Somatic complaints and isoniazid (INH) side effects in Latino adolescents with latent tuberculosis infection (LTBI)

Patient Education and Counseling 52 (2004) 31–39

Somatic complaints and isoniazid (INH) side effects in Latino adolescents with latent tuberculosis infection (LTBI)$ J. Berga, E.J. Blumbergb, C.L. Sipanb, L.S. Friedmanc, N.J. Kelleyb, A.Y. Verab, C.R. Hofstetterb,d, M.F. Hovellb,* a

School of Nursing, University of California Los Angeles, 4254 Factor Building, 700 Tiverton, Los Angeles, CA 90095, USA b Center for Behavioral Epidemiology and Community Health, Graduate School of Public Health, San Diego State University, 9245 Sky Park Court, Suite 230, San Diego, CA 92123, USA c Division of General Pediatric and Adolescent Medicine, University of California San Diego Medical Center, 200 W. Arbor Drive, San Diego, CA 92103-8449, USA d Department of Political Science, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-4427, USA Received 8 April 2002; received in revised form 12 November 2002; accepted 18 November 2002

Abstract This study examined the potential effects of INH side effects and non-specific somatic complaints on medication adherence in 96 Latino adolescents participating in a controlled trial designed to increase isoniazid (INH) adherence. These participants (who received usual medical care) were interviewed monthly over 9 months. Participants were questioned regarding medication taking, the frequency of 15 INH-related side effects from the Physician’s Desk Reference (PDR) [1], and 21 non-specific somatic complaints. Participants were aged 12–19 years, 53.1% were male, 66.7% were born in Mexico, 73% had no health insurance, and 52.5% were classified as bicultural. Approximately 70% of participants experienced at least one side effect during the trial. Side effects that occurred while taking INH were not significantly related to total number of pills taken; somatic complaints that occurred during 9 months of INH were significantly negatively related to cumulative adherence. Females reported significantly more somatic complaints at baseline than males. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Adherence; Adolescents; INH; Side effects; Somatic complaints

1. Introduction Adolescents report, and may experience, more physical symptoms than young adults [2]. Results from a large-scale cross-national WHO survey of 11, 13, and 15-year-old adolescents indicated that a large number of students reported high levels of symptoms. Health complaints experienced at least weekly included headache, abdominal pain, backache, dizziness, feeling low, irritability, nervousness, and difficulty sleeping [3]. Few studies have examined selfreports of physical symptoms that are not associated with a physical pathology in adolescents. Results of these studies indicate that although somatic complaints are common in $ This research was supported by grants awarded to Melbourne Hovell from the National Heart, Lung and Blood Institute (#1RO1HL5573801), the Alliance Healthcare Foundation (#98-36), and the Universitywide AIDS Research Program, University of California (#IS99-SDSUF-206). * Corresponding author. Tel.: þ1-858-505-4772; fax: þ1-858-505-8614. E-mail address: [email protected] (M.F. Hovell).

adolescents, most do not limit their daily functioning, and females report more somatic complaints than males [4–9]. Several studies have associated somatic or subjective healthrelated complaints with stress, anxiety or depression [10,11]. It has been reported that somatic complaints such as headaches, abdominal pain and musculo-skeletal pain are common in early adolescents, and they are major determinants of adolescents’ requests for health services [12]. Adolescents also have more problems than other age categories adhering to a variety of therapeutic regimens, in part due to age-related cognitive and developmental issues [13]. However, both adults and children, across all diseases, demonstrate poor adherence to medication-taking behavior. General medication non-adherence rates range from 20 to 80%, depending on the regimen [14]. Adolescence is an important time in life, involving the shift from primarily parental regulation to self-regulation of behavior [15]. Adolescents may not understand the longterm consequences of behavior, and often test limits imposed by authority figures [13,16]. They also use the services of

0738-3991/$ – see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0738-3991(02)00268-9

