SHORT REPORT

Hepatitis C infection is not associated with systemic HIV-associated

non-hodgkin’s lymphoma: A cohort study

Laura Waters1, Justin Stebbing2, Sundhiya Mandalia1, Anne Marie Young2, Mark Nelson1, Brian Gazzard1 and Mark Bower2,*1Department of HIV Medicine, The Chelsea and Westminster Hospital, London, United Kingdom2Department of Oncology, The Chelsea and Westminster Hospital, London, United Kingdom

Immunosuppression induced by the human immunodeficiencyvirus (HIV) increases the risk of developing non-Hodgkin’s lym-phoma (NHL). As the hepatitis C virus (HCV) has been implicatedin the development of B cell lymphomas, we compared the inci-dence of systemic NHL during HIV infection compared to HIVand HCV co-infection. Of 5,832 individuals studied during the eraof highly active anti-retroviral therapy (HAART), 102 patientswere diagnosed with systemic NHL. The incidence of systemicNHL was 6.9 of 104 patient years during HIV infection comparedto 7.1 of 10

4patient years during HIV alone (p ¼ 0.9). In this

immunocompromised patient population, there was no associationbetween HCV infection and an increased risk of lymphoma.' 2005 Wiley-Liss, Inc.

Key words: hepatitis C; HIV; non-Hodgkin’s lymphoma

The use of HAART has resulted in marked declines in HIV-related morbidity and mortality, by mainly reducing the incidenceof opportunistic infections1 High grade B-cell non-Hodgkin’s lym-phoma (NHL) is an AIDS defining illness, having first beendescribed in association with HIV in the early 1980s.2 NHL occursat a greatly increased frequency in HIV-infected populations anddespite a reduction in its incidence during the HAART era, itremains the second commonest AIDS defining malignancy afterKaposi’s sarcoma.3–7

Many of the 200 million individuals infected with HCV andthe 50 million individuals infected with HIV are co-infectedwith both viruses.8–10 As well as shared routes of transmission,there are many interactions between these small RNA viruses inwhich infection is often characterised by parenteral transmissionfollowed by a seroconversion illness and then a long latentperiod lasting many years.11 Once established, HIV-1 infectionseems to increase the persistence of the hepatitis C virus, thelevel of HCV RNA and progression of HCV-related disease.12–16

There are conflicting reports concerning whether HCV infectionalters the course of HIV.17 Some studies before the advent ofhighly active anti-retroviral therapy (HAART) suggested that sur-vival and progression to AIDS were the same in patients withHCV/HIV co-infection as in those with HIV alone18,19 whereasothers suggested an adverse effect.13,20 In the pre-HAART era,HCV infection was deemed an irrelevance as it was HIV thataffected morbidity and mortality. With the increased life expect-ancy of individuals with HIV, however, HCV has emerged as aproblem that adversely affects survival of individuals withHIV.8,16,21

HCV is a well-established risk factor in the etiology of hepato-cellular carcinomas and of mixed cryoglobulinemia Type II, acondition that can evolve to malignant lymphoma in 8–10% ofaffected cases.22 In the non-HIV setting, data from case–case com-parisons and case–control studies indicate several-fold higherprevalence of HCV infection (as indicated by the presence of anti-bodies or HCV RNA) among B cell lymphoma patients comparedto control populations.23 Attempts have been made to evaluateany relationship between HCV co-infection and the risk of HIVassociated lymphoma. Only small cohort studies have been pub-lished previously in this setting and these demonstrate no relationbetween dual infection by HIV and HCV and subsequentincreased risk of lymphoma.24,25 Using prospectively collected

cohort data from a single centre we have compared the risk ofHIV-positive individuals developing NHL, comparing mono-infected individuals to those co-infected with HCV.

Material and methods

HIV-positive patients at the Chelsea and Westminster cohortare seen at regular intervals for clinical assessment, trial follow-upand immunologic assessments. All HIV patients who haveattended the Chelsea and Westminster since routine prospectivedata collection commenced in 1989 were identified and we havedefined HAART as therapy consisting of at least 3 antiretroviraldrugs in accordance with published guidelines (dual nucleosideanalogues alone are not considered HAART).26–28 Our studyfocuses on a cohort that has continued to be followed-up since theHAART era began. We have defined this as 1 January 1996 whenHAART became routinely available at our institution (and others).Since 1998, staged HCV antibody testing has been introducedusing the Abbot IMX system (Maidenhead, UK). This has been inroutine clinical use for all new HIV-1 positive individuals since2003.

