Lung cancer in the Swiss HIV Cohort Study: Role of smoking, immunodeficiency and pulmonary infection

Article (PDF Available)inBritish Journal of Cancer 106(3):447-52 · January 2012with32 Reads
DOI: 10.1038/bjc.2011.558 · Source: PubMed
Abstract
Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs ≥500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking.

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Lung cancer in the Swiss HIV Cohort Study: role of smoking,
immunodeficiency and pulmonary infection
GM Clifford
*
,1
, M Lise
2
, S Franceschi
1
, M Egger
3
, C Bouchardy
4
, D Korol
5
, F Levi
6
, S Ess
7
, G Jundt
8
,
G Wandeler
3,9
, J Fehr
10
, P Schmid
11
, M Battegay
12
, E Bernasconi
13
, M Cavassini
14
, A Calmy
15
, O Keiser
3
,
F Scho
¨
ni-Affolter
3,16
and the Swiss HIV Cohort Study
17
1
International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France;
2
Epidemiology and Biostatistics Unit,
The Scientific Directorate, National Cancer Institute, Aviano, Via Franco Gallini 2, 33081 Aviano, Italy;
3
Institute of Social and Preventive Medicine (ISPM),
University of Bern, Finkenhubelweg 1, 3012 Bern, Switzerland;
4
Cancer Registry of the Canton of Geneva, 55 Boulevard de la Cluse, 1205 Geneva,
Switzerland;
5
Cancer Registry of the Canton of Zurich, Vogelsangstr. 10, 8091 Zurich, Switzerland;
6
Cancer Registry of the Canton of Vaud,
CHUV Falaises 1, 1011 Lausanne, Switzerland;
7
Cancer Registry of Basel, Scho¨nbeinstr. 40, 4003 Basel, Switzerland;
8
Cancer Registry of St Gallen
and Appenzell, Flurhofstr. 7, 9000 St Gallen, Switzerland;
9
University Hospital, University of Bern, Inselspital PKT2B, 3010 Bern, Switzerland;
10
University Hospital Zurich, University of Zurich, Ra¨mistrasse 100, 8091 Zurich, Switzerland;
11
Cantonal Hospital, Rorschacher Strasse 95,
9007 St Gallen, Switzerland;
12
University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland;
13
Ospedale Regionale, Via Tesserete 46, Lugano,
Switzerland;
14
University Hospital Lausanne, Rue du Bugnon 4, 1011 Lausanne, Switzerland;
15
University Hospital Geneva, Rue Micheli-Du-Crest 24,
1205 Geneva, Switzerland;
16
Coordination and Data Center, Swiss HIV Cohort Study, Mont-Paisible 16, CHUV, 1011 Lausanne, Switzerland
BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer
among HIV-infected persons, in addition to smoking.
METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer
Registries (1985 2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and
calendar period. Odds ratios (ORs) were estimated by conditional logistic regression.
RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its
strong association with lung cancer (OR for current vs never ¼ 14.4, 95% confidence interval (95% CI): 3.36 62.1). No significant
associations were observed between CD4 þ cell count and lung cancer, neither when measured within 1 year (OR for o200 vs
X500 ¼ 1.21, 95% CI: 0.49 2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not
significantly associated with lung cancer (OR for ever vs never ¼ 0.67, 95% CI: 0.29 1.52), and nor was a history of AIDS with
(OR ¼ 0.49, 95% CI: 0.19 1.28) or without (OR ¼ 0.53, 95% CI: 0.24 1.18) pulmonary involvement.
CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary
disease, but seems to be attributable to heavy smoking.
British Journal of Cancer (2012) 106, 447 452. doi:10.1038/bjc.2011.558 www.bjcancer.com
Published online 12 January 2012
& 2012 Cancer Research UK
Keywords: lung cancer; HIV; AIDS; immunodeficiency; smoking; casecontrol study
Lung cancer is one of the most common non-AIDS-defining
cancers to occur among HIV-infected persons (Dal Maso et al,
2009; Franceschi et al , 2010; Shiels et al, 2011), and shows two- to
seven-fold excess risks in comparison with the general population
(Grulich et al, 2007; Shiels et al, 2009; Franceschi et al, 2010).
In the Swiss HIV Cohort Study (SHCS) subjects, lung cancer risk is
three times that in the general Swiss population (Franceschi et al,
2010). A large part of this excess can be explained by the high
proportion of heavy smokers among HIV-infected persons
(Giordano and Kramer, 2005), particularly among intravenous
drug users (IDUs) (Clifford et al, 2005; Dal Maso et al, 2009).