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private office-based physicians less often than any other age group [17] and therefore serious health problems may remain undetected. Medication adherence is a concern for adolescents who are prescribed treatment for latent tuberculosis infection (LTBI). Our experience with adolescents in San Diego [18] showed that based on validated self-reported medication use, only 33–41% of the controls completed isoniazid (INH) treatment. Based on medical records, Morisky [19] reported that in the years 1992–1996, approximately onehalf (55.4%) of the adolescents treated by the Health Department in Los Angeles County who began LTBI treatment completed it. In a study in New York City, Kohn et al. [20] reported that with usual care, INH completion rates were 50%. Starr et al. [21] used an electronic monitoring device to assess adherence in Australian adolescents with LTBI and found that adherence to INH was 66%. Using school and medical records of students referred to tuberculosis (TB) centers in Israel, Bibi et al. [22] found that 56.7% of adolescents receiving usual care completed LTBI treatment with isoniazid. Thus, it appears that between approximately one-third and two-thirds [18–22] of adolescents complete INH treatment in absence of special interventions. The degree to which these low adherence rates are due to side effects is unknown. Studies focusing on iron deficiency, familial hypercholesterolemia, and contraception use in adolescents have reported that side effects may decrease medication taking [23–25]. Very few studies with children and adolescent participants document side effects of INH therapy. Alperstein et al. [26] interviewed parents of predominantly 6-yearold children enrolled in their study and reported that 18% (of N ¼ 67) attributed the following side effects to INH: itch, increased appetite, abdominal pain, and poor concentration. Another case report of INH side effects discusses neurotoxicity in one adolescent receiving a daily dose of both INH (400 mg) and pyridoxine (25 mg) [27]. The more common side effects of INH include: diarrhea; stomach pain; clumsiness or unsteadiness; dark urine; loss of appetite; nausea or vomiting; numbness, tingling, burning, or pain in hands and feet; unusual tiredness or weakness; and yellow eyes or skin. Rare side effects include: blurred vision or loss of vision, with or without eye pain; convulsions (seizures); fever and sore throat; joint pain; mental depression; mood or other mental changes; skin rash; and unusual bleeding or bruising [28]. Side effects of INH therapy are not common [29] and INH is well tolerated by most persons, especially children [30]. CDC guidelines advocate the monitoring of side effects monthly in a clinical evaluation of patients receiving prophylaxis [31]. INH remains the recommended LTBI regimen for children younger than 18 years of age [31]. The current recommended regimen for INH is a single daily dose of 10–15 mg/kg body weight in children (not to exceed 300 mg per dose), and 300 mg per day for adults [31]. INH was first recommended in 1965, and there have been a number of studies examining

the safety and efficacy of the drug [32–34]. In general, INH is considered safe and efficacious [35]. Progression from LTBI to active disease accounts for most cases of TB, and about 10% of infected individuals develop active TB [36,37]. This suggests that treatment of LTBI is important for populations at high risk of developing active TB [38]. Among adolescents, LTBI is most likely in teenagers from families who have emigrated from countries with high prevalence rates of active TB [39]. Estimates suggest that Latino youth are about five times more likely to be infected than the US population as a whole [40]. Thus, it is important to identify infected youth and provide preventive therapy. However, for such treatment to be effective, it is necessary to assure medication adherence and to determine the extent to which side effects may be a barrier to completion of treatment. To date, few studies have examined the relationship between potential side effects of preventive TB regimens and medication compliance in Latino adolescents. The purpose of the present analysis is to describe existing health complaints and explore the possible relationship between INH side effects, non-specific somatic complaints, and adherence to INH in Latino adolescents.

2. Methods 2.1. Study design This study examined only youth receiving usual medical care (i.e. Controls) from a controlled trial of counseling to enhance adherence to INH [18]. This design was chosen to avoid possible influences that might result from youth interacting with counselors in the two intervention groups. For example, youth in the experimental group receiving coaching to take INH might continue to take the medication even if minor side effects were experienced. The clinical trial employed a repeated measures experimental design to evaluate the effects of 6 months of adherence counseling on INH adherence. However, INH medication adherence was assessed monthly for up to 9 months by interview and urine testing. The present analysis examines whether INH side effects and/or non-specific somatic complaints were related to adherence to INH during the course of the trial. 2.2. Participants Participants were 96 Latino (self-identified) adolescents between the ages of 12–19 years (Mean ¼ 15:42 years (S:D: ¼ 1:6)) and included 45 (46.9%) females. The mean grade in school was 9.34 years (S:D: ¼ 1:45). Most participants were born in Mexico (66.7%), 60.4% reported ‘‘almost always’’ speaking Spanish, and 52.5% were classified as bicultural according to the Marin and Gamba scale of acculturation [41]. About 73% of participants had no health insurance at baseline; 52.7% had received a check-up

