Absolute and relative contraindications to pegylated-interferon or ribavirin in the US general patient population with chronic hepatitis C: results from a US database of over 45 000 HCV-infected, evaluated patients

Authors


Correspondence to:

Dr A. H. Talal, University of Buffalo, State University of New York, Department of Medicine, UB-CTRC, 875 Ellicot Street, Suite 6090, Buffalo, NY 14203, USA.

E-mail: ahtalal@buffalo.edu

Summary

Background

Chronic hepatitis C (HCV) treatment with pegylated-interferon (PEG-IFN)/ribavirin (RBV) is often limited by preexisting medical, psychiatric and psychosocial contraindications. However, limited data exist in general patient populations.

Aim

To evaluate the percentage of HCV-infected patients in the general US population who may have contraindications to PEG-IFN/RBV.

Methods

The General Electric (GE) Centricity dataset was used to screen the US population between 2004 and 2009 for HCV infection and contraindications to PEG-IFN/RBV. HCV diagnosis and contraindications were identified using ICD-9-CM codes or laboratory values. Only patients with an encounter 180 days prior to HCV diagnosis were included. Demographic differences were calculated using Pearson's chi-squared test. Frequencies and percentages for absolute and relative contraindications to PEG-IFN and/or RBV were determined and proportions and rates/1000 person-months were calculated.

Results

A total of 15 561 021 patients were screened, and 45 690 (0.3%) were HCV-positive and were evaluated. Those with contraindications were significantly younger, female, White, not currently married and receiving Medicare or Medicaid coverage (all P < 0.0001). 17.3% had at least one contraindication to PEG-IFN/RBV (5.5 events/1000 person-months); bipolar disorder (6.5%), anaemia (Hgb < 10 g/dL; 5.9%), pregnancy (1.9%) and neutropenia (neutrophils <750 cells/mm3; 1.2%) were most frequently cited.

Conclusions

Approximately, 17% of HCV-infected patients in the general US population had at least one contraindication to PEG-IFN/RBV. Most contraindications were relative and potentially modifiable. Clinical assessment of contraindications as relative and/or modifiable should be considered and used to determine if patients could benefit from current PEG-IFN–containing triple therapy or future PEG-IFN– or RBV-free regimens.

Introduction

Current estimates suggest that roughly 170 million people worldwide and 5 million people in the United States are infected with chronic hepatitis C (HCV).[1, 2] A large proportion are between 40 and 60 years of age and have often experienced an asymptomatic, slow progression of disease with increasing liver damage over decades.[1, 3] A recent analysis by the Centers for Disease Control found age-based HCV screening to be cost-effective[4] and recently released recommendations that all individuals born between 1945 and 1965 be screened with an HCV antibody test at least once. In addition, the development and recent US Food and Drug Administration approval of the new HCV protease inhibitors, telaprevir and boceprevir, has resulted in a renewed effort to screen, identify and treat undiagnosed HCV infections. As a result of various strategies designed to promote HCV evaluation and treatment, as well as improved treatment efficacy with decreased side effects, many newly diagnosed patients with HCV will likely be encouraged to pursue treatment.

Standard-of-care treatment of HCV infection involves combinations that continue to include pegylated-interferon (PEG-IFN) plus ribavirin (RBV).[5] Therapy with PEG-IFN and RBV is limited by absolute and relative medical and psychiatric contraindications.[5] Unfortunately, many of these contraindications coexist in patients infected with HCV and can limit treatment; these include substance abuse, psychiatric illness and mental health issues, and various preexisting medical conditions.[3] The impact of contraindications on the selection and treatment of HCV varies depending upon the methods, classification and patient populations evaluated. In the most controlled settings (e.g. clinical trials for drug approval), significant contraindications are eliminated by strict inclusion/exclusion criteria that often limit the generalisability of the results to key subgroups of those infected with HCV. In reports of HCV therapy in clinical practice, the rates of contraindications to PEG-IFN/RBV may not be accurately reported in individual studies due to small sample sizes (which might particularly affect identification and reporting of rare side effects), limitations in study methodologies (e.g. retrospective reviews without control groups) and varying definitions of contraindications. For example, 404 (30.2%) of 1337 patients were excluded when evaluated for interferon plus RBV treatment in a key registration trial.[6] In contrast, a retrospective analysis of patients with HCV infection treated at the Cleveland Clinic found 72% of 293 patients ineligible for treatment.[7]

