Epidemiological studies have demonstrated an increased risk of some non-AIDS-defining tumours in HIV-infected patients. Hodgkin's lymphoma (HL) represents the most common type of these non-AIDS-defining tumours [1,2]. A possible relation between HIV and HL was first reported in 1984  and it has been thereafter demonstrated that HIV infection increases the risk of developing HL, by approximately 10-fold, when compared with the general population [4–9]. The clinicopathological characteristics of HIV-related HL (HIV-HL) is widely reported to differ from that of HL in the HIV-uninfected population . HIV-HL is characterized by a more aggressive clinical presentation, with non-contiguous spread, a low frequency of mediastinal involvement, and frequent advanced stages with frequent involvement of bone marrow and liver. In contrast with the predominant nodular sclerosis histological subtype observed in HIV-negative young adults, the mixed cellularity subtype is predominant in HIV-infected patients [11–14]. More numerous Reed–Sternberg cells and a nearly constant association with Epstein–Barr virus has also been reported in HIV-HL [11,14–20]. Complete response rate and survival are far below that reported in the HIV-uninfected population [11,21–24].
Since the introduction of highly active antiretroviral therapy (HAART), HIV-associated morbidity and mortality have shown impressive declines . HAART has been associated with a dramatic decreased in the incidence of opportunistic infections and Kaposi's sarcoma. The impact of HAART on HL incidence still needs to be defined, although early data suggest no significant decline . The overall survival of patients with non-Hodgkin's lymphoma (NHL) has improved since the introduction of HAART  and seems to be correlated with the virological response to antiretroviral therapy and a decrease in AIDS-associated mortality.
Within a 15-year single-institution study we have evaluated the evolving characteristics and prognosis of HIV-HL. For this purpose, the patients were categorized on the basis of date for HL diagnosis, into a pre-HAART period (1987–1996) and a post-HAART period (1997–2001).
This study is based on patients diagnosed or treated in a single institution, the department of Immunology and Hematology, Hôpital Saint-Louis, Paris, France. All consecutive HIV-infected patients with a new, histologically proven, diagnosis of HL between 1 January 1987 and 31 December 2001, were included in the study. All patients were evaluated for the staging of HL at the time of diagnosis by physical examination, haematology and blood chemistry tests, lactic dehydrogenase (LDH) level, chest radiography, chest, abdomen, and pelvis computed tomography (CT) scans, and bone marrow biopsy. Patients were staged prior to treatment, using the Ann Arbor staging system . Pathological specimens were classified according to the recent World Health Organization proposal . At HL diagnosis, patients underwent an evaluation of HIV infection: T-cell subsets, plasma HIV-RNA, and history of antiretroviral therapy. HAART was defined as a combination therapy containing a protease inhibitor and/or a non-nucleoside reverse transcriptase inhibitor. Among the patients receiving HAART, the virological response was defined as a plasma HIV-RNA viral load (pVL) below 500 copies/ml.
Specific treatment for HL included different chemotherapy regimens: MOPP (mechlorethamine, vincristine, procarbazine substituted by cyclophosphamide since 2000, and prednisone) , ABVD (adriamycin, bleomycin, vinblastin, dacarbazine) , MOPP/ABV (adriamycin, bleomycin, vinblastin) hybrid , or CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) , combined in some patients with radiotherapy. One month after the end of therapy, a formal restaging work-up was performed. Complete response (CR) to chemotherapy was defined by the absence of clinically detectable disease and normalization of radiographic, CT scan or biopsy findings. Partial remission and progressive disease were considered as treatment failures.
HAART has been widely available in France since mid-1996, therefore patients were categorized on the basis of date for HL diagnosis, into the pre-HAART period (1 January 1987 to 31 December 1996) and the post-HAART period (1 January 1997 to 31 December 2001). Primary end-points of the study included comparison of the clinicopathological presentation of HL, the CR rate, and the overall and disease-free survival rates. Fischer's exact test was used to compare differences in the discrete variables, and non-parametric Mann–Whitney test was used for continuous variables. Overall survival, disease-free and event-free survival rates were estimated by means of the Kaplan–Meier product limit method, and compared by the log-rank test. P-values were considered significant if less than 0.05, and all tests of significance were two-sided.
