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FEBRUARY 2007
Main Article:
Managing the Side Effects of Hepatitis C Treatment in a Correctional Environment
Kay A. Bauman MD, MPH Medical Director State of Hawaii Department of Public Safety Steven K. DeWitt, MD Internist State of Hawaii Department of Public Safety Disclosures: The authors have nothing to disclose. Introduction: The side effects of therapy of hepatitis C virus (HCV) infection have limited the number of patients able to complete an effective course of treatment and can dissuade patients and clinicians from embarking on such treatment. This is true in the general population as well as the more controlled correctional environment. Rates of discontinuation of HCV therapy for laboratory abnormalities or other clinical adverse events range from 7 to 16% in both HCV treatment trials and clinical practice.1,2 At the Hawaii Department of Public Safety, we have implemented a successful HCV treatment program for infected inmates. Although treatment began for a few inmates as early as 1999, the main emphasis on treatment started in late 2002. Approximately 6,000 inmates reside in Hawaii's prisons and jails, both of which are contained in one system. Inmates reside in eight facilities on four islands in Hawaii and in four private contract facilities in four different mainland states. The prevalence of HCV in our system in 1999-2001 was found to be approximately 30% when our health department tested all inmates anonymously. Although testing for HIV is routinely offered to inmates by our health department, screening for HCV is conducted when an abnormal ALT is detected or there is a history of injection drug use, transfusions before 1992, known liver disease, HIV infection or hepatitis B virus (HBV) infection. In addition, HCV testing is offered to patients on hemodialysis and prior to treatment with either isoniazid or statins, or on patient request. After determining HCV seropositivity, our current major criteria for consideration for HCV treatment is an ALT greater than 1.5 times normal (we previously used twice normal, but as the literature suggests a small percent of persons with progressive disease may have minimal or no elevation of ALT, we reduced this level to 1.5 times normal). Viral load and genotyping are then done to determine duration of treatment required and the need for liver biopsy. At the current time, we only perform liver biopsies on HCV genotypes 1 and 4. We do not treat fibrosis level 0 or 1, although we have made rare exceptions. Our guidelines currently require an expectation for 12-18 months remaining in one's sentence, but exceptions are made for those committed to treatment and able to name an outside provider who will continue treatment. We previously required completion of or current participation in a drug treatment program but we have dropped that requirement for legal considerations. We do require sobriety and conduct random urine drug screens (after a signed agreement from the patient). In analyzing our clinical data, we noted that only 5% of 188 patients treated for HCV had discontinued HCV therapy for medical reasons and 2% stopped treatment on their own for reasons that may or may not have been related to side effects. An additional 4% had their HCV therapy stopped secondary to positive urine drug screens. No patient has had a positive drug screen since November 2002. All inmates are tested for HIV prior to treatment; only three inmates of our treated population were co-infected. While we suspect our approach to the management of treatment is similar to that of most providers, our ability to recognize and respond to HCV treatment-related toxicities is likely a significant factor contributing to the success we have had in achieving treatment completion. In this review we describe our approach to the management of the side effects we commonly encounter during HCV therapy. General approach to treatment We aim to assign a nurse at each facility to take responsibility for HCV management and also get the active participation of the nurse administrator. The overall management of HCV from diagnosis, evaluation and consideration of liver biopsy, explanation of the rationale for decisions not to treat (e.g., liver biopsy with fibrosis 0-1), to supportive care during treatment, all require the involvement of a consistent team of nurses and other providers. Most clinical visits (frequently timed with lab draws) are with the nurse on the treatment team. He or she assesses whether or not additional physician visits are also needed. Patient expectations play a major role in the subjective patient response to side effects. During counseling, we stress the potential benefits of the current treatment and use the term "chemotherapy" to describe the treatment course itself. Some believe this is too strong a term, but our experience supports using this term, as it better predicts for the patient the severity of the side effects. We believe forewarned is fore-armed. We explain the 60/40 "odds" of achieving a sustained viral response (SVR; non-detectable virus at 6 months post treatment) or "cure" for HIV-uninfected patients with genotype 1 HCV, but also the potential reduction in liver inflammation and the resultant delay in the complications from chronic HCV even in the absence of SVR.3 This we describe to the patient as "turning the clock back" on this disease. Common side effects Fatigue, headache, malaise, myalgias, arthralgias This combination of symptoms leads any list of HCV treatment side effects and is reported to occur in over 50% of treated patients; in some studies this proportion is as high as 72%.1-6 Most patients experience these symptoms to some degree. Liberal prescribing of analgesics may help with the aches. Further, we administer pegylated interferon injections on late afternoons on Fridays so patients have the weekend to recover. By Monday, they are usually able to tackle work once again. Rarely have our patients had to leave their work assignment