Background: Clinical observations suggest that patients with HIV/hepatitis C virus (HCV) may lose body weight during dual therapy, but this has not been confirmed analytically.
Objectives: To determine if the incidence and degree of weight loss among patients with HIV/HCV receiving highly active antiretroviral therapy (HAART) and pegylated (PEG)-interferon plus ribavirin were greater than in (1) HCV-monoinfected patients receiving PEG-interferon plus ribavirin and (2) HIV-monoinfected patients receiving HAART. Risk factors for weight loss among patients with HIV/HCV were also examined.
Methods: A retrospective cohort study was performed among HIV/HCV-coinfected, HCV-monoinfected, and HIV-monoinfected patients. Body weights were assessed up to 6 months before and up to 12 months after initiation of HCV therapy (HIV/HCV-coinfected and HCV-monoinfected subjects) and over 18 months on HAART (HIV-monoinfected subjects). The primary outcome was clinically significant weight loss (≥5% of baseline weight).
Results: Of 192 subjects, 63 had HIV/HCV, 64 had HCV alone, and 65 had HIV alone. Clinically significant weight loss occurred in 48 (76%) subjects with HIV/HCV versus 25 (39%) subjects with HCV (P < 0.001) and 2 (3%) subjects with HIV (P < 0.001), yielding adjusted hazard ratios (HRs) of 2.76 (95% confidence interval [CI]: 1.67 to 4.55) and 38.5 (95% CI: 8.5 to 174.7), respectively. Receipt of more than 2 nucleoside reverse transcriptase inhibitors increased the risk of clinically significant weight loss (adjusted HR = 8.17, 95% CI: 2.37 to 28.20).
Conclusions: The incidence of weight loss is greater in dually treated patients with HIV/HCV than in treated HCV- or HIV-monoinfected patients. Prospective studies should evaluate additional risk factors for weight loss and changes in body composition to elucidate the mechanism for this weight loss.
From the *Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; †Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA; ‡Center for Education and Research on Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA; §Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; ∥Jonathan Lax Treatment Center, Philadelphia FIGHT, Philadelphia, PA; ¶Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; #Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; and **Pathology and Laboratory Medicine Service, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.
Received for publication June 28, 2006; accepted November 15, 2006.
Supported by National Institutes of Health (NIH) research grants T32-AI055435 and F32-DK069080 (V. Lo Re), NIH research grant K08-MH01584 (R. Gross), the Penn AIDS Clinical Trial Unit U01-AI32783 (I. Frank, R. Gross, and J.R. Kostman), the University of Pennsylvania Center for AIDS Research grant P30-AI45008 (I. Frank and R. Gross), and an Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics cooperative agreement (grant HS10399).
Results were presented, in part, at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco, CA, December 16-19, 2005 (abstract V-612) and the 22nd International Conference on Pharmacoepidemiology and Therapeutic Risk Management in Lisbon, Portugal, August 24-27, 2006 (abstract 380).
Reprints: Vincent Lo Re, III, MD, MSCE, Center for Clinical Epidemiology and Biostatistics, Division of Infectious Diseases, University of Pennsylvania School of Medicine, 711 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021 (e-mail: email@example.com).
Approximately one third of patients with HIV are coinfected with hepatitis C virus (HCV) infection.1 Because HIV/HCV coinfection is common and patients with HIV are living longer because of highly active antiretroviral therapy (HAART), chronic HCV has emerged as a major cause of morbidity and mortality in this population.2,3 HIV/HCV coinfection is associated with more rapid progression of liver fibrosis and an increased risk of cirrhosis and hepatic failure compared with those conditions in patients with HCV alone.4-6 Although less effective than in HCV-monoinfected patients, HCV treatment can cure HCV and remains critical for long-term survival of patients with HIV/HCV.7-9
Case series suggest that up to 70% of patients with HIV/HCV may lose weight during dual treatment,10-12 but the incidence and degree of weight loss in dually treated patients with HIV/HCV have not been compared with the incidence and degree of weight loss in treated HCV- or HIV-monoinfected patients. Furthermore, the addition of the anti-HCV nucleoside analogue ribavirin to a HAART regimen already containing 1 or more nucleoside reverse transcriptase inhibitors (NRTIs) may potentiate mitochondrial toxicity, a clinical syndrome caused by mitochondrial DNA depletion, which can lead to lipoatrophy and weight loss.10,13-25 Nucleoside analogue use has not been examined as a risk factor for weight loss during dual HIV/HCV therapy, however.