J. Berg et al. / Patient Education and Counseling 52 (2004) 31–39

in the previous 2 years. The mean years of education completed for both mothers and fathers was just over 7 years and their mean combined annual income was US $25,113 (S:D: ¼ 14,777.08). 2.3. Recruitment and screening The 96 PPDþ adolescents were recruited from schools in San Diego County. ‘‘PPD’’ is an abbreviation of ‘‘purified protein derivative.’’ The tuberculin skin test indicates the existence of sensitivity in an individual due to a past or present mycobacterial infection. A student participating in the TB screening was considered PPDþ if, after 48–72 h following intradermal injection of PPD solution, an induration resulted that measured 10 mm or more in size [30]. All participants were screened and tested for TB using the Mantoux skin test, followed by a chest X-ray. Most were treated in community clinics. PPDþ adolescents were placed on an INH regimen and were enrolled in the study (Institutional Review Board approved), following parental and adolescent consent.

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self-esteem. Questions regarding the occurrence of somatic symptoms were asked for ‘‘the last 30 days,’’ to correspond with the time frame employed in the monthly interviews. 2.4.2. Monthly measures For each of the 9 months of the trial, monthly interviews were conducted as part of unscheduled home visits made to collect urine samples. If a youth was not found at home, two additional unscheduled visits were attempted followed by phone calls to complete the interview. Monthly interviews assessed self-reported medication adherence, attendance at clinic visits, occurrence of somatic symptoms (including INH side effects and non-specific complaints), self-esteem, risk behaviors, presence of foreign-born visitors in the home, and travel out of the US. To assess adherence, participants were asked, ‘‘In the last 30 days, how many days have you taken your INH, or tuberculosis medication?’’ during monthly interviews. The monthly adherence measures were valid based on correspondence with a urine biomarker [42,43]. 2.5. Outcome measures

2.4. Data collection For 9 consecutive months, adolescents were interviewed monthly in person or by phone about adherence and health complaints over the past 30 days. All interviews were conducted by trained bilingual interviewers (blind to condition), who were undergraduate students or members of the Latino community. Interviews were conducted in English or Spanish according to the youths’ preference. Every month, participants were asked how many pills they had taken in the last 30 days. To assess for the occurrence of side effects (15 items) and somatic complaints (21 items), participants were read a list of 36 symptoms and asked to state whether they experienced any of them in the last 30 days. The 15 INH-related side effects were obtained from the PDR [1]. The list of side effects taken from the PDR included all symptoms of INH that could easily be understood by the adolescents. They were described in non-technical language to increase comprehension. The items representing INH side effects were mixed in with the somatic complaints in order to avoid biasing responses from participants. Interviewers were blind to the classification (side effect versus non-specific somatic complaint) of all symptoms on the list. Participants reporting experience with a particular symptom of either type were asked to state if they had sought help from a doctor, clinic, pharmacist or other health professional for the specific symptom. 2.4.1. Baseline instrument All participants were interviewed at baseline regarding demographics, acculturation, health care barriers, risk behaviors, parenting practices (of their parents), past medicationtaking behavior, use of adherence aids, occurrence of somatic symptoms, TB knowledge and exposure, social support, and

Two adherence outcomes were used for analyses: the 30day measure repeated over 9 months, and the total number of pills taken over 9 months. Side effects and somatic complaints were analyzed individually or as cumulative sums (for each type of symptom separately) over time. 2.6. Statistical analyses The primary aim of this analysis was to determine whether the occurrence of INH side effects and non-specific somatic complaints impacted adherence to INH. This question was examined in several ways. To assess the overall effects of total reported INH side effects and somatic complaints on cumulative adherence (i.e. total number of pills consumed over time), ordinary least-squares regressions were computed with the cumulative number of pills as the dependent variable and the two types of symptoms as independent variables. These regressions were computed including 9 months of data. Regression analyses were computed a second time including alcohol use as a covariate, to control for possible side effects (related to hepatotoxicity) that may have resulted from concurrent use of alcohol and INH [1,44]. To examine whether these factors had an effect on adherence over time, a regression approach using a general estimating equations algorithm (GEE) was used (using SAS) [45] to estimate the linear effects of time, side effects, non-specific somatic complaints, and alcohol consumption (in secondary analyses), and the interactions of time by side effects, time by somatic complaints, and time by alcohol consumption [46]. Interaction terms indicate the combined effects of time, side effects, somatic complaints, and alcohol consumption on adherence. As with the regression analyses,

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J. Berg et al. / Patient Education and Counseling 52 (2004) 31–39

estimates were conducted for models including data from months 1 to 9. To control for potential reporting of baseline symptoms, all models were analyzed considering baseline somatic complaints. Additionally, analyses of variance (ANOVA) were conducted to examine baseline somatic complaints by various background variables including gender and indicators of socioeconomic status. All statistical analyses other than the GEE, which used SAS [45], were conducted using SPSS [47].

