delivered after 10 business days. 2.3 Company or Developer In-house procedure offered only at the CHUQ-CHUL. The requestor is an epert in this field of activity. 2.4 Licence(s): Not applicable. 2.5 Patent, If Any: None. 2.6 Approval Status (Health Canada, FDA): Not applicable. 2.7 Weighted Value: According to the requestor, the weighted value of the analysis is CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES 3.1 Targeted Patient Group The test is to target immunocompromised patients for whom ganciclovir (GCV) (aciclovir) and (or) foscarnet (FOS) treatment has failed. Suspicion of resistance by cytomegalovirus (CMV) to antiviral drugs is also part of the clinical indications for which the test may be prescribed. NAAT must be successful Targeted Disease(s) CMV is a virus of the herpes virus family, which includes the herpes simple virus, the Epstein-Barr virus, and the varicella zoster virus. Its prevalence is high: from 30% to 100% of people are infected with CMV, depending on the world area. It usually involves a minor infection. However, the severity of CMV infections in AIDS-infected individuals, following an organ or a hematopoietic stem cell transplant, as well as in people suffering from any disease that requires or induces severe cellular immunosuppression (lymphoma, prolonged corticosteroid therapy) justifies the use of antiviral, curative, and preventive treatments (Alain et al., 2009). The emergence of resistant CMV strains is a concern, especially when dealing with immunocompromised individuals (Drew, 2010; Kotton et al., 2010; Alain et al., 2009). Such a resistance generally arises upon prolonged eposure, over several 8 The absence of signal during PCR could be eplained by the absence of viral DNA or by the poor quality of the viral DNA preparation (the quality of the sequence is influenced greatly by the quality of the viral DNA preparation). 2
4 weeks to several months, and involves persistence of the viral load or the disease despite pharmacotherapy (Kotton et al., 2010; Alain et al., 2009). It affects nearly 5% of organ donors or hematopoietic stem cell recipients, and constitutes an unfavourable outcome factor following a transplant (Alain et al., 2009). The antiviral drugs most commonly used against CMV are ganciclovir, its prodrug valganciclovir (VGCV), cidofovir (CDV) and foscarnet (Hamilton, 2012). Generally, the viral load should be undetectable after three weeks of treatment (Alain et al., 2009). Treatment failure may be due to viral (resistance) and pharmacological (antiviral under-dosage or low uptake at the site of infection) causes, or to immunosuppression. Screening for mutations that confer resistance to antiviral drugs already administered allows distinguishing between non-responders or slow responders (high risk of relapse) and actual viral resistance, and adjusting the antiviral treatment accordingly (Alain et al., 2009). Mutations in the UL97 gene (protein kinase) or the UL54 gene (polymerase) are responsible for most cases of resistance to the previous antiviral drugs. Mutations in the UL97 gene are linked to cross-resistance to GCV and VGCV as well as aciclovir and its prodrug, valaciclovir. Late-stage mutations in the UL54 gene may lead to a cross-resistance to GCV and CDV, to a resistance to FOS, or to a cross-resistance to these three antiviral drugs (Alain et al., 2009). 3.3 Number of Patients Targeted The requestor epects a total of 200 tests to be performed at the CHUL (CHU de Québec) in the upcoming three years. 3.4 Medical Specialties Involved (and Other Professions, if Any) Mainly medical microbiology and infectious diseases. 3.5 Testing Procedure Genotyping enables the identification of known and unknown mutations from the viral particles isolated directly at the site of infection (Alain et al., 2009). The specimen may consist of plasma, whole blood, or a virus isolate (ASPC, 2011). The specimen may be kept at room temperature when delivered to a laboratory within 24 hours of collection (DUHS, 2011). However, it must be kept between 2 C and 8 C when delivered within 72 hours of collection. Finally, the plasma must be separated and stored in a sterile bag and be delivered frozen when the delivery period eceeds 72 hours (DUHS, 2011). The virus isolates must be frozen at all times and delivered on dry ice (ASPC, 2011). In order to determine the resistance of CMV to antiviral drugs, the CMV UL54 and UL97 genes are PCR-amplified and then sequenced. Bioinformatics analysis is then performed on the CMV sequencing data by comparing the sequence obtained with that of a reference wild-type genotype, and mutations are identified. The Public Health Agency of Canada suggests that the results should be interpreted with caution, as this test is for research purposes only (ASPC, 2011). The Duke University Laboratory uses amplification of the UL54 and UL97 genes by PCR followed by Sanger DNA sequencing to detect the mutations that confer CMV resistance to antiviral drugs (DUHS, 2011). This laboratory uses the M13 universal primer for the amplification of CMV DNA. The time required for completing this test in a clinical setting is 14 days (DUHS, 2011). 4 TECHNOLOGY BACKGROUND 4.1 Nature of the Diagnostic Technology Unique when considering the fact that phenotyping requires a time period that is much too long to be acceptable in a clinical setting. 3
