Currently, multiple regimens are available for treating H. pylori infection. These include proton pump inhibitors or polyphosphoinositide (PPI) (as well as similar medication[s]) to suppress acid production, in combination with antibiotic treatment, consisting of one or more agents such as amoxicillin, clarithromycin, or metronidazole. These first-line regimens generally achieve eradication rates in the 70%–90% range. Differences in eradication rates are dependent on the regimen used and the population being treated. Treatment failures are most often attributed to antibiotic resistance or poor patient compliance. Resistance to clarithromycin is an important factor associated with treatment failure, with high rates of treatment failure for standard first-line regimens in patients infected with clarithromycin-resistant strains of H. pylori. A 2002 survey from the United States estimated that 13% of H. pylori strains are resistant to clarithromycin and that the rate of resistance was rising in comparison to earlier studies.

Genetic factors may influence the success of H. pylori treatment through effects on PPI metabolism. Individuals with polymorphisms in the CYP2C19 gene, a component of the cytochrome P450 (CYP450) system, metabolize PPIs more slowly than normal. Genetic variation in the CYP450 enzyme system is one of the most extensively studied in the field of pharmacogenomics. This family of enzymes is found in the liver and is important for metabolizing and eliminating a large number of pharmacologic agents. Differences in PPI metabolism lead to variability in gastric acid suppression, with associated variability in gastric pH, and potential impact on the efficacy of H. pylori treatment. Observational research suggests that patients who are extensive metabolizers of PPIs have lower eradication rates following standard treatment for H. pylori, compared with poor metabolizers.

Three major CYP2C19 alleles determine enzymatic activity, as shown in Table 1. The *1 allele is the wild-type found in most individuals, while the *2 and *3 alleles are the most common polymorphisms that are known to impact enzymatic activity. Both the *2 and *3 alleles are examples of ‘null’ alleles, which have no enzymatic activity. Each null allele is caused by a single nucleotide change that results in a splice defect or a stop codon (AmpliChip package insert).

Table 1. CYP2C19 polymorphisms**				Table 2. CYP2C19 phenotypes**
Allele	Nucleotide change	Predicted Enzyme Activity		Allele	1	2	3
*1	None	Normal		1	EM	IM	IM
*2	681G>A	None		2		PM	PM
*3	636G>A	None		3			PM

**Adapted from AmpliChip package insert

EM extensive metabolizers

IM intermediate metabolizers

PM poor metabolizers

Polymorphisms of the CYP2C19 gene are relatively common and vary by ethnicity. Patients with no polymorphisms of CYP2C19 have two wild-type alleles and no reduction in their ability to metabolize PPIs. These patients are typically called extensive metabolizers (EM) (Table 2). Heterozygous polymorphisms are found in 27%–37% of the Caucasian population and 46%–50% of the Asian population. These patients have a minor reduction in their ability to eliminate PPIs, and are called intermediate metabolizers (IM). Homozygous polymorphisms of the CYP2C19 gene are found in 3%–6% of Caucasians and in 12%–20% of Asians. These patients eliminate PPIs from the circulation substantially much more slowly than unaffected patients, and are termed poor metabolizers (PM).

In patients treated with PPIs, intragastric pH has been shown to correlate with CYP2C19 status. Patients homozygous for a CYP2C19 mutation (PM) exhibit a less acidic pH when compared to patients without a CYP2C19 mutation, with heterozygous patients exhibiting intermediate values. Intragastric pH has important implications for treating H. pylori. H. pylori is more sensitive to antibiotics at less acidic pH levels. Less acidic pH levels also lead to greater stability and bioavailability of antibiotics. Therefore, it is expected that treatment of H. pylori will be more successful if there is maximal suppression of gastric acid production and higher intragastric pH levels.

Therefore, it has been proposed that a pharmacogenomics-based treatment regimen individualized by CYP2C19 status may improve the success rate of treatment for H. pylori. If CYP2C19 status is known prior to treatment, adjustments can be made in the selection of PPI and/or the dosing schedule to achieve optimal acid suppression in all patients. Improved eradication rates for H. pylori could lead to improved health outcomes by reducing the need for re-treatment following treatment failure, reducing recurrences of H. pylori-associated disorders, and reducing the morbidity and mortality associated with disease recurrence.

