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Increased incidence of cancer observed in HIV/hepatitis C virus-coinfected patients versus HIV-monoinfected

Meijide, Héctora,b; Pértega, Soniac; Rodríguez-Osorio, Iriaa; Castro-Iglesias, Ángelesa; Baliñas, Josefaa; Rodríguez-Martínez, Guillermod; Mena, Álvaroa,*; Poveda, Evaa,*

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doi: 10.1097/QAD.0000000000001448

Abstract

Introduction

Antiretroviral therapy (ART) has improved the survival of people living with HIV (PLWH), leading to a growing interest in the epidemiology of chronic illnesses, such as cardiovascular diseases or malignancies [1–7]. Cancer incidence in PLWH is expected to increase because of advances in treatment, demographic changes, immune dysfunction/reconstitution, aging, and continuous exposure to carcinogens [8–11]. Despite a decline of AIDS-defining cancers (ADCs), the risk of the most frequent non-AIDS-defining cancers (NADCs) remains higher than in the general population [12–14].

Globally, hepatitis C virus (HCV) coinfection is common among PLWH; in high-income countries, about 30% of PLWH are coinfected with HCV [15]. Liver disease progression is faster in HIV/HCV-coinfected patients than in HCV-monoinfected [16], and HCV is an increasingly frequent cause of death among PLWH. At the diagnosis of hepatocellular carcinoma (HCC), PLWH are younger and more frequently symptomatic with advanced tumors than HIV-negative patients [17]. With the improvement and the globalization of ART, the incidence of HCC has increased steadily in PLWH, driven primarily by HCV infection.

Regardless of the HIV infection, around 15% of cancer cases worldwide are attributable to infectious agents [18]. In addition to HCC, HCV infection has also been associated with an increased risk of developing many other nonliver cancers, with a higher incidence, mortality and a younger age at diagnosis and death than the general population [19,20]. Non-HIV-infected patients with chronic HCV infection have two- to three-fold increased risk of non-Hodgkin lymphoma (NHL) compared with the HCV-negative population [21,22].

There are few studies analyzing the impact of chronic HCV infection in PLWH, in terms of malignancy development and mortality [23,24]. The aim of this study is to analyze the incidence of cancer in PLWH infected and noninfected with HCV and determine the additional cancer risk in comparison to the general population.

Methods

Data collection

All PLWH older than 18 years and above at Complexo Hospitalario Universitario de A Coruña (CHUAC) between 1993 and 2014 were included in the cohort. Chronic HCV coinfection was defined by the presence of a measurable viral load by PCR, without acute hepatitis. Epidemiological, demographic, clinical, immunovirological data were recorded. Chronic hepatitis B virus (HBV) infection was defined by the presence of positive hepatitis B surface antigen for more than 6 months. Patients in care were defined as at least two visits to the outpatient clinic and a measure of CD4+ cell count. Loss of care was defined by the nonappearance for reasons other than death.

All cancers in PLWH were obtained through the hospital-coding department. The method of selection was based on the review of the medical records of patients recognized by the encoding unit with a previous diagnosis of HIV infection and cancer. Malignancies registered during the follow-up in the clinical record were also included. Cancers were classified into two groups: ADC and NADC. Second malignancy was defined as the appearance, simultaneously or not, of a different tumor with malignant histology and the possibility of metastasis due to the first cancer was excluded. The end of the observation period was determined by date of cancer diagnosis, death or last follow-up visit for patients lost to follow-up, whichever occurred first. Patients with cancer were followed until their last regular clinical visit, death or lost to follow-up, to analyze the development of second malignancies.

Patients who are diagnosed of HCV infection during the follow-up contributed in person-years to the HIV-monoinfected group from HIV diagnosis to HCV diagnosis and to the HIV/HCV-coinfected group after. In coinfected patients who received anti-HCV treatment, the follow-up was censored when achieved sustained viral response (if applicable).

Ethical considerations

The research protocol was reviewed and approved by the regional ethics committee (register code 2015/164). All clinical data were anonymized and de-identified prior to analysis and the identification numbers of the patients were blinded.

Statistical analyses

A descriptive analysis was performed for all the variables recorded. Quantitative variables are reported as mean ± SD or median (interquartile range). Qualitative variables are expressed as frequencies and percentages.

A comparison of HIV-monoinfected and HIV/HCV-coinfected patients was performed and the percentages were compared using the χ2 test. Quantitative parameters were compared by means of Student's t test.

