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Annals of Oncology
26. Pettengell R, Schmitz N, Gisselbrecht C et al. Rituximab purging and/or maintenance
in patients undergoing autologous transplantation for relapsed follicular lymphoma: a
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28. Gisselbrecht C, Schmitz N, Mounier N et al. Rituximab maintenance therapy after
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Annals of Oncology 27: 397–408, 2016
doi:10.1093/annonc/mdv606
Published online 17 December 2015
Non-AIDS-related malignancies: expert consensus
review and practical applications from the
multidisciplinary CANCERVIH Working Group
J.-P. Spano1,2,3*, †, I. Poizot-Martin4,5,†, D. Costagliola2,3, F. Boué6,7, O. Rosmorduc8,9, A. Lavolé10,
S. Choquet2,3,11, P.-E. Heudel12, V. Leblond8,11,13, J. Gabarre11, M.-A. Valantin2,3,14, C. Solas15,
A. Guihot8,16, G. Carcelain8,13, B. Autran8,13, C. Katlama2,3,14 & L. Quéro17,18
1
Department of Medical Oncology, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, AP-HP, Paris; 2INSERM, UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de
Santé publique, Paris; 3Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, UPMC Université Paris 06, Paris; 4Clinical Immunohaematology
Service, Université Aix-Marseille, AP-HM Sainte-Marguerite, Marseille; 5INSERM, U912 (SESSTIM), Marseille; 6Department of Internal Medicine and Immunology, Hôpital
Antoine Béclère, Clamart; 7Faculty of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre; 8Faculty of Medicine, Sorbonne Universités, UMPC Université Paris 06, Paris;
9
Hepatology Service, Hôpital Saint-Antoine, Paris; 10Pneumology Service, Hôpital Tenon, Paris; 11Department of Hematology, Groupe hospitalier Pitié-Salpêtrière-Charles
Foix, Paris; 12Medical Oncology Service, Centre Léon Bérard, Lyon; 13Centre for Research in Immunology and Infectious Diseases, Sorbonne Universités, UPMC Université
Paris 06, Paris; 14Department of Infectious Diseases, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, Paris; 15Laboratory of Pharmacokinetics and Toxicology, Hôpital de
La Timone, Marseille; 16Department of Immunology, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, Paris; 17Department of Oncology and Radiotherapy, Hôpital Saint
Louis, Paris; 18INSERM UMR_S 965, Université Paris Denis Diderot, Paris, France
Received 10 June 2015; revised 26 October 2015 and 29 November 2015; accepted 1 December 2015
Malignancies represent a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients.
The introduction of combined antiretroviral therapy has modified the spectrum of malignancies in HIV infection with a
decreased incidence of acquired immunodeficiency syndrome (AIDS) malignancies such as Kaposi’s sarcoma and nonHodgkin’s lymphoma due to partial immune recovery and an increase in non-AIDS-defining malignancies due to prolonged survival. Management of HIV-infected patients with cancer requires a multidisciplinary approach, involving both
oncologists and HIV physicians to optimally manage both diseases and drug interactions between anticancer and antiHIV drugs. The French CANCERVIH group presents here a review and an experience of managing non-AIDS malignancies in HIV-infected individuals.
Key words: cancer, AIDS, HIV, treatment, review
introduction
The CANCERVIH working group is a national French multidisciplinary network dedicated to human immunodeficiency virus
*Correspondence to: Prof. Jean Philippe Spano, Department of Medical Oncology, PitieSalpetriere Hospital, 47 bld l’hopital, Paris 75013, France. Tel: +33-1-42-16-04-72; Fax:
+33-1-42-16-04-69; E-mail: [email protected]
†
Both authors contributed equally to the work.
(HIV)-infected patients with cancer and funded by the French
National Cancer Institute (INCa).
The backbone of this network is based upon the creation of a
multidisciplinary national board, namely CANCERVIH, which
is closely associated with local or regional-specific multidisciplinary board from every center participating in this working
group. The national CANCERVIH is constituted by experts, and
also for some of them, more specifically specialized in AIDS and
non-AIDS malignancies. Since May 2014, the role of this unique
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
reviews
national board CANCERVIH is to analyze and to propose
therapeutic strategy for HIV-positive patients with malignancies
during bimonthly national web conference.
Each CANCERVIH expert carried out a systematic literature
review of non-AIDS-related malignancies using the Medline
database (from January 1990 to October 2015). Each expert of
the working group independently evaluated publications and
submitted preliminary recommendations to the CANCERVIH
expert panel. Each preliminary recommendation was then discussed within the CANCERVIH group and adopted by qualified
majority. One of the most recent and significant recommendation approved in France was to propose a systematic HIV
screening test for all new cases of malignancies in patients from
the general population, mentioned in the Morlat report [1].
Malignancies have always been a major feature of HIV/AIDS
from the start of the epidemics in the early 1980s with the
emergence of Kaposi’s sarcoma (KS) in young gay men with
an unusual immune deficiency later called Acquired Immune
Deficiency Syndrome (AIDS) to the large pandemics of current
times. While AIDS-related cancers—mostly virally induced
such as Kaposi’s sarcoma (KS), associated with HHV8, cervical
cancer associated with oncogenic human papillomavirus (HPV)
types [2–4] and non-Hodgkin lymphoma (NHL) associated
with Epstein Barr virus (EBV) in ∼30% of diffuse large B-cell
lymphoma [5–7] and 50% of Burkitt lymphoma—still represent
a major cause of mortality and morbidity in late presenters
worldwide, combined antiretroviral therapy enabling durable
control of viral replication has led to increased life expectancy
with malignancies therefore taking a longer time to develop.
