Colleen Corcoran

Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

Effects of Androgen Administration in Men with the AIDS Wasting Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

The AIDS wasting syndrome is characterized by loss of lean body mass out of proportion to weight [1, 2]. The few effective treatments that have been identified are short-term pharmacologic agonists. Because loss of lean body mass is associated with decreased survival in men with the AIDS wasting syndrome [3], development of therapeutic strategies to increase lean body mass is of critical importance. Half of all men with AIDS are hypogonadal [4], and serum androgen levels correlate with lean body mass among hypogonadal men with the AIDS wasting syndrome [5]. Previous studies in non-HIV-infected hypogonadal men show that androgen administration has a significant anabolic effect on body composition [6-10]. We hypothesized that loss of the potent anabolic hormone testosterone in men with the AIDS wasting syndrome may contribute to the critical loss of lean body mass. Therefore, we investigated the effects of physiologic testosterone administration in men with the AIDS wasting syndrome. Methods Patients In 1995 and 1996, 51 HIV-positive men (42 8 years of age) were recruited from the multidisciplinary HIV practice at the Massachusetts General Hospital and from newspaper, television, and radio advertisements. Weight, testosterone levels, and medication history were determined at a screening assessment. To be included in the study, patients had to have decreased free testosterone levels, defined as less than 42 pmol/L at screening (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]), and wasting, defined as weight less than 90% of ideal body weight or involuntary weight loss greater than 10% of baseline weight [11]. The CD4 count was not an inclusion criterion. We excluded patients with severe diarrhea (>6 stools/d); hemoglobin value less than 5.0 mmol/L (<8 g/dL); platelet count less than 50 000 cells/mm3; creatinine concentration greater than 177 mol/L (>2 mg/dL); new opportunistic infection within 6 weeks of screening; use of testosterone, anabolic steroids, growth hormone, ketoconazole, or systemic steroid therapy within 3 months before screening; or history of prostate cancer. In addition, patients receiving antiretroviral agents, including protease inhibitors, were required to be receiving a stable regimen for at least 6 weeks before study entry. Ten patients were receiving long-term, stable therapy with megestrol acetate for at least 8 weeks before study entry and were equally distributed between the two treatment groups (5 in the testosterone group and 5 in the placebo group). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Patients were randomly assigned to receive testosterone enanthate, 300 mg (Bio-Technology General Corp., Iselin, New Jersey), or placebo intramuscularly every 3 weeks by self-injection. Participants were stratified for weight less than or greater than 90% of ideal body weight and megestrol acetate use before randomization. Randomization was performed by the Massachusetts General Hospital Pharmacy by using a permuted block algorithm. The correspondence between patient code number and drug was generated by the study statistician; this list was available to the hospital pharmacist but not to the investigators or patients. The placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. The study drug was bottled by the Massachusetts General Hospital Pharmacy in containers labeled with the study name, expiration date, and patient code. Before the first injection, participants returned within approximately 2 weeks of the screening visit for a 3-day baseline inpatient visit to the General Clinical Research Center at the Massachusetts General Hospital for hormonal, nutritional, immune function, and body composition analysis, which included assessment by dual-energy x-ray absorptiometry, bioimpedance analysis, potassium-4040 K) isotope analysis, and measurement of urinary creatinine excretion. No patient experienced the onset of a new opportunistic infection, other complication, or substantial weight change between the screening and baseline visits. Patients were instructed on the proper technique for intramuscular injection; those who were unable to self-administer the study drug received injections every 3 weeks from the nursing staff of the General Clinical Research Center. Patients returned for an outpatient visit at 3 months for assessment of weight and determination of total-body potassium content and for a 3-day inpatient visit at 6 months; this visit was identical to the baseline evaluation. Patients also reported on response to therapy at the 6-month visit. Baseline data from 26 patients have been reported elsewhere [5]. Subsequent study visits were timed to correspond to the midpoint between study drug injections. Study drug compliance was confirmed by history, medication