However, HIV infection has been suggested to be associated
with increased lung cancer incidence even after controlling for
individually collected (Shiels et al, 2010) or hypothetically
modelled (Engels et al, 2006; Chaturvedi et al, 2007) smoking
history data. Further suggesting a link between lung cancer and
HIV-related immunodeficiency, large cohorts of HIV-infected
persons (Patel et al, 2008; Guiguet et al, 2009; Reekie et al, 2010)
have recently reported strong associations between declining
CD4 þ counts and lung cancer risk. Nevertheless, other record
linkage studies of cancer registries with cohorts of HIV-infected
persons (Clifford et al, 2005) and/or AIDS registries (Chaturvedi
et al, 2007; Polesel et al, 2010) have failed to observe any link
between CD4 þ cell counts and lung cancer risk, or any change in
risk between the pre-combined antiretroviral therapy (cART) and
cART era.
Although HIV is not considered to have any direct carcinogenic
effects (Bouvard et al, 2009), it has been hypothesised that HIV-
associated inflammation in the lungs might predispose to
Received 31 August 2011; revised 14 November 2011; accepted 25
November 2011; published online 12 January 2012
*Correspondence: Dr GM Clifford; E-mail: clifford@iarc.fr
17
The members of the Swiss HIV Cohort Study are listed in the
Appendix section.
British Journal of Cancer (2012) 106, 447 452
&
2012 Cancer Research UK All rights reserved 0007 0920/12
www.bjcancer.com
Clinical Studies
smoking-related lung damage (Engels et al, 2006), and lung cancer
in HIV-infected persons has been associated with a history of
AIDS-related pulmonary diseases (Kirk et al, 2007; Shebl et al,
2010), which are themselves related to immunodeficiency.
Our aim was to disentangle the independent effects of smoking,
HIV-related immunodeficiency and AIDS-related pulmonary dis-
eases on lung cancer among HIV-infected persons in Switzerland.
MATERIALS AND METHODS
The SHCS is an ongoing study that has been enrolling HIV-
infected persons since 1984 from seven large hospitals in Switzer-
land (http://www.shcs.ch) (Swiss HIV Cohort Study et al , 2010),
including 103 000 person-years (py) of follow-up until December
2009. Women contribute 31% of py and representation of HIV-
transmission categories are balanced between men having sex with
men (MSM), IDU and heterosexual/other (35, 29 and 36% of py,
respectively). Detailed information on all AIDS-related disease,
CD4 þ cell count and HIV-related treatments are collected at the
time of enrolment, and at each 6-month follow-up visit. Detailed
information on smoking history (in number of pack-years) has
been routinely collected from all HIV-infected persons under
active follow-up in the SHCS since April 2000, for whom current
smoking intensity, as well as number of cigarettes smoked per day,
is also recorded at each 6-month follow-up visit.
A total of 107 lung cancer cases were identified in SHCS
participants, of which 84 were identified from the SHCS database,
and 23 additional cases were identified through record linkage
with 8 Swiss Cantonal Cancer Registries (Franceschi et al, 2010). In
all, 10 patients with Kaposi sarcoma (KS) and 13 with lymphoma
localised in the lung were excluded. In addition, 6 prevalent cases
occurring before, or within 1 month of, SHCS enrolment and 10
diagnosed 46 months after the last SHCS follow-up date were
excluded, leaving 68 eligible incident cases occurring during active
SHCS follow-up (median follow-up from SHCS enrolment to lung
cancer diagnosis ¼ 7 years; interquartile range, 312 years).
Confirmation of histological subtype was available for 65 (94%)
of the 68 cases, including 21 adenocarcinoma (International
Classification of Disease in Oncology morphology codes (ICD-O)
codes 81403; 82523; 82533; 84813), 15 large cell carcinoma (80103;
80123; 80203; 80313; 80823), 14 squamous cell carcinoma (80703;
80713; 80723), 8 small cell carcinoma (80413) and 7 other specified
carcinoma (80463; 84303).
For each lung cancer case, five control subjects were matched at
random from eligible SHCS participants without lung cancer.
Eligible controls had at least the same length of follow-up as did
matched cases. Matching criteria were: (1) SHCS centre; (2) gender;
(3) HIV-transmission category (IDU, MSM, heterosexual/other);
(4) age at enrolment (as close as possible, up to a maximum of 9
years difference); (5) year at reference date (as close as possible,
but within the following calendar periods: 1985 1991; 1992 1996;
1997 April 2000; May 2000 2010). April 2000 was included as a
key date to match lung cancer cases and controls with respect to
the beginning of availability of smoking information. For 2 cases,
only 3 and 4 controls, respectively, could be matched, leaving 337
control subjects for this study (Table 1).
