Q J Med 1999; 92: 433-441
© 1999 Association of Physicians
Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia
From the Departments of Medicine, 1 Virology, and 2 Pathology, National Hospital, Oslo, Norway
Received 5 May 1999 and in revised form 2 June 1999
Dr K. Bjøro, Department of Medicine A, National Hospital, 0027 Oslo, Norway
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Summary |
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The clinical course of HCV infection in patients with primary hypogammaglobulinaemia appears to be more severe than in immunocompetent patients. We studied the long-term course of chronic HCV infection in 20 Norwegian hypogammaglobulinaemia patients with a 13–15 year known history of HCV infection. Twelve of 20 patients developed cirrhosis during the observation period (1984–1999), and the remaining eight also had chronic liver disease verified by liver biopsy in the majority of the cases. Eleven of the 20 patients are dead. Two died following liver transplantation for HCV cirrhosis. Five died due to terminal liver failure without receiving a liver allograft. Two patients died from other causes, but with advanced liver disease contributing to the outcome, while two deaths were unrelated to the HCV infection. Among patients with common variable immunodeficiency (CVI), five out of six are dead. Two patients cleared the hepatitis C virus 3 years following interferon monotherapy, while three patients achieved a sustained response to combination therapy with interferon and ribavirin. Viral load did not seem to have a major impact on disease progression. Our results emphasize the severity of hepatitis C virus infection in patients with hypogammaglobulinaemia. Patients with CVI appear to have the poorest prognosis.
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Introduction |
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Chronic hepatitis C virus (HCV) infection among patients with primary hypogammaglobulinaemia due to contaminated intravenous immunoglobulin preparations has been documented by several authors.1–4 While the clinical course of chronic HCV infection in immunocompetent patients is slowly progressive in most cases,5,6 HCV infection in patients with hypogammaglobulinaemia has been reported by several authors, including ourselves, to be more rapidly progressive.2,3,7,8 However, other studies have found the course of HCV infection in hypogammaglobulinaemia to be relatively favourable, at least on a short-term basis.9–11 Patients with common variable immunodeficiency, the predominant type of primary hypogammaglobulinaemia, may be especially susceptible to a rapid disease progression.3
We here report a 15-year follow-up of a well characterized group of patients with primary hypogammaglobulinaemia infected with hepatitis C virus. All patients were followed closely for the entire period, and factors which might affect outcome have been analysed. The results of combination treatment with interferon and ribavirin in seven of the patients are also reported. In immunocompetent patients with HCV infection, combination therapy with interferon and ribavirin increases the response rate,12,13 but the results of this therapeutic approach have not previously been reported in patients with primary hypogammaglobulinaemia and chronic HCV infection.
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Methods |
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Patients
A total of 20 HCV-RNA-positive patients were included in the study. These were selected from 93 patients with primary hypogammaglobulinaemia followed at the Section of Clinical Immunology and Infectious Diseases, Department of Medicine, The National Hospital, Oslo. The diagnosis of primary hypogammaglobulinaemia was based on established criteria14,15 and patients were classified as described elsewhere.16 In the larger patient group there were seven patients with X-linked agammaglobulinaemia (Bruton's type), 58 with common variable immunodeficiency (CVI) and two patients with the hyper-IgM syndrome (HIM). Twenty-six patients had been classified as congenital hypogammaglobulinaemia (CH). This group includes patients with clinical manifestations before the age of 2 years, but with no known cases in the family suggesting an X-linked inheritance. We have introduced the term congenital hypogammaglobulinaemia group to enable us to relate our findings to more precise diagnostic groups, and particularly to avoid inclusion of XLA cases without family history in the CVI group, since results of analysis of Btk mutations are not available.3,16 Genetic confirmation of the HIM diagnosis has not been performed, but the patients' phenotypes and immunological findings confirmed the diagnosis. Circulating B-cells have been measured in all patients to support the classification of patients. None of the CVI patients had affected first-degree relatives.
The majority of the patients had IgG levels below 2.0 g/l before IgG substitution therapy was initiated. The median age of the patients at the last follow-up was 44 years (range 14–76 years) and there were 54 males and 39 females. Among the HCV-RNA-positive patients there were five with XLA, six with CVI, six with CH and two with HIM. There were 16 males and four females among the HCV-RNA-positive patients.