From 1 January 1987 to 31 December 2001, 108 HIV-infected patients were diagnosed or referred with a diagnosis of HL, 61 patients before 1997 and 47 patients after 1997. The median follow-up period was 20 months (range, 1–129 months). The epidemiological and HIV-related characteristics of the study population are listed in Table 1. The diagnosis of HIV infection was performed prior to HL in 93 patients and simultaneously in the 15 others (14%) (seven patients in the pre-HAART period, and eight patients in the post-HAART period). No significant change was observed at baseline between the two study periods in term of previous diagnosis of AIDS, history of Kaposi's sarcoma, risk factor for HIV infection. A slight, non-significant increase of the CD4 cell count was noted in the post-HAART patients. However, in the most recent period, patients were more often male, older, and with a longer duration of HIV infection. The proportion of patients receiving antiretroviral therapy at the time of HL diagnosis has increased over time, from 37 to 74.5% (P = 0.0004) and the median duration of antiretroviral therapy was higher (36 months) among patients in the post-HAART group than in patients from the pre-HAART group (13 months) (P = 0.005).
Specific HL characteristics are provided in Table 2. Most patients were diagnosed with mixed cellularity subtype and extranodal involvement. There has been no significant change over time in the distribution of histological subtypes, staging, specific sites of extranodal disease, presence of B symptoms, Eastern Cooperative Oncology Group performance status, white blood cell count, haemoglobin level, and platelet count. Raised serum LDH level was more frequent in the post-HAART period (P = 0.04) and the association with the haemophagocytic syndrome tended to be more frequent in the recent period (18 versus 35.5%, P = 0.09). The chemotherapy regimens used did not differ significantly between the two periods, although the MOPP/ABV regimen has progressively replaced the ABVD regimen.
Response to chemotherapy
A slight, although not significant, increase in the CR rate was noted in the post-HAART population (74.5%) versus the pre-HAART population (64.5%). When patients were stratified according to the clinical staging (I, II or III versus IV), a statistically significant higher percentage of CR was registered for patients with stage I, II or III in the post-HAART period (100%), than for patients from the pre-HAART period (65%) (P = 0.006), whereas the difference was not significant among patients with stage IV disease (63 and 61.5%, respectively; P ≥ 0.99). Among the 73 patients who achieved CR, 16 of the 38 patients from the pre-HAART period, and six of the 35 patients from the post-HAART period, have relapsed. The median time to relapse was 10.2 and 10.5 months, respectively, in the two study periods. The probability to relapse was not different between the two groups (P = 0.18, log-rank test). However, in these patients, the 2-year cumulative probability of disease-free survival has increased over time: 60.5% [95% confidence interval (CI), 44.7–76.3%] in the pre-HAART period, and 78.7% (95% CI, 63.1–94.3%) in the post-HAART period (Fig. 1, P = 0.03).
Over the follow-up period, 47 of the 61 pre-HAART patients, and 17 of the 47 post-HAART patients have died. Patients diagnosed since January 1997 have a higher probability for prolonged survival than patients diagnosed before the introduction of HAART, with a median survival time not reached in the post-HAART period versus 19 months in the pre-HAART period (Fig. 1, P = 0.03, log-rank test). The estimated 1-year and 2-year survival probability were 65% (95% CI, 52.7–77.3 %), and 45% (95% CI, 32.3–57.8), respectively, in the pre-HAART period, and 75.6% (95% CI, 62.8–88.4%), and 62% (95% CI, 46.7–77.1%), respectively, in the post-HAART period. This decreased mortality in the post-HAART period was mainly due to a decrease in AIDS-associated deaths, from nine patients in the pre-HAART period to none in the post-HAART period. Deaths associated with chemotherapy-induced neutropenia and treatment toxicity were similar in the two groups (four in the pre-HAART and three in the post-HAART group). The proportion of deaths related to HL progression was stable over the two periods (65 and 59%, respectively).
Response according to HAART
Thirty-one of the 47 post-HAART patients (66%) and one from the pre-HAART period were on HAART at the time of HL diagnosis, with a median exposure time of 16 months (range, 0.2–47 months). Twelve post-HAART patients (25.5%) were naive to any antiretroviral therapy. Among these 12 patients, two died within a short period, and 10 started HAART during the first or second cycle of chemotherapy. All but one achieved a complete virological response with a pVL below 500 copies/ml in the months following the introduction of antiretroviral therapy. Therefore, during the overall study period, 42 patients were on HAART, either before HL diagnosis or concomitant of chemotherapy and 66 patients did not received HAART (no-HAART patients). Within the 42 on-HAART patients 29 (69%) had already completed or achieved complete virological response with a plasma HIV-RNA level below 500 copies/ml.