Markers of immunodeficiency (CD4 þ cell count; CD8 þ cell
count; CD4 þ /CD8 þ ratio; HIV viral load) were extracted from
the SHCS database at two time periods (12 years and o1 year)
before the reference date, defined for cases as the date of lung
cancer diagnosis, and for controls as that occurring after a similar
length of SHCS follow-up (to the exact day) as matched cases
before lung cancer. We additionally extracted CD4 þ cell counts at
23, 3 4, 4 5, 56, 67, 7 8, 8 9 and 9 10 years before the
reference date and calculated mean CD4 þ cell counts restricted to
cases and controls who (1) were under active follow-up and (2) had
a valid CD4 þ cell count, in each time period. If more than one
measurement for any marker of immunodeficiency was available
during any one time period, that closest to the reference date was
used. Matching was not retained in the long-term comparison and
numbers of cases and controls obviously decreased substantially as
follow-up went back in time. The nadir CD4 þ cell count, defined
as the lowest ever reported CD4 þ cell count while under active
SHCS follow-up, was also extracted for each subject.
Here, cART use was defined as the prescription of at least three
antiretroviral drugs, including a protease inhibitor or a non-
nucleoside reverse transcriptase inhibitor or three nucleosides,
including abacavir. Only persons who had used cART for 41
month before the reference date were classified as users.
The definition of AIDS-related pulmonary disease includes
recurrent bacterial pneumonia, pulmonary tuberculosis (TB), or
Pneumocystis jiroveci pneumonia, recorded at any time before the
reference date.
This study was approved by the local ethical committees of the
seven SHCS sites and of the International Agency for Research on
Cancer. Written informed consent was obtained from all SHCS
participants.
Statistical analysis
Logistic regression, conditioned on matching variables, was used
to calculate odds ratios (ORs) and corresponding 95% confidence
Table 1 Distribution of 68 lung cancer cases and 337 controls, according
to matching variables
Lung cancer Controls
N (%) N (%)
Centre
Basel 11 16.2 55 16.3
Bern 9 13.2 42 12.5
Geneva 15 22.1 75 22.3
St Gallen 7 10.3 35 10.4
Vaud 13 19.1 65 19.3
Zurich 13 19.1 65 19.3
Gender
Male 54 79.4 270 80.1
Female 14 20.6 67 19.9
HIV-transmission category
MSM 19 27.9 95 28.2
IDU 25 36.8 125 37.1
Het/other 24 35.3 117 34.7
Age at lung cancer
a
(years)
25 44 24 35.3 132 39.2
45 54 26 38.2 122 36.2
55 64 13 19.1 61 18.1
X65 5 7.4 22 6.5
Duration of follow-up before lung cancer
a
(months)
o24 11 16.2 55 16.3
24 59 13 19.1 65 19.3
X60 44 64.7 217 64.4
Calendar period at lung cancer
a
1985 1991 3 4.4 15 4.5
1992 1996 6 8.8 30 8.9
1997 April 2000 6 8.8 31 9.2
May 2000
b
2005 28 41.2 146 43.3
2006 2010 25 36.8 115 34.1
Abbreviations: Het ¼ heterosexual; IDU ¼ intravenous drug user; MSM ¼ men having
sex with men.
a
Or reference date for controls (date after a similar length of follow-up
in the SHCS as matched cases).
b
Truncation in mid-2000 to match for availability of
smoking information.
Lung cancer in the SHCS
GM Clifford et al
448
British Journal of Cancer (2012) 106(3), 447 452 & 2012 Cancer Research UK
Clinical Studies
intervals (95% CIs). Models were also adjusted for smoking status
(never/former, current with o30 pack-years, current with X30
pack-years, unknown).
RESULTS
Table 1 shows the distribution of the 68 lung cancer cases and
controls by matching variables. A majority of lung cancer cases
were male (79.4%), had been followed up in the SHCS for 45 years
before lung cancer diagnosis (64.7%) and were diagnosed after
1996 (86.8%). Intravenous drug users accounted for 36.8% of
cases. As a result of matching on these criteria, these proportions
were similar among controls. Lung cancer occurred at a mean age
of 50 years. Of the 64 lung cancer cases with follow-up post-cancer,
only 9 (14%) were still alive at 2 years after lung cancer diagnosis.
The associations of smoking, cART use, AIDS and nadir CD4 þ
cell count with lung cancer risk are shown in Table 2. Smoking
status was known for 52 lung cancer cases (76.5%) and 262
controls (77.7%) (i.e., those followed up in the SHCS after April
2000), of whom 96.2% (11.5% former, 84.6% current) of lung
cancer cases and 72.9% (24.0% former, 48.9% current) of controls
were smokers. Among controls, the prevalence of smoking was
96.0, 60.0 and 66.4% among IDU, MSM and heterosexual/others,
respectively. Lung cancer risk was very strongly associated with
current smoking (OR vs never ¼ 14.4, 95% CI: 3.3662.1), and was
also elevated, although not significantly so, among the few former
smokers (OR vs never ¼ 3.22, 95% CI: 0.6316.6). Former smokers
were at significantly lower risk than current smokers (OR ¼ 0.22,
95% CI: 0.08 0.59). Odds ratios were slightly higher among
current smokers who had smoked X30 (OR vs never ¼ 15.9, 95%
CI: 3.67 69.1) than o30 (OR vs never ¼ 11.5, 95% CI: 2.42 54.6)
pack-years. History of cART use was not significantly associated
with lung cancer risk (OR for ever vs never ¼ 0.67, 95% CI: 0.29
1.52). History of AIDS-related diseases, whether with pulmonary
disease (OR ¼ 0.49, 95% CI: 0.19 1.28) or without pulmonary
disease (OR ¼ 0.53, 95% CI: 0.241.18), was not more frequent
among cases than controls. Three, three and zero cases of
recurrent bacterial pneumonia, P. jiroveci pneumonia and TB,
respectively, were previously diagnosed among lung cancer cases.