All patients were seen regularly, at least twice a year, at the Section of Immunology and Infectious Diseases, Medical Department, The National Hospital. On each clinical visit, a complete biochemical liver status was obtained, including liver enzymes (alanine aminotransferase—ALT, alkaline phosphatase—ALP and gamma glutamine transpeptidase—GGT), bilirubin, albumin and coagulation factors. All patients with verified chronic HCV infection were examined by ultrasound of the abdomen, and in most patients a CT-scan of the abdomen was also performed. Liver biopsies were done when clinically indicated.
Two of the HCV-RNA-positive patients had a history of intravenous drug abuse (IVDA) (during the last 10 years and for both patients after contracting their HCV infection). Two patients had tattoos and two patients had a history of packed blood cells transfusion. One of the patients with a period of IVDA also had a high consumption of alcohol; all other patients have had a moderate or very low intake of alcohol.
Exposure to contaminated immunoglobulin
Of the 93 patients, 24 had received a HCV-contaminated intravenous immunoglobulin preparation (Gammonativ, KabiVitrum) during the period 1984–1986. We have previously demonstrated a very strong association between exposure to Gammonativ and HCV RNA positivity.3
Blood samples
Blood samples (serum) from all 93 patients were tested for HCV RNA by PCR methodology in the first blood sample available. When a blood sample from a patient was found to be HCV-RNA-positive, two blood samples obtained more than 6 months after the first sample, were tested if available. Testing for HCV RNA was always performed in blood samples obtained prior to any form of antiviral therapy. The lower limit of detection for the HCV RNA PCR method was 200 genome equivalents per ml. In the majority of the patients (81/93), blood samples from 1988–1994 have been tested. All patients positive in one sample were followed with yearly HCV RNA examination. In patients negative in two samples obtained at least 6 months apart and who were without signs of liver disease, no further HCV RNA examination was performed. HCV-RNA-negative patients with signs of liver disease have in most cases had regular (every second year) HCV RNA examinations. Quantification of viral load was performed in the first available blood sample in 18/20 HCV-RNA-positive patients. In six HCV-RNA-positive patients, three additional blood samples obtained over a period of 4 years prior to any antiviral therapy were examined for viral load to detect any spontaneous variations in this parameter. In two patients, blood samples were not available for viral quantification or genotyping.
Virology
HCV RNA was detected by PCR as described previously.3 Viral load was measured by bDNA (Quantiplex 2.0, Chiron). The lower limit of detection for the bDNA method was 0.2x106 genome equivalents per ml. Genotyping was performed in a single blood sample from each patient obtained prior to any antiviral treatment (Inno-Lipa, Innogenetics).
Blood samples from 89 patients were available for HGV RNA analysis, which used a PCR method, GBV-C Lcx (Abbott), with primers from the 5' non-coding region of the genome.17 These samples were also collected prior to any antiviral treatment.
As a control group for viral load, samples obtained prior to any treatment from 30 HCV patients, with no other known disease and with normal immunoglobulin levels, were examined. The genotype distribution among these patients was: genotype 1a/1b, 12 patients; genotype 2b, 7 patients; and genotype 3a, 11 patients. These patients had a median time from contracting HCV infection of 18 years (range 8–28 years).
Antiviral treatment
As reported previously,3 10 of the patients were treated with recombinant alpha interferon 2b for 6–12 months (Introna, Schering Plough) in 1989–1992. None of these patients achieved a sustained virological response. Seven patients (of whom five had been treated with interferon as monotherapy) were treated with recombinant alpha interferon 2b 3 MIU thrice weekly (Introna, Schering Plough) and ribavirin (Virazole, ICN Pharmaceuticals) 1000 or 1200 mg daily according to weight <75 kg or >75 kg, respectively, for 6 months in 1996. Blood samples obtained at start of therapy, after 3 months of therapy, at end of therapy and 6, 12 and 24 months following cessation of therapy were examined for HCV RNA both qualitatively and quantitatively. The study was approved by the local ethics committee.
Statistics
Comparison of variables was performed using the Yates' corrected 
2 test or Mann-Whitney U test where appropriate. Calculations were performed using Statistica, version 4.5 for Windows. For all tests a p value <0.05 was considered significant.
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Results |
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HCV RNA, genotypes and viral load
Twenty patients (21.5%) were HCV-RNA-positive, all testing positive in at least three different blood samples obtained over a period of more than 18 months in 1988–1994. Blood samples for HCV genotyping were available from 18 of these 20 patients. Genotype 3a was found in 17 patients and genotype 1a in one patient—the only patient who had not received Gammonativ.
