0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Age-Related Response to Interferon Alfa Treatment in Women vs Men With Chronic Hepatitis C Virus Infection FREE

Jun Hayashi, MD, PhD; Yasuhiro Kishihara, MD; Kumiko Ueno, MD; Kouzaburo Yamaji, MD; Yasunobu Kawakami, MD; Norihiro Furusyo, MD; Yasunori Sawayama, MD; Seizaburo Kashiwagi, MD, PhD
[+] Author Affiliations

From the Department of General Medicine, Kyushu University Hospital, Fukuoka, Japan.


Arch Intern Med. 1998;158(2):177-181. doi:10.1001/archinte.158.2.177.
Text Size: A A A
Published online

Background  Interferon alfa is used widely for patients with chronic hepatitis C virus (HCV) infection. Little is known, however, of the relationship between patients' sex and the effectiveness of interferon alfa treatment in these patients.

Methods  We treated 311 patients (199 men and 112 women) with human lymphoblastoid interferon (6 million units subcutaneously every day for 2 weeks and 3 times a week for 22 weeks) and observed them for an additional 6 months. Serum HCV RNA levels and genotype were tested by polymerase chain reaction before treatment. A liver biopsy was also done. For the purposes of this study, a complete response was defined as the elimination of HCV RNA for at least 6 months after the termination of treatment.

Results  The rate of complete response was 27.1% for men and 24.1% for women. With multiple logistic regression analysis, the HCV RNA level (P<.001), genotype (P<.001), patients' sex (P<.05), and the interaction between sex and age were associated with a complete response to interferon alfa. The rate of complete response was 33.3% in men aged 39 years and younger, 25.0% in men aged 40 years and older, 75.0% in women aged 39 years and younger, and 15.6% in women aged 40 years and older. The odds ratio by group was 1.00, 0.72, 4.38, and 0.21, respectively.

Conclusions  Our finding that women aged 39 years and younger are responsive to interferon alfa treatment suggests that hormonal activity, in particular the level of estrogen, may be associated with the sustained elimination of HCV.

Figures in this Article

PATIENTS WITH chronic hepatitis C virus (HCV) infection should receive careful treatment because they are at a high risk of developing hepatocellular carcinoma.1,2 Interferon alfa (IFN-α) reduces serum aminotransferase levels, improves histological activity,3,4 and eliminates HCV RNA in patients with chronic HCV infection,5,6 and its use is associated with a decreased incidence of hepatocellular carcinoma.7 It was previously reported that factors associated with the HCV infection itself are more important than patient characteristics for effective IFN-α treatment of patients with chronic HCV infection,6 and that the HCV RNA level and genotype were useful predictors of a complete response, results that were supported by other investigators.6,810

Little is known, however, of the relationship between patients' sex and the effectiveness of IFN-α treatment in patients with chronic HCV infection. The rate of response to IFN-α treatment by sex has been calculated in small-scale studies that found no significant differences between the sexes.8,10,11 It has conversely been shown that HCV appeared to be eliminated more commonly in women than in men, as men with antibodies to HCV tested positive for HCV RNA significantly more frequently than women. Similarly, among patients with HCV RNA, liver biochemical test results were less frequently abnormal in women than in men.12

In this study, we examined the relationship between the outcome of IFN-α treatment in 311 patients with chronic HCV infection categorized by sex and age who were treated with a 6-month course of natural IFN-α to clarify whether or not sex and age are predictive markers for the effectiveness of IFN-α treatment.

PATIENTS

We studied 311 Japanese patients (199 men and 112 women) with chronic HCV infection who were treated with IFN-α at Kyushu University Hospital, Fukuoka, Japan, from April 1, 1992, to March 31, 1995. Of these 311, 102 (32.8%) had a history of blood transfusion, but none had a history of alcohol or drug abuse or homosexuality. None of the women had estrogen replacement treatment. All patients had the antibody to HCV by the second-generation assay and did not have the hepatitis B surface antigen or the antibody to the human immunodeficiency virus. Before treatment, a liver biopsy was done for all patients. In all patients during the 6-month period, HCV RNA was detected before treatment. The HCV RNA of genotype 1b was found in 224 (72.0%), genotype 2a in 58 (18.6%), and genotype 2b in 29 (9.3%). The HCV RNA levels of serum RNA (logarithmic transformed copy numbers per 50 µL of serum) ranged from 2 to 7 copies per 50 µL.