One healthcare system in the United States that has extensively evaluated the impact of contraindications on initiation of HCV therapy is the Veterans Administration (VA) Medical System. Hepatitis C infection in this population is roughly 2–3 times more prevalent than in the general population and has been associated with high rates of psychiatric disorders and substance abuse.[8-12] The VA has a relatively closed network that utilises large electronic databases to connect VA clinics throughout the United States. Among 4084 veterans referred for HCV treatment over a 1-year period at 24 VA Medical Centers, 67.8% were deemed ineligible according to standardised HCV treatment criteria at the time of the study.[13] In a separate analysis of all VA patients diagnosed with HCV between 1999 and 2003 (n = 113 927), only 11.8% received a prescription for anti-viral therapy.[14] In both reports, substance abuse, underlying preexisting medical conditions (e.g. anaemia, advanced liver disease) and psychiatric and mental health issues were found to be frequent barriers to HCV treatment initiation.

While the impact of contraindications and treatment eligibility has been extensively evaluated in the VA system, limited data exist on the frequency of contraindications to PEG-IFN/RBV in the general US population.[8-14] The current analysis utilised a large nationwide electronic database to determine the percentage of patients in the general population with HCV who would be ineligible for therapy with PEG-IFN plus RBV because of contraindications.

Methods

Patients

We utilised data from the General Electric (GE) Centricity electronic medical record (EMR) dataset. In 2011, the GE Centricity EMR contained medical records for 21 948 827 patients who received health care from 18 927 providers throughout the United States. The GE EMR demographic is similar to the general patient population of the United States with regard to gender, age and race (Table 1).[15]

Table 1. Patient demographics of GE Centricity database vs. the general population of the United States in 2009[15]
 United States (2009)GE Centricity Database
Male population by age (%)
0–1725.121.5
18–3422.918.5
35–4414.112.6
45–5413.115.1
55–649.513.8
65–746.39.9
75–843.66.2
85+1.22.3
Female population by age (%)
0–1723.214.9
18–3421.524.1
35–4413.714.0
45–5413.215.6
55–6410.013.4
65–747.28.9
75–845.06.1
85+2.53.0
Population by race (%)
White72.571.3
Black or African American12.516.0
American Indian/Alaskan native0.90.5
Asian/Hawaiian/Pacific islander4.41.2
Other race6.73.0
Multiple races2.90.1
Hispanic/Latino ethnicity (%)15.57.9

All patients with a diagnosis of HCV between 1 January 2004 and 31 December 2009 were identified from the database. The diagnosis of HCV was established using the International Classification of Diseases, ninth edition, Clinical Modification codes (ICD-9-CM); codes included chronic HCV with or without mention of hepatic coma (codes 070.44 and 070.54), hepatitis C carrier (code V02.62), unspecific viral HCV with or without hepatic coma (codes 070.70 and 070.71) and acute HCV with or without hepatic coma (codes 070.41 and 070.51). The date of the first diagnosis was defined as the index date. Only those patients who had an encounter at least 180 days prior to the index date were included to ensure that patients had a pattern of seeking routine care within the system. To ensure that the diagnosis was correct, patients were further limited to those who either: (i) had two diagnosis codes for HCV within 395 days of each other or (ii) had a diagnosis for HCV and a confirmatory laboratory result within 180 days before or 395 days after the date of first diagnosis.

Observation period

We defined prevalent contraindications as those identified in the 180 days before or on the index date. Incident contraindications were those recognised the day after the index date and continuing until censorship via the first of any of the following: (i) the occurrence of a contraindication-related event (see below), (ii) the date of the patient's last encounter in the GE EMR dataset or (iii) 31 December 2009.

