AIDS Care, 2014 Vol. 26, No. 9, 1178–1185, http://dx.doi.org/10.1080/09540121.2014.892563

Hepatitis C treatment eligibility among HIV–hepatitis C virus coinfected patients in Oregon: a population-based sample Marissa M. Maiera*, Haiou Heb, Sean D. Schaferc, Thomas T. Wardd and Atif Zamane a

Division of Infectious Diseases, Oregon Health and Sciences University, Portland, OR, USA; bProgram Design and Evaluation Service, Oregon Health Authority, Portland, OR, USA; cHIV/STD/TB Program, Oregon Health Authority, Portland, OR, USA; d Section of Infectious Diseases, Portland Veterans Administration Medical Center, Portland, OR, USA; eDivision of Gastroenterology and Hepatology, Oregon Health and Sciences University, Portland, OR, USA (Received 19 August 2013; accepted 4 February 2014) Approximately 287,000 individuals in the USA are coinfected with HIV and hepatitis C. Recently, new hepatitis C regimens have become available, increasing rates of sustained virologic response in the monoinfected, with studies evaluating their success in the coinfected under way. Previous investigators estimated eligibility for hepatitis C therapy among the coinfected patients, but all had significant methodological limitations. Our study is the first to use a multiyear, statewide, population-based sample to estimate treatment eligibility, and the first to estimate eligibility in the setting of an interferon-free regimen. In a population-based sample of 161 patients infected with HIV and hepatitis C living in Oregon during 2007–2010, 21% were eligible for hepatitis C therapy. Despite the anticipation surrounding an interferon-sparing regimen, eligibility assuming an interferon-free regimen increased only to 26%, largely due to multiple simultaneous contraindications. Obesity was described for the first time as being associated with decreased eligibility (OR: 0.11). Active alcohol abuse was the most common contraindication (24%); uncontrolled mental health (22%), recent injection drug use (21%), poor antiretroviral adherence (22%), and infection (21%) were also common excluding conditions. When active drug or alcohol abuse was excluded as contraindications to therapy, the eligibility rate was 34%, a 62% increase. Assuming an interferon-free regimen and the exclusion of active drug or alcohol abuse as contraindications to therapy, the eligibility rate increased to 42%. Despite the availability of direct-acting anti-viral regimens, eligibility rates in HIV–hepatitis C virus (HCV) coinfection are modest. Many factors precluding hepatitis C therapy are reversible, and targeted interventions could result in increased eligibility. Keywords: coinfection; eligibility; hepatitis C; HIV; treatment

Introduction In the USA, 25% of people infected with HIV are also infected with hepatitis C (Centers for Disease Control and Prevention, 2013; U.S. Department of Veterans Affairs, 2009). Estimates of the number of coinfected people eligible for hepatitis C therapy are useful for economic and cost–benefit analysis, as well as health-care planning, training, and budgeting. In addition, descriptions of eligible and ineligible patients can help identify reversible factors, target populations requiring increased outreach, and clarify priorities for provider education. Previous studies of hepatitis C treatment eligibility among people with HIV have been conducted at academic medical centers (Adeyemi et al., 2004; Butt et al., 2009; Fleming, Tumilty, Murray, & Nunes, 2005; Mehta et al., 2006; Restrepo et al., 2005) or among veterans (Butt, McGinnis, Skanderson, & Justice, 2011; Fultz et al., 2003). Academic center investigators found eligibility rates for hepatitis C therapy of 18–39%, with one outlier of 55% (Mehta et al., 2006). Studies of veterans yielded estimated eligibility rates of 28% and 31%. Existing *Corresponding author. Email: [email protected] © 2014 Taylor & Francis

studies have been limited by misclassification bias in the use of International Classification of Diseases (ICD)-9 codes from medical records to ascertain eligibility (Butt et al., 2011), or selection bias by exclusion of patients with substance use or mental health diagnoses (Adeyemi et al., 2004). Meanwhile, since these studies were published, new therapies for hepatitis C have begun to emerge, and these are likely to increase both the number of patients eligible for treatment and the number who respond to treatment. Traditional dual therapy with ribavirin and interferon yields low rates of sustained virologic response (SVR) among the HIV and hepatitis C coinfected, with typical overall response rates of 27–40%, and even lower response rates of 14–29% among individuals with genotype 1 (Carrat et al., 2004; Chung et al., 2004; Torriani et al., 2004). The newly available triple therapy for hepatitis C (interferon, ribavirin, and a direct-acting antiviral protease inhibitor) has augmented SVR rates among the hepatitis C monoinfected, increasing SVR in the treatment-naive from approximately 40% to 75% (Hézode

