Cancer Incidence in People Living with HIV/AIDS in Israel,1981–2010

Introduction

People who are living with HIV/AIDS (PLWHA) have an increased risk of developing cancer. ¹ HIV infection is associated with a high prevalence of certain malignancies, such as Kaposi sarcoma (KS), which is caused by human herpes virus 8 (HHV-8); with high-grade non-Hodgkin lymphoma (NHL), some of which is caused by Epstein–Barr virus; and with invasive cervical carcinoma, which is associated with human papillomavirus (HPV). These cancers are considered as AIDS-defining conditions, ^2,3 worsening disease prognosis.

Antiretroviral treatment (ART) was introduced in Israel in 1997 and became available for all citizens in Israel. It has improved the immune function of PLWHA, reduced the risk of AIDS progression, and decreased AIDS-related mortality. ⁴ Despite these promising results, long-term studies have found that PLWHA remained at higher risk for developing malignancies. ^5,6 Along with the longer survival of PLWHA, they are susceptible to the consequences of aging and also have prolonged exposure to cancer risk factors, such as environmental or infectious agents. ⁷ Therefore, data are needed to appraise the cancer incidence among PLWHA, and also to evaluate the long-term achievements of ART.

The aims of this study were to assess, for the first time in Israel, the incidence of cancers among all PLWHA (both AIDS-defining and non-AIDS-defining malignancies) before and after the introduction of ART in Israel in 1997 and by different HIV transmission routes.

Materials and Methods

This cohort study included all PLWHA adult Israeli citizens who were reported between 1981 and 2010. Individuals diagnosed with HIV or AIDS in Israel are reported by law to the Ministry of Health since 1981 and recorded in the National HIV/AIDS Registry (NHAR). The reports contain demographic (name, identification number, family status, address, ethnicity, e.g., Jewish or Arabic, date, and country of birth), behavioral, and clinical data for each notification. In response to a possible reporting bias of newly diagnosed patients who may refrain from disclosing their risk behavior immediately upon diagnosis, the NHAR is periodically updated with continuous name-based reports from all the AIDS treatment centers and the regional health departments regarding behavioral and clinical changes since the initial notification. The completeness of the NHAR is estimated at 99% of all PLWHA who were diagnosed in Israel. ⁸

The Israeli Cancer Registry includes all subjects identified with malignancies since 1960. This name and identification number Registry utilizes passive compulsory notification of cancers from all medical institutions in Israel, based on record linkage with patient's files and the death registry. All cancers are recorded according to the International Classification of Diseases for Oncology (ICD-O, version 3), including histological findings and stage of the tumors. ⁹ The completeness of this registry is estimated at 93% for solid tumors. ¹⁰

As both NHAR and the Cancer Registry are identified, cross-matching was performed in December 2011, using the names, dates of birth, and identification numbers of all PLWHA and cancer patients. These registries are also periodically cross-linked with the National Civil Census to identify those who died or left Israel. Inclusion criteria for this study involved all adults older than 15 years of age who were diagnosed with HIV/AIDS and/or cancer between 1981 and 2010. Only PLWHA who were Israeli citizens were included in this study, as they could be traced if they had died or left Israel by the end of the follow-up period. Those who were diagnosed with cancer before or during their first visit to the HIV clinic were excluded. The dates of reporting of HIV/AIDS or cancer were obtained by cross-matching the NHAR with the Cancer Registry, respectively. All PLWHA who were free of cancer were followed from their HIV/AIDS reporting date to either developing malignancy, death, leaving Israel to go to another country, or December 2010, whichever occurred earlier. In cases in which PLWHA were diagnosed with two malignancies, only the first diagnosis was recorded in our study.

AIDS-defining cancers included Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer, while all other malignancies were classified as non-AIDS-defining cancers. Coinfections with tuberculosis were recorded by cross-matching the NHAR with the National Tuberculosis Registry, while infectious syphilis (primary or secondary) was recorded by cross-matching with the individual reports reported to the Ministry of Health. HIV/AIDS, tuberculosis, and syphilis are reportable conditions in Israel.

Results

From January 1, 1981 to December 31, 2010, 5,154 PLWHA who were Israeli citizens older than 15 years of age were reported to the Ministry of Health. During the study period, which involved 36,296 PY, 362 PLWHA (7.0%) developed malignancies, demonstrating a cancer incidence density of 997.4 cancer cases per 100,000 PY. Of all PLWHA with malignancies in the pre-ART period, 140 (77.8%) died, while 85 (45.2%) PLWHA with malignancies died in the post-ART period (p<0.01).

The incidence density of all malignancies among PLWHA who were diagnosed in the pre-ART period (1981–1996) was higher than in the post-ART period (1997–2010) across all age groups, demonstrating 1,232.0 and 846.7 cases per 100,000 PY, respectively, p<0.01 (Fig. 1a). PLWHA who developed any cancer were older, more likely to be Jewish and Israeli born, had HIV/AIDS reported before 1996, and were infected by homosexual contact or exposed to infected blood products (Table 1a). In multivariate analysis, older PLWHA, Israeli born, had HIV reported before 1996, and acquired the infection by homosexual contact or by exposure to infected blood products were predictive variables associated with cancer (Table 2a).