Contraindications

Contraindications were defined a priori as shown in Table 2. Patient electronic medical records containing any of those definitions during the prevalent or incident time periods were noted as having contraindications. Definitions for the contraindications are based on ICD-9-CM diagnosis and procedure codes and laboratory values. Absolute contraindications were defined as those for which treatment with PEG-IFN or RBV could not be modified or initiated for any reason, whereas relative contraindications were those that could be potentially modified through clinical interventions or were transient in nature.

Table 2. List of contraindications included in this manuscript
ContraindicationICD-9-CM Codes
History of uncontrolled seizures345.01, 345.11, 345.41, 345.51, 345.61, 345.71, 345.81, 345.91
Moderate to severe retinopathy362.05, 362.06
Hepatic decompensation572.2
Major depression with history of suicide attempt296.2 (E950–E957)
Acute myocardial infarction410
Haemoglobinopathies282.4, 282.6, 282.7
Acute coronary syndromes411.1
Bipolar disorder296.0, 296.4, 296.5, 296.6, 296.7, 296.8
Neutrophils <750 cells/mm3288.0
Haemoglobin <10 g/dL280, 281, 282, 283, 284, 285
Platelets <50 000 cells/mm3287.3, 287.4, 287.5, 289.84
History of kidney transplantV42.0, 996.81
History of organ transplantation other than liver/kidney996.83, 996.84, 996.85, 996.86, 996.87, V42.84
Pregnancy640–651, 671, V22.0, V23, V61.6, V61.7, V72.42, 658.1 and 659

Analysis

Descriptive statistics were calculated to characterise baseline demographics, including age at diagnosis, sex, race, marital status and insurance coverage. Differences in demographic characteristics between those patients who did and did not have contraindications at any time were compared using Pearson's Chi-squared tests.

Tabulations (frequencies and percentages) were created for patients who had contraindications before and after the index date. Prevalent contraindications were reported as the frequency for each contraindication in the 180 days prior to the index date, counting the contraindication only once even if it occurred more than once in the same patient. A prevalence proportion was then calculated for each contraindication by taking the number of patients with that contraindication within 180 days of their diagnosis date and dividing it by the total number of patients in the cohort. In addition, a standardised prevalence rate per 1000 person-months was calculated by dividing the total number of observations for each contraindication by the number of person-months observed in the preindex period multiplied by 1000. Similar analyses were performed for incident contraindications using the postindex evaluation period to calculate an incident proportion and incident rate per 1000 person-months.

The overall number of patients who had a diagnosis of any contraindication were reported and summarised for those who had 1, 2, 3, >3 and any contraindication by the end of the observation. The median observation time in months was calculated as follows: (i) from diagnosis to first event for all eligible patients with HCV with incident contraindications, and (ii) from 180 days prior to diagnosis to first event for patients with any contraindication.

Results

A total of 15 651 021 patients in the GE Centricity EMR cohort were evaluated because of an HCV diagnosis between 1 January 2004 and 31 December 2009. As shown in Figure 1, a total of 71 662 patients (0.45%) were found to have a diagnosis of HCV and were evaluated during this period. Of these, 19 310 (27%) did not have an encounter within 180 days prior to the index date and were excluded. An additional 6662 patients (9%) were excluded because they did not have either: (i) a confirmatory laboratory value 180 days before or 395 days after the index date, or (ii) a second diagnosis (or valid activity) within 395 days of the index HCV diagnosis. The remaining 45 690 patients were included in the analysis; by the end of follow-up, 7903 and 37 787 did and did not have any contraindications respectively.

Figure 1.

Patient flow diagram.

Overall, 17.3% of patients with HCV infection had contraindications to therapy. Baseline characteristics for the entire GE Centricity EMR cohort and those HCV infected with or without any contraindication are summarised in Table 3. Compared with HCV-positive patients without prevalent or incident contraindications, those with contraindications were younger, female, White, not currently married and receiving Medicaid or Medicare health coverage (all < 0.0001).

