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

Institut National de la Santé et de la Recherche Médicale (INSERM) U897.
Clinical Infectious Diseases (Impact Factor: 8.89). 09/2009; 49(7):1109-16. DOI: 10.1086/605594
Source: PubMed

ABSTRACT Human immunodeficiency virus (HIV)-infected patients are at higher risk of malignancies. In addition to 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 acquired immunodeficiency syndrome (AIDS)-defining and non-AIDS-defining malignancies.
Patients consecutively enrolled in the hospital-based Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort were included if the duration of follow-up was >3 months during the period 1998-2006. Multivariate modeling used an extended Cox proportional hazards model for time-dependent covariates and delayed entry.
The 4194 patients included in the study developed 251 first malignancies during 22,389 person-years. A higher incidence of AIDS-defining malignancies (107 cases) was independently associated with (1) both longer and current exposures to a plasma HIV RNA level >500 copies/mL (hazard ratio [HR], 1.27 per year [P<.001] and 3.30 [P<.001], respectively) and (2) both longer and current exposure to a CD4(+) cell count <200 cells/mm(3) (HR, 1.36 per year [P<.001] and 6.33 [P<.001], respectively). A higher incidence of non-AIDS-defining malignancies (144 cases) was independently associated with longer and current exposure to a CD4(+) cell count <500 cells/mm(3) (HR, 1.13 per year [P=.01] and 2.07 [P<.001], respectively) and male sex (HR, 1.69; P=.02) but not with plasma HIV RNA level (P=.49 and P=.10 for cumulative and current exposures, respectively).
Uncontrolled plasma HIV RNA level was independently associated with a higher likelihood of developing AIDS-defining malignancies, whereas immunosuppression was associated with a higher risk of developing any type of malignancies. Antiretroviral treatment should aim at reaching and maintaining a CD4(+) count >500 cells/mm(3) to prevent the occurrence of malignancy, this should be integrated to malignancy-prevention policies.