3. Results 3.1. Frequency of reported symptoms 3.1.1. INH side effects Almost 70% (69.8%) of participants reported experiencing at least one side effect at some point during the trial. On a monthly basis, the percentage of participants reporting side effects ranged from a low of 6.8% in month 5 to a high of 42.0% in month 2. The maximum number of side effects reported in any month (for one participant only) was seven. 3.1.1.1. Frequency of INH side effects by symptom. For ease of description, frequencies of reported INH side effects obtained from the nine monthly interviews were summed across time. Table 1 describes the frequency each symptom was ever reported, as well as the maximum number of months a given symptom was reported for any individual. Table 1 Self-reported INH side effects during 9 months on INHa Symptoms

Feeling more tired than usual Difficulty remembering things Numbness or tingling in the hands or feet Achy or stiff muscles in your arms and legs Stomach cramps Change in urine color Skin rash Bruising easily Fever Decreased appetite Vomiting Joint pain Yellowing of skin or eyes Tremors or shaking Nausea a

Across all months of INHb (N ¼ 96) n (%)c

Maxd

31 20 18 16 15 15 12 11 10 9 7 6 6 5 3

5 3 4 4 4 5 3 4 1 3 2 3 1 2 2

(32.3) (20.8) (18.8) (16.7) (15.6) (15.6) (12.5) (11.5) (10.4) (9.4) (7.3) (6.3) (6.3) (5.2) (3.1)

Table includes data for individuals who were on INH for less than 9 months. b Table arranged in order of frequency of symptom across all months. c n: number and percent of individuals that ever reported each symptom for at least 1 month; numbers and percents are not mutually exclusive. d Max: maximum number of months any individual complained about a symptom throughout the 9 months.

The most commonly reported INH side effects were feeling more tired than usual (32.3%), difficulty remembering things (20.8%), and numbness or tingling in the hands or feet (18.8%). Feeling more tired than usual and change in urine color were the symptoms reported for the most months (5 months each; experienced by one participant each). Six participants (three males and three females) reported yellow discoloration of skin or eyes, a symptom that, if true, may indicate serious liver damage. As indicated in Table 1, each of these individuals reported having the symptom for 1 month only (either during 1st, 2nd, or 8th month on INH). During the month when yellow discoloration was reported, four of the six adolescents also reported using alcohol, which may increase the likelihood of liver dysfunction. Two of the six also reported change in urine color during the month in which yellow discoloration was reported; none of the six reported vomiting, nausea, or decreased appetite during this month. Three of the participants indicated that they sought help from a doctor, clinic, pharmacist or other health professional about the complaint of self-reported yellowing. Reviews of medical charts of all six participants indicated that only one appeared to have reported experiencing any side effects to the clinic at any time, and in this individual, no record of yellowing of skin or eyes was noted. During the same month in which yellow discoloration was reported to investigators (2nd month on INH), this male participant complained of stomachaches at his 2nd month clinic appointment. The clinic staff/doctor suggested taking INH with meals. A week later the participant was still experiencing stomachaches with the addition of vomiting and nausea. The clinic discontinued INH and conducted the hepatic panel. The following week the problem was apparently resolved and the clinic restarted INH and added Pyridoxine to be taken 3 days per week. Of the five other participants who reported yellow discoloration, four continued to take INH during and after the month of reported yellowing. The fifth took INH during his reporting month of yellow discoloration (month 8) and was prescribed INH for 9 months. Compliance data were not obtained for the final month for this participant. 3.1.2. Somatic complaints Over 80% (82.3%) of participants reported experiencing at least one somatic complaint at some point during the course of the trial. On a monthly basis, the percentage of participants reporting somatic complaints ranged from a low of 14.1% in month 8 to a high of 60.7% in month 1. The maximum number of somatic complaints reported in any month (for one participant only) was 11. Of note, 85.4% of participants reported experiencing one or more somatic complaints at baseline (i.e. in the 30 days prior to the baseline interview). 3.1.2.1. Frequency of somatic complaints by symptom. Table 2 describes the frequency of each symptom for