At least one commercially available genetic test, the Roche AmpliChip Cytochrome P450® Genotyping test, has been approved by the U.S. Food and Drug Administration (FDA) as a class II medical device. This test examines polymorphisms in CYP2D6 and CYP2C19 isoenzymes of the cytochrome P450 enzyme system. Approval for this device was originally granted in December 2004 as an aid in determining treatment choice and individualizing treatment dose for therapeutics that are metabolized primarily by the CYP2D6 enzyme. The use of information on CYP2C19 polymorphisms was not addressed as part of the FDA approval process.

Policy:
(NOTE: For services provided August 1, 2017 and after, Horizon Blue Cross Blue Shield of New Jersey collaborates with eviCore healthcare to conduct Medical Necessity Determination for certain molecular and genomic testing services for members enrolled in Horizon BCBSNJ fully insured products as well as Administrative Services Only (ASO) accounts that have elected to participate in the Molecular and Genomic Testing Program (“the Program”). Beginning August 1, 2017, the criteria and guidelines included in this policy apply to members enrolled in plans that have NOT elected to participate in the Program.

To access guidelines that apply for services provided August 1, 2017 and after to members enrolled in plans that HAVE elected to participate in the Program, please visit www.evicore.com/healthplan/Horizon_Lab).

Please refer to a separate policy on Cytochrome p450 Genotyping (Amplichip) for Personalized Medicine Management in the Medicine Section (Policy #033).

For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

Genotyping to determine cytochrome p450 (CYP2C19) genetic polymorphisms is considered investigational for the purpose of managing the treatment of H. pylori infection.


Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: Validation of genotyping to improve pharmacologic treatment outcomes is a multistep process. In general, important steps in the validation process address the following:

• Analytic validity: measures technical performance, i.e., whether the test accurately and reproducibly detects the gene markers of interest.
• Clinical validity: measures the strength of the associations between the selected genetic markers and dose, therapeutic efficacy, and/or adverse events.
• Clinical utility: determines whether the use of genotyping for specific genetic markers to guide prescribing and/or dosing improves patient outcomes such as therapeutic effect, time to effective dose, and/or adverse event rate compared to standard treatment without genotyping.

For the CYP2C19 gene, the test examines for the two common polymorphisms associated with enzymatic activity (Table 1 above in the Description Section). Information from the manufacturer claims greater than 99% accuracy in detecting these common polymorphisms. However, a number of rare polymorphisms that have been identified are not tested for by the AmpliChip system. The results of the test are included in a report to the ordering physician that includes potential clinical implications of the result.

Observational research has suggested that there is a correlation between CYP2C19 status and success rates for eradication of H. pylori. For the most part, these studies are trials of different regimens for H. pylori eradication in which CYP2C19 status was evaluated as a secondary objective. The majority of studies that did not use rabeprazole reported lower eradication rates in extensive metabolizer (EM) patients compared with poor metabolizer (PM) patients. Eradication rates in PM patients are consistently in the 95%–100% range. The eradication rates for EM patients are substantially lower, ranging from 29%–80%, with eradication rates for intermediate metabolizer (IM) patients generally intermediate between the two. For trials that used rabeprazole, eradication rates according to CYP2C19 group were generally similar, although at least 1 study did report lower eradication rates for EM patients. Rabeprazole is the only PPI that is not metabolized by the CYP2C19 enzyme, and therefore eradication rates with regimens including rabeprazole may not vary according to CYP2C19 status.

A recent meta-analysis confirmed these findings. This analysis included clinical trials of H. pylori eradication that used dual or triple therapy antibiotic regimens, reported eradication rates by CYP2C19 status, and had a Jadad quality score of 2 or greater. The authors identified 19 trials that met their inclusion criteria, and reported pooled eradication rates by genetic status and specific PPI agent. For all PPIs, the pooled eradication rate was highest in the PM group (89%), intermediate in the IM group (83%), and lowest in the EM group (71%), with the difference between these groups significant at the p<0.0001 level. The difference in eradication rates by CYP2C19 status also appeared to vary by the specific PPI used. The greatest difference in eradication rates between EM groups and PM groups was seen for omeprazole (93% vs. 63%). The difference in eradication rates was less pronounced for lansoprazole (88% vs. 74%), and least evident for rabeprazole (81% vs. 77%).