Indeed, currently, all HIV-infected patients are likely to receive
combination anti-retroviral therapy (cART) irrespective of their
CD4 cell count. Lastly, due to multiple factors, the incidence of
non-AIDS-defining cancers in such patients is two to three times
more frequent than in the general population [8–10]. Several
guidelines and reviews have already been published for HIVinfected patients with cancer [11], cervical cancer [12], KS [13],
malignant lymphoma [14] and for chemotherapy in HIV-infected
patients [15]. The objective of this article was to provide an update
on current therapeutic approaches for the main non-AIDS-related
malignancies with a particular focus on drug–drug interactions.
epidemiology and risk factors
Cancer is a frequent comorbidity in HIV-infected individuals
and in 2010, represented 34% of the causes of death in France
[2]. In a meta-analysis of studies conducted in the cART era [9],
the relative risks compared with the general population differ
widely according to cancer type, the highest being for anal cancer
(47) and Hodgkin’s lymphoma (HL) (19) with lung cancer much
lower (3.5), whereas the relative risk for liver cancer depends a lot
on the frequency of HCV co-infection; these four cancers are
the most frequent non-AIDS-defining cancers in HIV-infected
individuals. Interestingly, the relative risks for breast and prostate cancer, two hormone-dependent cancers, were <1 (0.6 for
both) in the same meta-analysis.
After adjusting for the difference in age distribution between
individuals with AIDS or HIV infection and the general population, Shiels et al. showed that the differences in median age at
diagnosis were modest and most were not significant [16],
 | Spano et al.
Annals of Oncology
whereas Hleyhel et al. also found modest differences except for
liver cancer in HBV or HCV co-infected individuals (11 years
younger) [17], dismissing the hypothesis of general accelerated
aging in HIV-infected individuals [18, 19].
Recent papers on the risk of anal cancer in HIV-infected individuals show an increased risk in the cART era compared with
the pre-cART era [20–22]. This is consistent with the finding
that duration of immunodeficiency and not current CD4 cell
count level is a risk factor for anal cancer [23]. Palefsky and
Holly [24] have posited that immune suppression affects earlier
stages of HPV-related intraepithelial neoplasia, but plays a small
role in progression to invasive cancer.
The risk of HL, lung and liver cancers is also elevated in organ
transplant recipients [8], and immunodeficiency is a risk factor
for these cancers, even when accounting for tobacco exposure for
lung cancer or HBV/HCV status for liver cancer [23, 25].
Lung cancer is the only frequent cancer in HIV-infected patients
not known to be associated with viral infection and the proportion
of smokers is higher in HIV-infected individuals than in the
general population. Several studies have suggested that HIV infection is associated with the risk of lung cancer even after adjusting
for cigarette smoking [26–28], although Helleberg et al. have
shown that nonsmoking HIV patients did not have increased risk
of nonvirological cancers compared with nonsmoking controls
[29]. Persistent inflammation and activation, commonly described
in HIV patients even with controlled viral load under cART, have
been shown to increase the risk of lung cancer in non-HIVinfected individuals [30]. In addition, smoking may act synergistically on HIV infection to increase immune activation and therefore
the risk of lung cancer in smoking HIV-infected individuals [31].
Finally, given the link between the different cancers and immunodeficiency, one may expect a lower risk in treated patients
with recovered immunity (CD4 cell count >500/µl) or who initiate cART with maintained CD4 levels. However, in Silverberg
et al. paper, the relative risks in HIV-infected patients with a
current CD4 cell count >500/µl compared with non-HIVinfected individuals was still highly significant for anal cancer
(34) and HL (13.5), but no higher for lung (1.2) and liver cancer
(1.0) [25]. In the FHDH ANRS CO4, the relative risk in HIVinfected individuals with a CD4 cell count >500/µl for at least 2
years and a controlled viral load was still elevated relative to the
general population for HL (9.4) and liver cancer (2.4) but no
higher for lung cancer (0.9) [17].
The new WHO guidelines recommending initiation of cART
regardless of CD4 cell count should therefore result in decreasing excess risk in the future for the most frequent non-AIDS-defining cancers except for anal cancer in individuals diagnosed
with a low CD4 cell count [32].
nonsmall-cell lung cancer
diagnosis
The high prevalence of smoking in the HIV-infected population
is a primary contributor to the increased risk of nonsmall-cell
lung cancer (NSCLC) compared with the general population
[29, 33] and treatment of tobacco abuse is highly recommended
[34]. NSCLC represents 86%–94% of HIV lung cancer cases as in
the general population and adenocarcinoma is the most common
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Annals of Oncology
histological type [35]. The incidence of epidermal growth factor
receptor (EGFR) mutations and anaplastic lymphoma kinase
(ALK) rearrangement in HIV NSCLC is not known. However, a
low prevalence is expected according to the demographic characteristics of the HIV–NSCLC population. Indeed, such mutations
are observed more frequently in nonsmokers in the general
population. Most HIV-infected patients with lung cancer often
present common features at diagnosis, such as respiratory signs
and several symptoms due to advanced stage.
prognosis
The reasons for poorer prognosis in HIV–NSCLC cases compared
with the general population remain unclear [36–40]. A large recent
study based on cancer registry in the United States showed that
1058 HIV-infected patients with LC experienced higher cancerspecific mortality compared with 327 866 non-HIV-infected
patients with LC even after stratification on stage and treatment
[hazard ratio (HR), 1.28; 95% confidence interval (CI) 1.14–0.144],
suggesting a role played by persistent immunodepression [41].
However, from 2001 to 2004 in France, the 5-year survival rate in
HIV-infected patients with lung carcinoma (LC) was similar
compared with the general population (17%versus 17%) [42].
management
The therapeutic recommendations are based on NSCLC clinical
practice guidelines in the general population [43, 44].