J. Berg et al. / Patient Education and Counseling 52 (2004) 31–39 Table 2 Self-reported somatic complaints during 9 months on INHa Symptoms

Headaches Acne or pimples Dandruff Coughing Dizziness Increased appetite Backaches Blurry vision Hair loss Weight gain Faster hair growth Increased energy Trouble falling asleep Ringing in your ears Dry mouth Inability to concentrate Diarrhea Weight loss Dry skin Constipation Difficulty urinating

N ¼ 96 Across all months of INHb

Baselinec

n (%)d

Maxe

n (%)

37 35 26 25 25 24 23 21 19 19 16 13 12 12 11 10 9 8 5 3 1

8 6 6 3 3 5 4 3 4 5 7 4 4 4 5 3 2 2 4 3 1

40 40 23 25 22 18 21 23 25 19 18 11 27 9 15 19 5 10 7 1 1

(38.5) (36.5) (27.1) (26.0) (26.0) (25.0) (24.0) (21.9) (19.8) (19.8) (16.7) (13.5) (12.5) (12.5) (11.5) (10.4) (9.4) (8.3) (5.2) (3.1) (1.0)

(41.7) (41.7) (24.0) (26.0) (22.9) (18.8) (21.9) (24.0) (26.0) (19.8) (18.8) (11.5) (28.1) (9.4) (15.6) (19.8) (5.2) (10.4) (7.3) (1.0) (1.0)

a

Table includes data for individuals who were on INH for less than 9 months. b Table arranged in order of frequency of symptom across all months. c Baseline data related to the 30 days prior to completion of the baseline interview. d n: number and percent of individuals that ever reported each symptom for at least 1 month; numbers and percents are not mutually exclusive. e Max: maximum number of months any individual complained about a symptom throughout the 9 months.

non-specific somatic complaints, and the maximum number of months for which symptoms were reported. The most commonly reported non-INH-specific somatic complaints over time were headaches (38.5%), acne (36.5%), and dandruff (27.1%). Headaches, acne, and dandruff were also the symptoms reported as occurring during the most months, for 8 months (one person), 6 months (two people), and 6 months (one person), respectively. The frequencies of specific somatic complaints reported at baseline are also presented in Table 2. The most commonly reported complaints at baseline were headaches (41.7%), acne (41.7%), and trouble falling asleep (28.1%). 3.2. Relation of INH side effects and somatic complaints to adherence 3.2.1. Regression results To assess the overall effects of total reported INH side effects and somatic complaints on cumulative adherence (i.e. total number of pills consumed over time) over 9 months, an ordinary least-squares regression was computed, with the cumulative number of pills taken as the dependent variable

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and the cumulative numbers of INH side effects and somatic complaints, respectively, as the independent variables. To control for potential pre-existing symptoms, these regressions also included baseline somatic complaints. The dependent variables were normally distributed. Logarithmic transformations were conducted on all independent variables to adjust skewed distributions. Table 3 presents statistics regarding the regression equation, Fð3; 92Þ ¼ 2:76, P < 0:05. This model explained a significant 8% of the variance in adherence to INH. While this equation included the independent variables INH side effects over 9 months, somatic complaints over 9 months, and somatic complaints reported at baseline, the t-statistics (see Table 3) indicate that somatic complaints over 9 months was the only individual significant predictor of pill taking. This relationship was negative, suggesting that the greater the number of somatic complaints over 9 months, the lower the adherence to INH medication during that period. INH side effects that occurred during the 9 months were not significantly related to total number of pills taken. Two additional exploratory regression models were computed to determine the effects of inclusion of gender and alcohol, respectively. A square root transformation was applied to the alcohol variable to adjust skewness. Including gender in the model in addition to somatic complaints and side effects rendered the overall equation non-significant. However, the regression equation including alcohol in addition to the other independent variables was significant (see Table 3), Fð4; 91Þ ¼ 3:35, P < 0:05, explaining 13% of the variance in adherence. As indicated in Table 3, cumulative alcohol use was significantly negatively related to adherence, as were somatic complaints over 9 months. Cumulative alcohol use was significant although only 36.5% of participants reported using alcohol to some degree for 1–8 months. No one reported using alcohol for all 9 months. 3.2.2. Results from regression using a general estimating equations (GEE) approach GEE were used to determine whether the occurrence of INH side effects and non-specific somatic complaints impacted adherence to INH on a monthly basis, over time. Analyses were conducted using nine repeated measures (i.e. monthly adherence for 9 consecutive months). The dependent variables were the numbers of pills reported taken monthly, for each month, coded to dichotomous variables representing the achievement (or not) of 90% compliance on a monthly basis (i.e. 0 ¼ less than 26; 1 ¼ greater than or equal to 27). This approach was used to adjust for skewed 30-day (monthly) measures that could not be repaired by transformation. All independent variables representing monthly side effects and somatic complaints were also coded to dichotomous variables (i.e. 0 ¼ no symptoms; 1 ¼ experienced symptoms) for similar reasons. To control for potential reporting of pre-existing symptoms, all models were analyzed with and without baseline somatic complaints. All models were also analyzed with and