Viral load prior to any antiviral treatment was measured in 18 patients, with mean and median values 7.8 and 6.1x106 genome equivalents/ml, respectively (range 0.2–22.0). In four patients, viral load was <0.2x106 genome equivalents/ml, while four patients had levels of HCV RNA
10x106 genome equivalents/ml. The control group had very similar mean and median values of viral load of 8.4 and 5.2x106 genome equivalents/ml, respectively (range <0.2–48). The viral load among control patients with genotype 3a did not differ from that of the whole control group.
In six HCV-RNA-positive patients with primary hypogammaglobulinaemia from whom serial blood samples obtained prior to antiviral treatment were available, viral load was stable over 4 years, with less than 50% variation between samples. In two of these cases viral load was measured over a time during which the liver disease progressed from a clinically and histologically relatively mild type to severe liver disease with cirrhosis.
There was no significant correlation between patient age and viral load (p=0.34). Patients with advanced liver disease tended to have higher viral load, but one patient with cirrhosis and liver failure had low levels of HCV RNA (<0.2x106 genome equivalents/ml) as determined by bDNA. There were no differences in viral load between the different types of primary hypogammaglobulinaemia (see Table 2
). The viral loads listed in Table 1 are those measured in the first available blood samples from each patient. In most cases this was obtained prior to development of cirrhosis. Those patients who later developed cirrhosis tended to have higher viral loads than those with milder liver disease, median value 9.0 vs. 4.4x106 genome equivalents/ml. Viral load varied, however, considerably among patients who did or did not develop cirrhosis, and the differences were not statistically significant. The duration of HCV infection (time from contracting HCV infection to viral load assessment) was not associated with the viral load measured in different blood samples.
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Only two patients were both HGV-RNA- and HCV-RNA-positive, one of whom died due to bacterial meningitis while the other has only mild liver disease. Two patients were HGV-RNA-positive but HCV-RNA-negative.
Liver function tests
All HCV-RNA-positive patients with primary hypogammaglobulinaemia developed biochemical signs of liver disease. As described previously,3 only a minority of the patients developed an acute hepatitis following exposure to the HCV-contaminated immune globulin. Most patients (18/20) have had continuously elevated ALT levels when not treated with interferon or interferon/ribavirin.
Clinical course
All 20 HCV-RNA-positive patients were followed until death, or if alive, until 1 April 1999. Complete patient data are listed in Table 1
. The survival curve of the patient population is given in Figure 1. A total of 11 patients died during the observation period. Five deaths were directly caused by terminal liver failure, without a liver transplantation. Two patients died from causes unrelated to liver disease (bacterial meningitis and suicide respectively). Two patients who died from renal failure and septicaemia, respectively, also had advanced liver disease which probably contributed to the fatal outcome. Two patients have received liver allografts due to HCV cirrhosis. One of these died 18 months after liver transplantation for HCV cirrhosis, due to aggressive recurrent HCV infection. The other patient who received a liver allograft died 5 weeks following the transplantation due to a brain abscess with Aspergillus fumigatus.
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Mortality among CVI patients was very high (Table 2
) (five out of six patients died). The CVI patients were older at the time of contracting HCV infection than patients with other types of hypogammaglobulinaemia, with mean age 34 years vs. 17.5 years among the other patients. When comparing the age (at contracting HCV infection) of patients developing advanced liver disease (patients 2, 3, 4, 6, 8, 11, 16, 18, 20 in Table 1) with those who have not developed cirrhosis (patients 1, 7, 9, 10, 13, 14, 15, 17, 19), the difference in age was not statistically significant (p=0.09). Patients 5 and 12 were excluded from the analysis as they both died from non-liver-related causes prior to developing cirrhosis. Liver biopsy was done in 17/20 patients (first biopsy obtained median 8.5 years, range 4–14 years following contracting the HCV infection). Two patients were not biopsied due to severe bleeding disorders while one refused biopsy. In seven patients, the first biopsy revealed histological signs of cirrhosis. The time from first exposure to the contaminated immunoglobulin to histological or clinical signs of cirrhosis was mean 8.8 years, range 4.5–15 years.
Twelve patients developed cirrhosis during the observation period. In ten it was confirmed by biopsy or autopsy, while in two cases CT, ultrasound examination and clinical signs were all strongly indicative of cirrhosis. One of these patients died of septicaemia with clinical signs of advanced liver failure (autopsy refused). In the other case a liver biopsy was not obtained due to severe thrombocytopenia.