We conducted a retrospective cohort study to determine if the incidence of clinically significant weight loss (defined as ≥5% of baseline body weight) was greater in HIV/HCV-coinfected patients who received HAART plus pegylated (PEG)-interferon and ribavirin compared with (1) HCV-monoinfected patients who received PEG-interferon and ribavirin and (2) HIV-monoinfected individuals who received only HAART. We also sought to examine risk factors for weight loss in dually treated patients with HIV/HCV. Hypothesized risk factors included NRTI type, number, and duration of use as well as ribavirin dosage.
Study Design and Subjects
We performed a retrospective cohort study among dually treated HIV/HCV-coinfected, treated HCV-monoinfected, and treated HIV-monoinfected subjects cared for at the Hospital of the University of Pennsylvania (HUP), Penn Presbyterian Medical Center (PPMC), Philadelphia Veterans Affairs Medical Center (PVAMC), and Jonathan Lax Center (JLC), all in Philadelphia, PA.
HCV-monoinfected patients were eligible for inclusion if they (1) had hepatitis C viremia before HCV therapy, (2) had HCV genotype 1 only, (3) underwent a liver biopsy, (4) received at least 2 months of HCV therapy with PEG-interferon α-2a or α-2b plus ribavirin (to limit early withdrawals attributable to adverse effects from HCV therapy), and (5) had no laboratory evidence of HIV infection. HIV-monoinfected patients were eligible if they (1) had laboratory evidence of HIV infection (positive HIV antibody test result and/or viral load), (2) had been maintained on the same regimen of antiretroviral drugs for at least 3 months between January 2001 (the approximate date when HCV therapy was first used in patients with HIV/HCV) and December 2004, (3) had an HIV viral load <5000 copies/mL on HAART at baseline observation, and (4) had a negative HCV antibody test result. HIV/HCV-coinfected patients were eligible if they met criteria 1 through 4 for HCV-monoinfected subjects and criteria 1 through 3 for HIV-monoinfected subjects. We focused on HCV genotype 1 subjects, because this is the predominant genotype among patients with HCV in the United States.26 A liver biopsy was required for HCV-infected subjects, because the degree of hepatic fibrosis and inflammation were considered important potential confounding variables. We excluded patients who had an active opportunistic infection or malignancy, because these conditions can alter body weight, and patients who were positive for HBV surface antigen.
Potentially eligible subjects were identified by the results of HIV tests (HIV antibody and/or HIV viral load) and HCV tests (HCV antibody and/or HCV viral load) generated from computerized laboratory records at the HUP, PPMC, PVAMC, and JLC. A list of all treated HCV-infected patients was obtained from all sites. All eligible patients with HIV/HCV were included in the study. A random sample of eligible HCV- and HIV-monoinfected patients was taken to achieve the desired sample size. The study was approved by the Institutional Review Boards of the University of Pennsylvania and JLC.
Main Outcome Measures
The primary outcome was clinically significant weight loss, defined as weight loss ≥5% of baseline body weight at 12 months of HCV therapy or HAART or at withdrawal from HCV therapy or HAART, whichever was first. This magnitude was chosen because it is associated with increased morbidity in patients with HIV.27,28
Risk factors for clinically significant weight loss were examined only in the dually treated HIV/HCV cohort. Hypothesized weight loss risk factors during HIV/HCV therapy included NRTI type, number of NRTIs (≤2 vs. ≥3 NRTIs), duration of NRTI use (months), and ribavirin dose (low [≤800 mg/d] vs. high [≥1000 mg/d]). Additional risk factors evaluated included gender, age, race, baseline body mass index (BMI), baseline CD4 cell count, HIV viral load, METAVIR stage of hepatic fibrosis and grade of inflammation,29 and hepatic steatosis.