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FIG. 1.

(a) Incidence density of cancer of all 5,154 Israeli citizens >15 years living with HIV/AIDS before and after the introduction of antiretroviral therapy by age group, 1981–2010. (b) Incidence density of AIDS-defining cancer of all 5,154 Israeli citizens >15 years living with HIV/AIDS before and after the introduction of antiretroviral therapy by age group, 1981–2010. (c) Incidence density of non-AIDS-defining cancer of all 5,154 Israeli citizens >15 years living with HIV/AIDS before and after the introduction of antiretroviral therapy by age group, 1981–2010.

The incidence density of AIDS-defining malignancies was higher in the pre-ART than that the post-ART period, demonstrating 777.0 and 467.2 cases per 100,000 PY, respectively, p<0.01. The incidence was higher in the younger age groups in the pre-ART period, but higher for PLWHA older than 55 years of age in the post-ART period (Fig. 1b). PLWHA who developed AIDS-defining cancers were older, more likely to be Jewish and Israeli born, had HIV/AIDS reported before 1996, and were infected by homosexual contact or were exposed to infected blood products (Table 1b). In multivariate analysis, older PLWHA, being male, being Israeli born, had HIV reported before 1996, and acquired the infection by homosexual contact were predictive variables associated with AIDS-related cancers (Table 2b).

The incidence of non-AIDS-defining malignancies has increased between the pre-ART and the post-ART period from 376.5 to 455.0 per 100,000 PY, respectively, p=0.01, and was associated with age (Fig. 1c). PLWHA who developed AIDS-defining cancers were older, more likely to be Jewish and Israeli born, had HIV/AIDS reported before 1996, were infected by homosexual contact or were exposed to infected blood products, and also developed tuberculosis (Table 1c). In multivariate analysis, older PLWHA, being Israeli born, had HIV reported before 1996, were infected by exposure to infected blood products, and developed tuberculosis were predictive variables associated with non-AIDS-related cancers (Table 2c).

Cox proportional regression models adjusted for age and time of follow-up showed that PLWHA who acquired the infection by homosexual transmission were at the greatest risk of developing cancers of all causes before 1996, while those who were infected by contaminated blood products were at highest risk after 1997 (Fig. 2a). PLWHA who acquired the infection by homosexual transmission were at the greatest risk of developing AIDS-defining cancers before 1996, while this group and those who were infected by contaminated blood products were at highest risk after 1997 (Fig. 2b). PLWHA who acquire the infection by infected blood products were at the greatest risk of developing cancers of all causes before 1996, while those who were infected by homosexual contact were at highest risk after 1997 (Fig. 2c).

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FIG. 2.

(a) Adjusted Cox proportional hazard regression curve comparing cancer diagnoses among people living with HIV/AIDS by transmission route and time of reporting. (b) Adjusted Cox proportional hazard regression curve comparing AIDS-defining cancer diagnoses among people living with HIV/AIDS by transmission route and time of reporting. (c) Adjusted Cox proportional hazard regression curve comparing non-AIDS-defining cancer diagnoses among people living with HIV/AIDS by transmission route and time of reporting.

Both the IR and SIR of all AIDS-defining cancers, including KS, NHL, and invasive cervical cancer, were higher in the pre-ART period than the post-ART period. The IR and SIR of all non-AIDS-defining cancers were also higher in the pre-ART period (Table 3). The most common non-AIDS-defining cancers were Hodgkin's lymphoma (nine cases in the pre-ART period vs. seven cases in the post-ART period, age-adjusted SIR of 165.2 and 36.9, respectively), followed by malignancies of the lung (eight vs. seven cases, age-adjusted SIR of 73.5 and 18.1, respectively), malignancies of the liver (four vs. five cases, age-adjusted SIR of 102.6 and 400.0, respectively), and anal malignancies (four vs. four cases, age-adjusted SIR of 71.3 and 18.5, respectively).

Of all homosexuals who developed malignancies, a higher rate developed AIDS-defining cancers before ART was introduced than after its marketing (N=56, 75.3% and N=22, 51.1%, respectively, p=0.01), while non-AIDS-related cancers were more prevalent in the post-ART than the pre-ART period (N=20, 27.4% and N=22, 48.9%, respectively, p=0.01). KS has shown the most substantial decrease among homosexuals between the pre-ART and the post-ART period (N=42, 56.8% and N=12, 26.7%, respectively, p<0.01). In contrast, the rate of anal carcinoma among homosexuals has increased between the two periods, although it did not achieve statistical significance (N=4, 5.4% and N=4, 8.8%, respectively, p=0.3).

Discussion

This 30-year incidence study, which included all 5,154 PLWHA reported in Israel, found that 7.0% developed cancer, while the incidence density was lower in the post-ART period for both the AIDS and the non-AIDS-defining cancers than before ART was introduced. The decreasing rates of cancer between the two periods may be related to the improving efficacy and tolerability of ART, which has increased patient's adherence. ART's protective effects may include decreased immune activation and cytokine levels, boosting immune response, increased CD4 levels, and ART-related suppression of oncogenic viruses. ¹¹ Due to the success of ART, PLWHA are now living longer and not succumbing to death due to other causes, resulting in a greater cumulative chance of cancerous events.