None of the patients developed focal liver lesions suggestive of malignancy, and alpha fetoprotein values remained normal in all patients.
Previous interferon treatment
As reported previously,3 10 patients were treated with interferon monotherapy in 1989–1992. None of these patients achieved a sustained viral response (HCV-RNA negativity) at 6 months follow-up. One patient became HCV-RNA-negative during treatment, but committed suicide after 3 months of interferon treatment.
Interferon/ribavirin treatment
Four out of seven patients treated with interferon and ribavirin completed the 6 months course with only minor or moderate side-effects. Dose reduction of interferon was necessary in one patient due to influenza-like symptoms, and of ribavirin in another patient due to severe haemolysis (decline in haemoglobin levels >4 g/dl). One patient terminated the treatment of both drugs himself after 2 months due to extreme fatigue.
In six patients, ALT levels normalized within 4 weeks of the start of treatment. During treatment, five patients became HCV-RNA-negative; one patient was negative at 1 month of treatment while the other four became HCV-RNA-negative after 1–3 months of treatment. All five were also HCV-RNA-negative at end of treatment. HCV RNA became negative (qualitative method) during therapy in six patients. Three patients had a sustained virological response, being HCV-RNA-negative with normal ALT levels at 6, 12 and 24 months after end of treatment. Two of these three sustained responders had previously had an unsustained response to interferon monotherapy. Two of the sustained responders had low levels of HCV RNA prior to therapy (being HCV-RNA-positive with HCV RNA levels <0.2 and 0.8x106 genome equivalents/ml by bDNA, respectively), while the third sustained responder had relatively high pre-treatment HCV RNA level (13.0x106 genome equivalents/ml). Viral load prior to treatment in the four patients who did not have a sustained response, ranged from 6.5 to 10.5x106 genome equivalents/ml). Patients who were HCV-RNA-positive at the end of treatment and/or at 12 months following also had increased ALT levels at these time-points. The patient who stopped treatment after 2 months, had a complete and sustained response, both virologically and biochemically. Patients relapsing, both virologically and biochemically, had levels of HCV RNA after termination of treatment comparable to that observed prior to treatment.
Patients alive today
Of the nine patients alive today, five are HCV-RNA-negative and have normal ALT levels; three following interferon/ribavirin therapy and two who became HCV-RNA-negative >3 years following interferon monotherapy. The remaining four patients who are HCV-RNA-positive have moderately elevated ALT levels, in the range 60–300 U/l (reference ranges <45 and <35 U/l for men and females, respectively). Two of these have signs of progressive and severe liver disease (patients 14 and 17) while two have only moderately severe liver disease (patients 10 and 15).
The patients (1 and 13) who became HCV-RNA-negative late after interferon monotherapy and who have remained so for more than 4 years, were both HCV-RNA-positive in multiple blood samples (4 and 5 samples, respectively) obtained during the period 1988–1992 and were both non-responders to interferon monotherapy in 1990–1991. They were HCV-RNA-positive at end of treatment, and at regular follow-up intervals for more than 3 years before, they became HCV-RNA-negative, without any further treatment or clinical events, in 1994. They have both remained HCV-RNA-negative in multiple samples obtained during 1994–1999. The viral load prior to interferon treatment in these two patients was low. The `spontaneous' clearance of HCV RNA was accompanied by normalization of ALT levels. In one of these patients, a liver biopsy obtained prior to the spontaneous conversion to HCV RNA negativity demonstrated liver cirrhosis. Her clinical condition has been stable during the last 3 years, without signs of disease progression as evaluated by liver function tests, ultrasound examination and a CT scan. The other patient who `spontaneously' became HCV-RNA-negative has a mild liver disease and no signs of progressive liver disease today. Follow-up biopsies (1999) from these two patients did not reveal any histological progression.
Follow-up biopsies (1999) were obtained from another five patients who were alive as of 1 April 1999. In two patients who were HCV-RNA- negative (patients 7 and 17), no further histological progression was observed. Of three HCV-RNA-positive patients, one had developed histological changes compatible with cirrhosis (patient 14) while two had relatively mild inflammatory changes (patients 10 and 15).