METHODS

Paired blood specimens were obtained every 2 weeks during the treatment, every 4 weeks for at least 3 months before entry, and 6 months after the cessation of treatment. All serum specimens were separated and stored at −20°C until tested for antibody to HCV, HCV RNA, HCV RNA genotype, and HCV RNA levels. Antibodies to HCV (HCV EIA II, Abbott Laboratories, North Chicago, Ill)13 were examined using enzyme-linked immunosorbent assay. Assays for hepatitis B surface antigen and human immunodeficiency virus antibody were done using commercial serological tests.

TREATMENT REGIMEN

The patients were given subcutaneous injections of natural IFN-α (human lymphoblastoid interferon, Sumyferon, Sumitomo Co, Tokyo, Japan). A dose of 6 million units was given daily for the first 2 weeks, then 3 times a week for the next 22 weeks. The total dose given was 480 million units during a 24-week period. This schedule of IFN-α treatment is currently in wide use in Japan. Fully informed written consent was obtained from each patient, and the trials were approved by the Ethics Committee of Kyushu University Hospital.

DEFINITION OF RESPONSE TO IFN-α

In this study, a complete response was defined as negative results on HCV RNA tests by the end of the scheduled treatment and sustained negativity beyond 6 months; partial response as negative results on HCV RNA tests by the end of the scheduled treatment, but the virus reappeared during the 6-month follow-up; and no response when HCV RNA was not eliminated at any time during the observation period.

HCV RNA BY POLYMERASE CHAIN REACTION

Ribonucleic acid was extracted from 50 µL of serum by Sepa Gene RV (Sanko Junyaku, Tokyo, Japan), and complementary DNA was synthesized using random primers and reverse transcriptase (Super Script II; GIBCO BRL, Gaithersburg, Md). The HCV RNA was detected by 2-stage polymerase chain reaction (PCR) using primers from the 5‘-noncoding region of the HCV genome, as previously described.14

GENOTYPE OF HCV RNA

The HCV RNA genotype was determined by 2-stage PCR using universal and type-specific primers from the putative C gene of the HCV genome with a modification of the method of Okamoto et al15 and Hayashi et al.16 The genotype nomenclature was based on the system proposed by Simmonds et al.17

HCV RNA LEVEL BY COMPETITIVE PCR

The level of HCV RNA was determined by means of competitive PCR using a modification of the methods of Hayashi et al16 and Kato et al.18 By recombinant PCR, we obtained mutant HCV RNA with the Eco RI site in the 5‘-noncoding region. This mutant HCV complementary DNA fragment was cloned into the pGEM-4z vector, which is a cloning and transcription vector (Promega Corp, Madison, Wis). In vitro RNA transcription from Pvu II-digested pGEM-4z was done using T7RNA polymerase (Riboprobe Gemini System II; Promega Corp) according to the manufacturer's instructions. Primers and a probe were constructed for the 5‘-noncoding region. The amplified products were analyzed by electrophoresis after the digestion of mutant HCV RNA by Eco RI, mutant HCV RNA being demonstrated at 106 and 112 base pairs and HCV RNA from patients at 218 base pairs. The size of the PCR product for each patient was compared with that of the diluted mutant HCV RNA.

STATISTICAL ANALYSIS

Statistical analysis was performed using a commercially available software package (BMDP Statistical Software Inc, Los Angeles, Calif) for the IBM 3090 system computer.19 The BMDP 4F program (ie, 2-way and multiway frequency tables, measures of association, and the log-linear model)was used for the χ2 test with the Bonferroni correction for multiple comparison.