Surgery should be the treatment of choice in early-stage
disease. Patients with locally advanced disease should be offered
chemoradiotherapy.
In first-line metastatic disease, patients should be screened for
EGFR mutations and ALK rearrangement. In the absence of an
oncogenic driver, standard chemotherapy regimens are indicated, with particular attention to drug interactions [45, 46].
Prospective studies should be strongly encouraged. In July
2015, the IFCT (Francophone Thoracic Cancerology Intergroup)
completed a phase II, multicenter study dedicated to HIV NSCLC
evaluating carboplatin and pemetrexed (NCT01296113 clinical
Trials.gov). The National Cancer Institute (NCI) promotes a
phase I Pharmacokinetic Study of Erlotinib for advanced NSCLC
in persons with HIV Infection (NCT02134886 clinicalTrials.gov).
Preclinical in vivo assessment showed that CYP3A4 inhibitors
alter the exposure of erlotinib: ritonavir resulted in a 3.0-fold increase in erlotinib area under curve [47]. Consequently, pending the
results of the NCT02134886 trial, erlotinib should be used with
caution in patients on a ritonavir-containing antiretroviral regimen.
For second-line treatment in advanced disease, two phase III
trials have demonstrated an improvement in overall survival in
the general population with immune checkpoint inhibitors
(nivolumab) compared with docetaxel with a better toxicity
profile (respectively, 9.2 versus 6 months, HR, 0.59; 95% CI
0.44–0.79 for squamous NSCLC and 12.2 versus 9.4 months,
HR 0.73; 96% CI 0.59–0.89 for nonsquamous NSCLC) [48, 49].
The efficacy and safety of such novel therapy have to be proven
in HIV-NSCLC. One phase I study of ipilimumab plus nivolumab in advanced HIV-associated solid tumors is currently
recruiting (NCT02408861 clinicalTrials.gov). Given the potential impact of such novel therapies on HIV infection, there is an
urgent need for prospective studies.
Volume 27 | No. 3 | March 2016
screening
In the general population, the randomized National Lung
Screening Trial showed a significant 20% lung cancer mortality
reduction and a 6.7% overall mortality reduction in current
or heavy smokers aged 55–74 years (with at least a 30-pack-peryear smoking history) undergoing three annual low-dose computed tomography (CT) chest scans versus radiography [50].
A recent study, the ANRS EP48 HIV CHEST, demonstrated that
chest CT was a safe and effective procedure to detect lung
cancers, most of them at early stages, in HIV-infected heavy
smokers [51]. However, another lung cancer screening trial of
224 HIV-infected current/former smokers were not convincing,
given that, in this study, only one lung cancer was detected in
678 patient years [52]. Finally, there is insufficient evidence to
recommend NSCLC screening with low-dose CT in asymptomatic persons.
hepatocellular carcinoma
diagnosis
Between 1996 and 2009, there was an increase in the proportion
of in-care HIV-infected patients with cirrhosis, decompensated
cirrhosis and hepatocellular carcinoma (HCC). The risk factors
associated with a higher likelihood of cirrhosis and HCC in
HIV-infected patients were hepatitis B virus (HBV), hepatitis C
virus (HCV), age, diabetes, low CD4+, alcohol abuse, Hispanic
ethnicity. [53]. In addition, those who did not undergo a screening program exhibited more advanced tumor stage and liver
failure or cirrhosis decompensation than those diagnosed
through screening [53, 54]. Therefore, active HCC-screening programs in the HIV-infected patients may lead to better survival
(61% versus 15% at 36 months) [54]. British HIV Association,
European Association for Study of the Liver (EASL), European
Society for Medical Oncology (ESMO) and American
Association for the Study of Liver Disease (AASLD) guidelines
recommend screening for patients with hepatitis and HIV co-infection [55–58]. Strength of recommendation regarding active
HCC-screening programs is 1B according to grade system [56].
While achievement of a sustained viral response in HCV-infected
patients is associated with a low risk of developing clinical decompensation, the risk of developing an HCC is not fully abrogated
but is attenuated by 50%–75% following HCV clearance. The
new interferon-free anti-HCV regimens with short treatment
duration and fewer side-effects, available in both HCV-infected
and co-infected patients from 2015, should similarly decrease the
HCC risk in these patients.
treatment
curative treatment. According to the Barcelona Clinic Liver
Cancer (BCLC) staging system, liver transplantation (LT),
resection or radiofrequency ablation are recommended as early
HCC treatment options (Figure 1) [54, 56]. LT should be
considered in patients with a solitary lesion of <5 cm or three
nodules <3 cm (Milan Criteria) that are not suitable for resection.
HCC represents a growing indication for the requirement of LT
in HIV-infected patients who fulfill these criteria [59–62].
When a long waiting time (>6 months) for LT is anticipated,
patients may be offered additional liver resection, local ablation
doi:10.1093/annonc/mdv606 | 
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Annals of Oncology
HCC
Stage 0
PS 0,
child-pugh A
Very early
stage
1 HCC <2 cm
Carcinoma
in situ
1 nodule
Portal
pressure
/bilirubin
No
Resection
Stage A-C
PS 0–2,
child-pugh A-B
Intermediate
stage B
Multinodular
PS 0
Early
stage A
1 HCC or
3 nodules
<3 cm, PS 0
Stage A-C
PS >2,
child-pugh C
Advanced
stage C
Portal invasion
N1,M1; PS 1–2
Terminal
stage D
3 nodules £ 3 cm
Chemo
embolization
Yes
Sorafenib
Supportive care
Associated
diseases
No
Yes
Liver
transplantation
PEI/
RF
PEI: percutaneous ethanol injection; RF: radiofrequence; PS: performance status;
HCC: hepatocellular carcinoma
Figure 1. Curative and palliative treatment assignment of hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging
system (adapted from a previous study [56]).