5 4.2 Brief Description of the Current Technological Contet Studying the drug resistance phenotype remains the reference method as it is essential for determining the effectiveness of antiviral drugs (Alain et al., 2009). This genotyping technique was developed because of the four-week period required to complete phenotyping and because of the subjectivity involved in results analysis (James and Prichard, 2011; Alain et al., 2009). Genotyping has become the preferred method in most laboratories as it is more practical for the detection of resistance mutations (James and Prichard, 2011; Drew, 2010). There are mainly three genotyping protocols that allow for a quick diagnosis of the mutations responsible for antiviral resistance: restriction endonuclease analysis, real-time PCR, and DNA sequencing (Lurain and Chou, 2010). The gold standard among the aforementioned genotyping methods is DNA sequencing (Lurain and Chou, 2010). Sanger 9 DNA sequencing is currently the gold standard in that regard, even though the threshold for detecting minor mutations is relatively high (from 20% to 30% of the population) (Kampmann et al., 2011; Schuurman et al., 1999). New methods such as pyrosequencing (Ronaghi, 2001) or ultradeep sequencing have been developed for a more thorough detection of mutations in a mied virus population (Fo et al., 2009). Following PCR amplification, Sanger sequencing yields longer sequences reads with fewer errors than ultra-deep sequencing (James and Prichard, 2011). While this feature is not important in the case of the UL97 gene, as it is rather short, it becomes relevant when studying mutations in the much longer UL54 gene. The large size of the UL54 gene, as well as the variety of mutation sites known to confer a resistance to antiviral drugs, require the DNA sequencing of at least 2,500 base pairs (James and Prichard, 2011). Irrespective of the DNA sequencing method selected, the interpretation of the mutations detected must be carried out using published data on documented resistance mutations. In a clinical setting, it is essential to be in a position to differentiate polymorphisms and mutations responsible for antiviral resistance (Piret and Boivin, 2011). Phenotyping remains the most important method for producing adequate data on mutations that confer resistance to antiviral drugs (Kotton et al., 2010; Alain et al., 2009). 9 Also referred to as fluorescent dideoy sequencing following nucleic acid amplification. 4
6 4.3 Brief Description of the Advantages Cited for the New Technology The related benefits mentioned by the requestor are direct use of the specimen with no viral amplification through cell culture, speed, identification of the mutation that gives rise to antiviral resistance, evaluation of the cross-resistance to another antiviral drug as well as monitoring of the presence, loss or appearance of other mutations over time. 4.4 Cost of Technology and Options: Not analyzed. 5 EVIDENCE 5.1 Clinical Relevance Other Tests Replaced Replaces phenotyping (which has long been outperformed under clinical setting) Diagnostic or Prognostic Value In terms of results for patients, rapid genotypic detection of antiviral resistance, such as is the case with the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), and CMV, is an approach worth considering (Frobert et al., 2008) Therapeutic Value In terms of the therapeutic options associated with these test results, it is suggested to go from GCV to FOS if genotyping finds a mutation of the UL97 gene associated with a fivefold increase in the resistance to ganciclovir (Kotton et al., 2010). Mutations in the UL97 gene that provide a lower level of resistance may be treated with an increased GCV dosage (between 5 mg/kg and 10 mg/kg twice a day, if renal functions are normal), although genotyping of the UL54 gene is suggested. It is suggested to go from GCV to FOS in the case of a mutation of the UL54 gene that confers a resistance to GCV. Generally, CDF is not recommended as an alternative in cases of resistance to GCV due to a common cross-resistance to GCV-CDV, unless no mutation has been detected in the UL54 gene and the infection is not severe. Other options are also proposed in the case of antiviral resistance under the international guidelines on the treatment of CMV infections in patients with transplanted organs (Kotton et al., 2010). 5.2 Clinical Validity COMPONENT PRESENCE ABSENCE NOT APPLICABLE Sensitivity Specificity Positive Predictive Value (PPV) Negative Predictive Value (NPV) Likelihood Ratio (LR) ROC Curve 5