Table 3. Descriptive characteristics of the underlying cohort (all patients seen in the GE Centricity EMR) and in patients with HCV with and without contraindications
 In all patients (with or without HCV) (N = 15 651 021)In patients with HCV and without prevalent or incident contraindi-cations (N = 37 787)In patients with HCV and with prevalent or incident contraindications (N = 7903) 
 Frequency (N)Percentage (%)Frequency (N)Percentage (%)Frequency (N)Percentage (%)P-valuea
  1. a

     Comparison between HCV patients with and without contraindications.

Age (years)<0.0001
<508 719 10555.712 63733.4354944.9 
50-653 668 78023.421 99558.2376947.7 
65+3 262 93020.831548.35857.4 
Unknown2060100 
Sex<0.0001
Male6 684 01842.721 04655.7341343.2 
Female8 959 30257.216 73344.3448856.8 
Unknown770108020 
Race<0.0001
White4 449 03428.413 53835.8347644.0 
Black881 1025.6482512.894512.0 
Hispanic381 1402.49052.42052.6 
Other/unknown9 939 74563.518 51949.0327741.5 
Marital status<0.0001
Married5 679 55736.311 83631.3197024.9 
Never married5 164 37833.013 43035.5327441.4 
Divorced506 0633.231658.488411.2 
Widowed526 1263.49772.62393.0 
Separated63 7350.44521.21241.6 
Other/unknown3 711 16223.7792721.0141217.9 
Payer<0.0001
Commercial5 497 38635.110 68728.3178722.6 
Medicaid581 8843.727767.390711.5 
Medicare2 185 35914.0632216.7196324.8 
Self pay439 4332.819025.02713.4 
Unknown6 946 95944.416 10042.6297537.6 

The prevalence and incidence frequencies, proportions and rates of contraindications are summarised in Table 4. The median observation time for all eligible patients with HCV, those with incident contraindications and those with any contraindications were 21.7, 33.3 and 32.1 months respectively. The most common contraindications were bipolar disorders (6.5%), anaemia (5.9%) and pregnancy (1.9%); these three contraindications were frequently cited in both the prevalent and incident time periods. Of note, common conditions in the general population such as myocardial infarction, acute coronary syndromes and depression were infrequently identified as contraindications in the current analysis (0.6%, 0.1% and 0 respectively). Of the 7903 individuals with any contraindication, 87.6% (n = 6928) had only one contraindication to therapy.

Table 4. Prevalence and incidences of contraindications
 Prevalent contraindications in the 6 months before diagnosis (N = 45 690)Incident contraindications after diagnosis over a median follow-up time of 33 months (N = 45 690)Total patients with contraindications at the end of observation (N = 45 690)
N %Standardised rate per 1000 Person-Monthsa N %Standardised Rate per 1000 Person-MonthsaObservation Months N %Standardised Rate per 1000 Person-MonthsaObservation Months
MeanMedianMeanMedian
  1. a

     Standardised rate per 1000 person-months is calculated as (n × 1000)/sum (observation months for 45 690 patients), where n is number of patients with specific contraindication within a specific observation period. 45 690 is the total number of patients included in this analysis.

  2. b

     For pregnancy, events in the same patient could have occurred more than once when at least 9 months apart.

Any contraindication        790317.35.535.732.1
1 contraindication        692815.24.835.331.7
2 contraindications        8461.90.638.234.6
3 contraindications        1200.30.141.139.5
>3 contraindications        9<0.1041.237.6
History of uncontrolled seizures1300150034.632.0280.1037.834.1
Hepatic decompensation1730.40.63960.90.333.631.65691.20.434.831.4
Moderate to severe retinopathy10050032.834.160034.136.5
Major depression with history of suicide attempt100     10014.214.2
Acute myocardial infarction1480.30.51400.30.140.637.02880.60.238.335.7
Haemoglobinopathies420.10.2270.1037.137.7690.2036.135.3
Neonates and infants2320.50.8     2320.50.235.434.5
Acute coronary syndromes1700.1420.1044.641.5590.1041.939.2
Bipolar disorder20304.47.49552.10.835.632.829856.52.133.729.9
Neutrophils <750 cells/mm31610.40.63960.90.339.235.55571.20.440.937.6
Platelets <50 000 cells/mm31400.30.53670.80.332.829.55071.10.435.033.0
Haemoglobin <10 g/dL6781.52.520094.41.735.132.026875.91.938.134.7
History of kidney transplantation810.20.3680.10.143.840.51490.30.144.040.8
History of organ transplantation other than liver/kidney1001007.57.520025.625.6
Allergy to interferon or ribavirin1300110050.349.7240.1047.745.8
Pregnancyb4690.11.75781.30.532.128.98581.90.633.430.2