To compare mono-infected (HIV-1 alone) with co-infected(HIV-1/HCV) individuals and risk of lymphoma, person years atrisk (PYAR) was estimated from entry into the cohort to either (i)end of study period, (ii) the development of NHL, (iii) the lastrecorded visit or (iv) if the patient had died during their follow upthen their death date. To keep the coefficient of the PYAR con-stant, this was log transformed and used as the offset in the Pois-son regression. The data were analysed using the Genmodprocedure in SAS version 8.0 with loge link and Poisson error dis-tributions. This fits generalized linear models allowing timedependent measures of probability; all p-values presented are 2-sided. All of the cases of AIDS-related NHL were biopsy-provenand primary central nervous system lymphomas were excludedfrom the analysis.

Results

A total of 5,832 patients were eligible for analysis, representing34,133 patient-years of follow-up were collected. A total of 3,642(62.4%) patients from the cohort were tested for anti-HCV anti-bodies and of these 362 (9.9%) were HCV seropositive. There wasno difference in the rate of testing between the patients who devel-oped NHL and those who did not (�2, p ¼ 0.31).

During the HAART era, 102 individuals were diagnosed withsystemic NHL representing 682 years at risk. The lymphomaswere high Grade B cell NHL in 98 cases and 20 of these 98 werediagnosed with Burkitt’s lymphoma. Three patients had high

*Correspondence to: Department of Oncology, Chelsea and West-minster Hospital, 369 Fulham Road, London SW10 9NH, UK.Fax: þ44-208-746-8863. E-mail: m.bower@imperial.ac.ukReceived 25 November 2004; Accepted after revision 21 December

2004DOI 10.1002/ijc.20988Published online 8 March 2005 in Wiley InterScience (www.interscience.

wiley.com).

Int. J. Cancer: 116, 161–163 (2005)' 2005 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

grade T cell lymphomas and one had a natural killer/T cell lym-phoma. Of these 102 individuals, 63 were tested for HCV. Ofthese 63 cases, 7 (11%) were positive for HCV. By comparison,355 of 3,586 (9.9%) HIV infected patients who did not developNHL were seropositive for HCV. There was no statistically signif-icant difference between the HCV seropositivity rate betweenpatients with NHL and those without (�2, p ¼ 0.75, Table I).

The number of cases of NHL in the HCV seropositive groupwas 7 of 362 (1.9%) as compared to 56 of 3,287 (1.7%) in theHCV seronegative population. A further 2,183 patients were nottested for HCV serology and 39 (1.8%) of these patients devel-oped NHL.

The incidence of systemic NHL was calculated in all 3 groupsand was found to be 6.9 of 104, 7.1 of 104 and 7.5 of 104 patientyears for the HCV positive, HCV negative and untested groupsrespectively. The time adjusted rate ratios for NHL in the 3 groupsshowed no statistically significant differences (Table II).

Discussion

We demonstrate no association between HCV infection and sys-temic NHL in the largest cohort of HIV-1 positive individuals inEurope. The epidemiological link between HCV and NHL is con-troversial and most data originates from retrospective case–controlstudies and meta-analyses based on such results. One meta-analy-sis of 48 published studies that including 5,542 patients with NHLshowed that mean HCV seroprevalence in patients with NHL was13% (95% confidence interval [CI] ¼ 12–14%), and was highest inItaly (20%) and Japan (14%). Ten studies compared HCV preva-lence in B-cell NHL (17%) and healthy controls (1.5%) (odds ratio[OR] ¼ 10.8; 95% CI ¼ 7.4–16). Thus patients with NHL were 3and 4 times as likely to be HCV-infected than healthy controls andindividuals with other haematological malignancies respectively.29

Although we did not demonstrate any increase in NHL rates inthe HCV/HIV co-infected compared to the HIV mono-infectedindividuals in our cohort, this may in part, be due to the low num-bers of cases involved, for example only 7 individuals in the co-infected group developed NHL. HIV significantly increases NHL

risk30 but the impact of HCV is probably much smaller, thereforea far larger study would be needed to detect any difference inNHL rates.