AIDS Care et al., 2009; Jacobson et al., 2011; Kwo et al., 2010; McHutchison et al., 2009). Studies of the effectiveness of direct-acting anti-viral therapies for coinfected patients are under way. If direct-acting anti-viral agents improve SVR rates in this population as anticipated, we expect that many coinfected individuals will embark on hepatitis C therapy. New therapies for genotype 1 will be interferonsparing initially (i.e., reduced duration), with interferonfree regimens emerging thereafter. Interferon-free regimens ought to increase the number of patients eligible for therapy because the neuropsychiatric side effects of interferon are a primary reason for withholding treatment. In the USA, uncontrolled major depressive illness is considered an absolute contraindication to its use (Ghany, Strader, Thomas, & Seeff, 2009), while in European countries uncontrolled depression or psychosis is considered absolute contraindications to its use (European Association for the Study of the Liver, 2011). Because interferon-free therapies are likely to expand treatment opportunities for patients with concurrent mental illness, we aimed to estimate treatment eligibility under scenarios of interferon-based and interferon-free regimens, considering people with depression or psychosis to be eligible for treatment under the latter. We also aimed to compare treatment eligibility across European and US settings where prevailing opinions differ about the degree to which drug or alcohol abuse contraindicates therapy, though these are somewhat in flux. Prior injection drug use is a risk factor for hepatitis C acquisition, and alcohol use is a risk factor for more rapid progression of liver fibrosis (Ghany, Strader, Thomas, & Seeff, 2009). Some studies suggest lower adherence (Marcellin et al., 2011) and lower SVR rates (Grebely et al., 2007; Matthews, Kronberg, & Dore, 2005; Sylvestre et al., 2005) among frequent intravenous drug users, and some intravenous drug users have been reinfected after achieving SVR (Aspinall et al., 2013). Due to concerns such as these, many providers, particularly in the USA, are hesitant to treat people who are actively using alcohol and drugs. In the USA, Veterans Affairs (VA) guidelines until recently considered ongoing alcohol or drug abuse to contraindicate hepatitis C virus (HCV) treatment; recently updated guidelines recommend referral to an addiction specialist prior to treatment initiation (U.S. Department of Veterans Affairs, 2012). The American Association for the Study of Liver Diseases (AASLD) recommends individualizing treatment decisions for active users willing to participate in a rehabilitation program (Ghany, Strader, Thomas, & Seeff, 2009). European guidelines say that patients “should be drug-free … for at least 6–12 months” but make no general recommendations for treatment of active drug users; they also recommend attempting alcohol rehabilitation before undertaking treatment (European Association for the Study of the Liver, 2011).

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We hypothesized that our population-based sample would lead to a higher eligibility rate than previously estimated due to lower prevalence of comorbidities, and that an interferon-free regimen would increase the estimated percentage of patients eligible for treatment, particularly patients with coexisting mental health diagnoses.

Materials and methods We conducted a multi-year cross-sectional study of Oregon patients with both HIV and hepatitis C using data collected via the Centers for Disease Control and Prevention’s (CDC) Medical Monitoring Project (MMP). Overview: the MMP The MMP is a CDC-led public health surveillance project that compiles data on patients receiving medical care for HIV in the USA. Annual data collection began in Oregon in 2007. Patients are randomly selected by a three-stage sampling process described elsewhere (Blair et al., 2011). Four hundred Oregon participants were selected each year and only Oregon participants are represented in this study. Health department staff conduct individual interviews and review medical records; these are the primary data sources for the MMP. Medical record and interview data are transmitted to the CDC. The CDC then validates the data and returns data-sets to Oregon MMP staff. Each participant provided informed consent. The Oregon Health and Sciences University Institutional Review Board reviewed and approved the current analysis of MMP data for estimating hepatitis C treatment eligibility. Sample selection To identify individuals among MMP participants who had hepatitis C, we included all Oregon MMP participants during 2007–2010 who had evidence in the medical record of either a positive hepatitis C antibody test or detectable hepatitis C RNA. We excluded patients who had only interview or medical record data, but not both. We assumed that anyone with a positive hepatitis C antibody had chronic hepatitis C. Case definition We determined hepatitis C eligibility using AASLD and VA clinical guidelines, prescribing guidelines, and clinical practice (available by contacting author). We added serious infection (an infection that required IV antibiotics or antibiotic therapy of longer than one week duration) in the last year as a variable used in clinical practice, because in our experience most practitioners will not start hepatitis C therapy in someone with active serious

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infection. When guidelines disagreed, we used the more conservative guideline. We then used medical record data and interview responses to assess the status of each contraindication, as well as describe demographic and clinical variables. To evaluate the set of labs that defined decompensated liver disease (total bilirubin, albumin, and platelets) and abnormal hematologic or biochemical parameters (creatinine, white blood cell count, and hemoglobin), three clinicians (M. M., A. Z., M. C.) independently reviewed each set of labs and determined whether a provider who routinely treats hepatitis C-infected patients would consider the patient eligible for therapy. Agreement between two of the three clinicians determined eligibility for these two variables. Statistical analysis We calculated means and frequencies with 95% confidence intervals for participant characteristics, treatment eligibility, and the distribution of contraindications to therapy. We used bivariate and multivariate logistic regressions to identify factors associated with treatment eligibility. Variables examined in bivariate analyses include age, race-ethnicity, gender, sexual orientation, level of education, geographic residence, source of income, homelessness, source of insurance, incarceration, noninjection drug use, and obesity (body mass index [BMI] ≥ 30 kg/m2). Variables found in bivariate analyses to be associated with the outcome (p < 0.10) were entered into multivariate models using forward step-wise logistic regression controlling for age and gender. We completed additional analyses to understand which specific eligibility criteria explained any significant adjusted associations between participant characteristics and treatment eligibility. For each participant characteristic found to be significant in adjusted analyses, we examined the association between each eligibility criterion and the participant characteristic using chi-square tests. We estimated eligibility for hepatitis C therapy in an interferon-free regimen by excluding contraindications related to poor mental health. In the USA, ongoing intravenous drug use and alcohol abuse remain at least a relative contraindication to treatment, while outside the USA, substance use is not consistently considered to be a contraindication. Therefore, we evaluated the impact on eligibility of removing ongoing drug and alcohol use as a contraindication. All analyses were conducted with SPSS 19.0. Results Of the 874 HIV-positive patients participating in the MMP during 2007–2010, 162 patients had documentation of either a positive hepatitis C antibody or detectable

hepatitis C RNA. We excluded one patient who had only medical record data, yielding a sample size of 161 participants. Participant characteristics are described in Table 1. Most participants were male, white, aged ≥ 45 years, gay or lesbian, and urban. Overall, 21% (34) of participants were eligible for hepatitis C treatment. Active alcohol abuse was the most common contraindication to treatment (24%); uncontrolled mental health (22%), injection drug use in the last year, (21%), poor antiretroviral adherence (22%), and infection (21%) were also common excluding conditions (Table 2). Thirty-four (21%) participants had only one contraindication to therapy, 41 (26%) had two contraindications to therapy, and 44 (27%) had three or more contraindications to therapy. Assuming an interferon-free regimen were to be used (making people with depression or psychosis eligible), we estimated 26% (n = 42) of participants would be treatment eligible (a 24% increase). If substance use were to be removed as a contraindication to therapy, the percent of coinfected individuals eligible for treatment increased to 34% (n = 55). Assuming an interferon-free regimen was to be used and substance use were not considered a contraindication to therapy, the percent of eligible individuals increased to 42% (n = 67; Table 3). In the bivariate analysis (Table 4), female gender (OR: 1.73), age ≥ 55 (OR: 2.56), white ethnicity (OR: 3.96), and salaried income (OR: 2.29) were positively associated with treatment eligibility, while noninjection drug use in the last year (OR: 0.26) and obesity (OR: 0.23) were negatively associated with eligibility. In the multivariate analysis (Table 5), older age (OR: 2.82), white ethnicity (OR: 5.05), and derivation of income from salary (OR: 3.02) were associated with increased odds of eligibility, while noninjection drug use (OR: 0.21) and obesity (OR: 0.11) were associated with decreased odds of treatment eligibility. When we compared the contraindications to therapy between older and younger individuals, the older age group was significantly less likely to have required drug or alcohol rehabilitation in the last year (3% vs. 11%, p = 0.05). In addition, older individuals were more likely to have no contraindications to therapy and if they did have a contraindication, they were more likely to have multiple (hence contraindications were clustered among fewer individuals). When we compared the contraindications to therapy among white and nonwhite participants, white participants had significantly fewer contraindications due to hematologic or biochemical parameters, AIDS-defining opportunistic illnesses, or drug or alcohol rehabilitation (14% vs. 44%, p < 0.001; 9% vs. 26%, p = 0.013; and 4% vs. 22%, p = 0.001, respectively). Among those with a salaried income, there were significantly fewer mental health or drug or alcohol rehabilitation

AIDS Care Table 1. Participant characteristics. Participant characteristic (N = 161)a

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Table 2. Distribution of contraindications to hepatitis C treatment. Number (N)

Gender (161) Male Female Age (161) 18–34 35–44 45–54 55–64 65 + Ethnicity/race (159) White Latino/Hispanic African-American Asian or Hawaiian/Pacific Islander Native American/Alaskan Native Geographic residence (158) Rural Nonrural Education (161) Grade 12 or less Some college Bachelor or post Income source (161) Salary, wages Supplemental Security Income or Social Security Disability Other Insurance source (158) Private Nonprivate Incarcerated in last year (161) Yes No Homeless in last year (161) Yes No Sexual orientation (160) Heterosexual Gay, lesbian, bisexual, other Noninjection drug use in last year (161) Yes No Poor health literacy (84) Yes No BMI (157) Underweight (BMI < 18.5) Normal (BMI 18.5–24.99) Overweight (BMI 25–29.99) Obese (BMI ≥ 30)

Percent (%) Source of contraindication

141 20

88 12

4 30 52 50 25

3 19 32 31 16

110 9 14 7

69 6 9 4

19

12

17 141

11 89

79 60 22

49 37 14

40 86

25 53

35

22

61 97

39 61

24 137

15 85

25 136

16 85

65 95

41 59

47 114

29 71

27 57

32 68

3 73 52 29

2 47 33 19

Note: an < 161 is due to missing or unavailable data, or response was declined.

AASLD guidelines Decompensated liver disease Abnormal hematologic or biochemical parameters Uncontrolled mental health Pregnant or not using contraception Severe medical comorbidities (coronary artery disease, diabetes mellitus, stroke, and congestive heart failure) Poor adherence to HAART regimen Prescribing guidelines Uncontrolled HIVa: CD4 < 100 cells/ mm3 or CD4 100–199 cells/mm3 with HIV VL > 5000 copies/ml VA guidelines Active alcohol abuse Injection drug use within one year Drug or alcohol rehabilitation within one year Life-determining extra-hepatic conditions AIDS-defining OI Clinical parameter Infection within one year

2007–2010 N = 161 Number (%) 22 (14) 31 (19) 36 (22) 0 (0) 13 (8)

35 (22) 9 (6)

38 (24) 34 (21) 11 (7) 26 (16) 19 (12) 33 (21)

Note: ASLD, American Association for the Study of Liver Diseases; HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; VA, veterans affairs; AIDS, acquired immune deficiency syndrome; OI: opportunistic infection. a N = 158 due to unavailable data.

exclusions (10% vs. 26%, p = 0.03; and 0% vs. 9%, p = 0.048, respectively). When we explored the decreased odds of eligibility among non-IV drug users, we found there were significantly more exclusions due to injection drug use in the last year, as well as infection in the last year (40% vs. 13%, p < 0.001 and 32% vs. 16%, p = 0.021, respectively). Among participants who were obese, there were significantly more exclusions due to active alcohol abuse (38% vs. 21%, p = 0.045). While the finding was not statistically significant (possibly due to the small sample size) in bivariate analysis, Native Americans were less likely to be eligible for therapy than non-Native Americans (OR: 0.16). We compared baseline characteristics of Native Americans versus non-Native Americans and found they were significantly more likely than non-Native Americans to have been incarcerated (38% vs. 12%, p = 0.001) or homeless (29% vs. 14%, p = 0.08) in the last year. We explored contraindications to therapy in Native

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Table 3. Estimation of treatment eligibility using step-wise removal of alcohol and drug use as contraindications to therapy, among regimens using interferon and those that are interferonfree. Interferon used in regimen

Eligibility Original definition: alcohol and drug considered contraindications to therapy Intravenous drug excluded from contraindications to therapy Alcohol abuse excluded from contraindications to therapy Intravenous drug and alcohol abuse excluded from contraindications to therapy

Interferon-free regimen Patients Patients eligible eligible (%) (N)

Patients eligible (N)

Patients eligible (%)

34

21

42

26

41

26

52

32

42

26

50

31

55

34

67

42

Americans versus non-Native Americans, and found they were significantly more likely to have uncontrolled mental health issues, poor antiretroviral adherence, and an infection in the last year (57% vs. 17%, p < 0.001; 43% vs. 19%, p = 0.043; and 38% vs. 18%, p = 0.034, respectively). Discussion To our knowledge, ours is the first US study of hepatitis C eligibility to employ a population-based sample, to estimate eligibility using an interferon-free regimen, and to thoroughly examine factors associated with eligibility. Contrary to our expectations, we found that hepatitis C treatment eligibility among a population-based sample of coinfected patients was 21% (95% confidence interval: 15–27.4%), lower than most prior studies which revealed eligibility rates of 25–39% (Adeyemi et al., 2004; Butt et al., 2011; Fleming et al., 2005; Fultz et al., 2003; Restrepo et al., 2005). We documented more exclusions due to alcohol or drug use, nonadherence, and psychiatric diagnoses than prior investigators (Adeyemi et al., 2004; Butt et al., 2011; Restrepo et al., 2005). We think our finding of lower treatment eligibility than other studies is due to two main factors: differing ascertainment methods and sample populations. Some of

the prior literature used only medical records to determine contraindications to therapy (Adeyemi et al., 2004; Butt et al., 2011; Restrepo et al., 2005); some used an additional questionnaire that was administered by medical staff, thereby introducing the potential for recall bias (Butt et al., 2009; Fleming et al., 2005; Fultz et al., 2003). We reviewed medical records and interviewed patients in a nonclinical environment, and we think this resulted in increased self-reporting of drug use, alcohol use, and nonadherence. In addition, we suspect that community providers may have referred their most stable patients to the tertiary care centers where other studies were done. We found that an interferon-free regimen would probably result in a modest increase in eligibility among coinfected patients (from 21% eligible to approximately 26% eligible). The increase was modest because many individuals had multiple coexisting contraindications to therapy. However, if substance use is not considered to strictly contraindicate therapy, eligibility increases to 34%. If substance use is not considered a contraindication to therapy and if an interferon-sparing regimen is used, eligibility increases to 42%. Our data demonstrate that multiple barriers to therapy exist for many patients, and a multidimensional approach will be needed to mitigate those barriers. Targeted interventions addressing mental health, substance use, and medical comorbidities, when combined with interferon-free regimens, could markedly augment therapeutic opportunities for coinfected patients. In addition, assessing the risk–benefit profile of hepatitis C treatment in those with ongoing substance use on an individualized basis and integrating addiction and mental health specialists into the hepatitis C care of these patients could also result in meaningful increases in eligibility. Finally, our study also highlights populations for which low rates of eligibility are not well explained, notably obese individuals. Strengths of our sample and approach include its multi-year, statewide, population-based sample, our estimation of eligibility with an interferon-free regimen, and clinical review of labs (rather than using the mean or most recent lab). This study is the first to identify multiple factors associated with eligibility rates, and most clearly defines contraindications to therapy in a reproducible manner. It also is one of the few to utilize both medical record abstraction and a structured interview as data sources. Moreover, ours is one of the few studies using data from the modern antiretroviral time period and the only one to our knowledge that explores the impact of varying levels of treatment eligibility with regard to alcohol and substance abuse. Our study has some limitations. We assumed that everyone with hepatitis C antibody had chronic infection as few participants had hepatitis C viral loads. Among

AIDS Care

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Table 4. Distribution of eligibility for hepatitis C treatment and factors associated with eligibility for hepatitis C treatment in bivariate analysis. Participant characteristic (N = 161)a Gender (161) Male Female Age (161) 18–54 55 + White ethnicity (159) Nonwhite White Native American ethnicity (159) Non-Native American Native American Geographic residence (158) Nonrural Rural Education (161) Grade 12 or less Any college Income source (161) No salary or wage income Salary or wage income Insurance source (158) Private Nonprivate Incarcerated in last year (161) No Yes Homeless in last year (161) No Yes Sexual orientation (160) Heterosexual Gay, lesbian, bisexual, and other Noninjection drug use in last year (161) No Yes Obese (BMI ≥30; 157) No Yes

Number

Treatment eligible (%)

Bivariate OR (95% CI)

141 20

28 (20) 6 (30)

ref. 1.73 (0.61–4.90)

86 75

12 (14) 22 (29)

ref. 2.56 (1.17–5.62)

49 110

4 (8) 30 (27)

ref. 3.96 (0.89–17.65)

140 19

33 (24) 1 (5)

ref. 0.16 (0.02–1.24)

141 17

28 (20) 5 (29)

ref. 1.68 (0.55–5.17)

79 82

13 (17) 21 (26)

ref. 1.75 (0.81–3.79)

121 40

21 (17) 13 (33)

ref. 2.29 (1.02–5.16)

61 97

17 (28) 17 (18)

ref. 0.55 (0.26–1.18)

137 24

32 (23) 2 (8)

ref. 0.30 (0.07–1.34)

136 25

32 (24) 2 (8)

ref. 0.28 (0.06–1.26)

65 95

13 (20) 20 (21)

ref. 1.07 (0.49–2.33)

114 47

30 (26) 4 (9)

ref. 0.26 (0.09–0.70)

128 29

31 (24) 2 (7)

ref. 0.23 (0.05–1.03)

Note: an < 161 is due to missing or unavailable data, or response was declined.

the HIV-hepatitis C coinfected, more than 90% do not clear the virus (Adeyemi et al., 2004; Danta et al., 2008), so we believe that our assumption of chronic infection was reasonable. Some of the prior studies examined eligibility among those with a measurable hepatitis C viral load (Adeyemi et al., 2004; Butt et al., 2009, 2011); however, we know that hepatitis C viral loads are obtained for only a minority of coinfected patients (22% in one VA sample; Fultz et al., 2003). Studies that only include individuals who have had their hepatitis C viral load tested may overestimate eligibility. Finally,

our study methodology varied from other published research in our use of “serious infection” as a contraindication to therapy. This would result in an underestimation of eligibility. However, when we excluded this variable, only 23% of participants were eligible for hepatitis C therapy (a 2% absolute increase). Our results highlight areas where infectious disease, hepatology, and mental health can develop interventions to increase treatment eligibility. This is important, because liver disease is a leading cause of death in HIV-positive individuals and is the leading cause of death among

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Table 5. Factors associated with eligibility for hepatitis C treatment in multivariate analysis. Multivariate

Gender Male Female Age 18–54 55 + White ethnicity Nonwhite White Income source No salary or wage income Salary or wage income Noninjection drug use in last year No Yes Obese (BMI ≥ 30) No Yes

OR

95% CI

2.29

0.68–7.71

2.82

1.18–6.76

5.05

1.04–24.53

3.02

1.19–7.68

0.21

0.07–0.70

0.11

0.02–0.55

hospitalized and nonhospitalized coinfected patients (Bica et al., 2001; Martín-Carbonero et al., 2001; Salmon-Ceron et al., 2005; Weber et al., 2006). Until recently, hepatitis C treatment regimens were modestly successful at best and were accompanied by significant toxicities that precluded their use in many coinfected individuals, particularly those with comorbid mental health diagnoses for whom interferon could not safely be used. The direct-acting anti-viral regimens under investigation are not only interferon-sparing, but also have a more tolerable side effect profile and higher efficacy, at least among the hepatitis C monoinfected. As investigational studies are published assessing the efficacy and tolerability of direct-acting anti-viral agents in the HIV–HCV coinfected, health-care providers and health systems will be called upon to reassess who is a good candidate for therapy. Ultimately, we anticipate that the novel therapies will give coinfected patients with mental health conditions the opportunity to cure their hepatitis C, an opportunity that was previously unrealistic for many. Acknowledgments The authors thank Tyler Smith, N.D. for his astute insight into the MMP, Michael Chang, M.D. for assistance in reviewing laboratory results, and Kari Greene. They also thank the Oregon Health Authority for its logistical support.

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