Table 1. Immunological and virological criteria necessary for
considering liver transplant in HIV-related patients (adapted from
Nunnari et al. [64])
Immunological criteria
No AIDS-defined opportunistic infections within the previous year
CD4 cell count >200 cells/μl or >100 cells/μl in cases of therapy
intolerance
Virological criteria
• Undetectable HIV viral load (<50 copies/ml) in the last 12 months or
effective therapeutic options for HIV infection during the posttransplant period
•
•
AIDS, acquired immunodeficiency
immunodeficiency virus.
syndrome;
HIV,
human
using radiofrequency or chemoembolization (see infra) in order
to minimize the risk of tumor progression. The results of a case–
control study on HCC patients who were scheduled for an LT
(21 HIV-infected patients and 65 non-HIV-infected controls)
demonstrated that there was a trend toward a higher dropout
rate among HIV-infected patients compared with non-HIVinfected ones (23% versus 10%) on a waiting list for an LT,
despite both groups exhibiting similar initial tumor stages [63].
OS following LT at 1 and 3 years reached 81% and 74% in HIVinfected patients, compared with 93% and 85% in non-HIVinfected, respectively (P = 0.08). Due to the higher dropout rate
 | Spano et al.
among the HIV-infected patients, HIV infection may therefore
impair the results of LTs for HCC on an intent-to-treat basis,
though it was found to have no significant impact on OS or
relapse-free survival after LT.
Conversely, there were no differences observed in HCC recurrence (7% versus 14%, respectively) or survival rates (65%
versus 70% at 3 years) between the 30 HIV-infected patients and
the 125 non-HIV-infected controls who underwent LT for HCC
[61]. The criteria for considering LT in HIV-infected patients
have recently been outlined and are similar to those applied to
non-HIV-infected patients, except for those with specific immunological and virological features (Table 1) [64].
noncurative treatment. For HIV-infected patients, candidates
for transarterial chemoembolization include those with either
Child–Pugh A or B liver function and those with BCLCclassified intermediate stage B HCC, including patients with
unresectable, multinodular or large tumors (as recommended
for non-HIV-infected patients) (Figure 1).
A more aggressive clinical course of HCC was evidenced in
an HIV/HCV-co-infected group, defined as exhibiting shorter
survival time. In a recent multivariate analysis, α-fetoprotein
level, Child–Pugh C classification, and the size of the largest
nodule emerged as independent prognostic factors, while HIV
status was not associated with survival [65].
Owing to the absence of large randomized trials, it is difficult
to confirm the efficacy and tolerance of the reference treatment,
sorafenib, in HIV-infected patients undergoing HAART. However,
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Annals of Oncology
a recent study involving 27 patients reported a median OS of 12.8
months and time to progression of 5.1 months with this combination, similar to the findings reported in the pivotal SHARP study.
The same applied to the tolerance (Grade 3–4 adverse event)
observed: diarrhea 14.8%; hypertension 11%; hand–foot skin reaction 14.9%; all of which suggest that this treatment may also
benefit HIV-infected patients. However, most HIV-infected
patients are excluded from clinical trials, partly due to the risk of
potential drug interactions and side-effects [66, 67].
screening
Surveillance of patients at risk for HCC should be carried out by
abdominal ultrasound every 6 months. Noninvasive diagnosis
of HCC (i.e. without liver biopsy) is only possible in cirrhotic
patients and requires state-of-the-art imaging techniques (multiple-phase multidetector CT scan and/or dynamic contrastenhanced MRI), with identification of the typical vascular hallmark of HCC (hypervascular in the arterial phase with washout
in the portal venous or delayed phases).
anal cancer
diagnosis
HIV-infected patients with anal carcinoma are younger than
non-HIV-infected patients with a median age at diagnosis of 45
versus 60 years, respectively. A majority of HIV-infected
patients with anal cancer are men and most of them have sex
with men [68].
The prevalence of HPV infection is ∼90% in HIV-infected
patients with anal cancer [69, 70]. In the EDITH V study,
Abramowitz et al. reported that HIV-infected patients had a
higher proportion of multiple HPV infection than non-HIVinfected patients with an under-representation of the HPV16
genotype. The proportion of multiple HPV infections was significantly higher among HIV-infected than among non-HIVinfected patients (56.0% versus 19.6%, respectively) [69]. Anal
intraepithelial neoplasia (AIN) of all grades affects ∼70%–80%
of HIV-infected men who have sex with men, with high-grade
intraepithelial neoplasia in 25%–50% [71, 72]. In this population, disease progression rates from high-grade intraepithelial
neoplasia to invasive anal cancer have been reported to be
∼15% [73].
prognosis
Several retrospective studies have reported overall 5-year survival of 62%–67% after chemoradiotherapy in HIV-infected
patients which is comparable with the rate for HIV-uninfected
patients (Table 2). However, some studies have reported highlocal recurrence rates (30–60%) and low sphincter preservation
in HIV-infected patients in comparison with HIV-uninfected
patients (25%–30%). This higher local recurrence rate observed
in some studies may be due to lower tolerance of chemoradiotherapy among HIV-infected patients resulting in prolonged overall
treatment time compared with HIV-uninfected patients [77].
treatment
The treatment of anal cancer in HIV-infected patients does not
differ from non-HIV-infected patients.