The proportion of cancer among PLWHA in our study was generally similar to that reported from other countries. ¹² The risk for developing malignancies remained significantly more elevated in PLWHA than in the general population. It may be that advancing age and greater cumulative exposure to environmental (such as tobacco and alcohol) or viral (HHV-8, HPV, hepatitis B, or Epstein–Barr viruses) carcinogens are associated with an increased risk of malignancies. It is therefore imperative to understand how anticancer regimens and ART interact in order to develop optimal treatment approaches.

Although all AIDS-defining cancers have decreased between the pre-ART and post-ART periods (especially KS), AIDS-related cancers still remained the most common malignancies in the PLWHA population in Israel, as was also found in the United States. ³ NHL and invasive cervical cancers also remained the most common malignancies in the post-ART period in our study. It might be that the damage done by the initial HIV infection, on-going immune reactivation, ¹³ suboptimal immune reconstitution, ¹⁴ and perhaps long-tern ART exposure continue to increase the risk of PLWHA for KS ¹⁵ and other AIDS-related cancers. Cervical cancer, which is also characterized by a viral etiology, has a long lag time between primary infection and clinical disease. As such, the initiating event for cancer that manifests itself clinically in the early periods of widely available ART could have taken place when the patients were exposed to less than optimal ART or when no therapy was available. ¹⁵

The number of PLWHA with invasive cervical cancer increased between the pre-ART and the post-ART period, as was also found in another study. ¹⁶ It may a result of the greater number of HIV-infected women diagnosed in the post-ART period (N=1,350 vs. N=319 in the pre-ART period in our study) and also a result of increasing awareness among women and physicians to screen for cervical cancer. ¹⁶ It is also possible that HIV-infected women are more exposed sexually to HPV than the general population or that HPV coinfection has a relatively long latency before its oncogenic effects become relevant in PLWHA. ¹¹

The incidence of non-AIDS-defining cancers among PLWHA has decreased between the pre-ART and the post-ART period, in line with other studies ⁷ and contradicting results published by others. ^6,11 It might be that the longer survival of PLWHA and the relative older age of the newly diagnosed PLWHA in the post-ART compared to the pre-ART period were related to the greater risk of cancer. Unlike other studies, ¹¹ we did not find an increased incidence of anal carcinoma in the post-ART period. It is probably due to the relatively small size of the specific cancer types detected in PLWHA in Israel, as also suggested in an Italian publication, which found similar results. ⁷

Although PLWHA who acquire the infection by homosexual transmission were at highest risk of developing AIDS-defining cancers in both the pre-ART and the post-ART periods, the rate of malignancies among them has decreased between the two periods, especially the incidence on KS. However, the rate of non-AIDS-defining cancers has increased between the pre-ART and the post-ART period, especially the rate of anal carcinoma, in line with other studies focusing on homosexuals. ^17,18 It was suggested that the relatively high adherence of ART affects carcinogens that occur at low CD4 levels, such as HHV-8. The reduction may also be related to the adaptation of safer sex practices that have reduced the transmission of HHS-8, as almost 50% of cancers are linked to environmental and lifestyle factors. ¹⁸

Our study is noteworthy, as it is the first study describing the natural history through 30 years of all PLWHA with Israeli citizenship who have free access to HIV treatment and care, in updated National databases characterized by high completeness and good quality. Yet it is subject to several limitations. First, we had no data regarding the specific ART used by each patient. However, as all PLWHA who are citizens are entitled to unrestricted clinical and laboratory follow-up and free ART, it is probable that most patients are prescribed the most updated available therapy, which supports adherence. Second, data regarding other cancerous cofactors, such as smoking, family history, and viral infection, were not available nor were laboratory data pertaining to CD4 counts. However, we believe that these cofactors remained unchanged among PLWHA, and that the bias, if it occurs, is nondifferential and conservative. Third, the SIR calculation is more subject to overdiagnosis bias in the PLWHA than that of the general population, as PLWHA are more commonly screened for malignancies. Fourth, regular screening of PLWHA led to early diagnosis and possible better survival than the general population, causing lead time bias. Fifth, survival bias may have also affected our results between the pre-ART and post-ART periods, as the life expectancy of HIV-infected individuals had increased after the introduction of the ART; thus, they live long enough to develop AIDS. We therefore analyzed the results by adjusting to age and time of follow-up.

In conclusion, both AIDS-related and non-AIDS-related cancers decreased after the introduction of ART and their diagnoses were strongly associated with age. The incidence density of AIDS-defining malignancies was higher in the pre-ART than in the post-ART period, while the incidence of non-AIDS-defining malignancies showed the opposite trend, and increased between the pre-ART and the post-ART period. Yet, cancers remain an important prognostic factor in PLWHA and the initiation of age-related cancer screening and ART early in the course of HIV infection can sustain high levels of immune function and reduce malignancies.