Patients on HAART have a higher, although not statistically significant, complete response rate (74%) than patients who did not received HAART (64%). These 42 on-HAART patients have a higher probability for prolonged survival than the 66 patients who did not received HAART, with a median survival time not reached in patients on HAART versus 20 months in the no-HAART patients (Fig. 2, P = 0.05, log-rank test). The estimate 1-year and 2-year survival probability were 75% (95% CI, 61.1–88.7%), and 63% (95% CI, 46.5–78.9%), respectively, in on-HAART patients, and 66% (95% CI, 54.4–78%), and 46% (95% CI, 33.4–58.2%), respectively, in no-HAART patients. Within the on-HAART patients group, the results were very similar in the 29 patients who achieved a complete virological response with an estimate 1-year survival probability of 75% (95% CI, 58.1–91.3%). The disease-free survival was also significantly prolonged in the 31 on-HAART patients who achieved CR than in the 42 no-HAART patients who achieved CR (Fig. 2, P = 0.02).
Hodgkin's lymphoma has been reported to occur with an increased incidence (five- to ten-fold higher) in HIV-infected patients when compared with the age-adjusted rate of HL in the general population or the uninfected homosexual controls from the Multicenter AIDS Cohort Study . This incidence does not appear to decrease since the introduction of HAART . Furthermore, HL still occurs in patients with HAART-induced HIV suppression. Since 1997, more than 40% of the HIV-HL patients had undetectable pVL at HL diagnosis. This proportion of patients with undetectable viral load is very similar to that observed in the population of HIV-infected patients in France (DMI2 database, http://www.b3e.jussieru.fr/sc4/Base) and in the US . In the same period of time, only 20% of the patients with HIV-NHL had virological response to HAART at the time of lymphoma diagnosis . These data suggest that recent, effective control of HIV infection with HAART does not decrease the risk of developing HL. However, it has been recently reported that the incidence of NHL decreased over time under HAART and it may took longer to restore an effective protection against the HL risk.
HAART may have a direct or indirect impact on the overall survival of these patients. In this large single-institution study, over a 15-year follow-up period, survival has significantly increased since 1997 as the median survival was 19 months in the pre-HAART era and was not reached in the post-HAART era. This difference was not explained by the disease characteristics as most clinical and histopathological features remain the same since the introduction of HAART. The CR rate has slightly increased between the two study periods whereas the chemotherapy regimens used have not differed significantly, although the ABVD regimen was progressively replaced by the MOPP/ABV regimen. HAART may have increased tolerance to chemotherapy, and improved respect of dose-intensity schedules, as previously reported for NHL . The quality of the response was identical as the relapse rate was similar in both periods. However, patients with HIV-HL diagnosed in the post-HAART era survived significantly longer than patients diagnosed before the introduction of HAART. This increased survival was mainly associated with a reduced AIDS-associated mortality. Patients from the post-HAART period had a slightly better CD4 cell count at HL diagnosis and more than 40% of them had already controlled HIV replication under HAART. Most of the other patients started HAART during the first or second cycle of chemotherapy and rapidly benefited from HIV control. Overall, patients who received HAART during the study period had a prolonged overall survival and disease-free survival probability than patients who did not received HAART.
These findings suggest that improvement in the control of the underlying HIV disease with HAART and subsequent immune restoration is pivotal to improve the outcome of HIV-HL as has been demonstrated in patients with HIV-associated NHL . The concomitant administration of HAART and chemotherapy represents an important issue, because of the potential higher risk of toxicity, mainly haematological and neurological. In this study, combining HAART with chemotherapy was not associated with a higher mortality associated with treatment toxicity. Previous reports have demonstrated than concomitant HAART and intensive chemotherapy is a feasible and effective approach . However, HIV-HL remains associated with a lower survival than HL in the HIV-uninfected population [15,17] and even if the survival has improved over time, HIV-HL often remains fatal. Optimal therapy has not yet been defined. The outcome of patients with HIV-HL should be improved by the use of more effective chemotherapy regimens to increase the CR rate as well as the duration of the response. In parallel, the effective control of HIV replication and active prevention of infectious complications appear pivotal to further improve long-term survival.
The authors thank Professor Elisabeth Bouvet, Dr Bernard Cardon, Dr Valérie Garrait, Dr Jacques Gilquin, Professor Pierre-Marie Girard, Dr Enrique Gonzales-Canali, Dr Véronique Joly, Dr Pascale Longuet, Dr Sophie Matheron, Professor Jean-Michel Molina, Dr Ségolène Neuville, Professor Willy Rozenbaum, and Professor Patrick Yeni for providing clinical information and patient care.
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