No significant associations or trends with lung cancer were
observed for nadir CD4 þ cell count (OR for o50 vs X200 ¼ 0.73,
95% CI: 0.34 1.55).
The associations of various measures of immunodeficiency with
lung cancer risk are shown in Table 3, measured at two different
time periods with respect to lung cancer diagnosis (within 1 year
and 1 2 years before), and according to two statistical models
(unadjusted and adjusted for smoking). No significant associations
were observed between lung cancer and CD4 þ cell counts, neither
when measured within 1 year (OR for o200 vs X500 ¼ 1.21, 95%
CI: 0.492.96) or 1 2 years (OR ¼ 0.96, 95% CI: 0.41 2.24) before
lung cancer diagnosis. Similarly, no significant associations or
trends with lung cancer were observed for CD8 þ cell counts
(Table 3). A CD4 þ /CD8 þ ratio lower than 25 within 1 year
of lung cancer diagnosis showed an association with lung cancer
risk of borderline statistical significance (OR ¼ 2.15, 95% CI:
1.00 4.59), but this relationship was not seen at 1 2 years before
lung cancer diagnosis (OR ¼ 1.07, 95% CI: 0.49 2.36). Although
data on HIV viral load were available for a smaller number of cases
(n ¼ 54, 79%) and controls (n ¼ 269, 80%), no evidence of an
association of lung cancer with higher viral load was observed
within 1 year of lung cancer diagnosis (OR for X10,000 vs
o500 ¼ 1.10, 95% CI: 0.442.75).
Adjustment for smoking had no material effect on any of the
above findings (Table 3), nor did a sensitivity analysis excluding
Table 2 Relative risk for lung cancer by selected characteristics at reference date
a
Lung cancer Controls
N % N %OR
b
(95% CI)
Smoking-adjusted
OR
c
(95% CI)
Overall 68 337
Smoking status
Never 2 3.8 71 27.1 1
Former 6 11.5 63 24.0 3.22 (0.63 16.6)
Current 44 84.6 128 48.9 14.4 (3.36 62.1)
Unknown 16 75
Pack-years
d
o30 16 36.4 62 50.8 11.5 (2.42 54.6)
X30 28 63.6 60 49.2 15.9 (3.67 69.1)
Unknown 0 6
History of cART use
Never 18 26.5 77 22.8 1 1
Ever 50 73.5 260 77.2 0.67 (0.29 1.52) 0.73 (0.31 1.70)
History of AIDS-defining disease
No 54 79.4 229 68.0 1 1
Yes, without pulmonary disease
e
8 11.8 62 18.4 0.53 (0.24 1.18) 0.60 (0.27 1.36)
Yes, with pulmonary disease
e
6 8.8 46 13.6 0.49 (0.19 1.28) 0.62 (0.22 1.72)
Nadir CD4+ cell count, cells per ml
X200 31 45.6 142 42.4 1 1
50 199 26 38.2 124 37.0 0.96 (0.54 1.71) 1.07 (0.57 2.02)
o50 11 16.2 69 20.6 0.73 (0.34 1.55) 0.87 (0.39 1.90)
Unknown 0 2
Abbreviations: cART ¼ combined antiretroviral therapy; CI ¼ confidence interval; OR ¼ odds ratio.
a
See the ‘Materials and Methods’ section for definition of reference date.
b
Conditioned upon matching variables.
c
Conditioned upon matching variables and adjusted for smoking status (never/former, current with o30 pack-years, current with
X30 pack-years, unknown).
d
Current smokers only.
e
Includes recurrent bacterial pneumonia, pulmonary tuberculosis, or Pneumocystis carinii pneumonia.
Lung cancer in the SHCS
GM Clifford et al
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British Journal of Cancer (2012) 106(3), 447 452& 2012 Cancer Research UK
Clinical Studies
subjects of unknown smoking status (e.g., smoking adjusted OR
for o200 vs X500 CD4 þ cell counts at 1 2 years before lung
cancer ¼ 0.93, 95% CI: 0.31 2.76). Among controls, there were no
significant correlations between any of the markers of immuno-
deficiency with smoking status (data not shown).
Figure 1 shows mean CD4 þ cell counts from 10 years to o1
year before the reference date in lung cancer cases and controls.
There was no evidence of any difference in CD4 þ cell counts
between cases and controls in any time period before the reference
date.
DISCUSSION
Our carefully matched case control study within the SHCS
suggests no evidence for a significant effect of HIV-related
immunodeficiency on lung cancer risk in this high-risk population
(Franceschi et al, 2010). None of the classic markers of HIV-related
immunodeficiency, including low CD4 þ cell counts, high HIV
viral load nor history of AIDS or AIDS-related pulmonary disease,
showed any clear association with lung cancer in the SHCS.
A strong relationship between declining CD4 þ cell counts and
lung cancer risk was recently reported by the French Hospital HIV
Database (FHVD) (Guiguet et al, 2009), with a relative risk of 4.8
(95% CI: 2.8 8.0) for 100 199 vs 4500 latest CD4 þ . Similarly
strong relationships with CD4 þ cell counts have been reported in
two additional studies from the United States and Europe (Patel
et al, 2008; Reekie et al, 2010). Although the CIs around our risk
estimates are not entirely incompatible with those of previous
studies, the findings from the SHCS show no or little association.
The reasons for these inconsistencies are unclear, but not all
previous studies were supplemented by data linkage with cancer
registries to the same extent of the SHCS. Indeed, the FHVD has
since been estimated to be only 67% complete with respect to lung
cancer diagnosis (Lanoy et al, 2011). Thus, in HIV cohorts that
do not obtain comprehensive cancer ascertainment, the more
immunosuppressed patients may be overrepresented among lung
Table 3 Relative risk of lung cancer, by markers of immunodeficiency at two different time periods before cancer diagnosis
One to two years before lung cancer
a
Within one year before lung cancer
a
Lung cancer Controls Lung cancer Controls
N % N %OR
b
(95% CI)
Smoking-adjusted
OR
c
(95% CI) N % N %OR
b
(95% CI)
Smoking-adjusted
OR
c
(95% CI)
Overall 68 337 68 337
CD4+ cell count, cells per ml
X500 23 39.0 100 34.2 1 1 20 29.4 119 36.4 1 1
200 499 26 44.1 146 50.0 0.76 (0.41 1.43) 0.59 (0.30 1.16) 38 55.9 159 48.6 1.41 (0.78 2.54) 1.11 (0.59 2.10)
o200 10 16.9 46 15.8 0.96 (0.41 2.24) 0.97 (0.40 2.34) 10 14.7 49 15.0 1.21 (0.49 2.96) 1.19 (0.47 3.04)
Unknown 9 45 0 10
CD8+ cell count, cells per ml
X1000 28 47.5 122 41.9 1 1 26 38.2 132 40.4 1 1
500 999 25 42.4 128 44.0 0.84 (0.46 1.53) 1.05 (0.55 1.98) 35 51.5 156 47.7 1.15 (0.65 2.05) 1.11 (0.60 2.04)
o500 6 10.2 41 14.1 0.64 (0.25 1.67) 0.57 (0.20 1.58) 7 10.3 39 11.9 0.92 (0.37 2.29) 0.77 (0.30 1.97)
Unknown 9 46 0 10
CD4+/CD8+ ratio, %
X0.50 25 42.4 125 43.0 1 1 22 32.4 140 42.8 1 1
0.25 0.49 22 37.3 109 37.5 1.01 (0.53 1.90) 0.78 (0.39 1.55) 26 38.2 120 36.7 1.38 (0.74 2.57) 1.14 (0.58 2.23)
o0.25 12 20.3 57 19.6 1.07 (0.49 2.36) 0.92 (0.40 2.09) 20 29.4 67 20.5 2.15 (1.00 4.59) 2.12 (0.94 4.77)
Unknown 9 46 0 10
HIV viral load, copies per ml
o500 37 68.5 192 71.4 1 1 40 72.7 207 74.5 1 1
500 9999 12 22.2 36 13.4 1.79 (0.83 3.86) 2.05 (0.90 4.67) 8 14.5 37 13.3 1.15 (0.492.70) 1.27 (0.50 3.21)
X10 000 5 9.3 41 15.2 0.66 (0.24 1.79) 0.44 (0.15 1.29) 7 12.7 34 12.2 1.10 (0.44 2.75) 0.81 (0.32 2.07)
Unknown 14 68 13 59
Abbreviations: CI ¼ confidence interval; OR ¼ odds ratio.
a
Or before the reference date in controls (see the ‘Materials and Methods’ section for definition).
b
Conditioned upon
matching variables.
c
Conditioned upon matching variables and adjusted for smoking (never/former, current with o30 pack-years, current with X30 pack-years, unknown).
1400
1200
1000
800
600
400
200
CD4 cell count (cells per l)
0
9–10
Number of
Lung Cancer 24
31
146
34
158
38
185
35
199
42
218
50
241
60 59
268
292
68
327
113
Controls
8–9
7–8 6–7
Years before reference date
5–6
4–5
3–4 2–3 1–2
<1
Lung cancer
Controls
Figure 1 Box plots
a
of CD4 þ cell counts at yearly intervals prior to
reference date
b
, among lung cancer cases and controls.
a
Horizontal lines in
box plots represent 10th, 25th, 50th (median), 75th and 90th (percentiles).
b
See Materials and Methods section for definition of reference date.
Lung cancer in the SHCS
GM Clifford et al
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Clinical Studies
cancer cases as a consequence of investigations of AIDS-related
pulmonary diseases. Alternatively, the inability to completely rule
out KS and lymphoma localised in the lung, which contributed up
to 50% of lung neoplasms in the pre-cART era (Parker et al, 1998),
could lead to erroneous interpretations, given the strong associa-
tions of these two AIDS-defining cancers with declining CD4 þ cell
counts. In this study, histological verification allowed the exclusion
of 10 lung KS and 13 lung lymphomas. Otherwise, the distribution
of histological types were similar to those reported in other series
of HIV-positive lung cancer, as well as in age-matched series of
HIV-negative cases (Lavole et al, 2006).
Although confirmed as a very strong risk factor for lung cancer
(16-fold increase in risk for X30 pack-years), smoking behaviour
was not statistically related to markers of immunodeficiency in the
SHCS and hence would appear not to be a strong confounder of the
association between these markers and lung cancer. However,
confounding by smoking behaviour is more problematic when
comparing lung cancer between HIV-positive and HIV-negative
subjects (Engels et al, 2006; Chaturvedi et al, 2007; Shiels et al,
2010; Engsig et al, 2011). In the face of such a strong relationship,
even with adjustment for smoking measures at an individual level
(Levine et al, 2010; Shiels et al, 2010), there remains potential for
residual confounding through unmeasured differences in the
patterns (e.g., duration of the habit and time since quitting among
former smokers) of tobacco use between HIV-positive and HIV-
negative ever smokers. A two-fold excess risk of lung cancer is also
consistently seen among immunosuppressed kidney transplant
recipients (Grulich et al, 2007; van Leeuwen et al, 2010), which
might suggest a role of immunodeficiency. However, smoking is
also associated with indications for kidney transplant, so that
confounding by smoking history is also difficult to rule out in this
scenario (Wen et al, 2008).
History of AIDS-related pulmonary disease, and in particular
recurrent pneumonia, was recently linked to an increase in lung
cancer risk in the large HIV/AIDS Cancer Match study (Shebl et al,
2010), suggesting that HIV-related chronic inflammation might
potentiate the carcinogenic effects of smoking in the lung (Engels
et al, 2006). However, this study had to use hypothetical scenarios
to address the problem of confounding by smoking behaviour
(Shebl et al, 2010), which is a risk factor for both pulmonary
infections (notably TB (Lin et al, 2007; Gajalakshmi and Peto,
2009)) and lung cancer. Although our sample size was much
smaller, we were unable to reproduce evidence of such an effect in
the SHCS, where only 8.8% of lung cancer cases had a history of
AIDS-related pulmonary disease (and none with TB). This
proportion was actually slightly lower than among matched
controls, as was the proportion of patients with a history of AIDS.
In agreement with the lack of association with CD4 þ cell counts
and history of AIDS, there was no evidence for an effect of cART
use on lung cancer in the SHCS. Although other studies have
suggested that lung cancer incidence is increasing in the era of
cART (Bower et al, 2003), this phenomenon may be largely an
artefact of the increased survival of HIV-infected persons and the
inability to fully adjust for ageing and corresponding exponential
increase in lung cancer by age (Franceschi et al, 2010). Indeed,
other studies have suggested that the age-standardised incidence of
lung cancer is decreasing over time in persons infected with HIV
(Silverberg et al, 2009; Shiels et al, 2011).
If confirmed, the lack of an effect of immunodeficiency on lung
cancer risk would not lend support to a role of infection in lung
cancer aetiology. Although infection with human papillomavirus
has been suggested to have a role in lung cancer, recent large
studies in non-HIV infected persons have provided evidence
against this hypothesis, particularly among smokers (Simen-Kapeu
et al, 2010; Koshiol et al, 2011).
The SHCS has many strengths, including the duration and
regularity of follow-up and comprehensiveness of clinical and
laboratory information. Approximately half of HIV-infected
persons in Switzerland have been enrolled in the SHCS, and both
genders and different risk categories are well represented. The
supplementation of cancer diagnoses through linkage with cancer
registries (Clifford et al, 2005) meant a more comprehensive
registration of lung cancer, and the availability of histological and/
or cytological confirmation for a majority of cases. The use of a
nested case control approach allowed careful matching for many
important correlates of lung cancer risk, smoking and immune
status. The principal weakness of the study is the relative small
number of lung cancer cases that have accrued in the SHCS, which
limits the extent to which small effects of HIV-related immuno-
deficiency can be ruled out.