over the course of the treatment, although at times some accommodations have had to be made. In patients with preexisting chronic pain, whether back, neck, shoulder or other, this pain may worsen on treatment. Warning the patient of this possibility prior to treatment can help the patient prepare for the possible need for additional analgesics. We rarely use narcotics in this situation. During treatment, we are liberal with prescribing what our system calls "medical rec", where patients are allowed to get outside to walk but are not be expected to participate in the strenuous exercise such as basketball or other games. Causes for fatigue developing during HCV treatment is often detected by laboratory evaluation. Conditions such as anemia, neutropenia, thrombocytopenia and thyroid abnormalities can be detected early with proper laboratory surveillance. Table 1 lists our routine laboratory monitoring schedule. The managing physicians review all laboratory tests. Depression Rates of depression during HCV treatment range from 16 to 36%.1,2,6 At our largest facility, patients are reviewed by the psychiatrist or other mental health worker prior to treatment; at small facilities mental health screening is conducted by the primary care physician. No specific depression inventory is used. Exclusion from treatment on the basis of psychiatric reasons, specifically depression, is rare, but a patient with a history of depression with previous suicide attempts may be ruled out for therapy. It is also likely in our system that poorly-controlled psychotic patients do not get to the evaluation-for-treatment stage. The pre-treatment psychiatry visit does, however, alert the mental health team that HCV therapy is being considered so that some patients with pre-existing mental health problems maybe followed more closely during their HCV therapy. This pro-active approach has resulted in no patients stopping treatment for psychiatric side effects and there have been no suicide attempts in patients during treatment. There have been unusual personality changes in a small number of patients while on treatment; nonetheless these inmates were highly motivated to complete treatment and were successful in achieving SVR. During therapy anti-depressants, usually selective serotonin reuptake inhibitors (SSRIs), such as fluoxetin, are liberally prescribed. Although most psychotropic medicines in our facilities are prescribed by psychiatrists, patient management is conducted by primary care physicians. In our system, we do not use anti-depressants as prophylaxis for depression. Nausea, anorexia, weight loss The reported rates for nausea and/or anorexia range from 21 to 47%.1,2,6 As part of our counseling, we inform patients that lighter weight people seem to do better with HCV treatment. Thus, the expected loss of appetite and weight may actually help achieve the desired long-term positive response. Usually the gastrointestinal symptoms associated with HCV treatment occur in the mornings, so by evening the patient is able to eat. If a normal weight patient begins losing weight we allow extra calories, usually as an evening snack, for weight stabilization. Patients with diabetes mellitus may need to reduce or stop hypoglycemic medication during HCV treatment, even if significant weight loss has not occurred. Costly nutritional supplement drinks are required only rarely. Local skin reaction A large number of our patients have a local skin reaction to the weekly pegylated interferon injections; the literature gives a range of 7 to 58% for this complication.2,6 With this reaction, the injection site appears inflamed; edges of the reaction are not well demarcated. Effectiveness of steroid cream varies. As with other reactions, advising patients beforehand prepares them. The skin condition lasts throughout interferon therapy, but resolves over time upon completion. Fever, chills, and rigor Fever occurs in as many as 37 to 56% of patients and 23 to 43% experience chills/rigor.1,2,6 Usually, these complaints can be managed with antipyretics. However, three of our patients had severe rigors associated with interferon injections. One male patient elected to quit therapy because rigors occurred with his first injection and he did not want to suffer it again. A female experiencing a similar severe rigor tried a second injection (timed away from her insulin injection to make sure a cross-reaction wasn't occurring), but after an almost shock-like reaction recurred, therapy was discontinued. A third patient had a similar reaction, but only after several months of treatment. He continued therapy and rigors did not occur with each injection. Hematologic complications Anemia, defined as a hemoglobin < 11.0 g/dL can occur in 19 to 36% of patients.1,6 It is usually hemolytic in nature and related to the ribavirin. We use the nationally recommended parameters and schedule for ribavirin dose reduction for Hgb < 10.0 g/dL (Tables 2 and 3). Leukopenia, defined as WBC < 3.0 x 109/L, occurs in 17 to 45% of treated patients and is more commonly related to interferon.1,6 Our current dose reduction parameters and schedule for WBC < 1.5 x 109/L or absolute neutrophil count < 0.75 x 109/L are noted in Tables 2 and 3. We have not needed to stop therapy in any of our patients due to anemia or leukopenia. Thrombocytopenia, defined as platelets < 100 x 109/L occurs in 4 to 11% of patients.1,6 Three of our patients had HCV therapy stopped for severe thrombocytopenia, with platelet counts < 50 x 109/L. Platelet transfusions are administered to patients with compensated cirrhosis who begin therapy with platelets < 100 x 109/L. Surprisingly many of these patients are able to continue treatment although the viral response rate is lower than others with healthier livers. To date, we have not used cellular growth factors, such as granulocyte colony stimulating factor (GCSF), to avoid lowering doses of either pegylated interferon or ribavirin, but we have recently revised our HCV treatment guidelines to add the use