Table 2. Results from studies of anal cancer in HIV-infected patients treated during cART era
Authors
Date of
publication
Patients
(n)
Treatment
Median follow-up
(months)
Cleator et al. [74]
2000
12
58
Stadler et al. [75]
2004
8
Wexler et al. [76]
2008
32
Oehler-Janne et al. [77]
2008
40
Seo et al. [78]
2009
10
Hogg et al. [79]
2009
21
Abramowitz [80]
2010
44
Fraunholz et al. [81]
2010
21
Munoz-Bongrand et al. [82]
2011
20
RCT
5-FU/MMC
RCT
5-FU/CDDP
RCT
5-FU
MMC or CDDP
RCT
5-FU
MMC or CDDP
RCT
5-FU/MMC
RCT
5-FU/MMC
RCT
5-FU/CDDP
RCT
5-FU/MMC
RCT
5-FU/CDDP
Local
control rate
Overall
survival rate
82%
64%
24
50%
75%
35
91%
84%
60%
(5 years)
67%
(3 years)
65%
(5 years)
36
92%
38%
61%
(5 years)
100%
94%
37
81%
71%
27
82%
87%
53
81%
59%
32.5
70%
50%
92%
(3 years)
73%
(3 years)
85%
(3 years)
67%
(5 years)
39%
(5 years)
37.2
Clinical complete
response rate
RCT, radiochemotherapy; 5-FU, 5-fluorouracil; CDDP, cisplatin; MMC, mitomycin C.
Volume 27 | No. 3 | March 2016
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Whenever possible, management of patients is recommended
in centers with both specific expertise and a multidisciplinary
approach, in order to provide optimal care [11, 83].
For localized anal cancer (tumor size ≤2 cm without lymph
node involvement), exclusive radiotherapy is recommended.
For locally advanced anal cancer (tumor size >2 cm or lymph
node involvement), standard therapy combines radiotherapy
with concurrent 5-FU-MITOMYCINE C chemotherapy [84].
It has been reported that HIV-infected patients exhibit lower
treatment tolerance with higher rates of severe acute skin,
gastrointestinal and hematologic toxicities during chemoradiotherapy, which leads to prolonged overall treatment time
compared with non-HIV-infected patients [68,74,77,81,82].
New radiation techniques, such as intensity-modulated radiation therapy or volumetric modulated arc therapy may decrease
skin, bowel or hematological radiotherapy-induced toxicities.
Localized relapse or persistent disease following chemoradiotherapy is treated using abdominoperineal resection with a
permanent iliac colostomy [85].
5-FU plus CDDP combination chemotherapy is the most
common treatment regimen used for recurrent or metastatic
anal cancer [86, 87].
screening
There are no definitive guidelines for the screening of anal
cancer. Screening for people at high risk for AIN consists in
anal cytology testing (Pap tests) and digital anal examination. If
digital anal examination reveals a macroscopic lesion or the anal
Pap test reveals any abnormalities, high-resolution anoscopy
should be carried out.
Annals of Oncology
In advanced cases, six to eight cycles of ABVD are recommended, leading to complete response rates of >85%, which is
similar to that for non-HIV patients [90, 91, 93, 94]. A German
group used the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP)
baseline combination in advanced HIV-HL patients, achieving a
2-year OS rate of 87%, though resulting in 7% toxic mortality
[90]. For this reason, ABVD should be kept as the standard of
choice, but if BEACOPP is used no more than six cycles should
be administered given that, in the German study, three of four
patients with fatal neutropenic sepsis had experienced their fatal
event after the seventh and eighth cycle of BEACOPP.
Some prognostic factors have been identified for HIV-HL
cases: high IPS [91, 94], stage III–IV [91], no complete response
[90] and CD4 <200 cells/µl [94].
While the use of granulocyte colony-stimulating factor as a
support following AVBD is controversial in non-HIV patients,
it is necessary in HIV+ patients due to the increased hematological toxicity that causes frequent delays in administering
ABVD [93].
salvage therapy
The standard of care in refractory or relapsing patents is the
same for both HIV-positive and -negative patients, i.e. salvage
treatment followed by high-dose therapy and autologous stemcell transplant. HIV infection has been proven to not impair
graft collection or engraftment, and early and long-term adverse
events occur in a similar fashion to those observed in non-HIVinfected patients [95]. New drugs are now available for HIVnegative patients, such as brentuximab vedotin, which can be
used in the same way as for HIV-infected patients [96].
Hodgkin’s lymphoma
Unlike other tumors, the risk of HL was found to not be reduced in
the ART era, mixed cellularity (MC) remains the most frequent
histology but frequency of nodular sclerosis clearly increases [88].
The histologic subtypes of 848 HIV-HL patients are MC, nodular
sclerosis and classical HL not otherwise specified in 35%, 30% and
38%, respectively [88]. In the French ANRS CO16 LYMPHOVIR
cohort of 68 patients, histological distribution was 42 MC and 12
scleronodular HL. Fourteen cases could not be classified because
the diagnosis was done on bone marrow, liver or small-needle biopsies [89]. The oncogenic role of EBV appears highly significant, as
most cases of HIV-HL are associated with this virus. HIV-HL
patients often present with advanced disease (stage III or IV), extranodal involvement, high frequency of B symptoms, altered performance status, higher International Prognostic Score (IPS) and
older age [89–93]. Nevertheless, patients with limited-stage disease
(I or II) represent 20%–35% of all cases.
first-line therapy
In stages I or II, the standard treatment consists of chemotherapy [two to four cycles of doxorubicin, bleomycin, vinblastine
and dacarbazine (ABVD), according to prognostic factors collected during staging], followed by involved-field irradiation.