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Predictor

Over 9 months

Over 9 months, including alcohol use

2

R ¼ 0.358, R2 ¼ 0.128, Fð4; 91Þ ¼ 3:352, P ¼ 0.013

R ¼ 0.287, R ¼ 0.082, Fð3; 92Þ ¼ 2:757, P ¼ 0.047 S.E.

b

17.554 2.355 27.843

11.613 12.354 10.981

0.203 0.023 0.393

173.037

15.970

B Sum of INH side effects over 9 months Sum of somatic complaints at baseline Sum of somatic complaints over 9 months Sum of alcohol use over 9 months Constant

t

P 1.512 0.191 2.536

0.134 0.849 0.013

10.835

0.000

B 16.148 2.527 23.266 18.570 178.537

S.E.

b

11.398 12.107 10.962 8.478 15.850

0.187 0.025 0.328 0.222

t

P 1.417 0.209 2.122 2.190 11.264

0.160 0.835 0.037 0.031 0.000

J. Berg et al. / Patient Education and Counseling 52 (2004) 31–39

Table 3 Predictors of cumulative number of pills (N ¼ 96)

J. Berg et al. / Patient Education and Counseling 52 (2004) 31–39

without alcohol use over time over 9 months. A log transformation was applied to the somatic complaints variable at baseline to adjust a skewed distribution; alcohol variables across all months were re-coded to dichotomous variables for similar reasons. All GEE results were non-significant. There were no significant interactions between time and INH side effects, time and somatic complaints, or time and alcohol use. Including baseline somatic complaints in the models did not change the relationships observed in absence of baseline symptoms. Thus, results suggest that monthly side effects and somatic complaints experienced over time, baseline reports of somatic symptoms, and alcohol use over time were not related to changes in adherence to INH over 9 months. 3.2.2.1. Analysis of power. Assuming a two-sided test, a ¼ 0:05, N ¼ 96, with nine repeated measures, a 2% increase/decrease in slope can be detected with more than 90% power [48]. 3.3. Characteristics of individuals reporting baseline somatic complaints ANOVAs were conducted to determine if there were any differences in the number of reported baseline somatic complaints by gender, level of acculturation, foreign-born status, and having insurance. There was a significant main effect for gender, Fð1; 94Þ ¼ 7:40, P < 0:01. Females reported a 35% higher mean (natural log) number of somatic complaints than males.

4. Discussion One of the more important reservations among health care providers who are considering INH treatment for LTBI among adolescents is the trade off between prevention of active TB and possible serious medication side effects in otherwise healthy adolescents. This concern was raised by some of the physicians treating adolescents in this trial. Experiencing side effects could also potentially decrease medication adherence. For these reasons it was important to explore the relationship between possible side effects and adherence as well as document the prevalence of side effects and other somatic complaints in this sample. Our findings indicate that although the adolescents acknowledged the presence of side effects during the study, there was no significant relationship between side effects and medication adherence among participants. Throughout the trial, almost 70% of participants reported experiencing at least one side effect that could potentially be attributed to INH. The most frequently reported side effects during the trial were fatigue, memory problems, numbness or tingling in the extremities, and achy or stiff muscles. Fatigue and numbness or tingling in the extremities are among the more