Data were abstracted from subjects' charts and recorded on structured data collection forms. Baseline demographic, clinical, and laboratory data were abstracted from dates closest to the initial HCV treatment evaluation (HCV-infected subjects) or visit representing initial observation on HAART (HIV-monoinfected subjects). We defined “time 0” as the initiation date of HCV therapy for both HCV-infected cohorts and the visit date for the sixth month of observation on HAART for the HIV-monoinfected cohort. Body weights obtained closest to but before and including time 0 (to obtain at least 3 weights) represent “interval A” for each subject (Fig. 1), and their mean represents the baseline weight. Weights taken after time 0 represent “interval B.” Interval B body weights were abstracted at 3-month intervals (obtaining the weight from the visit nearest to a 3-month interval) during 12 months of HCV therapy (HCV-infected subjects) or an additional 12 months on HAART (HIV-monoinfected subjects). At each 3-month interval, records over the prior 3 months were reviewed for continued use of PEG-interferon, ribavirin, HAART, and appetite stimulants or anabolic agents to counteract weight loss (specifically megestrol acetate, dronabinol, or oxandrolone). If a patient discontinued HCV therapy and/or HAART, that patient's body weight and reason for withdrawal were recorded at the nearest 3-month interval. A 10% random chart reabstraction was performed to validate the accuracy of data collection.
Clinically significant weight loss was compared between (1) HIV/HCV-coinfected and HCV-monoinfected cohorts and (2) HIV/HCV-coinfected and HIV-monoinfected cohorts. A sample size of 62 subjects per group was targeted to have 80% power to detect a 20% difference in clinically significant weight loss between each pair of treatment groups, and this provided 80% power to detect a hazard ratio (HR) of significant weight loss of 2.0. Cox proportional hazards regression was used to determine unadjusted and adjusted HRs of significant weight loss with 95% confidence intervals (CIs) and to examine risk factors for weight loss among subjects with HIV/HCV.30 Potential confounders evaluated included age, gender, race, height, HIV/HCV risk factors, baseline CD4 cell count, baseline HIV viral load, degree of liver fibrosis and inflammation, duration of NRTI use, antidepressant use, and testosterone use.
Changes in weight from baseline were determined for each cohort. The difference between the rate of weight change before and during HCV therapy was examined to determine how HCV therapy affected body weight. Time 0 body weights were subtracted from initial observation date weights to determine interval A rates of weight change, whereas weights at 6 and 12 months after time 0 were subtracted from time 0 weights to determine 6- and 12-month interval B rates of weight change, respectively. The median difference in the rate of weight change before time 0 (interval A) and after time 0 (interval B) was calculated for both HCV-infected cohorts and assessed for significance using Wilcoxon signed rank tests. The differences were then compared between the 2 cohorts using Wilcoxon rank sum tests.
All data were analyzed using STATA 8.2 (Stata Corporation, College Station, TX). Statistical significance was declared with 2-sided P values <0.05.
A total of 192 subjects (n = 63 HIV/HCV-coinfected subjects, n = 64 HCV-monoinfected subjects, and n = 65 HIV-monoinfected subjects) were included in the study (see Fig. 2). Subjects with HIV/HCV were younger, were more commonly African American, had a history of injection drug use, had higher HCV viral loads, had lower BMIs, and more commonly received 800 mg/d of ribavirin compared with HCV-monoinfected subjects (Table 1). Compared with HIV-monoinfected subjects, subjects with HIV/HCV were older, more commonly had a history of injection drug use, had higher median CD4 cell counts, and had longer durations of NRTI use (see Table 1).
Thirty-three (52%) subjects with HIV/HCV withdrew from HCV therapy versus 22 (34%) HCV-monoinfected subjects (P = 0.04). Comparing subjects with HIV/HCV with subjects with HCV, the most common reasons for HCV treatment discontinuation were lack of virologic response (13 [21%] subjects with HIV/HCV vs. 5 subjects with HCV [8%]; P = 0.04), flu-like symptoms (4 [6%] subjects with HIV/HCV vs. 8 subjects with HCV [13%]; P = 0.24), and depression (7 [11%] subjects with HIV/HCV vs. 6 subjects with HCV [9%]; P > 0.5). Weight loss caused HCV treatment discontinuation in 1 HCV-monoinfected and 2 HIV/HCV-coinfected subjects. There were no differences in baseline characteristics between HCV-infected subjects who completed 12 months of HCV therapy and those who withdrew. Only 3 (5%) HIV-monoinfected subjects discontinued HAART (attributable to depression, pregnancy, and loss to follow-up).