diaries, outpatient injection records, empty vial counts, and serum testosterone levels. History of medication use was assessed at each visit. The change in fat-free mass assessed by dual-energy x-ray absorptiometry was the primary clinical end point; changes in weight, muscle mass, total body potassium content, and quality of life were secondary end points. Body Composition Analysis Body composition was determined by four methods: 1) dual-energy x-ray absorptiometry to assess fat and fat-free mass (Hologic-2000 densitometer, Hologic, Inc., Waltham, Massachusetts; precision error, 3% for fat and 1.5% for fat-free mass [12], 2) 40K isotope analysis to assess total-body potassium content in a whole-body counter with sodium iodide detectors fixed above and below the patient at the xiphoid level (Canberra Nuclear, Meriden, Connecticut; precision error < 2.5% on the basis of repeated calibration with a known potassium chloride source [Appendix]), 3) urinary creatinine excretion averaged over 3 days (during which the patient received a meat-free diet) multiplied by a constant of 18 kg of muscle per gram of urinary creatinine and indexed for height to determine the percentage of predicted muscle mass [13, 14], and 4) bioimpedance analysis to determine total-body water content (Bioelectrical Impedance Analyzer Model BIA-101, RJL Systems, Clinton Turnpike, Michigan; correlation with deuterium oxide equivalent to R = 0.99 [15]). Lean body mass was derived from total-body potassium content by using the Equation of Forbes and Lewis of 68.1 mEq of potassium per kg of lean body mass [16]. Nutritional Assessment Weight was measured on the first day of each visit after an overnight fast. The percentage of ideal body weight was calculated on the basis of standard height and weight tables [17]. Patients were instructed on completion of a 4-day food record, which was analyzed for total calorie, fat, protein, and carbohydrate content (Minnesota Nutrition Data Systems, version 8A/2.6, Minneapolis, Minnesota) by the Clinical Research Center dietitian. Patients received an isocaloric, meat-free, protein-substituted diet 3 days before and during the inpatient assessments at baseline and at 6 months, during which creatinine excretion and nitrogen balance were measured. Total urinary nitrogen excretion was measured by the Kjeldal technique from consecutive 24-hour collections averaged over 3 days. Nonurinary nitrogen losses were assumed to be constant at 4 g/d [13, 18, 19]. Nitrogen intake was derived from total protein intake divided by a constant of 6.25 g of protein per g of nitrogen [19]. Calorie and protein intake were monitored on a daily basis and were modified to match the reports in the outpatient food records immediately before these visits. Resting energy expenditure was measured by indirect calorimetry with a metabolic cart. Energy requirements were calculated by using the Harris-Benedict equation [20]. Patient Reports of Response to Therapy Each patients perceived well-being was assessed at the end of the study by using nine linear analogue-scale questions on the overall treatment effect, change in quality of life, personal appearance, weight, and appetite (Table 1) [21]. A Karnofsky score was also determined at each visit. Table 1. Assessment of Patient Response to Therapy* Exercise Functional Testing Exercise history was assessed by a standardized questionnaire adapted from the study by Kohl and coworkers [22]. Exercise functional status was determined at the baseline and final visits by the physical therapy department of the Massachusetts General Hospital by using the 6-minute walk test, the timed sit-to-stand test, and the timed get-up-and-go test [23-25]. The distance covered in 6 minutes, the number of times the patient was able to move from a sitting to standing position in 10 seconds, and the time to cover a distance of 3 meters after standing from a seated position was recorded for each patient. Biochemical and Immunologic Assays Hematocrit and serum levels of follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, and prolactin were measured at the baseline and final visits by using published methods [26]. Serum levels of total and free testosterone were measured by radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) with intra-assay coefficients of variation of 5% to 12% for total testosterone and 3.2% to 4.3% for free testosterone. CD4 cell counts were measured by flow cytometry (Becton Dickinson Immunocytochemistry Systems, San Jose, California). Viral burden was determined by using the Amplicor HIV-1 monitor test (Roche Molecular Systems, Branchburg, New Jersey). Statistical Analysis Sample size was based on the change in lean body mass in response to testosterone administration among adult men with acquired hypogonadism [8]. A change of 3.2% 4.0% was expected over 6 months. With 20 patients in each group, the study had an 80% chance of seeing an effect of testosterone at a two-sided