This treatment provides similarly good results to those found
for non-HIV patients, with reported complete remission rates of
>90% [90, 91].
 | Spano et al.
antiretroviral treatments
The current guidelines, in 2015, recommend starting ART in
any HIV-infected patient independently of CD4 lymphocyte
count [97]. Indeed, the early control of HIV replication is associated with optimal survival, less comorbidities and a massively
reduced risk in HIV transmission. In patients receiving antiretroviral therapy, antiretroviral treatment should be continued
during chemotherapy [97–102]. However, ART has to be
adjusted to avoid drug interactions with chemotherapy leading
potentially to higher toxicity (Table 3). The following should
preferably be used: nucleoside reverse-transcriptase inhibitors,
such as abacavir, emtricitabine or lamivudine; non-nucleoside
reverse-transcriptase inhibitors—mostly rilpivirine; all integrasestrand transfer inhibitors, except elvitegravir; CCR5 antagonists.
The management of antiretroviral drug and cytotoxic agent coadministration often requires expert knowledge and experience
in order to reduce drug interactions and maintain virus control,
with decisions made based on treatment history and drug-resistance tests.
pharmacological aspects and drug
interactions
The pharmacological issues involved in the treatment of HIVinfected patients with malignancies not only concern
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Annals of Oncology
Table 3. Toxicities from antiretroviral treatment
Toxicities
Nucleoside reverse-transcriptase inhibitors
Tenofovir
Decreased bone-mineral density, osteomalacia, increased risk of fractures, decreased eGFR, Fanconi syndrome
Emtricitabine/lamivudine
Abacavir
Rash, nausea, diarrhea, ischemic heart disease, systemic hypersensitivity syndrome (HLA B*5701-dependent)
Stavudine
Pancreatitis, steatosis, peripheral neuropathy, lipodystrophy, dyslipidemia, hyperlactatemia
Didanosine
Pancreatitis, steatosis, peripheral neuropathy, lipodystrophy, hyperlactatemia, ischemic heart disease, obliterative portal venopathy
Zidovudine
Nail pigmentation, nausea, steatosis, myopathy, rhabdomyolysis, dyslipidemia, hyperlactatemia, anemia, lipodystrophy
Non-nucleoside reverse-transcriptase inhibitors
Rilpivirine
Rash, hepatitis, decreased eGFR, depression, sleep disturbances, headache
Efavirenz
Rash, hepatitis, dizziness, sleep disturbances, depression, dyslipidemia, gynecomastia, decreased plasma 25-(OH) vitamin D,
teratogenesis
Nevirapine
Rash, hepatitis, systemic hypersensitivity (CD4 and gender-dependent)
Etravirine
Rash
Protease inhibitors
Atazanavir
Jaundice cholelithiasis, decreased eGFR, nephrolithiasis, nausea, diarrhea, dyslipidemia
Darunavir
Rash, dyslipidemia
Lopinavir
Dyslipidemia, nausea, diarrhea, decreased eGFR, ischemic heart disease
Indinavir
Dry skin, nail dystrophy, jaundice, nephrolithiasis, abdominal fat, dyslipidemia, diabetes mellitus, nausea, diarrhea, ischemic heart
disease
Fosamprenavir
Dyslipidemia, rash, nausea, diarrhea, ischemic heart disease
Saquinavir
Dyslipidemia, nausea, diarrhea
Tipranavir
Dyslipidemia, hepatitis, intracranial hemorrhage, diabetes mellitus, nausea, diarrhea
Integrase-strand transfer inhibitors
Raltegravir
Nausea, myopathy, rhabdomyolysis, mood change
Dolutegravir
Rash, nausea, decreased eGFR due to inhibition of renal tubular creatinine secretion without affecting the glomerular filtration itself,
headache, systemic hypersensitivity syndrome (<1%)
Elvitegravir
Nausea, vomiting, hyperbilirubinemia, decreased eGFR due to inhibition of renal tubular creatinine secretion without affecting the
glomerular filtration itself, headache
Fusion inhibitor
Enfuvirtide
Nodule injection, hypersensitivity
CCR5 inhibitor
Maraviroc
Caution must be taken in the event of hepatitis co-infection and pre-existing liver damage, and in patients with heart failure
eGFR, estimated glomerular filtration rate.
antineoplastic agents but all treatments that may concern cancer
disease management, such as antiemetics, analgesics, corticosteroid therapy or antimicrobial agents (Table 4). The potential
of antiretrovirals to cause drug interactions is also well known
and has been thoroughly documented [46, 103–108].
Drug–drug interactions can be classified into two categories:
(i) Pharmacokinetic interactions caused by shared metabolic
pathways and transporters between both the antiretrovirals
and the anticancer drugs. These mostly concern the cytochrome P450 (CYP) enzyme system, particularly the CYP3A4/
5 isoenzyme. Other isoenzymes, such as CYP1A2, CYP2C9,
CYP2D6 or the phase-II UDP-glucuronosyltransferase 1A1
(UGT1A1) enzyme, can also be a cause for concern. These
interactions generally result in the inhibition or induction
of CYP isoenzymes or UGT1A1 by antiretrovirals, which
leads to increased or decreased metabolism exposure of
drug substrates to the same enzyme.
(ii) Pharmacodynamic interactions are caused by synergistic or
antagonistic effects and can lead to overlapping toxicities or
decreased treatment efficiency.
Volume 27 | No. 3 | March 2016
The antiretroviral drug classes with the highest risk of pharmacokinetic interactions are protease inhibitors (PI) and non-nucleoside reverse-transcriptase inhibitors (NNRTI). PIs are
potent inhibitors of CYP3A (except tipranavir), with ritonavir
being the most potent, which may potentially increase the exposure of several antineoplastic agents, leading to severe acute
toxicities. In contrast, NNRTIs, except rilpivirine and the PI
tipranavir, are inducers of CYP3A, which may increase the risk
of treatment failure by decreasing anticancer-drug exposure.