Cancer incidence rates were estimated for both ADC and NADC. Crude incidence rates were expressed as the number of cases per 100 000 person-years of follow-up, and the follow-up was determined from the date of HIV diagnosis to the end of the observation period. Cancer incidence rates in this cohort were then compared with that observed in the Spanish general population, computing the standardized incidence ratios (SIRs) for coinfection groups and their 95% confidence intervals, with the Byar's approximation of Poisson model. Age-SIRs were also determined for each group using the age strata of the reference population. For this purpose, cancer incidence data published for Spain in the GLOBOCAN 2012 statistics were used [25]. A comparison of mortality outcomes between the coinfection groups was evaluated using the χ2 test. Logistic regression analyses were also performed to predict the death rate after 1 year.

A competing risk approach was used to estimate the probability of cancer at different time points in the follow-up after HIV diagnosis. Death before cancer was considered a competing risk event. The death-adjusted cumulative incidence for the marginal probability of cancer was obtained and the cumulative incidences in the competing risk data were compared using the modified log-rank test [26].

To compare the subdistribution hazard ratios (SHRs) for cancer occurrence between HIV-monoinfected and HIV/HCV-coinfected patients, multivariable analyses were conducted using modified Cox regression hazard models [27]. This analysis has been carried out for both ADC and NADC (all cancers and excluding HCC).

Data management and analyses were performed using SPSS, version 19.0 for Windows (IBM Corp., Armonk, New York, USA). The cumulative incidence in competing risk analyses was calculated using the cmprsk package of R (Gray B. cmprsk: subdistribution analysis of competing risks. Available from http://cran.r-project.org/web/packages/cmprsk/index.html. Accessed 2 February 2016). P < 0.05 (two-sided) was considered statistically significant.

Results

A total of 2318 patients were included in the cohort, of which, 1461 (63.0%) were HIV-monoinfected patients and 857 (37.0%) were HIV/HCV-coinfected. The prevalence of chronic HBV infection was 2.6% in the first group and 6.4% in the second. One hundred and forty-nine (17.4%) coinfected patients received anti-HCV therapy (all with interferon based regimens); of these, 71 (47.6%) achieved sustained viral response. The main characteristics of the cohort population are shown in Table 1.

Table 1
Table 1:
Baseline characteristics and comparison between HIV-monoinfected patients and HIV/ hepatitis C virus-coinfected patients.

Cancer incidence rate and comparison with general population

In the study, the number of person-years at risk was 27 086, with an average of 11.7 ± 7.4 years per patient. A total of 185 patients (117 HIV-monoinfected and 68 HIV/HCV-coinfected) had at least one malignancy during follow-up, with an overall incidence rate of 696.0 cases per 100 000 person-years of follow-up (829.1 in HIV-monoinfected patients and 545.4 in HIV/HCV-coinfected patients). Crude incidence rates for ADC and NADC in HIV-monoinfected patients and HIV-HCV-coinfected patients are presented in Table 2.

Table 2
Table 2:
Observed cancers among the HIV-infected patients as compared to the general population (GLOBOCAN 2012).

After computing age-standardized rates, a statistically significant increased incidence rate was observed for all types of cancer when compared with the incidence in general population (SIR = 3.8; 95% CI: 3.3–4.4). HIV/HCV-coinfected patients, in comparison to HIV-monoinfected, showed a higher SIR for NADC and a lower SIR for ADC (Table 2). For all age groups, a higher cancer incidence was observed in comparison to the general population, reaching statistically significance for groups between 18 and 64 years (Fig. 1). Monoinfected HIV patients showed higher incidence rates for groups between 18 and 44 years, whereas HIV/HVC-coinfected patients showed higher incidence for ages between 45 and 64 years. The 5.13% of HIV-monoinfected and 0.58% of HIV/HCV-coinfected patients of the cohort was older than 64 years (at the end of follow-up or cancer diagnosis); eight cancers were found in this age group (all in monoinfected) (Fig. 1).

Fig. 1
Fig. 1:
Age-specific incidence rates of cancer in HIV-monoinfected and HIV/hepatitis C virus (HCV)-coinfected patients, comparatively with that in the general population (GLOBOCAN 2012).