The BMDP program LR was used for the stepwise logistic regression analysis, which was done to evaluate the relationship between the clinical features and the proportion of patients with chronic HCV infection responding completely to IFN-α treatment. All categorical clinical features (ie, sex [male=0, female=1], age [≤39 years=0, ≥40 years=1], serum alanine aminotransferase level [≤99 IU/L=0, ≥100 IU/L=1], histological features [chronic persistent hepatitis=0, chronic active hepatitis=1, severe chronic active hepatitis=2, and cirrhosis=3], and HCV RNA genotype [1b=0, 2a=1, 2b=2]), were handled as dichotomous variables. Using this method, the most significant associated variable was entered into the model. After adjusting for that variable, the next most significant variable was added to the model. This procedure was continued until no more variables met the entry criteria. A P value of .05 or less was considered statistically significant.

Of 311 patients treated with natural IFN-α, 81 (26.0%) had a complete response, 123 (39.5%) had a partial response, and 107 (34.4%) had no response. Of 199 men, 54 (27.1%) had a complete response, 68 (34.2%) had a partial response, and 77 (38.7%) had no response; of 112 women, 27 (24.1%) had a complete response, 55 (49.1%) had a partial response, and 30 (26.8%) had no response. The frequency of a partial response was significantly higher in women than in men (P<.01), but the frequencies of a complete response and no response did not differ between the sexes (Table 1).

Table Graphic Jump LocationTable 1. Outcome of Interferon Alfa Treatment by Sex

To clarify the effectiveness of IFN-α treatment, properties of HCV and patient characteristics were compared based on sex (Table 2). No significant difference was found in the number of patients having a complete response by sex, based on pretreatment levels of alanine aminotransferase and histological features of the liver. Those who had a complete response included 37 (16.5%) of 224 patients with genotype 1b, 33 (56.9%) of 58 with genotype 2a, and 11 (37.9%) of 29 with genotype 2b. Significant differences were noted in the number of complete responses between genotypes 1b and 2a (P<.001) and between 1b and 2b (P<.01). No significant differences were noted in the number of patients with a complete response by sex and genotype. The frequency of a complete response was significantly higher in patients with HCV RNA levels of less than 4 by competitive PCR (65.1%) than in those with levels greater than 5 (16.1%) (P<.001). Of 144 patients with HCV RNA levels above 6, only 6.9% had a complete response. No significant difference was found, however, in the number of patients with a complete response by sex and HCV RNA level.

Table Graphic Jump LocationTable 2. Clinical Features of Patients With Chronic Hepatitis C Virus (HCV) Infection

To search for predictive factors that would influence the response to IFN-α treatment, we used multiple logistic regression analysis. The HCV RNA level (P<.001), genotype (P<.001), sex (P=.05), and interaction between sex and age were associated with a complete response to natural IFN-α. As the HCV RNA level decreased, there was a tendency for the probability of a complete response to increase. For patients with genotypes 2a and 2b, there was an increased probability of having a complete response. Moreover, a significant correlation was found when women were grouped by age (Table 3).

Table Graphic Jump LocationTable 3. Factors Contributing to Complete Response to Interferon-Alfa Treatment in Patients With Chronic Hepatitis C Virus (HCV) Infection: Results of a Stepwise Logistic Regression Analysis

In the men, the rate of complete response ranged from 20.0% to 47.4% for those younger than 60 years and decreased to 10.6% in those aged 60 years and older. A complete response in women ranged from 71.4% to 80.0% in those aged 39 years and younger, 25.0% in the 40- to 44-years age group, 16.7% to 18.2% in the 45- to 59-years age group, and 8.6% in those aged 60 years and older (Figure 1). The rate of complete response was significantly higher in women (80%) than in men (20%) in the 35- to 39-year-old group (P<.05), but there were no sex differences in other age groups. The rate of response to IFN-α treatment was remarkably decreased in women 40 years of age and older, but it did not decrease with aging in the men.