Discussion

Current treatment regimens for HCV continue to include combination therapies containing both PEG-IFN and RBV. While treatment regimens are effective, medical, psychological or psychosocial contraindications frequently limit their use. The overall incidence and prevalence of contraindications to PEG-IFN and RBV in the general, non-Veteran US patient population has only been described in smaller clinic-based studies. This study evaluated contraindications to HCV treatment in the general US population in nearly 46 000 patients from the national GE Centricity EMR database. Overall, 17.3% of patients with HCV infection had contraindications to therapy. The most frequently reported contraindications were bipolar disorder (6.5%), anaemia (5.9%) and pregnancy (1.9%) with the majority of patients having only one contraindication. Although end-stage liver disease can result from HCV infection, our results found relatively low rates of hepatic decompensation (1.2%) limiting PEG-IFN/RBV selection in the general US population. These data suggest that there are a large number of patients with HCV infections who are contraindicated to PEG-IFN/RBV–based therapies and that there remains an unmet medical need to address this population.

The GE Centricity EMR is based on patient encounters with participating clinicians and is therefore limited by: (i) the need for active collection and data entry by healthcare providers, (ii) nondocumented encounters with providers outside the system potentially resulting in incomplete medical histories, (iii) a large proportion of treating physicians are primary care providers (≈70%), and not gastroenterologists/hepatologists, which could limit reporting of HCV-related information and (iv) lack of prescription drug data thereby limiting the ability to evaluate the impact of the observed contraindications to PEG-IFN/RBV (and contraindications from concomitant medications) on the actual prescribing of PEG-IFN/RBV. These limitations suggest that our results may underestimate the actual number of HCV patients with contraindications to PEG-IFN/RBV.

As stated previously, the Veterans Health Administration healthcare system database has conducted studies assessing contraindications to treatment in veterans with chronic HCV.[10-14] However, an often-cited limitation of these VA HCV data is the potential lack of generalisability to the broader US population.[10-14] To further assess HCV relative and absolute contraindications in the general US population with data in this special population, this study reviewed data from a similar analysis in a cohort of 101,444 HCV-infected veterans using data extracted from the national Veterans Health Administration healthcare system database. This study among veterans showed that 28.6% experienced a contraindication (73% had only one contraindication) with anaemia (12.5%), bipolar disorder (7.4%) and hepatic decompensation (7.1%) being the most commonly cited factors (data not shown). We also looked at the intolerance rates to PEG-IFN/RBV from 4 Roche clinical trials and found that 23.7% of the 1924 enrolled patients experienced either a ≥35% reduction in PEG-IFN or RBV dose, death, patient noncompliance or withdrawal due to an adverse drug event (data on file, Roche). Taken together, we believe that our results are reflective of the broad incidence of factors that limit PEG-IFN/RBV use in the general US population.

Although certain contraindications to PEG-IFN and/or RBV preclude their use in certain patient populations, many contraindications can potentially be managed through clinical interventions. For example, in both the VA and general population analyses, anaemia was identified as a common contraindication. In clinical practice, however, anaemia is often a relative contraindication to therapy that often can be managed via a number of different interventions (e.g. RBV dosage reduction, erythropoietin-stimulating agents, blood transfusion). In addition, although pregnancy is considered an absolute contraindication, it is a transient condition in which HCV treatment could be offered after the birth of the infant. As such, many contraindications observed in the current analysis are relative (and/or modifiable) or transient and therefore many patients could potentially benefit from current PEG-IFN–containing triple therapies or future PEG-IFN– or RBV-free regimens.