The study period has been divided into two (1993–2003 and 2004–2014) and the crude incidence of ADC and NADC is shown in Table 2. The crude incidence of ADC in HIV-monoinfected patients was much higher during the first period (682.6 cases per 100 000 person-years) than in the second (282.3 cases per 100 000 person-years). Conversely, the incidence in coinfected patients was lower during the first period than in the second (61.2 versus 196.1 cases per 100 000 person-years).

At HIV diagnosis, patients with NADC were older (36.6 ± 11.7 years) than those with ADC (35.3 ± 13.1 years) and those without cancer (31.9 ± 9.7), P < 0.001. At cancer diagnosis, patients with NADC were also older (47.8 ± 10.4 years) than those with ADC (40.0 ± 11.9 years), P < 0.001.

Cancer location

The description of the location of all cancers is included in Table S1, http://links.lww.com/QAD/B57. The NHL was the most common cancer (26.5%), the majority of them (90.2%) were B-cell high-grade lymphomas. Comparatively with the general population the SIR of NHL in HIV-monoinfected patients was SIR = 19.1 (95% CI: 12.1–40.7) and in HIV/HCV-coinfected patients was SIR = 12.2 (6.1–20.7). The 82.9% of NHL in HIV-monoinfected were diagnosed between 1993 and 2003, whereas in the coinfected group most of the NHL was diagnosed between 2004 and 2014 (78.6%). The NHL was diagnosed 0.5 years (0–2.6) after HIV diagnosis in monoinfected patients and 7.8 years (2.1–10.4) in coinfected patients, P < 0.001. The time of ART exposure was also much shorter in monoinfected than in coinfected patients [1.0 years (0–2.4) versus 6.2 (2.4–8.2), P < 0.001]. The incidence of Hodgkin lymphoma (HL) was higher than for the general population in monoinfected patients (SIR = 16.1; 95% CI: 5.0–51.3) and in coinfected patients (SIR = 21.7; 6.7–67.9).

Lung cancer (LC) is the most incident NADC. The main histological type of LC was adenocarcinoma (60.0% of the cases) and most LC was diagnosed in advanced stages (78.0% in stage III or IV). The incidence was higher than in the general population for both groups: HIV-monoinfected patients (SIR = 4.2; 2.8–6.5) and HIV/HCV-coinfected patients (SIR = 4.1; 2.7–6.3). All HCC (18 cases) appeared in HIV/HCV-coinfected patients, with the majority of being cirrhotic (94.4%). The SIR in coinfected was SIR = 24.0 (10.6–54.3).

Cumulative incidence of cancer in the follow-up

Figure 2 shows the cumulative incidence of ADCs and NADCs at different time points in the follow-up after HIV diagnosis. Globally, the cumulative incidence of cancer reached 3.5% (95% CI: 2.7–4.2%) at 5 years after HIV diagnosis and 6.4% (5.4–7.4%) at 10 years. The probability for a PLWH of being alive and cancer-free at the same time points was 88.8% and 79.3%, respectively. The 10 and 20 years cumulative incidence of ADC was 3.8% and 4.3% in monoinfected patients and 1.1% and 1.7% in coinfected patients. On the contrary, the cumulative incidence of NADC was 2.3% (10 years) and 3.6% (20 years) in monoinfected, in coinfected patients was 1.9% and 4.8%, respectively.

Fig. 2
Fig. 2:
Competing risk analysis of AIDS-defining and non AIDS-defining cancer incidence in the follow-up after diagnosis of HIV patients.

During the follow-up, ADCs were less frequent in HIV/HCV-coinfected patients than in HIV-monoinfected patients. On the contrary, no differences were observed in the incidence rate of NADC between coinfected and monoinfected patients. However, after adjusting for age at HIV diagnosis, sex and transmission route, a higher cumulative incidence of NADC was observed for HIV/HCV-coinfected patients when compared with HIV-monoinfected patients (adjusted SHR = 1.80; 95% CI: 1.15–2.81). After excluding the HCC, the cumulative incidence of NADC remains higher in coinfected patients (adjusted SHR = 1.26; 1.02–1.94) (Table 3).

Table 3
Table 3:
Cumulative incidence of cancer in HIV-monoinfected and HIV/hepatitis C virus-coinfected patients.

Cancer prognosis

Seven (3.8%) patients developed a second neoplasia; five of them had ADCs as their first cancer [four Kaposi's sarcoma (KS) and one NHL] and two NADCs (HL and prostate). Regarding the second tumor, six of seven were NADCs and the median time from the first to the second malignancy was 6.0 years (3.2–12.5).