of erythropoietin to help prevent ribavirin dose reduction due to drug-induced anemia. The literature supports the importance of maintaining a full ribavirin dose early in treatment for best results. The importance of the full dose of pegylated interferon is not as clearly addressed in the literature, so we have not included the use of GCSF in our management. Although there are limited data suggesting GCSF can increase the number of WBCs in patients receiving HCV therapy and can thus permit higher interferon dosing, improvements in SVR have not yet been demonstrated.7 A major challenge to treating HCV in corrections is economic: can we afford these growth factors on top of the cost of HCV therapy itself? Our approach has been very conservative, but we added the erythropoeitin to our formulary with the reasoning that this will enhance success of an investment for treatment of $30,000 or more (for genotypes 1 and 4). Bacterial infections One patient's HCV treatment was discontinued after three hospitalizations for cellulitis while on therapy. The infection first began in a tattoo acquired while on treatment. Our pre-treatment counseling specifically forbids the acquistion of new tattoos while on treatment, but on review of our consent form, it did not include this statement. Since this patient was insistent on continuing treatment and denied knowing of this mandate, treatment was initially continued; two additional episodes of infection ensued and treatment was terminated due to recurrent severe infections. Severe jaundice Although mild elevations of bilirubin are reported in 11 to 28% of patients,6 severe elevations of bilirubin, defined as bilirubin > 12.0 mg/dL have not been reported. Therapy was discontinued in one or our patients experiencing severe jaundice with a bilirubin > 20 mg/dL while on treatment. His abdominal ultrasound was negative. He recovered well after stopping both medications and it was not clear which drug was the cause of this adverse event. Decompensation of liver disease One patient died after therapy had started. His pre-treatment liver biopsy showed stage 3 fibrosis and not cirrhosis, thus making him a candidate for treatment. Of note, his laboratory studies showed low platelets and a normal albumin. These were consistent with compensated cirrhosis, which did not show in his biopsy, likely due to sampling variability. His pre-treatment physical exam did show edema. A review of his care at a mortality conference after his death attributed his worsening liver disease to underdiagnosing cirrhosis, perhaps missed by biopsy. It is known that the biopsy only reaches small pieces of the liver and can underdiagnose severity of disease. Interestingly, he was a responder to treatment at both 12 and 24 weeks of care. Although his hemoglobin fell at the beginning of treatment, it was not below the threshold that triggers a change in the ribavirin dose. A later drop in hemoglobin, after six months of treatment did prompt a decrease in his ribavirin dose. Investigation for other etiologies accounting for the drop in hemoglobin such as gastrointestinal bleeding was not conducted. After eight weeks of treatment, his WBC decreased and required a reduction in the interferon dose. After 24 weeks the patient's WBC rose to 10.2 x 109/L but this was overlooked in terms of a search for an infectious source. After eight and a half months of treatment, he was hospitalized with an upper gastrointestinal bleed. HCV treatment was stopped, esophageal varices were diagnosed and portal hypertension was noted. He developed methicillin resistant S.aureus bacteremia secondary to an infected shoulder joint leading to acute renal failure and further hepatic failure. He continued to decompensate and expired of sepsis. This case illustrates not only the seriousness of liver dysfunction and the complexities of the management of such patients but also the limitations of HCV therapy in patients with more advanced liver disease. Summary It has been our experience that the vast majority of HCV-infected inmates receiving HCV therapy can complete their treatment without serious adverse events. Some of our success may be explained by our careful selection of patients to receive HCV therapy; however, our criteria for treatment are reasonable and inclusive. Further, few of our patients were HIV-HCV co-infected and rates of successful treatment completion in co-infected patients may differ from those we observed. We have learned that managing the side effects of HCV therapy takes committed providers and an educated nursing team. It also requires pre-treatment education of the patient and reassurance about the unpleasant effects these strong medications can cause. Close and careful monitoring of laboratory parameters is necessary with orders for medication dose changes if needed. Awareness of the potential complications of HCV therapy and the management of these adverse effects is critical to maintaining therapy. Nonetheless, if these challenges are addressed, sustained virologic responses in patients on HCV treatment in corrections can match or exceed the responses of programs in our communities. References: 1 Fried, MW, Shiffman, ML, Reddy, KR, et al. Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C Virus Infection. N Engl J Med. 2002;347 (13):975-982. 2 Zeuzem, S, Feinman, SV, Rasenack, J et al. Peginterferon Alfa-2a in Patients with Chronic Hepatitis C. N Engl J Med. 2000;343(23):1666-1672. 3 Coverdale, SA, Khan, MH, Byth, K., et al. Effects of Interferon Treatment Response on Liver Complications of Chronic Hepatitis C: 9-year Follow-Up Study. Am J Gastroenterol. 99(4):636-644. 4 Pegylated Interferon (Peg-Intron) for Chronic Hepatitis C. The Medical Letter. 2001;43(1107): 54-55. 5 Interferon Plus Ribavirin for Chronic Hepatitis C. The Medical Letter. 1999;41(1054):53-54. 6 Physicians' Desk Reference. 2006(60):3073-3088. 7Patients with Chronic Hepatitis C. Federal Practitioner Supplement. 2003(20):28. |
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