Effects of Testosterone and Progressive Resistance Training in Eugonadal Men with AIDS Wasting: A Randomized, Controlled Trial

Substantial loss of lean body and muscle mass occur among HIV-infected patients with relatively preserved body weight (1); these changes are associated with reduced functional status and strength (2). Protease inhibitor therapy has not been shown to increase muscle mass in patients with AIDS wasting (3), suggesting the need for successful anabolic strategies in these patients. Testosterone therapy and progressive resistance training increase lean body mass in hypogonadal men with AIDS wasting (4-6). However, most men with AIDS wasting have normal testosterone levels (7). We assessed the independent effects of progressive resistance training and testosterone in eugonadal men with AIDS wasting. Baseline (2) and screening data (7) from a subset of participants were previously reported. Methods Patients From 1997 to 1999, 54 HIV-infected men with AIDS-related wasting (weight<90% ideal body weight or self-reported weight loss>10%) and a normal serum level of free testosterone (>42 pmol/L) were recruited through community advertisements and contact with physicians in the multidisciplinary HIV practice at the Massachusetts General Hospital, Boston, Massachusetts, and other community clinics. Exclusion criteria were new opportunistic infection diagnosed within 6 weeks of the study; other contraindication to exercise; use of a new antiretroviral agent within 8 weeks of the study; abnormal prostate-specific antigen level; symptomatic prostatism; prostate malignancy; bipolar disorder; use of parenteral nutrition, megestrol acetate, glucocorticoids, androgen, estrogen, growth hormone or other anabolic agent within 3 months of the study; hemoglobin value less than 90 g/L or greater than 170 g/L; platelet count less than 50 000 cells/mm3; or serum creatinine concentration greater than 177 mol/L (2.0 mg/dL). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Eligible patients were stratified for weight less than 90% of ideal body weight or 90% or greater than ideal body weight. Using a 2 2 factorial design, we randomly assigned patients to receive intramuscular injections of testosterone enanthate (200 mg/wk; Bio-Technology General Corp., Iselin, New Jersey) or placebo and to progressive resistance training (three times per week) or no training for 12 weeks. The study statistician used a permuted-block algorithm with blocks of 8 to perform randomization; the code was available only to the hospital pharmacy that bottled the study drug. Placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. Compliance with drug therapy was confirmed by history, outpatient injection records, and vial counts. Patients assigned to training participated in supervised progressive strength training and aerobic conditioning three times per week for 12 weeks. During each session, patients began by performing 20 minutes of aerobic exercise on a stationary bicycle at a target heart rate of 60% to 70% of their age-predicted maximum, in accordance with American College of Sports Medicine recommendations (8). A cool-down period of 15 minutes and normalization of heart rate preceded resistance training. Training was performed isotonically on the following computerized equipment (Life Fitness, Franklin Park, Illinois): leg extension, leg curl, leg press, latissimus dorsi pull-down, arm curl, and triceps extension. A one-repetition maximum weight was established at baseline for each patient on each machine in the best of three efforts. Patients increased resistance as follows: weeks 1 and 2, 2 sets, 8 repetitions/set, 60% one-repetition maximum; weeks 3 through 6, 2 sets, 8 repetitions/set, 70% one-repetition maximum; weeks 7 through 12, 3 sets, 8 repetitions/set, 80% one-repetition maximum. Patients were asked to refrain from exercise for 2 weeks before the baseline visit and to refrain from any exercise or activity beyond normal daily activity during the study. Food intake was ad libitum; caloric intake was determined by using a 4-day food record (Nutrition Data System for Research, version 12A/2.91, Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota). Resting and predicted energy expenditure were calculated (VMAX 29N, SensorMedics, Inc., Loma Linda, California). Clinical End Points Clinical end points were assessed at baseline and 12 weeks. Lean body mass and fat mass were measured by using dual-energy x-ray absorptiometry (QDR-4500 Densitometer, Hologic, Inc., Waltham, Massachusetts) with a precision error of 1.5% for fat-free mass (9). Cross-sectional muscle areas of the leg and arm were assessed by performing computed tomography of the midfemur and humerus (General Electric High Speed Helical CAT Scanner, Milwaukee, Wisconsin; SE 3% for arm muscle area and 1% for leg muscle area). The location of the midfemur and humerus were determined from the scout image. Upper- and lower-extremity