Place holder to copy figure label and caption

The rates of complete response to interferon alfa treatment in patients with chronic hepatitis C virus infection, based on sex and age. Closed circles indicate men; open circles, women; and asterisks, P<.05 when comparing women vs men.

Graphic Jump Location

The outcome of IFN-α treatment for these 311 patients based on sex and age is shown in Table 4. Patients were separated into 4 groups by sex and age: group 1 consisted of men younger than 40 years; group 2, men older than 40 years; group 3, women younger than 40 years; and group 4, women older than 40 years. The rate of complete response in each group was 33.3%, 25.0%, 75.0%, and 15.6%, respectively, significantly higher in group 3 than in groups 1 (P<.01), 2 (P<.001), and 4 (P<.001) and higher in group 1 than in group 4 (P<.05). The odds ratio of group 3 was 4 times that of group 1, 6 times that of group 2, and 20 times that of group 4.

Table Graphic Jump LocationTable 4. The Odds Ratio of a Complete Response to Interferon-Alfa Treatment in Patients With Chronic Hepatitis C Virus Infection by Sex and Age

In the present study of the effectiveness of IFN-α treatment for patients with chronic HCV infection, focused on patient's sex, we obtained evidence that age was associated with response to the treatment in women, but not in men. Although there was no significant male-female difference in the overall rate of complete response to IFN-α treatment, being a younger woman (<40 years) was a favorable marker for successful treatment. This study also confirmed that the HCV RNA genotype and the HCV RNA level are important factors of response to IFN-α treatment.6,810 To exclude bias, the relation between the outcome of treatment and patients' sex was investigated, based on these HCV markers.

Histological features are also useful predictive markers. In this study, the response rate was low in patients with advanced liver disease, especially in women. This is consistent with the results of multiple logistic regression analysis showing that older women had a low response because most patients with advanced liver disease were 40 years of age and older. The duration of hepatitis was not correlated with the response to IFN-α treatment in a previous study,6 but the relationship is difficult to determine because the onset of hepatitis is uncertain in many cases. Therefore, we excluded it and other factors such as a history of blood transfusion, antibody to c100 (which is the first-generation assay for antibody to HCV), and antibody to GOR (which is isolated from the plasma of a chimpanzee infected with a human non-A, non-B hepatitis agent) that did not correlate with the response to IFN-α treatment.6

In contrast to previous studies in which only the biochemical response was assessed, this study defined a complete response as a sustained return to normal serum aminotransferase levels and the disappearance of HCV RNA by PCR. Because serum aminotransferase levels return to normal in some patients, either during treatment or within 6 months, those with a complete response in the previous studies may have had HCV RNA in the serum and thus were at risk of the reactivation of chronic hepatitis C.20 Therefore, we defined a complete response as the elimination of HCV RNA from the serum that was sustained for 6 months after the cessation of IFN-α treatment. This study indicates that HCV RNA is more easily eliminated from younger women than older women.

The relationship between the response to IFN-α treatment and aging is controversial. Other investigators reported that older age was not an unfavorable marker for IFN-α treatment,21,22 whereas Garson et al23 reported that patients who had a complete response were significantly younger than those who had no response. Moreover, Horiike et al22 reported that elderly patients with a low level of HCV RNA respond well to IFN-α treatment. Their studies were done on a small series, and they defined a response to IFN-α treatment as the return of aminotransferase levels to normal after the cessation of treatment, with no attention given to the status of HCV RNA. We obtained clear findings that an older age (≥40 years) was one of the unfavorable markers of the elimination of HCV RNA from the serum of patients with chronic HCV infection.

Of interest was the finding that the response to IFN-α treatment was better in women than in men among patients younger than 40 years and that the response decreased remarkably in women aged 40 years and older. Why HCV appears to act differently in younger and older women, however, is unclear. During perimenopause (from age 40 years), ovulation can be erratic, and plasma gonadotropin levels frequently reach menopausal level, even when plasma estrogen levels are within the menstrual range.24,25 These data suggest that the decreased rate of a complete response to IFN-α treatment may correspond with decreases in estrogen levels. Interleukin 1, associated with an inflammatory response, is stimulated by low concentrations of estrogen and progesterone. A low concentration of estrogen allows peripheral blood monocytes to secrete more interleukin 1.26 The spontaneous production of interleukin 1β by peripheral mononuclear cells has been shown to be significantly higher in patients with chronic hepatitis C than in healthy control subjects, then decreased in those with a complete response after the administration of IFN-α.27 This cytokine production may alter the effectiveness of IFN-α treatment in perimenopausal and menopausal women with chronic HCV infection.