As mentioned, the clinical data on whether HCV infection altersthe natural history of HIV infection are conflicting. From a largecohort of HIV-infected individuals in Switzerland, Greub et al.31

reported that HCV seropositivity increased the likelihood of pro-gression to a new AIDS-defining clinical event or death with amedian of 28 months of follow-up. This decrease in survival did notseem to be due to a reduced responsiveness of patients with co-infection to HAART because there was no association betweenHCV seropositivity and probability of reaching an HIV RNA levelbelow 400 copies/mL. The increase in CD4 cell count in response toantiretroviral therapy did seem to be less in patients with HCVinfection than in those with HIV alone, however. Interestingly, theauthors hypothesised that HCV could have a direct pathogenic effecton lymphocytes, impairing the recovery of HIV-related immunefunction with antiretroviral therapy, thus explaining the progressionto AIDS and the delay in CD4 cell count recovery in patients withHCV. Other recent studies have reported similarly compromisedCD4 cell responsiveness in HIV-HCV infected individuals despiteHIV RNA suppression. Supporting this, HCV replication in lym-phoid cells has been shown in HIV-1 positive patients.32

More recently, Sulkowski et al.33 showed no difference in therisk of death or in the risk of developing a new AIDS-defining ill-ness in patients with and without HCV. Survival was reduced inHCV-infected patients with baseline CD4 cell counts from50 cells/mm3 through 200 cells/mm3. This difference was not sus-tained in a multivariate model that included an adjustment forHAART. Patients with HCV infection had an increased but nonsignificant likelihood of progression to a CD4 cell count below200 cells/mm3; this association between CD4 cell count and HCVinfection was not demonstrated in a multivariate regression analy-sis. This clinical cohort study suggests no affect on disease pro-gression and our data presented demonstrates no effect of HCV onNHL incidence.

An association between lymphoma and a number of oncogenicviruses is well-established for retroviruses (human T-call lym-photrophic virus 1 [HTLV1] and HIV) and � herpesviridae (Kaposi’ssarcoma-associated herpesvirus [KSHV] and Epstein-Barr virus).34–36

HCV is well established in the aetiopathogenesis of hepatocellularcarcinoma although it is intriguing that liver cancers do notseem to occur significantly more commonly in HIV infected indi-viduals, even in those with advanced immunosuppression.37–39 It istempting to speculate that non-retroviral RNA viruses such asHCV lack the mechanisms required to induce carcinogenesis in thesetting of HIV though this may be a function of premature death insuch individuals. The genomes of the � herpesviridae are largeand encode cellular homologues of growth factors and oncogenesand as such, have well described mechanisms to induce carcino-genesis.

Support for the potential role of HCV in lymphomagenesisderives from observations that effective HCV treatment has beenparalleled by reduction of detectable lymphocytes with thet(14;18) translocation40 and regression of rare cases of splenicmarginal zone lymphoma have been described after successfultreatment of HCV infection.41 Our data, however, do not support arole of HCV in the development of HIV-associated systemicAIDS-related NHL.

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TABLE II – THE INCIDENCE AND RATE RATIOS OF SYSTEMICNON-HODGKIN’S LYMPHOMA (NHL) FOR PATIENTS TESTED

SEROPOSITIVE, SERONEGATIVE OR UNTESTED FOR HEPATITIS C(HCV) INFECTION

No.patients

NHLcasesno (%)

NHL/10,000patientyears

Rateratio

95%CI

p-Value

HCVþ 362 7(1.9) 6.9 0.97 0.44–2.12 0.936HCV� 3287 56(1.7) 7.1 1 — —Not tested 2183 39(1.8) 7.5 1.06 0.71–1.60 0.771

TABLE I – HEPATITIS C (HCV) SEROPREVALENCE IN PATIENTSWHO DID AND DID NOT DEVELOP HIV-ASSOCIATED SYSTEMIC

NON-HODGKIN’S LYMPHOMA (NHL)

NHL No NHL

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162 WATERS ET AL.

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163HCV AND NHL