muscle strength were measured by using the quantitative muscle function test (10, 11). Peak isometric force of shoulder flexion, shoulder extension, elbow flexion, elbow extension, knee flexion, knee extension, dorsiflexion, and grip were measured on the best of two repetitions (10, 12). Z scores were calculated for upper- and lower-extremity strength (MVCT Computer Analysis Software, Boston, Massachusetts) by standardizing to a group of healthy male controls (11, 12). Serum levels of total and free testosterone were measured by using a radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) (4). CD4 cell counts were measured by using flow cytometry (Becton-Dickinson Immunocytochemistry Systems, San Jose, California); viral load was measured by using the Amplicor HIV-1 Monitor (Roche Molecular Systems, Branchburg, New Jersey). Other tests were done according to published methods (13). A digital prostate examination was performed at each visit. Statistical Analysis The effects of training and testosterone were simultaneously assessed in the same factorial model. In the primary analysis, we used analysis of covariance to assess change from baseline at 3 months simultaneously in the testosterone arm (testosterone recipients vs. placebo recipients) and the training arm (trained patients vs. nontrained patients), controlling for baseline values. To test for an interaction between testosterone and training, we used analysis of covariance with an interaction term. Change in lean body mass was the primary clinical end point for the effect of testosterone, and change in cross-sectional muscle area was the primary end point for the effect of resistance training. Change from baseline was also determined within each individual treatment group and was compared with zero change by using analysis of covariance. The t- test was used to compare treatment groups at baseline. All available data are included in the analysis. Results are reported as the mean SD. Results No patient withdrew from the study because of an adverse event or side effect; dropout rates did not differ by group (Appendix Figure). Patients had lost significant weight but were not severely ill or low weight at study entry (Table 1). Seventy-six percent of patients were receiving antiretroviral therapy and 72% were receiving highly active antiretroviral therapy. Seventy-six percent of patients had previously had an opportunistic infection. Appendix Figure. Flow of participants through the study. Table 1. Results of Factorial Analysis Changes in response to testosterone therapy and training are shown in Table 1. Lean body mass and muscle area increased significantly in response to training and testosterone therapy. Muscle strength on elbow flexion and shoulder extension and overall upper-extremity Z score increased in response to testosterone therapy. The change in muscle area correlated with the change in muscle strength (R =0.48; P =0.001 for mid-thigh muscle area and strength on knee extension). No interaction was found between testosterone therapy and training. Levels of high-density lipoprotein (HDL) cholesterol increased in response to training but decreased in response to testosterone therapy. Levels of total and free testosterone increased in response to testosterone therapy, and levels of gonadotropin and sex hormonebinding globulin decreased. Caloric intake did not change significantly between the groups. The CD4 count did not change significantly in response to training or testosterone therapy (P >0.2). Viral load decreased in testosterone-treated patients. Use of antiretroviral therapy did not change in any study group. Levels of aspartate aminotransferase or prostate-specific antigen did not change significantly (P >0.2). No patient developed new prostate nodules. Three patients developed breast tenderness or gynecomastia (two were receiving testosterone and one was receiving placebo). Compliance with the training program was 78% among patients who completed the study; compliance with testosterone therapy was 98%. Discussion Previous studies suggest that testosterone therapy, alone (4, 5) and in combination with resistance training, increases lean body mass in hypogonadal men with AIDS wasting (6). However, recent data indicate that androgen levels are normal in most HIV-infected men (7), and the independent effects of testosterone and supervised exercise in eugonadal men with AIDS wasting are not known. The patients in our study generally had normal body weight and a normal Karnofsky score but had lost substantial weight. Most patients had a history of opportunistic infection, and although they were not cachectic or malnourished, they had reduced muscle mass (2). Previous studies have shown that resistance training in combination with testosterone or anabolic steroid therapy increases lean body mass (6, 14, 15). In contrast, we found that training had a significant effect (increase of 2.3 kg) on lean bod