Incidence of Clinically Significant Weight Loss
Clinically significant weight loss occurred in 48 (76%, 95% CI: 65% to 87%) subjects with HIV/HCV compared with 25 HCV-monoinfected subjects (39%, 95% CI: 27% to 51%; P < 0.001) and 2 HIV-monoinfected subjects (3%, 95% CI: 0% to 7%; P < 0.001). The HR for clinically significant weight loss in subjects with HIV/HCV was 2.78 (95% CI: 1.71 to 4.52) compared with HCV subjects. Adjustment for age and METAVIR grade of fibrosis yielded little change in the HR (adjusted HR = 2.76, 95% CI: 1.67 to 4.55). The HR for clinically significant weight loss in subjects with HIV/HCV was 44.1 (95% CI: 10.7 to 182.0) compared with HIV subjects. After adjusting for age, the HR was similar (adjusted HR = 38.5, 95% CI: 8.5 to 174.7).
Change in Body Weight From Baseline
At 3 and 6 months after time 0, the median loss in body weight from baseline was greater in dually treated HIV/HCV-coinfected subjects compared with treated HCV-monoinfected subjects and treated HIV-monoinfected subjects, who actually gained weight over time (Table 2). The median weight loss at 9 and 12 months after time 0 was also greater among subjects with HIV/HCV compared with HCV- and HIV-monoinfected subjects (see Fig. 1).
Differences in the Rate of Weight Change
For both HCV-infected cohorts, the median rates of weight loss for the first 6 months of interval B were significantly greater than during interval A, with subjects with HIV/HCV showing larger differences in weight loss for the 2 intervals than HCV-monoinfected subjects (Table 3). For subjects who remained on HCV therapy for 12 months, the median rate of body weight loss between 6 and 12 months continued to be greater for HIV/HCV-coinfected subjects (n = 24) versus HCV-monoinfected subjects (n = 42).
The median rate of weight change for interval A and the first 6 months of interval B for the HIV/HCV and HIV-monoinfected cohorts was also compared. The median rate of body weight loss during the first 6 months of interval B and between 6 and 12 months was greater for subjects with HIV/HCV than for HIV-monoinfected subjects.
Appetite Stimulant or Anabolic Agent Use
Eleven (17%) subjects with HIV/HCV received an appetite stimulant or anabolic agent during HCV therapy (6 received megestrol acetate, 3 received dronabinol, and 2 received oxandrolone). The median weight change from baseline when any of these medications were administered was −4.53 kg (interquartile range [IQR]: −7.86 to −3.17 kg), and the median percent body weight change was −5.4% (IQR: −10.4% to −4.0%). The median weight changes after receipt of megestrol acetate (median duration of 6 months), dronabinol (median duration of 8 months), and oxandrolone (median duration of 6 months) were −0.91 kg, 4.1 kg, and 0.68 kg, respectively.
Risk Factors for Weight Loss in Subjects with HIV/Hepatitis C Virus
After controlling for all other hypothesized risk factors and METAVIR stage of fibrosis, receipt of 3 or 4 NRTIs increased the risk of clinically significant weight loss (adjusted HR = 8.17, 95% CI: 2.37 to 28.20). The duration of NRTI use (adjusted HR = 1.00, 95% CI: 0.99 to 1.01) and ribavirin dose (adjusted HR = 1.88, 95% CI: 0.87 to 4.06) were not risk factors for weight loss. No individual NRTI increased the risk of clinically significant weight loss. Age, gender, race, ethnicity, BMI, degree of hepatic fibrosis and inflammation, testosterone use, and antidepressant use were also not associated with weight loss.
In this study, we found that the incidence of clinically significant weight loss was substantially greater in dually treated HIV/HCV-coinfected subjects compared with treated HCV- or HIV-monoinfected subjects. The degree of weight loss was also greater among the HIV/HCV cohort compared with both monoinfected cohorts. Body weights for HIV/HCV-coinfected and HCV-monoinfected subjects were stable before initiation of HCV therapy, but both cohorts lost weight after HCV treatment initiation, with the rate of weight loss being greater for dually treated subjects with HIV/HCV.