A single randomized, controlled trial was identified for use of genetic testing in selecting the treatment regimen for H. pylori infection. This study randomized 300 Japanese patients to a pharmacogenomics-based treatment regimen versus a standard treatment regimen. The pharmacogenomics regimen included testing for CYP2C19 genetic status, esophagogastroduodenoscopy (EGD), and H. pylori culture with sensitivity testing to clarithromycin. In the pharmacogenomics group, the dose of PPI was adjusted according to CYP2C19 genetic status, and the antibiotic regimen was adjusted according to H. pylori sensitivity to clarithromycin.

Eradication rates following initial treatment were 96% (95% CI: 91.5–98.2%) in the pharmacogenomics-based treatment versus 70.0% (95% CI: 62.2–77.2%) in the standard therapy group (p<0.001). When analyzed according to genetic status, the improvement in eradication rates in the pharmacogenomics group was greater for EM patients (100% vs. 58%) and IM patients (95% vs. 72%), compared to PM patients (91% vs. 91%). Eradication rates also varied by clarithromycin-resistant status, with particularly low eradication rates occurring in the standard treatment group for EM patients with clarithromycin resistance (0%) and IM patients with clarithromycin resistance (48%).

Patients who failed eradication following first-line treatment were re-treated. By intent-to-treat analysis, eradication rates following re-treatment were 97.8% (95% CI: 94.3–99.6%) for the pharmacogenomics group compared to 88.0% (95% CI: 81.7–92.7%) for the standard regimen group (p<0.001). When analyzed by per-protocol, the eradication rates were 99.3% (95% CI: 96.3–100%) for the pharmacogenomics group compared to 95.7% (95% CI: 90.8–98.4%) for the standard treatment group (p=NS).

This study demonstrates how pharmacogenomics can be used to individualize medication regimens, and how a clinical trial can be constructed to evaluate the impact of a pharmacogenomics-based treatment approach. This study is also notable in that it addresses a common, real-life clinical problem, and uses commercially available technology for pharmacogenomics-based decision-making.

While the single available randomized, controlled trial reports an increased rate of H. pylori eradication in the pharmacogenomics strategy compared with a standard approach, this study does not provide definitive evidence that use of a pharmacogenomics-based treatment regimen improves health outcomes. There are numerous variations in the treatment regimen within the experimental group that make it difficult to determine which specific aspects of the treatment regimen may have led to benefit. In particular, it appears that clarithromycin resistance is an important factor in treatment success, and that there may be an interaction between clarithromycin resistance and CYP2C19 status. From the data reported in the study, it is hard to separate the potential impact of clarithromycin resistance on eradication rates from the impact of pharmacogenomically tailored PPI dosage schedules.

In addition to the limitations on internal validity, the clinical relevance of the study is also limited for several reasons. The treatment approach used was relatively intensive, including genetic testing for CYP2C19, EGD with biopsy for all patients, and testing of H. pylori isolates for clarithromycin resistance. This treatment approach is much more intensive than that generally used in the United States, where the diagnosis of H. pylori is usually made by noninvasive methods, and initial empiric treatment is instituted without isolating H. pylori or testing for resistance. Furthermore, the patient population was from Japan, limiting the generalizability of the results, especially given the ethnic differences in CYP2C19 genetic status.

Alternative treatment strategies exist for eradicating H. pylori that address some of the issues raised by CYP2C19 variability but do not rely on testing for CYP2C19 status. For example, empiric treatment with higher-dose PPI for all patients might be reasonable, particularly for non-Asian populations in which CYP2C19 mutation rates are lower. This approach may be as effective as regimens tailored by pharmacogenomics, with little additional risk. The use of a PPI that is less susceptible to CYP2C19 status, such as rabeprazole, might also be justified, given that there is no reason to suspect other advantages to use of omeprazole or lansoprazole. Ideally, a clinical trial will evaluate whether a tailored pharmacogenomics approach is superior to other empiric approaches such as these.