In the mortality analysis, 124 patients (64.6% of patients with ADC and 68.9% with NADC) died after cancer diagnosis, with a median survival of 6 months (0–14). One-year mortality was 39.2% in ADCs (95% CI: 28.8–50.1) and 53.8% in NADCs (44.3–63.0), with an odds ratio = 1.8 (1.0–3.3) and P = 0.055. The comparison of mortality between HIV-mono and HIV/HCV-coinfected patients is shown in Table 1.

Discussion

In 2318 PLWH followed for 26 580 person-years, 8.0% of patients developed at least one cancer. This is in accordance with other previously published data, such as a large French study of 99,817 PLWH followed for 18 years in which 7.7% presented with at least one tumor [13], or the recently published data from the Veterans Aging Cohort Study (VACS) from North America, in which the 7.8% of the PLWH developed at least one cancer [28]. In our cohort, PLWH has double risk of developing a NADC than the general population, after adjustment for sex and age.

The analysis revealed a higher incidence of ADC in HIV-monoinfected than in coinfected patients. KS accounted for approximately 50% of ADC in HIV-monoinfected patients (41.3%), but only 12.5% of the ADC in coinfected patients. KS affects mainly to MSM, and the proportion of MSM in the coinfected group was lower in our cohort. KS is frequently an early manifestation of HIV infection, sometimes the first one; in this study, some coinfected patients were diagnosed with HCV infection months or years after HIV infection, and they were considered monoinfected up to the HCV-coinfection diagnosis. Active drugs users had less access to the health system during the 1990s; this could also contribute to the lower incidence of ADC in coinfected versus monoinfected patients during the first period (1993–2003).

The timing of cancer incidence after HIV diagnosis differed between ADC and NADC, being much shorter in ADC as shown previously [12]. However, in this study, we found that HIV/HCV-coinfected patients developed both ADC and NADC significantly later than HIV-monoinfected patients. Coinfected patients were mostly IDUs, with a higher mortality due to other reasons (violence, substance abuse, etc.), which could compete with the risk of early cancer development.

The competing risk analysis showed that, after adjusting for age at HIV diagnosis, sex transmission route and considering death without cancer a competitive risk; coinfected patients had a higher cumulative incidence of NADC than HIV-monoinfected. The weight of HCC in the incidence of NADC in the coinfected group is unquestionable but, when the HCC is excluded from the analysis, the cumulative incidence of NADC remains significantly higher in coinfected than in monoinfected patients (adjusted SHR = 1.26). HCV infection appears to have a role in cancer incidence and mortality and a higher incidence of lung, digestive tract and kidney cancers in HCV-infected patients has been reported previously. The molecular mechanism is unknown, but extrahepatic manifestation of hepatitis C with a chronic inflammatory condition, such as glomerulonephritis, cryoglobulinemia or lichen planus, can play a role [29–31]. HCV eradication reduces liver-related and nonliver-related mortality in patients with chronic HCV infection [32]. Nevertheless, the specific role of HCV eradication in cancer development is unknown.

The HCC represents the 34.6% of the NADC in HIV/HCV-coinfected patients. In our study, the HCC incidence in coinfected patients was 1.42/1000 person-years, close to that reported in other recent study with a mainly European population (1.59/1000 person-years) [33] but below the 4.44/1000 person-years published in a huge US Veterans cohort [17]. The older age, ethnic variability and earlier HIV-infection acquisition in the US cohort may explain this difference. Gjærde et al.[34] reported an alarming increase in HCC incidence between 2001 and 2014 (up to 2.3/1000 person-years); in our cohort, all HCCs were diagnosed after 2003 and the incidence will presumably continue to grow over the following years. The development of new drugs against HCV and the eradication of HCV co-infection in PLWH may improve the prognosis of coinfected patients. Nonetheless, the impact on HCC incidence is not well established. Recent data suggest the increased risk of HCC early recurrence in patients treated with direct-acting antivirals for HCV infection, but more studies are needed to confirm these preliminary data [35,36].