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Discussion |
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Five years ago we described the prevalence of HCV infection (18 cases) in a relatively large group of Norwegian patients with primary hypogammaglobulinaemia.3 We have documented that these patients were infected during the period 1984–1986 and we therefore know the duration of HCV infection in these patients accurately. Our patient group is now slightly expanded, as we here present data on 20 patients with primary hypogammaglobulinaemia and chronic HCV infection. In this paper we report a very poor long-term outcome, with a mortality of >50% during the observation period of 15 years. The majority of our patients were relatively young when exposed to the contaminated immunoglobulin. Most of the deaths among these patients can be directly ascribed to the chronic HCV infection. This development of HCV infection and liver disease is far more serious than that observed among HCV-infected immunocompetent patients.5,6 It is difficult to estimate the average survival time of HCV infected immunocompetent patients because precise time of infection often is unknown. The risk of developing cirrhosis has been estimated to be in the range of 10–30% within 15–20 years.18–20 The 5-year risk of decompensation among immunocompetent patients with HCV cirrhosis has been estimated at 18%.21 Thus, the mortality from HCV infection among immunocompetent patients during the first 20 years after infection is low, probably far less than 10%.
The particular type of hypogammaglobulinaemia may seem to be of importance for the development of significant and severe clinical liver disease, as nearly all patients with common variable immunodeficiency (CVI) have done extremely poorly during the observation period. These patients were, however, generally older at the time of contracting the infection. The mortality among the XLA-patients is also high. Our number of patients is too small to permit any definite conclusions concerning independence of type of hypogammaglobulinaemia and age. We have recently reported that patients with CVI are more prone to develop non-B, non-C hepatobiliary disease than patients with other types of hypogammaglobulinaemia.22 One might therefore speculate that additional presence of various types of hepatobiliary disease might thus have accelerated the course of the HCV infection in these patients, similar to the accelerating effect of alcohol on the progression of HCV disease.23 Recent reports, by Morris et al.24 and ourselves22 have not demonstrated any aetiological significance of hepatitis G virus (HGV) infection among primary hypogammaglobulinaemia patients with liver disease. None of our HCV-infected patients had signs of granulomatous liver disease which has been described in patients with primary hypogammaglobulinaemia.22,25
A possible correlation between viral load and rapidity of disease progression has been seen in other severe viral diseases, e.g. infection with human immunodeficiency virus (HIV) and infection with cytomegalovirus (CMV).26–29 Among our patients there was a trend towards higher viral load among patients with more advanced liver disease, but the difference was not statistically significant and the viral load among our hypogammaglobulinaemia patients was not higher than that observed among a control group of immunocompetent HCV patients. Thus, viral load does not seem to be of major importance in disease progression in these patients.
In our previous report,3 several of the patients were found to be infected with more than one HCV genotype. The method used for genotyping in the present study detects the dominating genotype in serum and does not reveal HCV genotypes present at much lower concentrations. Genotype 3a (Simmonds) is the same genotype we found in all patients tested previously: genotype V according to Okamoto. Patients with HCV genotype 3a have been considered to have a relatively favourable prognosis in immunocompetent patients.30 There is, however, some dispute on the significance of HCV genotype on disease progression in chronic HCV infection.31
Two patients became HCV-RNA-negative >3 years following interferon monotherapy. Among 24 patients in our material known to have been exposed to Gammonativ, only five were HCV-RNA-negative and without signs of liver disease when tested approximately 5–6 years following the exposure. The clearance rate of HCV among patients with primary hypogammaglobulinaemia appears therefore to be very low.
Treatment with recombinant interferon alpha alone did not have any beneficial effect on HCV infection in our patient population.3 The more favourable effect reported in some other studies of HCV infection and hypogammaglobulinaemia9 may be due to lower viral load, HCV genotype and, in particular, to shorter time from contraction of disease to treatment. Combination treatment with interferon and ribavirin has been reported to increase the response rate in chronic HCV infection.12,13 No data on such treatment in HCV infected patients with hypogammaglobulinaemia have to our knowledge been reported. Our results with this treatment are promising, as 3/7 of our patients had a sustained virological response, being HCV-RNA-negative 12 months or more after end of treatment.
The data presented here emphasize the severity of chronic HCV infection in patients with hypogammaglobulinaemia. During the observation period of 15 years, the mortality among our patients has been considerable. High priority should be given to detecting and treating such patients with interferon and ribavirin as early as possible after infection.
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Acknowledgments |
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Bjørg-Guri Gutigaard and Bodil Lunden provided excellent technical assistance.
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References |
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