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    • "HAART attenuated the cancer risk independently from CD4 cell-counts in line with previous observations [13,18,19]. Nevertheless, the threshold when to start HAART to reduce the risk of malignancy is less clear. "
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    ABSTRACT: To estimate the cancer risk of HIV-infected patients in the HAART era with respect to a general reference population and to determine risk factors for malignancy. Long term (1996-2009) cancer incidence of the Bonn single centre HIV cohort was compared to the incidence of the reference population of Saarland using standardized incidence ratios (SIR). Poisson regression analysis was used to identify predictors of cancer risk. 1,476 patients entered the cohort, enabling 8,772 person years of observation. 121 tumours in 114 patients, 7 in-situ and 114 invasive cancers, were identified. Malignancies associated with infectious agents such as Kaposi sarcoma (SIRs: male: 5,683; female: 277), non-Hodgkin lymphoma (SIRs male: 35; female: 18), anal cancer (SIRs male: 88; female: 115) as well a cervical carcinoma (SIR female: 4) and Hodgkin?s disease (SIR male: 39) and liver cancer (SIR male: 18) were substantially more frequent in HIV-infected patients than in the general population (p< 0.001, each), whereas all other types of cancer were not increased. Poisson regression identified HAART (incidence rate ratio IRR (95% CI): 0.28 (0.19-0.41), p<0.001), CD4 count (IRR per 100 cells/μl increase: 0.66 (0.57-0.76), p<0.001), hepatitis B (IRR: 2.15 (1.10-4.20), p = 0.046) and age (IRR per 10 year increase: 1.23 (1.03 - 1.46), p = 0.023) as independent predictors for the occurrence of any type of cancer. HAART and preserved CD4 cells preferentially reduce the risk of malignancies associated with oncogenic infections.
    European journal of medical research 03/2011; 16(3):101-7. DOI:10.1186/2047-783X-16-3-101 · 1.50 Impact Factor
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    • "In one study, uncontrolled viral replication (RNA >4 log10 copies/ml) was associated with the occurrence of non-AIDS severe clinical events, including NADM (9.5% of non-AIDS clinical events) [35]. In another study, an uncontrolled HIV-RNA level was associated with the occurrence of an ADM but not of a NADM [30]. We were unable to find such association in our study in multivariate analysis. "
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    ABSTRACT: Non-AIDS-defining malignancies (NADM) are becoming a major cause of mortality in the era of highly active antiretroviral therapy. We wished to investigate the incidence, risks factors and outcome of NADM in an urban cohort. We carried out an observational cohort of HIV patients with 12,746 patient-years of follow up between January 2002 and March 2009. Socio-demographics and clinical characteristics of patients diagnosed with NADM were retrospectively compared with the rest of the cohort. Causes of death and risk factors associated with NADM were assessed using logistic regression. Survival analyses were performed with Kaplan-Meier estimates. Cancer incidences were compared with those of the general population of the Brussels-Capital Region using the standardized incidence ratio (SIR). Forty-five NADM were diagnosed. At inclusion in the study, patients with NADM were older than patients without NADM (47 years vs. 38 years, p < 0.001), had a longer history of HIV infection (59 months vs. 39 months, p = 0.0174), a lower nadir CD4 count (110 cells/mm3 vs. 224 cells/mm3, p < 0.0001) and a higher rate of previous AIDS events (33% vs. 20%, p = 0.0455) and of hepatitis C virus co-infection (22.2% vs. 10%, p = 0.0149). In multivariate analysis, age over 45 at baseline (OR 3.25; 95% CI 1.70-6.22) and a nadir CD4 count of less than 200 cells/mm3 (OR 3.10; 95% CI 1.40-6.87) were associated with NADM. NADM were independently associated with higher mortality in the cohort (OR 14.79; 95% CI 6.95-31.49). Women with cancer, the majority of whom were of sub-Saharan African origin, had poorer survival compared with men. The SIR for both sexes were higher than expected for Hodgkin's lymphoma (17.78; 95% CI 6.49-38.71), liver cancers (8.73; 95% CI 2.35-22.34), anal cancers (22.67; 95% CI 8.28-49.34) and bladder cancers (3.79; 95% CI 1.02-9.70). The SIR for breast cancer was lower in women (SIR 0.29; 95% CI 0.06-0.85). Age over 45 and a nadir CD4 count of less than 200 cells/mm3 were predictive of NADM in our cohort. Mortality was high, especially in sub-Saharan African women. Cancers with increased incidences were Hodgkin's lymphoma and anal, bladder and liver cancers in both sexes; women had a lower incidence of breast cancer.
    Journal of the International AIDS Society 03/2011; 14(1, article 16):16. DOI:10.1186/1758-2652-14-16 · 5.09 Impact Factor
    • "In early reports assessing immunologic and virologic parameters associated with NHL, nadir CD4 count or low time-weighted mean CD4 count appeared to correlate with a high risk of NHL, which would support hypotheses that a long-term immunocompromised state may promote emergence of NHL [3,25]. Contemporary studies, however, have demonstrated that cumulative HIV viremia, particularly recent exposure to viremia, and the latest CD4 count measured before the onset of symptomatic NHL may be the most HIV-specific predictive factors for NHL oncogenesis [11,12,14,15,24,26,27]. Our analysis correlates with prior studies documenting low CD4 counts in patients with virologic failure immediately before the onset of NHL. "
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    ABSTRACT: In the HAART era, the incidence of HIV-associated non-Hodgkin lymphoma (NHL) is decreasing. We describe cases of NHL among patients with multi-class antiretroviral resistance diagnosed rapidly after initiating newer-class antiretrovirals, and examine the immunologic and virologic factors associated with potential IRIS-mediated NHL. During December 2006 to January 2008, eligible HIV-infected patients from two affiliated clinics accessed Expanded Access Program antiretrovirals of raltegravir, etravirine, and/or maraviroc with optimized background. A NHL case was defined as a pathologically-confirmed tissue diagnosis in a patient without prior NHL developing symptoms after starting newer-class antiretrovirals. Mean change in CD4 and log10 VL in NHL cases compared to controls was analyzed at week 12, a time point at which values were collected among all cases. Five cases occurred among 78 patients (mean incidence = 64.1/1000 patient-years). All cases received raltegravir and one received etravirine. Median symptom onset from newer-class antiretroviral initiation was 5 weeks. At baseline, the median CD4 and VL for NHL cases (n = 5) versus controls (n = 73) were 44 vs.117 cells/mm3 (p = 0.09) and 5.2 vs. 4.2 log10 (p = 0.06), respectively. The mean increase in CD4 at week 12 in NHL cases compared to controls was 13 (n = 5) vs. 74 (n = 50)(p = 0.284). Mean VL log10 reduction in NHL cases versus controls at week 12 was 2.79 (n = 5) vs. 1.94 (n = 50)(p = 0.045). An unexpectedly high rate of NHL was detected among treatment-experienced patients achieving a high level of virologic response with newer-class antiretrovirals. We observed trends toward lower baseline CD4 and higher baseline VL in NHL cases, with a significantly greater decline in VL among cases by 12 weeks. HIV-related NHL can occur in the setting of immune reconstitution. Potential immunologic, virologic, and newer-class antiretroviral-specific factors associated with rapid development of NHL warrants further investigation.
    AIDS Research and Therapy 12/2010; 7(1):44. DOI:10.1186/1742-6405-7-44 · 1.46 Impact Factor
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