The overall incidence of contraindications we observed is lower than that previously reported in the VA system and from reports of patients in general clinical practice. For example, studies of VA patients throughout the United States have shown that only 29.4–32.2% of patients with HCV infection met criteria for treatment for PEG-IFN/RBV.[9, 11, 13] The differences in rates observed in our study and those in other cohorts predominantly involve the definitions and categories of contraindications used. For example, we did not evaluate current or past alcohol or substance abuse because these are no longer considered to be absolute contraindications to IFN-based therapy.[16] Furthermore, we utilised a very conservative definition of depression that we limited to only patients with a documented history of a suicide attempt. In both the VA and general population analyses, these factors accounted for a large proportion of contraindications to therapy. While we tried to ensure evaluation of only active patients in the healthcare system (e.g. by restricting our analysis to those receiving care at least 180 days before the index date), we did not evaluate patient non-adherence with their overall health care as a contraindication to treatment as did other groups.[7, 9, 11, 13, 17] Lastly, only 0.5% (n = 71 662) of the entire GE Centricity EMR dataset was identified as HCV infected, a percentage well below the national average of roughly 2%.[2] The reasons for the low overall prevalence of HCV infection and hepatic decompensation within the GE Centricity EMR are unknown; however, they may reflect limitations of the current database and/or data collection procedures (described above) to accurately capture all diagnoses on individual patients. As such, our results may under-report the overall incidence and types of contraindications to PEG-IFN/RBV within the observed cohort.

We included HCV and HIV coinfected patients in our analysis. Compared with veterans who were mono-infected with HCV, HIV-HCV coinfected veterans have increased rates of comorbid conditions, and a greater likelihood of having multiple, overlapping comorbidities that could complicate and limit treatment options.[18] In addition, now that HCV protease inhibitors are included as a component of treatment with PEG-IFN/RBV for genotype 1 chronic HCV-infected patients,[5] we did not assess the impact that these agents would have had on the incidence of contraindications. With increased rates of anaemia[19, 20] and absolute contraindications due to drug–drug interactions,[21] we would expect that the overall rates of contraindications would increase in patients on a 3-drug regimen. Lastly, how these data will impact future interferon- and/or ribavirin-free containing regimens has yet to be determined.

In conclusion, in the largest evaluation of contraindications to PEG-IFN/RBV treatment in the general US patient population performed to date, we found the majority (82.7%) of patients with HCV infection were without an absolute or relative contraindication to treatment with PEG-IFN/RBV. Of those with contraindications, bipolar disorder, anaemia and pregnancy were the most frequent contraindications observed. These data may be helpful to health and public policy administrators in estimating the percentage of patients who may be eligible for treatment with PEG-IFN/RBV in combination with HCV protease inhibitors and future all-oral interferon-free therapy.

Authorship

Guarantor of the article: Dr Andrew H. Talal.

Author contributions: AHT, JL, RH, JH, and EK designed the research study. All authors were involved with the manuscript's study concept and design, the analysis and interpretation of its data, and the content development and draft of the final manuscript. All authors approved the final version of the manuscript.

Acknowledgement

Declaration of personal interests: Drs Talal, Pandya, Martin, and Jacobson have nothing to declare relevant to this manuscript which evaluates contraindications in the US general population in a large EMR database. Dr LaFleur has received research grant support from Genentech, Inc. and F. Hoffmann La-Roche Ltd. Dr Han, Dr Korner, and Mr. Hoop are all employees of Genentech, Inc.

Declaration of funding interests: This study was funded in part by Genentech Inc. and F. Hoffmann-La Roche Ltd. Data were extracted by General Electric (GE) Centricity's electronic medical record (EMR) dataset (GE) through a grant provided by Genentech Inc. and F. Hoffmann-La Roche Ltd. Additional statistical analyses, including administrative support, were provided by Genentech, Inc and Dr Korner, Dr Han, Dr LaFleur and Mr Hoop. Third-party writing assistance for this manuscript, furnished by Andrew D. Luber, Pharm D, and Sue Currie, PhD, Health Interactions, was provided by Genentech Inc. and F. Hoffmann-La Roche Ltd.

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