Integrase inhibitors—namely, raltegravir with almost no drug
interactions and dolutegravir ‘with the exception of’ elvitegravir used as boosted by cobicistat—offer a favorable drug–drug
interaction profile, partly due to a predominant metabolism
‘through’ glucuronidation by UGT1A1. Boosted PIs, NNRTIs
and elvitegravir/cobicistat should generally be avoided in
chemotherapy regimens that include drugs metabolized by
CYP3A (Table 4).
Pharmacodynamic interactions particularly concern NRTIs.
Zidovudine, no longer used in western countries, must be
avoided due to its increased risk of myelotoxicity with all
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Annals of Oncology
Table 4. Drug–drug interactions: principal recommendations for the use of antiretrovirals in association with major anticancer agents
Antineoplastic agents
Antiretrovirals not recommended ‘or’ requiring close specific
monitoring ‘and/or’ dose adjustment if co-administered;
Potential interactions; multidisciplinary discussion highly
advised
Authorized antiretrovirals±TDM and clinical
monitoring; No clinically significant interaction
expected
Alkylating agents
Cyclophosphamide
Ifosfamide
Bendamustine
Boosted PI
NNRTI except rilpivirine
Elvitegravir/cobicistat with cyclophosphamide/ifosfamide
Zidovudine
Tenofovir with ifosfamidea
Anthracyclines
Daunorubicin
Doxorubicin
Epirubicin
Antibiotic cytotoxics
Bleomycin
Dactinomycin
Boosted PI
NNRTI
Elvitegravir/cobicistat
Zidovudine
Zidovudine with dactinomycin
Rilpivirine
Etravirine only with bendamustine
Raltegravir, dolutegravir elvitegravir/cobicistat only
with bendamustine
Maravirocb, enfuvirtide
NRTI except zidovudine
Raltegravir, dolutegravir maraviroc, enfuvirtide
NRTI except zidovudine
Antimetabolites
Methotrexate
Pemetrexed
Cytarabine
Capecitabine
Fluorouracil
Gemcitabine
Mercaptopurine
Immunosuppressants,
immuno-modulators
Dacarbazine
Everolimus
Procarbazine
Temsirolimus
Monoclonal antibodies
Alemtuzumab
Bevacizumab
Cetuximab
Rituximab
Panitumumab
Trastuzumab
Platinum derivatives
Cisplatin
Carboplatin
Oxaliplatin
Zidovudine
Proteasome inhibitor
Bortezomib
Taxanes
Docetaxel
Paclitaxel
Topoisomerase I and II
inhibitors
Etoposide
Irinotecan
Boosted PI
Elvitegravir/cobicistat with everolimus/temsirolimus
NNRTIe
Zidovudine
Boosted PI
NNRTI
Elvitegravir/cobicistat, raltegravir, dolutegravir
maraviroc, enfuvirtide
NRTI (zidovudine only with bleomycin)
Boosted PI
NNRTIc
Elvitegravir/cobicistat, raltegravir, dolutegravir
maraviroc, enfuvirtide
NRTIa,d except zidovudine
Elvitegravir/cobicistat only with procarbazine/
dacarbazine
Raltegravir, dolutegravir maravirocb, enfuvirtide
NRTI except zidovudine
All antiretrovirals
(zidovudine can be considered according to
accompanying drugs)
Elvitegravir/cobicistat with cisplatin
Zidovudine, tenofovira
Boosted PI
NNRTI except rilpivirine
Elvitegravir/cobicistat
Zidovudine
Boosted PI
NNRTI except rilpivirine
Elvitegravir/cobicistat
Zidovudine
Boosted PI
NNRTI except rilpivirine
Elvitegravir/cobicistat
Zidovudine
Boosted PI
NNRTI
Elvitegravir/cobicistat only with carboplatin/
oxaliplatin
Raltegravir, dolutegravir, maraviroc, enfuvirtide
NRTI except zidovudine and tenofovir
Rilpivirine
Raltegravir, dolutegravir, maraviroc, enfuvirtide
NRTI except zidovudine
Rilpivirineb
Raltegravirb, dolutegravirb, maravirocb, enfuvirtide
NRTI except zidovudine
Rilpivirine
Raltegravir, dolutegravir, maraviroc, enfuvirtide
NRTI except zidovudine
Continued
 | Spano et al.
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Annals of Oncology
Table 4. Continued
Antineoplastic agents
Antiretrovirals not recommended ‘or’ requiring close specific
monitoring ‘and/or’ dose adjustment if co-administered;
Potential interactions; multidisciplinary discussion highly
advised
Authorized antiretrovirals±TDM and clinical
monitoring; No clinically significant interaction
expected
Tyrosine kinase inhibitors
Imatinib
Dasatinib
Erlotinib
Gefitinib
Lapatinib
Nilotinib
Pazopanib
Sorafenib
Sunitinib
Vinca alkaloids
Vinblastine
Vincristine
Vinorelbine
Boosted PI
NNRTIe
Elvitegravir/cobicistat
Zidovudine
Raltegravirb, dolutegravirb, maravirocb, enfuvirtide
NRTI except zidovudine
Boosted PI
NNRTI except rilpivirine
Elvitegravir/cobicistat
Zidovudine
Rilpivirineb
Raltegravirb, dolutegravirb, maravirocb, enfuvirtide
NRTI except zidovudine
a
Potential additive nephrotoxicity of tenofovir with ifosfamide, pemetrexed, methotrexate and platinum derivatives. Close monitoring of renal function
advised.
b
Increase and/or decrease in antiretroviral exposure possible due to mild or moderate inhibitory effects of various anticancer agents on CYP isoenzymes;
clinical and pharmacological monitoring may be advised.
c
Rilpivirine inhibits the active renal tubular secretion of creatinine and should be used with caution in combination with methotrexate and pemetrexed.