Because women do have a response to IFN-α treatment, as shown in Table 1, and in this study HCV RNA was eliminated during treatment more often in women than in men, hormonal activity, in particular the level of estrogen, may be associated with the sustained elimination of HCV in patients undergoing IFN-α treatment for HCV infection. Hormone levels should be measured before treatment. A pertinent subject for investigation would be the results of a combination of estrogen replacement therapy28 and IFN-α therapy for older women.

Accepted for publication May 29, 1997.

Reprints: Jun Hayashi, MD, PhD, Department of General Medicine, Kyushu University Hospital, Higashi-Ku, Fukuoka 812-82, Japan.

Bruix  JBarrera  JMCalbet  X  et al.  Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 1989;21004- 1006
Link to Article
Colombo  MKuo  GChoo  QL  et al.  Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet. 1989;21006- 1008
Link to Article
Davis  GLBalart  LASchiff  ER  et al.  Treatment of chronic hepatitis C with recombinant interferon alfa: a multi-center randomized, controlled trial. N Engl J Med. 1989;3211501- 1506
Link to Article
Di Bisceglie  AMMartin  PKassianides  C  et al.  Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med. 1989;3211506- 1510
Link to Article
Hagiwara  HHayashi  NMita  E  et al.  Detection of hepatitis C virus RNA in serum of patients with chronic hepatitis C treated with interferon-α. Hepatology. 1992;1537- 41
Link to Article
Hayashi  JOhmiya  MKishihara  Y  et al.  A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C. Am J Gastroenterol. 1994;892151- 2156
Nishiguchi  SKuroki  TNakatani  S  et al.  Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;3461051- 1055
Link to Article
Yoshioka  KKakumu  SWakita  T  et al.  Detection of hepatitis C virus by polymerase chain reaction and response to interferon-α therapy: relationship to genotypes of hepatitis C virus. Hepatology. 1992;16293- 299
Link to Article
Lau  JYDavis  GLKniffen  J  et al.  Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet. 1993;3411501- 1504
Link to Article
Suzuki  TTanaka  EMatsumoto  AUrushihara  ASodeyama  T Usefulness of simple assays for serum concentration of hepatitis C virus RNA and HCV genotype in predicting the response of patients with chronic hepatitis C to interferon α 2a therapy. J Med Virol. 1995;46162- 168
Link to Article
Tsubota  AChayama  KArase  Y  et al.  Factors useful in predicting the response to interferon therapy in chronic hepatitis C. J Gastroenterol Hepatol. 1993;8535- 539
Link to Article
Hayashi  JKishihara  YYamaji  K  et al.  Transmission of hepatitis C virus by health care workers in a rural area of Japan. Am J Gastroenterol. 1995;90794- 799
Hayashi  JNakashima  KKishihara  Y  et al.  Improved detection of antibodies to hepatitis C virus by the second-generation assay in patients with chronic non-A, non-B liver disease. J Infect. 1993;26287- 294
Link to Article
Choo  QLKuo  GWeiner  AJOverby  LRBradley  DWHoughton  M Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science. 1989;244359- 362
Link to Article
Okamoto  HSugiyama  YOkada  S  et al.  Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol. 1992;73673- 679
Link to Article
Hayashi  JYoshimura  EKishihara  Y  et al.  Hepatitis C virus RNA levels determined by branched DNA probe assay correlated with levels assessed using competitive PCR. Am J Gastroenterol. 1996;91314- 318
Link to Article
Simmonds  PAlberti  ABonino  F  et al.  A proposed system for the nomenclature for genotypes of hepatitis C virus. Hepatology. 1994;191321- 1324
Link to Article
Kato  NYokosuka  OHosoda  KIto  YOhto  MOmata  M Quantitation of hepatitis C virus by competitive reverse transcription-polymerase chain reaction: increase of the virus in advanced liver disease. Hepatology. 1993;1816- 20
Dixon  WJBrown  MBEngelman  LJennrich  RI BMDP Statistical Software Manual.  Berkeley University of California Press1990;
Chemello  LCavalletto  LCasarin  C  et al.  Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-alpha in chronic hepatitis C. Ann Intern Med. 1996;1241058- 1060
Link to Article
Bresci  GCorso  LDRomanelli  AMGiuliano  GPentimore  F The use of recombinant interferon alfa-2b in elderly patients with anti-HCV-positive chronic active hepatitis. J Am Geriatr Soc. 1993;41857- 862
Horiike  NMasumoto  TNakanishi  K  et al.  Interferon therapy for patients more than 60 years of age with chronic hepatitis C. J Gastroenterol Hepatol. 1995;10246- 249
Link to Article
Garson  JABrillanti  SWhitby  M  et al.  Analysis of clinical and virological factors associated with response to alpha interferon therapy in chronic hepatitis C. J Med Virol. 1995;45348- 353
Link to Article
Richardson  SJSenikas  VNelson  JF Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987;651231- 1237
Link to Article
MacNaughton  JBanah  MMcCloud  PHee  JBurger  H Age-related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol (Oxf). 1992;36339- 345
Link to Article
Polan  MLDaniele  AKuo  A Gonadal steroids modulate human monocyte interleukin-1 (IL-1) activity. Fertil Steril. 1988;49964- 968
Kishihara  YHayashi  JYoshimura  EYamaji  KNakashima  KKashiwagi  S IL-1β and TNF-α produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C. Dig Dis Sci. 1996;41315- 321
Link to Article
Salamone  LMPressman  ARSeeley  DGCauley  JA Estrogen replacement therapy: a survey of older women's attitudes. Arch Intern Med. 1996;1561293- 1297
Link to Article