The scientific evidence does not permit conclusions on whether the use of a pharmacogenomics-based treatment regimen for H. pylori improves eradication rates. In the single randomized, controlled trial comparing a pharmacogenomics-based treatment regimen with a standard regimen, eradication rates after first-line treatment were higher for the pharmacogenomics group compared with the standard treatment group. However, because of numerous variations in treatment protocol within the pharmacogenomics group, it is not possible to determine whether the improvement resulted from the tailored PPI dosages according to CYP2C19 genetic status, or due to other variations in the treatment protocol unrelated to CYP2C19 status. It is possible that other clinical factors, such as clarithromycin resistance, or other treatment factors, such as length of antibiotic treatment, may have influenced eradication rates. Therefore, additional trials are needed to address the issues noted above, including alternative treatment regimens, before conclusions can be made on whether a pharmacogenomics-based treatment regimen improves H. pylori eradication rates compared to a standard treatment regimen. Since the impact of this testing on clinical outcomes (clinical utility) is not currently known, this testing is considered investigational.

An updated literature search did not identify new clinical trials that compared a clinical strategy of genetic testing and tailored pharmacologic regimens with usual care. The identified literature consisted primarily of studies in which a single treatment regimen was used and in which all patients were tested for CYP2C19 status. Eradication rates were then compared among patients who were EM, IM, and/or PM. Kang et al. performed a study of this type in 327 Korean patients with H. pylori infection. The treatment regimen consisted of amoxicillin, clarithromycin, and a PPI (either pantoprazole or esomeprazole) for 7 days. The eradication rate was higher in the PM group compared to the EM group (97.4% vs. 83.3%, p=0.016). Mielhke et al (10) studied 103 consecutive patients who had failed at least one prior treatment regimen and had H. pylori infection that was resistant to metronidazole and clarithromycin. All patients were treated with moxifloxacin, rifabutin, and esomeprazole for 7 days. Eradication rates were higher in PM/IM patients (93.1%) compared with EM patients (78.8%), but this difference did not reach statistical significance (p=0.14).

No published guidelines were identified that addressed whether to use genetic testing as part of a treatment protocol for H. pylori eradication. Expert opinion does not appear to favor the use of genetic testing for this purpose. Rather, alternative strategies to mitigate the differences in eradication rates by genetic status are suggested. Klotz recommends using higher doses of PPIs in all patients as an alternative to genetic testing and tailoring of PPI dose. Sheu and Fock suggest that the use of PPIs that are less influenced by genetic status, such as rabeprazole, might be the preferred agents for H. pylori eradication.

In summary, new research on genetic testing for treatment of H. pylori confirms previous studies demonstrating that eradication rates of H. pylori may differ according to CYP2C19 genetic status. Routine testing of CYP2C19 genetic testing is not recommended in current clinic practice.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Genetic Testing for Helicobacter Pylori Treatment
CYP2C19 Testing for H. Pylori Treatment
Helicobacter Pylori Treatment, Genetic Testing
H. Pylori Treatment, Genetic Testing

References:
1. TEC Assessments 2008, “Pharmacogenomics-based Treatment of Helicobacter pylori Infection.”

2. AmpliChip CYP450 test package insert. Roche Diagnostics/Roche Molecular Systems. Indianapolis, IN; July 2006. Available online at http://www.amplichip.us/documents/CYP450_P.I._US-IVD_Sept_15_2006.pdf . Last accessed February 2008.

3. Sapone A, Vaira D, Trespidi S et al. The clinical role of cytochrome P450 genotypes in Helicobacter pylori management. Am J Gastroenterol 2003; 98(5):1010-5.

4. Schwab M, Schaeffeler E, Klotz U et al. CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori. Clin Pharmacol Ther 2004; 76(3):201-9.

5. Sheu BS, Kao AW, Cheng HC et al. Esomeprazole 40mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment Pharmacol Ther 2005; 21(3):283-8.

6. Furuta T, Shirai N, Takashima M et al. Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 2001; 11(4):341-8.

7. Padol S, Yuan Y, Thabane M et al. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol 2006; 101(7):1467-75.

8. Furuta T, Shirai N, Kodaira M et al. Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther 2007; 81(4):521-8.

9. Kang JM, Kim N, Lee DH et al. Effect of the CYP2C19 polymorphism on the eradication rate of Helicobacter pylori infection by 7-day triple therapy with regular proton pump inhibitor dosage. J Gastroenterol Hepatol 2008; 23(8 Pt 1):1287-91.