A recent study by the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) has demonstrated a reduction of NHL incidence in monoinfected PLWH, but this favorable impact is minimized in hepatitis-coinfected patients [24]. In our study, the incidence of ADC in HIV-monoinfected patients decreases with the time, probably related with ART exposure and immune restoration, but the incidence in coinfected (most of cases NHL) is increasing, despite the ART exposure, in accordance with the COHERE Study, where HIV/HCV-coinfected patients receiving ART had higher risk of NHL than HIV-monoinfected patients (HR = 1.73). Several studies in HIV-uninfected persons have investigated the association between chronic HCV and lymphoma development, with odds ratios between 2.0 and 2.5 [37]. All these data suggest that HCV-coinfection has a role in the development of NHL, which becomes more evident when controlling the immunosuppression caused by the HIV-infection. Diverse mechanisms have been proposed, such as a direct oncogenic role of HCV, an immune dysregulation or a more prevalent coinfection by other viruses involved in lymphoma development (mainly herpes viruses). Without the eradication of viral hepatitis, it is expected that the incidence of NHL in coinfected will increase.

The immune status is closely related to the development of ADC. With the introduction of ART, many studies have observed a progressive decline in the incidence of ADC [28,38,39]. The inverse relation between CD4+ cell count and NADC incidence is controversial. Some studies have documented the impact of a higher CD4 and ART exposure on lower NADC incidence (mainly in virus related-NADC), whereas others have not [28,40,41]. We found differences in CD4+ cell count and ART exposure between HIV-monoinfected and HIV/HCV-coinfected patients at cancer diagnosis, but these differences were related to the higher incidence of ADC in the monoinfected group. No differences between mono- and coinfected patients were found when patients with NADC were compared. A recent analysis from the START study, published by Borges et al.[42], demonstrated that immediate ART initiation in patients with more than 500 CD4+ cells/μl significantly reduces risk of cancer, mainly at the expense of infection-related cancer.

This study has several limitations. First, the retrospective design cannot ensure that all patients with cancer were included, mainly those with ambulatory treatment (skin tumors or high-grade cervix lesions). However, the regular monitoring in the HIV unit and the low mobility of the patients minimized this bias. Data regarding tobacco and alcohol consumption were not available, and we were unable to control for them in the multivariate analysis, and presumably their prevalence was higher in the coinfected group, which would be an important confounder. The cancers in this study were classified as ADC and NADC; currently, some studies use the infection-related and unrelated cancers classification for grouping cancers as infections and immunosuppression could play a role, but this classification also has some inaccuracies. In addition, the treatment data and anatomic stage from the registries, particularly in the first years of the study period, may have been incomplete. GLOBOCAN provides estimates of cancer incidence, mortality, and prevalence for countries and world regions. Incidence data are derived from population-based cancer registries that vary in coverage and may capture the population of an entire country, but more often cover smaller areas, such as mayor cities, plus it is a point in time record and, in this study, it is used comparatively with a cohort followed for 22 years; despite these limitations, GLOBOCAN 2012 is a key source of information on the profile of cancer and represents the best estimates available. Finally, comparison with GLOBOCAN in persons older than 64 years must be interpreted with caution as this age group is under-represented in our cohort (3.45% globally). Nevertheless, it is expected than the incidence increases with the progressive aging of PLWH.

In conclusion, malignancies are an important comorbidity in PLWH, with a higher incidence than in the general population. After adjusting for epidemiological factors and mortality without cancer, HIV/HCV-coinfected patients presented more NADC than HIV-monoinfected patients, even excluding the HCC. Treatment of HCV infection and HIV replication control are fundamental strategies, but the valuable role of cancer-screening programs and early treatment must be assessed.

Acknowledgements

A.M., H.M., I.R. and A.C. designed the study. H.M., J.B., A.M., A.C. and G.R. encoded and collected the data. H.M., S.R., A.M. and I.R. interpreted and analyzed the data. H.M., S.R. and A.M. drafted the article. E.P and A.C. reviewed the manuscript and contributed substantially to revisions. Vanesa Balboa from the Unidad de Epidemiología Clínica y Bioestadística of Complexo Hospitalario Universitario de A Coruña, has contributed in the statistical analysis.

This work was supported in part by grants from Fondo de Investigación Sanitaria (CPII14/00014, PI13/02266, CM13/00328), and Fundación Profesor Novoa Santos, A Coruña.

All authors critically reviewed and gave final approval of the article.

Conflicts of interest

The authors declare no conflicts of interest.

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* Álvaro Mena and Eva Poveda contributed equally in this work.

Keywords:

AIDS-defining cancer; cancer incidence; hepatitis C virus coinfection; HIV; non-AIDS-defining cancer

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