Comparison of overlapping peptide sets for detection of antiviral CD8 and CD4 T cell responses

Increasing efforts are directed towards the development of effective vaccines through induction of virus-specific T cell responses. Although emerging data indicate a significant role of these cells in determining viral set point in infections such as HIV, there is as yet no consensus as to the best methods for assaying the breadth of these responses. In this study, we used sensitive interferon gamma-based intracellular cytokine staining (ICS) and Elispot assays to determine the optimal overlapping peptide set to screen for these responses. Twenty persons with established HIV infection were studied, focusing on responses to the highly immunogenic Nef protein. Six different HIV-1 Nef peptide sets were used, ranging in length from 15 to 20 amino acids (aa), in overlap from 10 to 11 amino acids, and derived from two different B clade sequences. A total of 54 CD8 T cell responses to Nef peptides were found in this cohort, of which only 12 were detected using previously defined Nef optimal epitopes. No single peptide set detected all responses. Though there was a trend of the shorter peptides detecting more CD8 T cell responses than the 20 amino acid long peptides and longer peptides detecting more CD4 T cell responses, neither was statistically significant. There was no difference between an overlap of 10 or 11 amino acids. All responses detected with the six different sets of overlapping peptides were towards the more highly conserved regions of Nef. We conclude that peptides ranging from 15 to 20 amino acids yield similar results in IFN-gamma-based Elispot and ICS assays, and that all are likely to underestimate the true breadth of responses to a given reference strain of virus.

Prevalence of Hypogonadism among Men with Weight Loss Related to Human Immunodeficiency Virus Infection Who Were Receiving Highly Active Antiretroviral Therapy

Previous studies have indicated that there is a significant prevalence (50%) of hypogonadism among men with acquired immunodeficiency syndrome (AIDS)-associated wasting, and for these patients testosterone administration has been shown to increase lean body mass and improve quality of life. However, the prevalence of hypogonadism is not known among men with weight loss related to human immunodeficiency virus (HIV) infection who are receiving highly active antiretroviral therapy (HAART). From 1997 through 1999, we investigated total and free testosterone levels in 90 men who were <90% of ideal body weight or had weight loss of >10% from preillness weight; 71% of these subjects were receiving HAART. Twenty-one percent of the subjects receiving HAART had low free testosterone levels. No correlation was seen between weight, CD4 cell count, medication status, and other clinical factors. These data suggest that hypogonadism remains relatively common in men with AIDS wasting, despite treatment with HAART. HIV-infected men with wasting syndrome should be screened for hypogonadism and receive physiological androgen replacement therapy if they are hypogonadal.

Isolated antibody to hepatitis B core antigen in human immunodeficiency virus type-1-infected individuals.

We screened 651 human immunodeficiency virus (HIV)-1-infected subjects for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBs). Of a total of 387 subjects who tested negative for both HBsAg and anti-HBs, 142 underwent further testing for isolated presence of antibody to hepatitis B core antigen (anti-HBc). Of these 142 subjects, 60 (42%) tested positive for anti-HBc (isolated anti-HBc). Individuals coinfected with HIV-1 and hepatitis C virus (HCV) were more likely to have isolated anti-HBc than were subjects with HIV-1 alone (80% vs. 16%, respectively). Our findings suggest that individuals with HIV-1/HCV coinfection for whom there is no serological evidence for hepatitis B virus when screened with HBsAg and anti-HBs will be positive for anti-HBc in >75% of cases. A screening strategy that tests only for HBsAg and anti-HBs in HIV-1-infected patients will miss a large number of individuals with isolated anti-HBc.

Sustained Anabolic Effects of Long-Term Androgen Administration in Men with AIDS Wasting

Fifty-one human immunodeficiency virus-positive men with hypogonadism and wasting were randomized to receive testosterone enanthate, 300 mg i.m. every 3 weeks, or placebo for 6 months, followed by open-label testosterone administration for 6 months. Subjects initially randomized to placebo gained lean body mass (LBM) only after crossover to testosterone administration (mean change +/- standard error of the mean, -0.6 +/- 0.7 kg [months 0-6] vs. 1.9 +/- 0.7 kg [months 6-12]; P = .03). In contrast, subjects initially randomized to testosterone continued to gain LBM during open-label administration (2.0 +/- 0.7 kg [months 0-6] vs. 1.6 +/- 0.6 kg [months 6-12]; P = .62) and had gained more LBM at 1 year than did subjects receiving testosterone for only the final 6 months of the study (3.7 +/- 0.8 kg vs. 1.0 +/- 1.0 kg; P = .05). Testosterone administration results in sustained increases in LBM during 1 year of therapy in hypogonadal men with AIDS wasting.

Antiretroviral Drug Resistance Mutations in Antiretroviral-Naive Prisoners

We assessed the incidence of antiretroviral drug resistance in a cohort of 25 antiretroviral-naive, human immunodeficiency virus-positive inmates in Massachusetts. Silent mutations, unexpected mutations at resistant sites, and resistance mutations were recorded. Among these inmates, we found a prevalence of drug resistance mutations that was equivalent to the prevalence previously found in nonprison populations in the same state.

The Use of Testosterone in the AIDS Wasting Syndrome

AIDS wasting syndrome (AWS) is a complication of advanced HIV disease characterized by loss of lean body mass. The loss of endogenous anabolic hormones, such as testosterone, is thought to contribute to muscle loss. Studies have shown that more than half of male AIDS patients have low testosterone levels, and increased AIDS severity is correlated with increases in the presence of hypogonadism. Hypogonadism among HIV-infected patients is marked by decreased muscle mass and functional capacity, fatigue, and reduced quality of life. Recently, a 6-month randomized, placebo-controlled trial was conducted on the effects of administering testosterone intramuscularly to hypogonadal HIV-infected men. Patients receiving testosterone experienced significant increases in muscle and lean body mass as well as improved quality of life, appearance, and well being. A 6-month open label extension confirmed a sustained anabolic effect. As an alternative to intramuscular injection, transdermal patches are now available, offering similar benefits and more stable testosterone levels. Transdermal testosterone studies have been initiated in women as well, with promising results. Synthetic testosterone analogues, such as Oxandrolone and nandrolone decanoate, also have been studied in AWS patients. Trials of both resulted in significant weight gain at certain doses, but also demonstrated a significant risk of liver damage. Other anabolic agents are also under investigation.

Neuropsychiatric Changes in HIV/Hepatitis C Coinfected Patients Undergoing Interferon Therapy

A large percentage of HIV-infected patients are coinfected with hepatitis C virus (HCV). Current treatment available for HCV combines interferon and ribavirin therapy for 6 months or longer. Interferon is associated with numerous neuropsychiatric side effects including depression, cognitive impairment, anxiety, and irritability. The potential for developing depression is particularly concerning with coinfection because the incidence of depression is higher in the HIV-seropositive population than in the general population. This article discusses the mechanism and prevalence of interferon-induced depression and the debate regarding appropriateness of treatment in certain segments of the HIV population. The role of antidepressants as both treatment and a prophylaxis against interferon-related depression is reviewed. Nurses have a critical role in the care of HIV/HCV coinfected patients who are undergoing treatment with interferon and ribavirin. They both assess for treatment readiness prior to initiation and provide close monitoring for the development of neuropsychiatric disturbances while on therapy.