Spectrum of malignancies among the population of adults living with HIV infection in China: A nationwide follow-up study, 2008–2011
Spectrum of malignancies among the population of adults living with HIV infection in China: A nationwide follow-up study, 2008- 2011
Weiming Zhu 0 1 2
Yurong Mao 0 1 2
Houlin Tang 0 1 2
Jennifer M. McGoogan 0 1 2
Zuo-Feng Zhang 1 2
Roger Detels 1 2
Na He 1 2
Zunyou WuID 0 1 2
0 National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing , China , 2 Department of Epidemiology, Fielding School of Public Health, University of California-Los Angeles , Los Angeles , California, United States of America, 3 Department of Epidemiology, School of Public Health, Fudan University , Shanghai , China
1 Editor: Isabelle Chemin, Centre de Recherche en Cancerologie de Lyon , FRANCE
2 Data Availability Statement: The dataset used in this research was retrieved specifically for this study from the Chinese National HIV/AIDS Comprehensive Response Information Management System that contains routine HIV care data. Data are available upon request from the Institutional Review Board of the National Center of AIDS/STD Control and Prevention (NCAIDS) or the Board of Directors of NCAIDS. Applications should be submitted to Ms. Mengchi Liu at
These results provide evidence of substantial AIDS-defining and non-AIDS-defining cancer
burden among adult Chinese PLHIV between 2008 and 2011. Although further study is
Although increasingly studied in high-income countries, there is a paucity of data from the
Chinese population on the patterns of cancer among people living with HIV (PLHIV).
Funding: This work was supported by the National
Health and Family Planning Commission of the
People?s Republic of China [grant number
131-16000-105-01]; the Fogarty International Center?s
AIDS Training and Research Program of the US
National Institutes of Health [grant number
D43TW000013-21S2]; the US?China Program for
Biomedical Collaborative Research [grant number
FDP-NIH AI035040]; and the National Natural
Science Foundation of China [grant number
81161120407]. The funders had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
warranted, China should take action to improve cancer screening, diagnosis, and treatment
for this vulnerable population.
Substantial evidence supports a strong link between HIV infection and increased incidence of a
broad spectrum of malignancies. In the early 1980s, the US Centers for Disease Control and
Prevention (CDC) identified Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and
invasive cervical cancer (ICC) as AIDS-defining cancers (ADCs). Diagnosis of any one ADC marks
progression to AIDS [
]. Prior to the introduction of antiretroviral therapy (ART) in the
mid1990s, incidence of ADCs among people living with HIV (PLHIV) was substantially elevated
over that of the general population. However, since the widespread scale up of ART, cancer
types/sites observed among PLHIV appears to have changed?incidence of KS and NHL has
fallen dramatically, while incidence of non-AIDS-defining cancers (NADCs) has risen [
In general, NADCs can be categorized by their infectious versus non-infectious etiologies. A
range of anogenital cancers and head and neck cancers, as well as some non-melanoma skin
cancers are associated with the oncogenic subtypes of Human Papillomavirus (HPV). Epstein-Barr
Virus (EBV), and in some cases, Human Herpesvirus 8 (HHV-8, the virus that causes KS), is
involved in many of the nine different subtypes of lymphomas, while Hepatitis B Virus (HBV)
and Hepatitis C Virus (HCV) are associated with liver cancer [
]. Not surprisingly, PLHIV are
known to be more susceptible to infection with these oncogenic viruses, and immunodeficiency
may also interact with the oncogenesis. However, PLHIV are also known to have higher rates of
exposure to cigarette smoke and alcohol, two of the top non-infectious carcinogens, which may
also partially explain the higher rates of not only lung and liver cancers among PLHIV, but also
cancers of the head and neck and cervix. Although the rise in NADCs may simply be a
consequence PLHIV having increased longevity in the ART era, there is evidence suggesting that there
are other factors at play. Compared to the general population, PLHIV are more often diagnosed
at earlier ages with more aggressive cancers that have already progressed to later stages [
Most cancer research has been performed among PLHIV of European or African heritage
]. Previous studies in Chinese populations (two hospital-based studies in Mainland
China, with 3,554 and 1,946 patients, respectively, and one registry-based study with 15,269
patients in Taiwan) reported that the risk of KS, NHL, cervical, liver, and anal cancers were
elevated among PLHIV compared to the general population [
]. However, the spectrum of
malignancies observed among China?s rapidly growing population of PLHIV has not yet been
systematically described. Furthermore, the cancer spectrum in the general Chinese population
differs from many developed countries. For instance, China has a higher incidence of liver,
esophagus, nasopharynx, stomach, and lung cancers . It is also not clear whether such
differences in cancer spectra exist between PLHIV in China, and PLHIV in other countries.
Thus, we conducted a nationwide follow-up study using data from China?s National HIV/
AIDS Surveillance Program and National Free ART Program (NFATP) to retrospectively
investigate the spectrum of malignancies among adult PLHIV in China.
Materials and methods
We conducted a nationwide follow-up study to examine the spectrum of malignancies among
Chinese adult PLHIV. To do this, we used routinely collected data for PLHIV who had been
diagnosed with HIV infection on or before 31 December 2011 and were still alive and in care
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as of 1 January 2008. All participants contributed observed time from 1 January 2008 (i.e., the
study start date) to 30 June 2012 (i.e., the study end date) and cancer cases were identified
during this follow-up time.
Setting and data source
The data used for this study were collected during the normal operation of China?s HIV/AIDS
Surveillance System and NFATP. All data related to China?s HIV response efforts are collected
and maintained in a real-time, web-based repository called the HIV/AIDS Comprehensive
Response Information Management System (CRIMS), which has been described elsewhere
]. In brief, CRIMS contains records for all individuals diagnosed with HIV in China, and
these records include contact and demographic information, testing and baseline clinical
information, dates and details of all follow-up visits, and ART regimens and related
assessments, as well as other health-related information (co-infections, co-morbidities) and dates
and causes of death. After a diagnosis of HIV infection, but prior to the initiation of ART,
PLWH are followed up once every 6 months. After ART initiation, patients are followed up 4
times in the first 3 months, and once every 3 months thereafter.
Study inclusion criteria were: 1) being 15 years of age, and 2) having been diagnosed with
HIV on or before 31 December 2011. All patient records in CRIMS meeting these study
inclusion criteria were extracted and then screened against exclusion criteria. Study exclusion
criteria were: 1) having died or been lost to follow-up prior to the start of the study on 1 January
2008, or 2) not having attended at least one follow-up visit prior to 30 June 2012, the date all
data were extracted. All remaining patients were included in the analysis.
Cancer cases were identified using reports of AIDS-related complications or causes of death at
each follow-up visit. We categorized cancer cases based on the International Classification of
Disease for Oncology, 3rd Edition (ICD-O-3) [
]. However, because approximately half of
lymphoma records were not specified as to their type, we combined all cases of NHL, Hodgkin
lymphoma (HL), and all other lymphomas together into a single category. This group was
treated as a single cancer type in all analyses.
The start of observed time was defined as either the study start date, 1 January 2008 (for those
already diagnosed with HIV), or the date of HIV diagnosis, whichever was later. The inferred
date of cancer incidence was defined as the median date between the date of cancer diagnosis
and the date of the previous follow-up visit. Participants with inferred date of cancer incidence
after the end of the study, 31 December 2011, were treated as cancer-free during the study
period. For cancer-free individuals, the end of follow-up was defined as either 1) the date of
last follow-up for those who were lost to follow-up, 2) the date of death, or 3) the end of the
study for those who were still living. Observed time was calculated as the difference between
first and last observation, expressed in person-years (PY).
Characteristics of participants were presented as number and percent. Sex-specific cancer
incidences were calculated for each malignancy site/type, and age-standardized incidence rates
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(ASIR) and standardized incidence ratios (SIR), along with their 95% confidence intervals
(CIs) were calculated. Direct standardization was used to calculate ASIR. Two different
standard populations were used: ASIR-China (ASIRC) was calculated using China?s 2010 census
], and ASIR-world (ASIRW) was calculated using the World Health Organization
(WHO) standard world population for 2002 to 2025 [
]. ASIRC and ASIRW were expressed
per 100,000 PY. SIR was obtained by dividing the numbers of observed cases (numerator) by
the expected numbers of cases (denominator). Expected cancer frequencies were determined
using the observed sex- and 5-year, age-specific incidence rates from China?s National Cancer
Registry in 2008 [
]. All CIs presented were calculated assuming a Poisson distribution. SAS
software version 9.3 (SAS Institute Inc., USA) was used for all analyses.
This study was approved by the Institutional Review Board of the National Center for AIDS/
STD Control and Prevention, China CDC, and by the Institutional Review Board of the
University of California, Los Angeles. No informed consent was sought since all individuals
diagnosed with HIV in China sign informed consent at the time of their initial entry into CRIMS,
which includes the future use of their data for epidemiological study. All records, once
extracted, were de-identified to ensure confidentiality.
Records of a total of 444,712 patients who met inclusion criteria were extracted. A total of
45,261 (10.2%) were excluded and therefore, 399,451 (89.8%) patients were included in the
analysis and contributed a total of 813,238.9 PY of observed time.
As shown in Table 1, a majority were 30?44 years of age (49.3%), male (69.8%), and Han
Chinese (67.9%), and most had a junior high school-level education or less (74.3%). The most
common HIV transmission route reported by participants was heterosexual contact (43.5%),
followed by injecting drug use (27.3%), and blood product receipt or donation (10.2%). At the
time of diagnosis, 62.0% of participants had not yet progressed to AIDS, while 38% had, and
baseline CD4 counts were low?25.6% had 350 cells/mm3, 22.1% had 200?399 cells/mm ,
and 27.2% had <200 cells/mm .
As shown in Table 2, 3,819 cancer cases were identified?2,808 among males, and 1,011
among females. The 5 most prevalent malignancies among males were lung cancer (n = 713),
liver cancer (n = 539), lymphoma (n = 299), brain and central nervous system (CNS) cancers
(n = 216), and stomach cancer (n = 137), and among females were lung cancer (n = 140),
cervical cancer (n = 128), lymphoma (n = 117), brain and CNS cancers (n = 105), and liver cancer
(n = 84).
Table 2 also presents sex-specific ASIRC and ASIRW results overall and by malignancy
site/type. Overall ASIRC was 776.4 per 100,000 (742.1?810.6) for males and 486.5 per 100,000
(436.4?536.6) for females. Excluding cancer cases with ill-defined or unspecified primary sites/
types, overall ASIRC was 691.8 per 100,000 (659.7?724.0) for males and 427.4 per 100,000
(380.5?474.2) for females. Overall ASIRW was 881.7 per 100,000 (839.6?923.7) for males and
508.9 per 100,000 (454.0?563.7) for females, higher compared to ASIRC. ASIRW was also
higher than ASIRC for both males and females when malignancies that were ill-defined/
unspecified were excluded.
ASIRW values were similar or greater than ASIRC values for all specific malignancy sites/
types for both males and females. Lung cancer had the highest ASIRC among males at 226.0
per 100,000 (206.7?245.4) followed by liver cancer at 145.7 per 100,000 (131.0?160.3) and
lymphoma at 63.1 per 100,000 (54.6?71.7). Lung cancer also had the highest ASIRC among
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females at 66.8 per 100,000 (52.5?81.1) followed by lymphoma at 48.0 per 100,000 (32.7?63.2),
stomach cancer at 47.8 per 100,000 (42.2?71.4), and cervical cancer at 47.6 per 100,000 (38.3?
Table 3 displays results of sex-specific SIR calculations overall and by malignancy site/type.
Overall SIR was 3.4 (3.3?3.5) for males and 2.6 (2.4?2.7) for females. After excluding
illdefined or unspecified malignancies, SIR for males was 3.1 (3.0?3.2) and for females was 2.3
(2.2?2.5). Highest SIR was observed for KS at 2,639.8 (2,208.7?3,130.5) among males, and
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Malignancy Site/Type (ICD-O-3 Code)
ICD-O-3: International Classification of Disease for Oncology [
], 3rd Edition, ASIRC: age-standardized incidence rate for China, ASIRW: age-standardized incidence
rate for the world, CI: 95% confidence interval, CNS: central nervous system
aASIRC is per 100,000, weighted by Chinese population in 2010 according to national census data [
], and CI calculated based on an assumed Poisson distribution
bASIRW is per 100,000, weighted by the World Health Organization?s world standard population data for 2002 to 2025 [
], and CI calculated based on an assumed
cBecause approximately half of lymphoma records did not specify Hodgkin or Non-Hodgkin lymphoma, combined observed and expected lymphoma figures were
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ICD-O-3: International Classification of Disease for Oncology [
], 3rd Edition, SIR: standard incidence ratio, CI: 95% confidence interval, CNS: central nervous system
aSIR is calculated using Chinese National Cancer Registry data for 2008 (Expected) [
], and CI calculated based on an assumed Poisson distribution
bBecause approximately half of lymphoma records did not specify Hodgkin or Non-Hodgkin lymphoma, combined observed and expected lymphoma figures were
1,593.5 (1,133.0?2,178.4) among females, and lymphomas (all types) was 13.9 (12.3?15.5)
among males and 16.0 (13.2?19.1) among females. Among males, high SIR was observed for
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cancers of the eye (10.3 [2.8?26.4]), brain and CNS (8.2 [7.1?9.3]), lung (4.8 [4.4?5.1]), and
liver (3.9 [3.6?4.2]). Among females, high SIR was found for other head and neck cancers
(16.0 [9.3?25.6]), and cancers of the eye (9.6 [1.9?28.1]), brain and CNS (8.8 [7.2?10.7]), lung
(4.2 [3.5?5.0]), and liver (4.0 [1.8?8.0]). ICC had an SIR of 3.8 (3.2?4.6).
We observed higher incidence of cancer among Chinese adults with HIV, compared to the
general Chinese population. As expected, both the incidence of ADC and NADC were
higher. These findings are supported by three previous studies in ethnic Chinese
populations: Zhang et al. (Hubei Province, 2004?2008) [
], Yang et al. (Beijing Municipality,
], and Chen et al. (Taiwan, 1998?2009) [
]. However, the finding of many
NADCs at higher incidence rates than ADCs was somewhat of a surprise, given that ART
coverage in China during the study period was <50% [
]. Further comparison of the cancer
spectrum between PLHIV in different populations indicates that both infectious and
noninfectious etiologies may play important roles in oncogenesis in the HIV-infected population
KS is well-known to be caused by HHV-8, and PLHIV are commonly infected with HHV-8.
In the pre-ART era, KS incidence was observed to be up to 2,000-fold greater among PLHIV,
and the more severe the immunodeficiency, the higher the likelihood of KS occurrence [
our study, 171 cases of KS were observed, which represented only 4.5% of all cancer cases
observed. Not surprisingly, KS SIR was high?2,639.8 among males and 1,593.5 among
females?as KS in the absence of HIV is very rare in Mainland China. However, the ASIRC of
KS (23.9 per 100,000 for males and 14.2 per 100,000 for females) was lower than in the Taiwan
], and in many previous studies in the United States, Europe and sub-Saharan Africa
]. The low prevalence of HHV-8 infection in Mainland China may be one cause
of lower KS incidence rate [
]. Previous studies have shown that the incidence rate and
SIR of KS has dropped dramatically since the introduction of ART [
], and we expect
a similar trend to develop in China, since ART coverage is still expanding under the NFATP as
China strives to meet the Joint United Nations Programme on HIV/AIDS (UNAIDS)
90-9090 Targets [
EBV infection is known to be associated with several forms of lymphomas, especially NHL and
HL, and increased incidence of NHL has been documented among those with more serious
immunodeficiency. China?s general population is known to have a high prevalence of EBV
infection?one recent study found EBV prevalence among Chinese children to be 50% by age
3 and 90% by age 8 [
]. Both Zhang et al. and Chen et al. found that NHL was the most
commonly observed malignancy [
], and Chen et al. found NHL incidence of 329 per 100,000
(SIR 23.7) for males and 256 per 100,000 (SIR 22.4) for females, whereas incidence of HL was
18 per 100,000 (SIR 9.4) for males and 14 per 100,000 (SIR 7.8) for females . However,
limitations in the data we collected meant we were only able to report incidence for all lymphomas
as a group?SIR of 13.9 for males, 16.0 for females, and ASIRC of 63.1 per 100,000 among
males and 48.0 per 100,000 among females, consistent with previous studies of NHL in the
post-ART era [
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A broad range of cancers, mostly affecting the anogenital and head and neck areas, are known
to be caused by infection with one or more of the high-risk subtypes of HPV [
PLHIV in China have a high prevalence of HPV co-infection. In one recent study, prevalence
of carcinogenic HPV infection among women with HIV was nearly 40% [
]. ICC is a major
health problem in China, causing the deaths of approximately 40,000 women annually. We
observed 128 cases of ICC in our cohort, for an ASIRC of 47.6 per 100,000 and SIR of 3.8,
consistent with previous studies in which females with HIV were estimated to be roughly 5 times
more likely to develop ICC [
]. Zhang et al. found a higher SIR of 68.1, and all 14
cancer cases observed among women in the study were ICC . However, in the Taiwan
study, incidence of ICC was 413 per 100,000, with SIR at 14.0 [
HPV infection is also common among Chinese men who have sex with men (MSM). A
recent study in three Chinese cities found high-risk subtype HPV infection among 51% of
participants overall, and among 70% of participants with HIV infection [
]. HPV-associated anal
cancer has risen to a steady high level among MSM globally [
]. However, very few cases of
anal cancer among PLHIV in Mainland China had previously been reported. Zhang et al.
found zero cases of anal cancer [
], Yang et al. found 3 among men [
], and we found only 2
(ASIRC: 0.2 per 100,000, SIR: 2.9). A possible explanation for the low incidence of anal cancer
thus far observed among men with HIV infection in China is the relatively low prevalence of
HIV among MSM during the study period. In our study, only 7.3% of participants reported
acquiring HIV infection via homosexual contact. However, the rapid increase of HIV infection
in recent years and a high prevalence of HPV infection among MSM in China predicts a rise
in anal cancer cases in the future, which may approximate the incidence rate in the Taiwan
cohort (45.3 per 100,000, SIR 18.5) [
HBV and HCV Infection
HBV and HCV infection are associated with hepatocellular carcinoma, which accounts for
>90% liver cancers. Liver cancer is known to be more prevalent and have higher incidence
in east and southeast Asia, with China alone having 50% of all new cases of liver cancer
worldwide in 2012 [
]. Incidence of liver cancer is higher among those with HIV in the US
and other European countries [
]. In China, HIV/HCV co-infection is
very common among former blood product donors and recipients as well as people who
inject drugs (PWID) , and the prevalence of HBV/HIV and HCV/HIV co-infection, and
HBV/HCV/HIV triple infection were 8.7%, 18.2%, and 3.3%, respectively, among PLHIV in
China?s NFATP [
]. As expected, a high SIR for liver cancer was found by Zhang et al. (6.0,
male and female combined) [
], and 14 liver cancer cases were identified by Yang et al.,
which accounted for 9% of all malignancies observed [
]. In our study, liver cancer had a
very high ASIRC among males, 145.7 per 100,000, similar to the Taiwan study (185 per
], and an SIR, 3.9 in males, 5.2 in females, similar to previous studies
Other infections may also impact incidence of cancers in PLHIV in China. For example,
Helicobacter pylori has been associated with stomach cancer. Abovementioned HPV infection
has also been associated with penile cancer, oral cavity cancers, other cancers of the head and
neck, and non-melanoma skin cancers, and EBV infection has been linked to nasopharyngeal
] Incidence rates of all these malignancies were elevated in our study with the one
exception?stomach cancer among male PLHIV was not elevated, which is notable since
China bears nearly half of the global burden of non-cardia gastric cancers [
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Previous studies have found that tobacco smoking, as well as the incidence rate of lung cancer
are higher among PLHIV than in the general population [
]. As anticipated, lung cancer
incidence was very high in our study?ASIRC of 226.0 per 100,000 among males and 66.8 per
100,000 among females, and SIR of 4.8 for males and 4.2 for females. The incidence rate of
lung cancer in our study was higher than the Taiwan cohort [
], which may be attributed to
higher prevalence of tobacco smoking in males in Mainland China (53%) than in Taiwan (32?
To the authors? knowledge the present study was the first ever nationwide investigation of
the spectrum of malignancies among PLHIV in China and adds to a literature containing
few such studies in middle-income country settings. The very large size and nationwide
scope of our cohort were two important strengths of our study, which facilitated detection of
cancers with low incidence and perhaps improved the overall accuracy of our incidence
Nevertheless, our study had several limitations. Firstly, only individuals who had been
diagnosed with HIV infection could be included in our analysis, and cancer incidence rate in
undiagnosed PLHIV remains unknown. Moreover, we could not evaluate cancer cases
among the 10.2% of cases (45,261 of 444,712) that were excluded due to either death or loss
to follow-up prior to the study?s start or no record of follow-up during the study period.
However, a near 90% inclusion rate suggests that our study population is indeed nationally
representative. Secondly, because original pathology findings were not included in CRIMS
records, their re-examination for accuracy of cancer diagnosis could not be performed. This
resulted in some cancer cases lacking a specific diagnosis (classified in our study as
illdefined/unspecified) and likely others being misdiagnosed, both of which may have
introduced some miss-classification bias that could have caused under- or over-estimation of
some incidence calculations. An example of this may be found in the surprisingly high
numbers of brain and CNS cancers observed in our study population. It is likely that some of
these cases were, in fact, primary CNS lymphomas [
]. Similarly, it is likely that some cancer
cases in our study population went undiagnosed. This too would have biased our results
toward under-estimation of cancer incidences. Thirdly, due to the lack of specificity in nearly
half of the lymphoma cases in the cohort, we had to classify all lymphomas together into a
single group. This prevented comparison of ADC and NADC incidence within the current
study and previous studies.
The findings from this study provide strong evidence of a substantial cancer burden among
adult PLHIV in China between 2008 and 2011. Although further study is clearly needed, these
results suggest that China should expect that this burden has grown during the period 2012 to
2018, and will continue to do so, as it pushes to further scale up the NFATP in an attempt to
meet the UNAIDS 90-90-90 Targets.[
] Meeting these goals will undoubtedly result in an
overall larger and older Chinese PLHIV population, which will require proactive and accurate
cancer screening as well as specialized treatment and case management.
The authors would like to acknowledge all healthcare professionals who are working hard
serving the needs of PLHIV in China, and to thank them for their contributions to national HIV/
AIDS surveillance and national cancer registry system data collection.
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Conceptualization: Weiming Zhu, Zuo-Feng Zhang, Roger Detels, Na He, Zunyou Wu.
Data curation: Weiming Zhu, Yurong Mao, Houlin Tang, Zunyou Wu.
Formal analysis: Weiming Zhu, Yurong Mao, Houlin Tang, Jennifer M. McGoogan.
Funding acquisition: Na He, Zunyou Wu.
Investigation: Weiming Zhu, Zunyou Wu.
Project administration: Zunyou Wu.
Resources: Zuo-Feng Zhang, Zunyou Wu.
Supervision: Zuo-Feng Zhang, Zunyou Wu.
Validation: Zunyou Wu.
Visualization: Zunyou Wu.
Methodology: Jennifer M. McGoogan, Zuo-Feng Zhang, Roger Detels, Na He, Zunyou Wu.
Writing ? original draft: Weiming Zhu, Zunyou Wu.
Writing ? review & editing: Weiming Zhu, Yurong Mao, Houlin Tang, Jennifer M.
McGoogan, Zuo-Feng Zhang, Roger Detels, Na He, Zunyou Wu.
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