10. Miehlke S, Schneider-Brachert W, Kirsch C et al. One-week once-daily triple therapy with esomeprazole, moxifloxacin, and rifabutin for eradication of persistent Helicobacter pylori resistant to both metronidazole and clarithromycin. Helicobacter 2008; 13(1):69-74.

11. Sheu BS, Fock KM. CYP2C19 genotypes and Helicobacter pylori eradication. J Gastroenterol Hepatol 2008; 23(8 Pt 1):1163.

12. Klotz U. Impact of CYP2C19 polymorphisms on the clinical action of proton pump inhibitors (PPIs). Eur J Clin Pharmacol 2009; 65(1):1-2.

13. Kuo CH, Wang SS, Hsu WH et al. Rabeprazole can overcome the impact of CYP2C19 polymorphism on quadruple therapy. Helicobacter 2010; 15(4):265-72.

14. Ward MB, Foster DJ. CYP2C19-guided design of a proton pump inhibitor dose regimen to avoid the need for pharmacogenetic individualization in H. pylori eradication. Eur J Clin Pharmacol 2011; 67(3):261-6.

15. Zhang L, Mei Q, Li QS et al. The effect of cytochrome P2C19 and interleukin-1 polymorphisms on H. pylori eradication rate of 1-week triple therapy with omeprazole or rabeprazole, amoxycillin and clarithromycin in Chinese people. J Clin Pharm Ther 2010; 35(6):713-22.

16. Helicobacter pylori Infection. Options for Testing and Treatment. Gstroenterol Hepatol (NY) Sep 2012;8(9):621-623.

17. Ma JD, LEE KC, Kuo GM. Clinical application of pharmacogenomics. J Pharm Pract. 2012 Aug;25(4):417-27.

18. Samer CF, Lorenzini KI, Rollason V, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013 Jun;17(3):165-84.

19. Papastergiou V, Georgopoulos SD, Karatapanis S. Treatment of Helicobacter pylori infection: meeting the challenge of antimicrobial resistance. World J Gastroenterol. 2014 Aug 7;20(29):9898-911.

20. Kuo CH, Lu CY et al. CYP2C19 polymorphism influences Helicobacter pylori eradication. World J Gastroenterol. 2014 Nov 21;20(43):16029-36.

21. Bang CS, Baik GH. Attempts to enhance the eradication rate of Helicobacter pylori infection. World J Gastroenterol. 2014 May 14;20(18);5252-62.

22. Papastergiou V, Georgopoulos SD, Karatapanis S. Treatment of Helicobacter pylori infection: meeting the challenge of antimicrobial resistance. World J Gastroenterol. 2014 Aug 7;20(29):9898-911.

23. Wang YK, Kuo FC, Liu CJ, et al. Diagnosis of Helicobacter pylori infection: Current options and developments. World J Gastroenterol 2015 Oct 28;21(40):11221-35.

24. UpToDate. Indications and diagnostic tests for Helicobacter pylori infection. Literature review current through May 2016. Topic last updated March 12, 2015.

25. Miftahussurur M, Yamaoka Y. Diagnostic Methods of Helicobacter pylori Infection for Epidemiological Studies: Critical Importance of Indirect Test Validation. Biomed Res Int 2016;2016:4819423 [Epub 2016 Jan 19].

26. Crowe SE. Indications and diagnostic tests for Helicobacter pylori infection. In: UpToDate, Feldman M, Grover S (Ed), UpToDate, Waltham, MA. (Accessed on May 8, 2017.)

27. Crowe S. Treatment regimens for Helicobacter pylori. In: UpToDate, Feldman M, Grover S (Ed), UpToDate, Waltham, MA. (Accessed on May 07, 2017.)

28. Crowe S. Treatment regimens for Helicobacter pylori. In: UpToDate, Feldman M, Grover S (Ed), UpToDate, Waltham, MA. (Accessed on March 30, 2018.)

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81225

G0452