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Cancer risk in HIV-infected patients: elite controllers are also concerned

Poizot-Martin, Isabellea,b; Laroche, Hélènea; Cano, Carla, E.a; Nicolino-Brunet, Corinnec; Zaegel-Faucher, Oliviaa; Bregigeon, Sylviea; Tamalet, Catherined,e; Dignat-George, Françoisec

doi: 10.1097/QAD.0000000000001736

aService d’Immuno-hématologie clinique, Aix-Marseille Université, APHM Sainte-Marguerite

bInserm U912 (SESSTIM)

cService d’hématologie et de biologie vasculaire, Aix-Marseille University, APHM-Conception Hospital

dAix-Marseille University, APHM-Timone Hospital, Fédération de Microbiologie Hospitalière

eURMITE CNRS-IRDUMR6236, Marseille, France.

Correspondence to Isabelle Poizot-Martin, Immuno-hematology Unit, APHM-Sainte Marguerite Hospital, 270 Bd Sainte Marguerite, 13009 Marseille, France. E-mail:

Received 6 October, 2017

Accepted 13 October, 2017

A 55-year-old man coinfected by HIV-1 subtype B and hepatitis C virus (HCV) genotype 3a since 1984 through intravenous drug use (IVDU). The patient was an HIV elite controller, displaying undetectable HIV plasma viral load (HIV-pVL) since HIV infection diagnosis, with CD4+ and CD8+ T-cell counts more than 1000 cells/μl and CD4+ : CD8+ ratio less than 1 (Fig. 1a and b), Centers for Disease Control and Prevention (CDC) classification system stage B3, never exposed to antiretroviral therapy. The patient was a heavy smoker (60 pack-year) and had rehabilitated from alcohol abuse in 2010. In May 2012, he was diagnosed with lung adenocarcinoma of the upper right lobe with mediastinal infiltration (cT3N2-bulkyM0, grade IIIb) on chest-computed tomography (CT) for investigation of a persistent cough. From June 2012 to November 2012, he received four cycles of radio-chemotherapy with cisplatine/pemetrexed and prophylaxis against opportunistic infections. CD4+ cell counts dropped by 25% at diagnosis and by 75% after radio-chemotherapy (Fig. 1b). HIV-pVL blipped to 75 copies/ml but suppressed spontaneously after 1 month. High proportions of activated CD8+HLA-DR+ (Fig. 1c; 66.3%, normal range <10%) and CD8+CD38+ cells (44.3%, normal range 5–17%), and of CD8+CD28 senescent cells (49.9%, normal range 20–30% [1]) were found before introduction of chemotherapy. Radio-chemotherapy resulted in 26% reduction of the primary tumour. Facing relapse in July 2013, the patient received three cycles of carboxyplatin/pemetrexed, but presented with complete right lung atelectasis that persisted despite endobronchial debulking and stent, leading to death of the patient in December 2013.

Fig. 1

Fig. 1

A 52-year-old man coinfected by HIV-1 subtype B and HCV-1a since 2000 through IVDU, CDC stage B2. He was an elite controller with undetectable HIV-pVL and HIV-DNA since HIV diagnosis, and CD4+ cell counts more than 600 cells/μl (Fig. 1d and e), high CD8+ cell counts (≥1000 cells/μl) and CD4+ : CD8+ one or less throughout the follow-up. The patient was naïve of antiretroviral treatment. He was a heavy smoker (30 pack-year) with history of alcohol abuse, rehabilitated since 2012.

In September 2016, liver echography prior to antiviral therapy against HCV revealed the presence of a pancreatic lesion. Thoraco–abdomino–pelvic CT (TAP-CT) detected a tumour mass of the pancreas head (20 mm) without intrahepatic/extrahepatic cholestasis or Wirsung canal involvement. CA19.9 was 8.6 U/ml (normal range <37 U/ml). In the absence of symptoms, the patient decided to postpone pancreas care against medical advice. In February 2017, the patient presented with jaundice, asthenia, weight loss, dark urines and pale stools. CA19.9 had increased to 62.3 U/ml. MRI and TAP-CT confirmed the presence of a pancreas head tumour, without vascular involvement. Pancreaticoduodenectomy resected a 6 × 5 × 3-cm primary tumour with unclear boundaries. Histology found a moderately differentiated pancreatic ductal adenocarcinoma, infiltrating the duodenum and the surrounding adipose tissue, with involvement of one lymph node and clean resection borders (pT3N1aMxR0). Gemcitabine-based adjuvant chemotherapy and prophylaxis against opportunistic infections were initiated in April 2017. At this time, HIV-pVL had blipped to 96 copies/ml but suppressed spontaneously 1 week later. HIV-DNA and T-cell counts remained stable. Antiretroviral therapy was not judged necessary. In June 2017, gemcitabine was replaced by LV5FU2 following recurrent noninfectious fever episodes. One week later, the patient presented with HIV-pVL 100 copies/ml and 760 CD4+ cells/μl. Increased proportions of CD8+CD38+ and CD8+CD28 T cells were observed (Fig. 1c).

Privileged status of elite controller regarding HIV suppression and immune preservation may misleadingly evoke an absence of HIV disease. Nevertheless, previous studies indicate that elite controller present increased risk of developing life-threatening complications, including cancer [2,3]. Consistently, we show two cases of elite controller presenting with non-AIDS-defining cancers. In addition to their elite controller status, the patients were heavy smokers and former alcoholics, which are major cancer risk factors in the general population. Both presented with chronic HCV infection and IVDU contamination, which are risk factors for non-AIDS-defining cancers [4]. Of note, both patients displayed CD4+ depletion and transient viral blips after cancer diagnosis. Significantly, total CD8+, activated CD8+CD38+ and CD8+HLA-DR+ cells, and senescent CD8+CD28 cells were above normal range in both cases. This is consistent with previous reports of higher rates of activated CD8+ cells in HIV-controllers compared with uninfected patients, which was associated with HCV-coinfection [5]. This proinflammatory and potentially protumoural cellular pattern is related to HIV-infection and may also be observed in elite controller bearing HCV-coinfection [2,3]. In agreement, expanded CD8+CD28 T cells from lung cancer patients also express the FOXP3 marker of regulatory T cells [6] and have been observed in several cancers [7–9]. Hence, elite controller cases presented here suggest that virally silent HIV infection may still foster carcinogenesis. Consistently, the prevalence of cervical premalignant lesions in female HIV-controllers is comparable with that of HIV-suppressors on antiretroviral therapy [10]. Therefore, guidelines for cancer screening in noncontroller HIV-infected patients may be applied to elite controller patients, in particular for HCV-coinfected ones.

The patients provided their written informed consent for the use of their medical records on a Computerized Specialized Medical Record: NADIS. This study was carried out in compliance with the international guidelines for human research protection as per the Declaration of Helsinki and The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP).

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Conflicts of interest

There are no conflicts of interest.

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