Figures

Place holder to copy figure label and caption

The rates of complete response to interferon alfa treatment in patients with chronic hepatitis C virus infection, based on sex and age. Closed circles indicate men; open circles, women; and asterisks, P<.05 when comparing women vs men.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Outcome of Interferon Alfa Treatment by Sex
Table Graphic Jump LocationTable 2. Clinical Features of Patients With Chronic Hepatitis C Virus (HCV) Infection
Table Graphic Jump LocationTable 3. Factors Contributing to Complete Response to Interferon-Alfa Treatment in Patients With Chronic Hepatitis C Virus (HCV) Infection: Results of a Stepwise Logistic Regression Analysis
Table Graphic Jump LocationTable 4. The Odds Ratio of a Complete Response to Interferon-Alfa Treatment in Patients With Chronic Hepatitis C Virus Infection by Sex and Age

References

Bruix  JBarrera  JMCalbet  X  et al.  Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 1989;21004- 1006
Link to Article
Colombo  MKuo  GChoo  QL  et al.  Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet. 1989;21006- 1008
Link to Article
Davis  GLBalart  LASchiff  ER  et al.  Treatment of chronic hepatitis C with recombinant interferon alfa: a multi-center randomized, controlled trial. N Engl J Med. 1989;3211501- 1506
Link to Article
Di Bisceglie  AMMartin  PKassianides  C  et al.  Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med. 1989;3211506- 1510
Link to Article
Hagiwara  HHayashi  NMita  E  et al.  Detection of hepatitis C virus RNA in serum of patients with chronic hepatitis C treated with interferon-α. Hepatology. 1992;1537- 41
Link to Article
Hayashi  JOhmiya  MKishihara  Y  et al.  A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C. Am J Gastroenterol. 1994;892151- 2156
Nishiguchi  SKuroki  TNakatani  S  et al.  Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;3461051- 1055
Link to Article
Yoshioka  KKakumu  SWakita  T  et al.  Detection of hepatitis C virus by polymerase chain reaction and response to interferon-α therapy: relationship to genotypes of hepatitis C virus. Hepatology. 1992;16293- 299
Link to Article
Lau  JYDavis  GLKniffen  J  et al.  Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet. 1993;3411501- 1504
Link to Article
Suzuki  TTanaka  EMatsumoto  AUrushihara  ASodeyama  T Usefulness of simple assays for serum concentration of hepatitis C virus RNA and HCV genotype in predicting the response of patients with chronic hepatitis C to interferon α 2a therapy. J Med Virol. 1995;46162- 168
Link to Article
Tsubota  AChayama  KArase  Y  et al.  Factors useful in predicting the response to interferon therapy in chronic hepatitis C. J Gastroenterol Hepatol. 1993;8535- 539
Link to Article
Hayashi  JKishihara  YYamaji  K  et al.  Transmission of hepatitis C virus by health care workers in a rural area of Japan. Am J Gastroenterol. 1995;90794- 799