7 Sensitivity Fluorescent dideoy sequencing following nucleic acid amplification (PCR) can detect a subpopulation of resistance mutations in a population that is still sensitive to antiviral drugs when mutation rates range from 20% to 30%. This sensitivity measure is based on sequencing performed data for the diagnosis of HIV type 1 (Lurain and Chou, 2010; Schuurman et al., 1999). New pyrosequencing and ultra-deep sequencing technologies enable detection even when the subpopulation of resistance mutations account for approimately 6% and of less than 1% of the total population, respectively (Lurain and Chou, 2010). Ultra-deep sequencing technology is still too costly and cannot be used for diagnosis purposes (Lurain and Chou, 2010). There are still too many uncertainties with regard to the cost and performance of new sequencing methods (Shendure et al., 2011). Nonetheless, ultra-deep sequencing is very promising for research on the effect of antiviral drugs on emerging resistance mutations (Lurain and Chou, 2010). Moreover, the resistance profile of CMV may vary from one collection site to another for the same patient. Consequently, what appears as the high sensitivity of genotyping may be misleading if the specimens analyzed from a single site, for instance serum, are not representative of the CMV population in one individual (James and Prichard, 2011). The international guidelines on the treatment of CMV infections in patients with transplanted organs suggest repeating the genotyping procedure two weeks after a first test has come back negative, if the viral load has not decreased or if the health status of the infected patient has not improved (Kotton et al., 2010). This second genotyping procedure must target both the UL97 and the UL54 genes (Kotton et al., 2010). 5.3 Analytical (or Technical) Validity Repeatability Reproducibility Analytical Sensitivity Analytical Specificity Matri Effect Concordance COMPONENT PRESENCE ABSENCE NOT APPLICABLE Correlation Between Test and Indicator Others Based on Test Type Reproducibility The reproducibility of this protocol is best if the concentration of the specimen under study corresponds to 1,000 copies/ml (Drew, 2010; Alain et al., 2009). The reproducibility and success of the genotyping procedure depend on the availability of validated phenotyping data on antiviral resistance mutations (Chevillotte et al., 2010). Genotyping does not yield quantitative results (unknown proportions of the virus population affected by the mutation(s)) (Drew, 2010). Furthermore, interpreting the results is a major challenge with this technique, given the number of irrelevant mutations that may be detected (Drew, 2010). 6
8 5.4 Recommendations for Listing in Other Jurisdictions No information has been found in that regard. However, it is a known fact that genotyping is a rapid method for identifying antiviral resistance mutations and that it is increasingly used in laboratories. 6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST 6.1 Impact on Material and Human Resources: Not assessed. 6.2 Economic Consequences of Introducing Test Into Quebec s Health and Social Services System: Not assessed. 6.3 Main Organizational, Ethical, or Other (Social, Legal, Political) Issues: Not assessed. 7
9 7 INESSS NOTICE IN BRIEF Genotyping of Cytomegalovirus (or Herpes Simple Virus) for Ganciclovir (Aciclovir) and Foscarnet Resistance (Code 40514) Status of the Diagnostic Technology: Established Innovative Eperimental (for research purposes only) Replacement for technology:, which becomes obsolete INESSS Recommendation: Keep test in the Inde Remove test from the Inde Reassess test Additional Recommendation: Draw connection with listing of drugs, if companion test Production of an optimal use guide Production of indicators, when monitoring is required 8
10 REFERENCES Agence de la santé publique du Canada (ASPC). Génotypage de la résistance du cytomégalovirus humain (CMVH) au antivirau (site Web). Ottawa, ON : ASPC; Available from: (viewed Feb 15, 2013). Alain S, Cotin S, Hantz S. Résistance du cytomégalovirus au antivirau. Virologie 2009;13(4): Chevillotte M, Ersing I, Mertens T, von Einem J. Differentiation between polymorphisms and resistanceassociated mutations in human cytomegalovirus DNA polymerase. Antimicrob Agents Chemother 2010;54(12): Drew WL. Cytomegalovirus resistance testing: Pitfalls and problems for the clinician. Clin Infect Dis 2010;50(5): Duke University Health System (DUHS). Cytomegalovirus (CMV) genotype (site Web). Durham, NC : DUHS; Available from: (viewed Feb 15, 2013). Fo S, Filichkin S, Mockler TC. Applications of ultra-high-throughput sequencing. Methods Mol Biol 2009;553: Frobert E, Cortay JC, Ooka T, Najioullah F, Thouvenot D, Lina B, Morfin F. Genotypic detection of acyclovir-resistant HSV-1: characterization of 67 ACV-sensitive and 14 ACV-resistant viruses. Antiviral Res 2008;79(1): Hamilton RJ, réd. Tarascon Pocket Pharmacopoeia. 13 e éd. Burlington, MA : Jones and Bartlett Learning; James SH et Prichard MN. The genetic basis of human cytomegalovirus resistance and current trends in antiviral resistance analysis. Infect Disord Drug Targets 2011;11(5): Kampmann SE, Schindele B, Apelt L, Buhrer C, Garten L, Weizsaecker K, et al. Pyrosequencing allows the detection of emergent ganciclovir resistance mutations after HCMV infection. Med Microbiol Immunol 2011;200(2): Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89(7): Lurain NS et Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010;23(4): Piret J et Boivin G. Resistance of herpes simple viruses to nucleoside analogues: Mechanisms, prevalence, and management. Antimicrob Agents Chemother 2011;55(2): Ronaghi M. Pyrosequencing sheds light on DNA sequencing. Genome Res 2001;11(1):
11 Schuurman R, Demeter L, Reichelderfer P, Tijnagel J, de Groot T, Boucher C. Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase. J Clin Microbiol 1999;37(7): Shendure JA, Porreca GJ, Church GM, Gardner AF, Hendrickson CL, Kieleczawa J, Slatko BE. Overview of DNA sequencing strategies. Curr Protoc Mol Biol 2011;Chapter 7:Unit
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