As repeatedly noted in HIV-infected cohorts, we observed a high
prevalence of smoking in the SHCS (73% among matched
controls), and the expected large increased risks for lung cancer
among smokers. However, an important finding of this study was
the confirmation that, although the lung cancer risk for former
smokers did not disappear, it was considerably less than that
among current smokers, as seen previously in a cohort of HIV-
infected females (Levine et al, 2010) and a number of large studies
in the general population (IARC, 2007). Thus, the beneficial effects
of quitting smoking appear, in relative terms, as important in HIV-
infected persons as in the general population (Peto et al, 2000),
although more important in absolute terms on account of their
heavy burden of lung cancer.
As HIV-infected persons live longer in the era of cART, it can be
expected that smoking will increasingly manifest its long-term
oncogenic potential and that this lethal cancer becomes an
increasingly important cause of death. Focusing on ways to help
to quit smoking (Elzi et al, 2006) would be effective in reducing
lung cancer in this high-risk population.
ACKNOWLEDGEMENTS
This study was performed within the framework of the Swiss HIV
Cohort Study, supported by the Swiss National Science Foundation
(Grant 3347-069366), assisted by grants from OncoSuisse (ICP OCS
01355-03-2003, KFS-02478-08-2009). Mauro Lise received a fellow-
ship from the Associazione Italiana per la Ricerca sul Cancro
carried out at the International Agency for Research on Cancer.
Conflict of interest
The authors declare no conflict of interest.
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APPENDIX
The members of the Swiss HIV Cohort Study are J Barth, M
Battegay, E Bernasconi, J Bo
¨
ni, HC Bucher, P Bu
¨
rgisser, C Burton-
Jeangros, A Calmy, M Cavassini, M Egger, L Elzi, J Fehr, M Flepp, P
Francioli (President of the SHCS), H Furrer (Chairman of the
Clinical and Laboratory Committee), CA Fux, M Gorgievski, H
Gu
¨
nthard (Chairman of the Scientific Board), B Hasse, HH Hirsch,
B Hirschel, I Ho
¨
sli, C Kahlert, L Kaiser, O Keiser, C Kind, T
Klimkait, H Kovari, B Ledergerber, G Martinetti, B Martinez de
Tejada, N Mu
¨
ller, D Nadal, G Pantaleo, A Rauch, S Regenass, M
Rickenbach (Head of Data Center), C Rudin (Chairman of the
Mother and Child Substudy), P Schmid, D Schultze, F Scho
¨
ni-
Affolter, J Schu
¨
pbach, R Speck, P Taffe
´
, A Telenti, A Trkola, P
Vernazza, V von Wyl, R Weber and S Yerly.
Lung cancer in the SHCS
GM Clifford et al
452
British Journal of Cancer (2012) 106(3), 447 452 & 2012 Cancer Research UK
Clinical Studies
    • "Smoking is highly prevalent among HIV-infected patients [1][2][3][4][5][6]and is strongly associated with increased prevalence of smoking-related chronic diseases.[5, 7, 8] Cardiovascular disease (CVD) risk, which is known to be heightened in HIV disease, [9][10][11][12][13]has been shown to decrease with increased time since quitting smoking in an HIV cohort.[14] Smoking-related characteristics, including degree of nicotine dependence,[15, 16] readiness to quit,[3, 15] and frequency of quit attempts,[15] have been explored for HIV-infected patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Cigarette smoking is widespread among HIV-infected patients, who confront increased risk of smoking-related co-morbidities. The effects of HIV infection and HIV-related variables on smoking and smoking cessation are incompletely understood. We investigated the correlates of smoking and quitting in an HIV-infected cohort using a validated natural language processor to determine smoking status. Method We developed and validated an algorithm using natural language processing (NLP) to ascertain smoking status from electronic health record data. The algorithm was applied to records for a cohort of 3487 HIV-infected from a large health care system in Boston, USA, and 9446 uninfected control patients matched 3:1 on age, gender, race and clinical encounters. NLP was used to identify and classify smoking-related portions of free-text notes. These classifications were combined into patient-year smoking status and used to classify patients as ever versus never smokers and current smokers versus non-smokers. Generalized linear models were used to assess associations of HIV with 3 outcomes, ever smoking, current smoking, and current smoking in analyses limited to ever smokers (persistent smoking), while adjusting for demographics, cardiovascular risk factors, and psychiatric illness. Analyses were repeated within the HIV cohort, with the addition of CD4 cell count and HIV viral load to assess associations of these HIV-related factors with the smoking outcomes. Results Using the natural language processing algorithm to assign annual smoking status yielded sensitivity of 92.4, specificity of 86.2, and AUC of 0.89 (95% confidence interval [CI] 0.88–0.91). Ever and current smoking were more common in HIV-infected patients than controls (54% vs. 44% and 42% vs. 30%, respectively, both P<0.001). In multivariate models HIV was independently associated with ever smoking (adjusted rate ratio [ARR] 1.18, 95% CI 1.13–1.24, P <0.001), current smoking (ARR 1.33, 95% CI 1.25–1.40, P<0.001), and persistent smoking (ARR 1.11, 95% CI 1.07–1.15, P<0.001). Within the HIV cohort, having a detectable HIV RNA was significantly associated with all three smoking outcomes. Conclusions HIV was independently associated with both smoking and not quitting smoking, using a novel algorithm to ascertain smoking status from electronic health record data and accounting for multiple confounding clinical factors. Further research is needed to identify HIV-related barriers to smoking cessation and develop aggressive interventions specific to HIV-infected patients.