Hayashi  JNakashima  KKishihara  Y  et al.  Improved detection of antibodies to hepatitis C virus by the second-generation assay in patients with chronic non-A, non-B liver disease. J Infect. 1993;26287- 294
Link to Article
Choo  QLKuo  GWeiner  AJOverby  LRBradley  DWHoughton  M Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science. 1989;244359- 362
Link to Article
Okamoto  HSugiyama  YOkada  S  et al.  Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol. 1992;73673- 679
Link to Article
Hayashi  JYoshimura  EKishihara  Y  et al.  Hepatitis C virus RNA levels determined by branched DNA probe assay correlated with levels assessed using competitive PCR. Am J Gastroenterol. 1996;91314- 318
Link to Article
Simmonds  PAlberti  ABonino  F  et al.  A proposed system for the nomenclature for genotypes of hepatitis C virus. Hepatology. 1994;191321- 1324
Link to Article
Kato  NYokosuka  OHosoda  KIto  YOhto  MOmata  M Quantitation of hepatitis C virus by competitive reverse transcription-polymerase chain reaction: increase of the virus in advanced liver disease. Hepatology. 1993;1816- 20
Dixon  WJBrown  MBEngelman  LJennrich  RI BMDP Statistical Software Manual.  Berkeley University of California Press1990;
Chemello  LCavalletto  LCasarin  C  et al.  Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-alpha in chronic hepatitis C. Ann Intern Med. 1996;1241058- 1060
Link to Article
Bresci  GCorso  LDRomanelli  AMGiuliano  GPentimore  F The use of recombinant interferon alfa-2b in elderly patients with anti-HCV-positive chronic active hepatitis. J Am Geriatr Soc. 1993;41857- 862
Horiike  NMasumoto  TNakanishi  K  et al.  Interferon therapy for patients more than 60 years of age with chronic hepatitis C. J Gastroenterol Hepatol. 1995;10246- 249
Link to Article
Garson  JABrillanti  SWhitby  M  et al.  Analysis of clinical and virological factors associated with response to alpha interferon therapy in chronic hepatitis C. J Med Virol. 1995;45348- 353
Link to Article
Richardson  SJSenikas  VNelson  JF Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987;651231- 1237
Link to Article
MacNaughton  JBanah  MMcCloud  PHee  JBurger  H Age-related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol (Oxf). 1992;36339- 345
Link to Article
Polan  MLDaniele  AKuo  A Gonadal steroids modulate human monocyte interleukin-1 (IL-1) activity. Fertil Steril. 1988;49964- 968
Kishihara  YHayashi  JYoshimura  EYamaji  KNakashima  KKashiwagi  S IL-1β and TNF-α produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C. Dig Dis Sci. 1996;41315- 321
Link to Article
Salamone  LMPressman  ARSeeley  DGCauley  JA Estrogen replacement therapy: a survey of older women's attitudes. Arch Intern Med. 1996;1561293- 1297
Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 65

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles