Role of uncontrolled HIV RNA level and
immunodeficiency in the occurrence of malignancy in
HIV-infected patients during the combination
antiretroviral therapy era: Agence Nationale de
Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort.
Mathias Bruyand, Rodolphe Thi´ ebaut, Sylvie Lawson-Ayayi, Pierre Joly,
Annie-Jeanne Sasco, Patrick Merci´ e, Jean Luc Pellegrin, Didier Neau,
Fran¸ cois Dabis, Philippe Morlat, et al.
To cite this version:
Mathias Bruyand, Rodolphe Thi´ ebaut, Sylvie Lawson-Ayayi, Pierre Joly, Annie-Jeanne Sasco,
et al.. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malig-
nancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Na-
tionale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort.. Clinical Infectious Diseases,
Oxford University Press (OUP): Policy A1 - Oxford Open Option C, 2009, 49 (7), pp.1109-16.
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Clin Infect Dis . Author manuscript
Page / 1 8
Role of uncontrolled HIV RNA level and immunodeficiency in the
occurrence of malignancy in HIV-infected patients during the combination
antiretroviral therapy era: Agence Nationale de Recherche sur le Sida
(ANRS) CO3 Aquitaine Cohort
Mathias Bruyand 1 2 , Rodolphe Thi baut
Luc Pellegrin 2 3 , Didier Neau 1 2 3 , Fran ois Dabis
1 2 , Sylvie Lawson-Ayayi 1 2 , Pierre Joly 1 , Annie-Jeanne Sasco 1 , Patrick Merci é1 2 3 , Jean
1 2 , Philippe Morlat 1 2 3 , Genevi ve Ch ne
1 2 , Fabrice Bonnet 1 2 3 *
Centre pid miologie et biostatistique
INSERM : U897 , Universit Victor Segalen - Bordeaux II
COREVIH, Coordination R gionale de la lutte contre linfection due au VIH
CHU Bordeaux , 33076 Bordeaux,FR
Service de m decine interne et maladies infectieuses
CHU Bordeaux , Groupe hospitalier Saint-Andr é , 1, rue Jean burguet 33000
* Correspondence should be adressed to: Fabrice Bonnet <firstname.lastname@example.org >
HIV-infected patients are at higher risk of malignancies. Besides traditional determinants, a specific deleterious effect of HIV and
immunodeficiency is speculated. We aimed at studying the association between immunological and virological characteristics of
HIV-infected patients in care and the risk of AIDS-defining and non-AIDS-defining malignancies.
Patients consecutively enrolled in the hospital based ANRS CO3 Aquitaine Cohort were included if their follow-up was >3 months
between 1998 and 2006. Multivariate modelling used an extended Cox proportional hazards models for time-dependent covariates
and delayed entry.
The 4,194 patients included developed 251 first malignancies during 22,389 person-years. A higher incidence of AIDS-defining
malignancies (107 cases) was independently associated with: (i) both longer and current exposures to plasma HIV RNA >500
copies/ml: Hazard ratio HR 1.27 per year; p<0.001 and HR 3.30; p<0.001, respectively, and (ii) both longer and current exposure to
CD4 count<200/mm : HR 1.36 per year; p<0.001 and HR 6.33; p<0.001, respectively. A higher incidence of non-AIDS-defining
malignancies (144 cases) was independently associated with longer and current exposure to CD4 count<500/mm (HR 1.13 per year;
p 0.01 and HR 2.07; p<0.001, respectively), and male gender (HR 1.69; p 0.02) but not plasma HIV RNA (p 0.49 and p 0.10 for
cumulative and current exposures).
Uncontrolled plasma HIV RNA was independently associated with a higher likelihood of developing AIDS-defining malignancies,
while immunosuppression was associated with a higher risk of developing any types of malignancies. Antiretroviral treatment should
aim at reaching and maintaining a CD4 count >500/mm to prevent the occurrence of malignancy, this should be integrated to
malignancy prevention policies.
MESH Keywords Adult ; CD4 Lymphocyte Count ; Cohort Studies ; Female ; Follow-Up Studies ; HIV Infections ; complications ; immunology ; Humans ; Incidence ;
Male ; Middle Aged ; Models, Statistical ; Multivariate Analysis ; Neoplasms ; epidemiology ; RNA, Viral ; blood ; Viral Load
Author Keywords HIV ; malignancy ; risk ; immunodeficiency ; CD4+ count
The association between HIV infection and the occurrence of certain types of malignancies has been established for a long time
Due to their high incidence rates among HIV-infected patients, Kaposi s sarcoma (KS), non-Hodgkin s lymphoma (NHL) and invasive
cervical cancer are considered as AIDS-defining malignancies . Their high incidence may be explained by cellular immunosuppression
and chronic infection with oncogenic viruses , . Since 1996, the substantial improvement in survival after HIV infection related to the
[1 3 ]
increasing use of combination antiretroviral therapy (cART) has been associated with changes in the spectrum of HIV morbidity and
mortality . Indeed, the incidence of non-AIDS-defining malignancies among people living with HIV is two to three times higher than
[4 –6 ]
within the general population and malignancies, whether AIDS-defining or not, have become the most frequent cause of death in
HIV-infected patients . Such an increase in the proportion of deaths due to malignancies may be explained by prolonged survival,
[6 –8 ]
Malignancy, HIV and immune deficiency
Clin Infect Dis . Author manuscript
Page / 2 8
overall ageing of the HIV-infected population and a decreasing mortality related to opportunistic infections
of traditional risk factors for malignancies, such as tobacco or alcohol consumption, infection with hepatitis B virus (HBV) or hepatitis C
virus (HCV) will act as contributing factors . In addition, the role of HIV related immunosuppression as a specific risk factor for
[14 –16 ]
non-AIDS-defining malignancies is strongly suspected, and a relationship between the risk of hepatocarcinoma and HIV related
immunosuppression was recently shown . Furthermore, a direct role of HIV in the occurrence of malignancies is suggested
Finally, as exposure to immunodeficiency or uncontrolled plasma HIV RNA viral load can be considered as cumulative over the time or
current, it remains unclear which type of exposure should be considered in assessing the risk of malignancy. Our objective was to
investigate the association between the occurrence of a first malignancy in HIV-infected patients and the immuno-virological
characteristics observed over time in a large cohort of HIV-infected patients in care, in which malignancies are prospectively recorded.
. The high prevalence
[9 –13 ]
[18 –22 ]
Data collected between January 1 , 1998 and December 31 , 2006 within the ANRS CO3 Aquitaine Cohort, a prospective
hospital-based cohort of HIV-1-infected patients under routine clinical management, in South-Western France, were used
was initiated in 1987 at the Bordeaux University hospital and in four other public hospitals by the Groupe d Epid miologie Clinique du
Sida en Aquitaine (GECSA). All adults who are in- or out-patients of the participating hospital wards, with HIV-1 infection confirmed by
Western blot testing and having given informed consent, are eligible in the cohort. Patients included in this analysis had (i) at least three
months of follow-up, (ii) at least two visits reported during the study period and (iii) at least one plasma HIV RNA and CD4 cell count
measurements documented during the study period. All morbid events are collected using the International Classification of Diseases 10th
revision codes. The codes corresponding to malignancies were extracted from the database to identify the cases. Malignancies diagnosed
before January 1 , 1998, or during the first three months of follow-up in the Aquitaine Cohort were considered as prevalent cases and
were not included in this study.
. This cohort
Risk factors and outcomes
The primary outcome was a confirmed diagnosis of a first malignancy during the follow-up period. All cases were validated through
histological reports or source medical files documenting the diagnosis. The following time-updated variables were considered: time spent
with a CD4 cell count less than two pre-defined thresholds; latest available CD4 cell count; time spent with plasma HIV RNA above
two pre-defined thresholds; latest available plasma HIV RNA measurement; duration of cART exposure and latest cART prescription. We
considered 200 CD4 /mm as a marker of severe immunosuppression and 500 CD4 /mm as a marker of immune restoration
used 500 copies/mL as the lowest threshold of plasma HIV RNA that could be detected throughout the 10-year study period. We also
considered the threshold of 10,000 copies/mL as a high level of HIV replication. To estimate the time spent with plasma HIV RNA above
the defined thresholds, we assumed that the value of the measurement reported at a given follow-up visit remained stable until the next
follow-up visit. We made the same assumptions to estimate the time spent in each CD4 cell count category and the duration of cART
exposure. When plasma HIV RNA or CD4 cell count value was missing at a recorded follow-up clinic visit, it was estimated using the
last observation carried forward method. Missing values were counted as such when the delay between the last available value and the
missing one was >6 months. cART was defined as a regimen including at least three antiretroviral drugs.
Proportional hazards regression models with delayed entry were used to estimate the association between time-updated variables,
gender, and the risk of occurrence of a first new diagnosis of malignancy for a given patient during the study period. Age was the baseline
time as, in such a Cox model, we assume that the risk of malignancy is strongly age dependent. However, this introduces a left truncation
problem and we considered a delayed entry at the date of the follow-up visit reporting the first plasma HIV RNA after January 1 , 1998.
In these survival analyses, the risk of malignancy is estimated as a function of ageing and age is not included as a variable in the models [
, . Patients without a diagnosis of malignancy and still alive on December 31 , 2006 were right-censored at the date of their last 25 26 ]
follow-up visit. The proportional hazards assumption was checked graphically and by testing interactions between covariates and time for
The main analyses considered separately AIDS-defining malignancies and non-AIDS-defining malignancies, while robustness
analyses considered KS and NHL.
In the models taking into account the latest measurement, plasma HIV RNA and CD4 cell count were considered as binary variables
(higher or lower than the threshold considered), and cART was considered as prescribed or not. All adjusted models considered the
following variables: CD4 cell count lower than the threshold pre-specified in the model (duration of exposure or latest measurement),
plasma HIV RNA higher than the threshold considered in the model (duration of exposure or latest measurement), cART exposure
(duration of exposure or last prescription) and gender. In addition to the latest values of plasma HIV RNA and CD4 cell count,
representing the current exposure, we calculated a cumulative exposure to clinically relevant cut-offs of these markers as malignancy
Malignancy, HIV and immune deficiency
Clin Infect Dis . Author manuscript
Page / 3 8
usually occurs after a long exposure to potential determinants and current values might be a consequence rather than a cause of
malignancy. Both types of summary statistics are studied in separate models since they are highly correlated. The models were compared
with the Akaike criterion (AIC), the lower the better fit.
In all analyses, patients affected by a malignancy that was not included in the outcome definition were right-censored at the time of the
diagnosis. This means that the follow-up of patients affected by an AIDS-defining malignancy was right-censored while the hazard of
non-AIDS-defining malignancies was estimated. As a history of malignancy was an exclusion criterion, no prevalent cases were included.
Due to incomplete data regarding traditional risk factors for non-AIDS malignancies (tobacco consumption, HBV and HCV
infections), they were not considered in the analyses performed on the entire dataset. Hence, a robustness analysis adjusted for these risk
factors, considering them as fixed-effect variables, was conducted on patients with available data concerning tobacco consumption, HBV
and HCV infections. SAS software (version 9.1, SAS Institute, Cary, NC) was used to perform the analyses.
During the study period 4,828 patients were followed-up in the ANRS CO3 Aquitaine Cohort, 324 of them had a diagnosis of
malignancy at study entry and were excluded from the analyses. In addition, 310 patients did not meet the study inclusion criteria. Thus,
among 4,194 eligible patients, accounting for 22,389 person-years (py), 251 first new diagnosis of malignancy were validated through
histological (111 cases) or medical reports (140 cases). The cohort was predominantly male (72 ), the 144 non-AIDS-defining
malignancies and the 107 AIDS-defining malignancies were experienced by 83 and 78 men. The incidence rates of AIDS-defining
malignancies were 5.2 cases per 1,000 py (95 Confidence Interval CI : 4.1 6.4) in men and 3.6 cases per 1,000 py (95 CI: 2.1 5.1)
in women. The incidence rates of non-AIDS-defining malignancies were 7.5 cases per 1,000 py (95 CI: 6.1 8.8) in men and 3.8 cases
per 1,000 py (95 CI: 2.3 5.3) in women. shows the distribution of malignancies and the characteristics of these patients.
Among the 97,893 follow-up visits recorded during the study period, 5,033 concerned patients affected by a malignancy. At least two
plasma HIV RNA and CD4 measuremens were reported among 4,145 patients (240 malignancies) and 4,155 patients (241 malignancies),
Both CD4 <200 cells/mm and plasma HIV RNA viral load >500 copies/mL were strongly and independently associated with a
higher risk of AIDS-defining malignancy, whatever the type of exposure considered (cumulative or current:
of exposure to cART was associated with a lower risk of AIDS-defining malignancy, while current exposure to cART and gender were not
related to the hazard of AIDS-defining malignancy (). table 2
). Each additional year table 2
Sixty-one cases of NHL were diagnosed over the study period among the 4,194 patients included, accounting for 57 of all diagnoses
of AIDS-defining malignancies. Current exposure to both plasma HIV RNA viral load >500 copies/mL and CD4 <200 cells/mm was
independently associated with a higher hazard of NHL: Hazard Ratio (HR) 3.02 (95 CI: 1.65 5.52; p <0.001) and HR 5.12 (95
CI: 3.01 8.70; p <0.001), respectively.
Considering the cumulative exposure, each year spent with plasma HIV RNA viral load >500 copies/mL and CD4 <200 cells/mm
was independently associated with a higher risk of NHL: HR 1.34 (95 CI: 1.19 1.51; p <0.001) and HR 1.31 (95 CI: 1.12 1.53; p
<0.001), respectively; whereas each year of cART exposure was associated with a lower risk of NHL: HR 0.86 (95 CI: 0.75 0.98).
In another adjusted model, each year spent with a plasma HIV RNA viral load >10,000 copies/mL was associated with a higher hazard
of NHL (HR 1.59; 95 CI: 1.38 1.83; p <0.001), while each year spent with a CD4 <200 cells/mm and each year of cART exposure
tended to be associated with a higher risk (HR 1.18; p 0.057) and a lower risk of NHL (HR 0.88; p 0.052), respectively. Thirty-nine
cases of KS were reported among the 4,194 patients, accounting for 36 of the AIDS-defining malignancies diagnosed. Multivariable
analyses considering cumulative exposure showed that each year spent with CD4 <200 cells/mm was associated with a higher hazard of
KS (HR 1.55, 95 CI: 1.24 1.93; p <0.001), whereas remaining with a plasma HIV RNA viral load >500 copies/mL did not affect the KS
hazard (p 0.22). Female gender was associated with a lower incidence of KS (HR 0.13; 95 CI: 0.03 0.53; p 0.005).
A CD4 cell count <500 cells/mm was independently associated with a higher hazard of non-AIDS-defining malignancy, whatever
the exposure considered ( ). Plasma HIV RNA and cART were not associated with the risk of non-AIDS-defining malignancy, table 3
whatever the model considered, while female gender was related to a lower hazard (
HIV RNA and considering the cumulative exposure led to similar results (data not shown). In analyses considering lower thresholds for
CD4 cell count, each year spent with CD4 <200 cells/mm was independently associated with a higher risk of non-AIDS-defining
malignancy (HR 1.16, 95 CI: 1.04 1.30; p 0.01).
). Analyses using higher thresholds for plasmatable 3