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common INH side effects listed in the United States Pharmacopeia, Drug Information (USP DI1) [28]. While these symptoms might be due to INH, they also could be due to many other events, such as lack of sleep and sports activities common among adolescents. Six adolescents reported the occurrence of yellow discoloration of the skin or eyes for 1 month during the course of the trial, which are side effects that might be specific to INH and might have been true reactions to the prescribed medication. During that same timeframe, we could find no objective data to support the notion that what was reported was jaundice or scleral icterus. All six had relationships with health care providers, and during the time in question, none had documentation of these symptoms in their medical record. Three of these teens reported to us that they sought help from a health professional regarding the complaint of yellowing. Only one had liver enzymes checked because of nausea and vomiting and he was told to continue INH. Therefore, all participants continued to take INH during and/or after the month of reported yellowing. Had the discoloration been INH-induced hepatotoxicity, more severe systemic illness and increased jaundice would have certainly occurred, and for more than 1 month. Given that these potentially serious symptoms were of short duration, were not confirmed by medical records, and did not result in clinicians discontinuing INH treatment, these symptoms that might have been INH side effects, were likely very minor and transient, were due to other incidental processes, or were incorrectly stated. Overall, our results indicate, as reported elsewhere [49], that INH is a relatively safe drug but adverse reactions may occur and careful monitoring is needed. Study participants had various somatic complaints at baseline and throughout the trial. The complaints that were most frequent and occurred for the most months and at baseline were headaches and acne. Consistent with previous findings [4], at baseline females reported more somatic complaints than males. Cumulative somatic complaints were significantly negatively related to cumulative adherence over 9 months, indicating that participants experiencing more somatic complaints during that period had lower levels of adherence. This finding suggests that the youths’ reaction to incidental somatic symptoms, even though unlikely to be due to INH consumption, resulted in discontinuing some of their medication. This may have been a superstitious association, but one that deserves attention by providers. If youth experience symptoms while taking a prescribed medication, they may attribute the symptom to the medication and discontinue the medication in response. Or, it is also possible that other factors might promote discontinuation of medication, and that adolescents might justify decreased adherence based on incidental somatic symptoms. In these instances, clinicians should review the nature of incidental symptoms both before and during prescribed medication regimens, in order to make decisions about differential diagnosis of true side effects and in order to advise youth to continue their medication

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appropriately. In any case, given the fact that over 80% of the youth reported somatic complaints prior to taking INH illustrates the importance of assessing all types of complaints prior to treatment. It is important to note that most of the side effects and somatic complaints our participants reported during the study were likely benign complaints, potentially attributable to a variety of causes. However, some of the somatic complaints might also represent true pathology that warrants medical care. The most accurate post-INH differential diagnosis can be performed only if the clinician is aware of the rate of specific symptoms prior to starting the medication. Thus, though not now common, clinicians should conduct a thorough somatic complaint history at the time they prescribe INH (or other medications). Doing so will make it possible to move more quickly to treatment of pathology that might be independent of the INH prescription. If providers are unaware of specific baseline complaints, they may not be as efficient in ruling out INH as a possible causal agent. Cumulative alcohol use was significantly negatively related to cumulative adherence over 9 months. This finding is consistent with Gilroy et al.’s [50] findings in an adult population (35 years of age) prescribed anti-TB treatment in which 61.3% of male participants who used alcohol did not complete that treatment. Whether those who reported alcohol consumption were less adherent because they were more susceptible to INH side effects, or because use of alcohol is a marker for general non-conforming behavior is an important topic for investigation, but was not evaluated in our study. 4.1. Practice implications In this community trial of Latino adolescents, medication side effects during the study were not associated with INH adherence, but somatic complaints were. Study participants reported a variety of health issues at baseline, consistent with the literature on somatic complaints in adolescents. Treating adolescents for LTBI opens the clinic door, and may provide a unique opportunity to treat non-TB-related health concerns as well as cementing a link between the Latino community and the health care provider. Monthly visits with health care providers should give adolescents the opportunity to discuss health issues and distinguish between adverse medication reactions and other symptoms. Such review may offer an opportunity to provide health education and anticipatory guidance to adolescents, as well as identify other diseases in this population. In addition, communities must assure that health care funding is adequate to allow the types of services required to provide the recommended level of service. Our findings also suggest that family practitioners, pediatricians and pulmonary specialists likely to provide LTBI treatment should be trained to review somatic complaints prior to initiating INH treatments and should review both somatic complaints in general as well as those possibly due to INH in order to more fully rule out INH as the basis for

side effects. As LTBI treatment provides long-term protection from active disease, control of TB requires treatment of adolescents, including those at high risk and those with co-existing health risk-taking behavior. Thus, specialized continuing education for health care providers may be important to maximize the number of infected youth who are treated and to maximize the quality of care and the level of adherence. The combination should decrease the rates of active TB as well as provide more complete adolescent medicine services for high-risk adolescents.

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