Our results provide controlled evidence confirming the suggestions of prior uncontrolled case series that reported a weight loss of ∼5 kg among patients with HIV/HCV during dual therapy. Garcia-Benayas et al10 reported a mean weight loss of 4 kg among patients with HIV/HCV (mean CD4 count = 573 cells/mm3, 100% on HAART) who completed 24 weeks of standard interferon plus ribavirin. Perez-Olmeda et al11 reported that 70% of subjects with HIV/HCV (mean CD4 count = 591 cells/mm3, 74% on HAART) receiving PEG-interferon α-2b plus ribavirin developed weight loss and that body weights declined an average of 4.6 kg after 24 weeks of HCV therapy. Moreno et al12 reported that 17% of patients with HIV/HCV (median CD4 count = 544 cells/mm3, 92% on HAART) developed weight loss exceeding 10 kg during 48 weeks of PEG-interferon α-2b plus ribavirin. None of these studies compared their results with those in treated HCV- or HIV-monoinfected patients, however.
Clinical observations have suggested that ribavirin might potentiate mitochondrial damage in subcutaneous adipose tissue when used concomitantly with other nucleoside analogues, leading to lipoatrophy and weight loss.10-12,18,20 To determine if nucleoside analogue use was associated with weight loss among dually treated patients with HIV/HCV, we examined NRTI type, number, and duration of use as well as ribavirin dose as risk factors. Receipt of more than 2 NRTIs increased the risk of weight loss, suggesting that mitochondrial toxicity might play some role in weight loss during dual HIV/HCV therapy. The type of NRTI and ribavirin dosage were not predictors of weight loss, however. Duration of NRTI use was also not associated with weight loss, suggesting that cumulative NRTI exposure before HCV therapy does not increase the risk of weight loss. Additional risk factors, such as anorexia, depression, and dietary changes, may be contributing to this adverse effect. Prospective studies investigating the metabolic toxicities of HCV therapy in patients with HIV should be performed and should examine these risk factors as well as changes in body composition to determine the precise mechanism for this weight loss.
The increased incidence of weight loss among dually treated HIV/HCV-coinfected patients has important clinical implications, particularly because longer durations of PEG-interferon plus ribavirin are being investigated to improve sustained virologic response rates.31,32 Because weight loss can be stigmatizing in the HIV population,33,34 its development among HIV/HCV-coinfected patients after the initiation of HCV therapy may prompt reduced adherence to PEG-interferon and/or ribavirin, decreasing the likelihood of a sustained virologic response. Awareness of substantial weight loss during dual HIV/HCV therapy could also represent a barrier to coinfected patients' willingness to initiate HCV treatment. Practitioners managing patients with HIV/HCV should therefore discuss the possibility of weight loss during dual therapy to prepare patients to cope with this adverse effect. Body weight in patients with HIV/HCV should be followed closely during HCV therapy. Because PEG-interferon α-2b and ribavirin are both dosed based on body weight, dose reduction of these medications may be required if body weight declines. The use of oral appetite stimulants should be considered to counteract weight loss. Dronabinol, in particular, promoted weight gain (median = 4.1 kg) in all subjects (n = 3) who were prescribed this medication. Additional studies should be performed to examine the efficacy of appetite stimulants in halting weight loss during HIV/HCV therapy.
Our study had several limitations. First, the retrospective design of the study did not allow all potential confounders to be collected and controlled for in analyses. In particular, depression and active use of alcohol and illicit drugs may not be routinely available in medical charts, and these variables may be associated with HIV and/or HCV and affect body weight. Second, body weights were recorded retrospectively from subjects' charts, and measurements were not performed in a standardized manner. Inaccuracies attributable to this lack of standardization would be nondifferential, however, and would bias results toward the null hypothesis. Because significant differences in the incidence and degree of weight loss were found, it is unlikely that this limitation meaningfully affected our results.
Our study demonstrates that the incidence and degree of clinically significant weight loss are greater in dually treated HIV/HCV-coinfected patients compared with treated HCV- and HIV-monoinfected patients. Future studies should examine changes in body composition, identify other potential risk factors for weight loss, and determine the role of appetite stimulants in preventing weight loss during dual HIV/HCV therapy.
The authors acknowledge the invaluable assistance that Kevin Haynes, PharmD, and Rose O'Flynn, PharmD, provided during the conduct of this study.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
hepatitis C virus; hepatitis C virus therapy; HIV; HIV/hepatitis C virus coinfection; weight loss