    Full-text · Article · Apr 2016
    • "In the Swiss HIV Cohort Study, between 1995 and 2011, cancers related to smoking accounted for 23 % of all cancers among PLWH [8]. Though some research has shown a strong relationship between declining CD4+ cell counts and the risk for lung cancer [29], others [28] have found no evidence of associations between lung cancer and immunodeficiency, adding further impetus to the need for effective smoking cessation strategies in PLWH. "
    [Show abstract] [Hide abstract] ABSTRACT: Cigarette smoking remains highly prevalent among persons living with human immunodeficiency virus (HIV), estimated to be 40-75 %, and is significantly higher than what is observed among the general population. Health risks of smoking in this population include cardiovascular disease; bacterial pneumonia, chronic obstructive pulmonary disease, and other respiratory conditions; lung cancer and other malignancies; adverse cognitive and neurological outcomes; low birth weight, preterm birth, and small-for-gestational-age infants; and overall mortality. Smokers with HIV now lose more life years to smoking than they do to the HIV itself. A majority of smokers living with HIV report being interested in cessation, and a significant proportion has made recent quit attempts. There is a general paucity of large, randomized controlled trials of smoking cessation interventions among smokers living with HIV, and among the existing research, cessation rates are suboptimal. Greater resources and effort should be allocated to developing and evaluating cessation treatment modalities for smokers living with HIV. Efforts to individualize and tailor treatments to address specific client needs and comorbidities are warranted. HIV care providers and other health professionals can play a key role in improving health among this population by regularly screening for smoking and promoting cessation.
    Full-text · Article · Sep 2015
    • "Consistent with previous studies, this cohort's most commonly diagnosed NADCs included lung cancer, HL, anal cancer, and prostate cancer, as these cancers are considered less associated with the degree of HIV immunosuppression than ADCs (Frisch, Biggar, Engels, Goedert, & AIDS-Cancer Match Registry Study Group, 2001). Diagnoses of lung cancer may be related to tobacco use; up to 85% of HIV-infected persons in the USA report ever smoking (Clifford et al., 2012; Giordano & Kramer, 2005; Tesoriero, Gieryic, Carrascal, & Lavigne, 2010), although HIV likely amplifies tobacco's effects on carcinogenesis (Chaturvedi et al., 2007; Engels, Brock, et al., 2006; Kirk et al., 2007; Shebl, Engels, Goedert, & Chaturvedi, 2010). With diagnoses doubling over the time periods analyzed, HL became one of the five most common NADCs among DC AIDS cases, echoing a trend documented in the greater US population (Biggar et al., 2006; Cinti, Gandhi, & Riddell, 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: Washington, DC (DC), has among the highest AIDS prevalence and cancer incidence in the USA. This study compared cancer diagnoses and survival among AIDS cases with AIDS-defining cancers (ADCs) to those with non-AIDS-defining cancers (NADCs) in DC from 1996 to 2006. Survival by cancer type and time period was also examined for 300 individuals diagnosed with AIDS who developed cancer; 49% of AIDS cases developed an ADC. ADC cases were younger at both AIDS and cancer diagnosis and had significantly lower median CD4 counts at AIDS diagnosis than NADC cases. The most frequent cancers were non-Hodgkin lymphoma (NHL; 44% of ADC), Kaposi's sarcoma (40% of ADC), and lung cancer (20% of NADC). There was no significant difference in distribution of cancers when comparing ADCs to NADCs, or over time (1996-2001 vs. 2002-2006). Survival among NHL, oral cavity, and lung cancer cases was 0.4, 0.8, and 0.3 years, respectively; the risk of death was approximately two times higher for each of these cancers when compared to other cancers. Given the high burden of cancer and HIV in DC, early highly active antiretroviral therapy initiation, routine cancer screening, and risk reduction through behavioral modification should be emphasized to prevent cancer among HIV-infected persons.
    Article · Feb 2015
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