Close monitoring of renal function advised.
d
Potential competition or inhibition of the metabolism of capecitabine and 5-fluorouracil by NRTI except abacavir, which may lead to increased
fluorouracil toxicity. Clinical relevance unknown.
e
Rilpivirine may be authorized under specific monitoring in some cases, according to the anticancer agents administered.
Boosted PI, protease inhibitors associated with ritonavir (atazanavir/r, darunavir/r, fosamprenavir/r, indinavir/r, lopinavir/r, saquinavir/r, tipranavir/r);
NNRTI, non-nucleoside reverse-transcriptase inhibitors (efavirenz, etravirine, nevirapine, rilpivirine); NRTI, nucleos(t)ide reverse-transcriptase inhibitors
(abacavir, emtricitabine, lamivudine, tenofovir, zidovudine).
anticancer drugs, whereas tenofovir should not be administered
along with potent nephrotoxic agents, such as cisplatin, methotrexate and ifosfamide. If no substitute for tenofovir can be
found, its administration should be accompanied by close monitoring of the patient’s renal function. Rilpivirine, associated with
prolongation of the QTc interval at supra-therapeutic doses,
should be used with caution in combination with drugs that
have the potential to increase the QT interval or in patients at
risk for Torsade de Pointes.
new perspectives in cancer treatment
in HIV-infected patients
The last 2 years have seen unprecedented progress in cancer
treatment with therapeutic monoclonal antibodies restoring
immune control of tumors by blocking the immune checkpoints
on tumor-infiltrating lymphocytes. The first successes registered
for anti-CTLA4 antibodies in melanoma were rapidly followed
by anti-PD1/L1 antibodies which showed durable tumor
responses on several cancer types including, apart from melanoma, tumors frequently involved in HIV-infected patients such
as NSLC, NHL or HL [109–111]. These therapeutic antibodies
should be as efficient in HIV-infected cancer patients and the
rationale for these treatments should be strengthened further
Volume 27 | No. 3 | March 2016
since T-cell overexpression of PD-1 and other immune checkpoints has been abundantly documented in HIV infection as
part of the immune exhaustion characteristics of HIV-related
immune deficiencies, particularly on T cells directed against
HIV itself and oncogenic viruses, such as EBV or hepatotropic
viruses [112, 113]. Therefore, the spectrum of action of these
antibodies should be even broader in this context and help
restore immune control of EBV+, HBV+ or HCV+ tumors. In
addition, it is also proposed these antiantibodies reactivate latently infected CD4+ cells expressing these immune checkpoints
and help purge the HIV reservoirs as part of a combined
regimen toward HIV cure. Whether the same successes and
good tolerability of anti-PD1/L1 antibodies observed in HIVnegative populations will be maintained in HIV+ patients is
nevertheless a challenging question and a number of studies are
in progress or due to start soon to answer these questions.
Indeed, another challenge is to evaluate their tolerance with
caution as, in this context, these therapeutic antibodies might
prompt a severe immune restoration syndrome by rapidly restoring immune competence. It is particularly important to
check their intestinal tolerability as the gut lymphoid tissues are
durably affected by HIV-related immune alterations and antiCTLA-4 antibody usage is strongly limited in HIV-negative
melanoma patients by the severe colitis induced by mucosal gut
lymphocyte reactivation. Once good tolerance and efficacy of
doi:10.1093/annonc/mdv606 | 
reviews
immune checkpoint blockers is established in HIV-infected
patients, one can envision a rapid revolution in the clinical management of cancers in HIV infection with the use of these antibodies becoming a top priority in HIV+ cancer medicine.
conclusion
A strong impetus for multidisciplinary collaboration in order to
optimize the management of HIV-infected patients with malignancies has emerged over the last few years. As patient management in this setting is, by necessity, multidisciplinary, the
development of multidisciplinary approaches involving hematologists, oncologists and HIV specialists has enabled the
CANCERVIH group, supported by the French National Cancer
Institute, to develop specific guidelines to target and aid HIVinfected patients. These patients are usually excluded from
early-phase clinical trials and cannot therefore access the most
innovative therapies. However, there is an urgent unmet need
for investigation of such therapies, particularly immune-based
therapies targeting the immune checkpoints at the interface of
immunity and tumor cell proliferation in HIV-infected patients.
acknowledgements
The authors thank the INCa for its institutional support,
Marianne Veyri for her administrative support and Jacques
Cadranel for revising the lung cancer section of the manuscript.
disclosure
J-PS declares some potential conflicts of interest: Adboard or
consultant: Gilead, Merck MSD, Roche, Teva Pharma Symposia:
BMS, GSK. DC declares that she has received in the past 3
years: travel grants, consultancy fees, honoraria and study grants
from various pharmaceutical companies including Gilead
Sciences, Janssen-Cilag, Merck-Sharp & Dohme-Chibret, and
ViiV Healthcare. SC declares a potential conflict of interest:
Consultant: Roche. Véronique LEBLOND has received honoraria
from Roche, Janssen, Gilead Sciences, GSK (board consultation,
speaker bureau). CK has received travel grants, consultancy fees,
honoraria and study grants from Bristol-Myers-Squibb (BMS),
Merck-Sharp & Dohme-Chibret and ViiV Healthcare. M-AV has
received honoraria for consulting/educational lectures and travel
grants from Janssen-Cilag, Gilead Sciences, ViiV Healthcare,
Bristol-Myers-Squibb and Merck/Schering-Plough. IP-M, FB,
OR, AL, P-EH, JG, CS, AG, GC, BA and LQ have declared no
conflicts of interest.
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Volume 27 | No. 3 | March 2016