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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2177-2183 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.097 Antiretroviral Treatment Regimens and Immune Parameters in the Prevention of Systemic AIDS-Related Non-Hodgkin's LymphomaFrom the Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College of Science, Technology and Medicine; and the Departments of HIV Medicine and Oncology, The Chelsea and Westminster Hospital, London, United Kingdom Address reprint requests to Mark Bower, PhD, FRCP, Department of Oncology, The Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10 9NH, United Kingdom; e-mail: m.bower{at}imperial.ac.uk
PURPOSE: Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens. PATIENTS AND METHODS: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL. RESULTS: From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P < .05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P < .02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P < .001). CONCLUSION: Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.
Non-Hodgkin's lymphoma (NHL), an AIDS-defining illness (ADI) following its first description at the onset of the HIV pandemic,1–4 remains the second most common tumor associated with HIV-1 infection following Kaposi's sarcoma (KS). Many individuals present with widespread disease—which occurs with a frequency at least 100 times greater than that observed in the general population5–8—and the risk of CNS involvement is increased, compared with HIV-negative counterparts.9,10 In those for whom it is available, highly active antiretroviral therapy (HAART) has decreased the morbidity and mortality associated with HIV, mainly by reducing the incidence of opportunistic infections in particular Pneumocystis carinii pneumonia.11,12 The protective effect of HAART has also been shown to result in a decreased incidence of KS and NHL13 and, for KS specifically, HAART leads to an increased time to disease progression14 and the resolution of individual lesions,15–17 explained by some as related to an improvement in immune function.18 In multivariate analyses, we have demonstrated that decreases in adaptive immune parameters (T- and B-cell counts) predispose individuals to KS, and increases in these parameters confer protection.19 Innate markers (natural killer counts) appear to have a less significant role in established disease.20 In addition,21 we have prospectively examined the protective role of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitor- (NNRTI-) based therapy (the two categories of HAART), particularly as there are data to suggest that certain PIs, such as ritonavir, have specific antitumor properties,22,23 including the ability to prevent angioproliferative lesions in mice.24 However, in the clinical comparison, both PI- and NNRTI-based HAART regimens were found to be equally effective in protection against KS,21 and ritonavir in particular has shown no chemo-protective effect.25 We therefore wished to establish whether NNRTI- or PI-based HAART conferred increased protection against AIDS-related NHL, and investigated changes in adaptive and innate immune function that may protect or predispose HIV-1 infected individuals.
The Chelsea and Westminster HIV cohort is one of the largest in Europe and we prospectively collect routine data on the individuals who attend. HIV-positive patients are seen at regular intervals for clinical assessment, trial follow-up, and immunologic assessments. All HIV patients who have attended the Chelsea and Westminster cohort since routine prospective data collection commenced in 1983 were identified, and we have defined HAART as therapy consisting of at least three antiretroviral drugs in accordance with published guidelines (dual nucleoside analogues alone are not considered HAART).26–28 This study focuses on a cohort who have continued to be followed up since the HAART era commenced, which we have defined as January 1, 1996, when HAART became routinely available at our institution (and others). All individuals who ceased follow-up before this date were excluded and all data analyzed were extracted from our local database in November 2003. For both PI-based therapy and NNRTI-based therapy, a nucleoside analog "backbone" is included, as per routine guidelines.26–28 Person-days of follow-up were converted to person-years at risk (PYAR). PYAR was estimated from entry into the cohort to either end of study period, the development of NHL, the last recorded visit or if the patient had died during their follow-up, then their death date. In order to keep the coefficient of the PYAR constant, this was log transformed and used as the offset in the Poisson regression. The data were analyzed using the Genmod procedure in SAS version 8.0 (SAS Institute, Cary, NC) with loge link and Poisson error distributions. This fits generalized linear models allowing time dependent measures of probability29; all P values presented are two-sided. The nadir immunologic cell counts used were the lowest ever recorded during follow-up, until the time of NHL diagnosis. If a patient had been diagnosed with NHL, the lowest ever cell counts before NHL diagnosis were used, otherwise, lowest ever observed at the time the data were censored. All of the cases of AIDS-related NHL were biopsy-proven and primary CNS lymphomas were excluded from the analysis. Median and interquartile ranges were used to create categoric data. A separate category was created for all variables with missing data. This ensured no degrees of freedom were lost when building multivariate models. Log linear models with single variables were initially used to estimate rate ratio (RR) of NHL incidence, intrinsically corrected for the length of time diagnosed with HIV. All variables found to approach significance (P < .2) in univariate log linear model were then used to build a multivariate model, which allowed the risk of a particular prognostic variable to be assessed while controlling for the others in the model. The final multivariate model presented was tested for its distributional assumptions using Cox Snell residual plots and adjusted for possible confounding or residual effects. Missing data was composed of less than 2.5% of all cases (none of the 102 individuals with systemic NHL had missing data) and risk ratios for this have not been presented. Total lymphocyte and subset analysis was performed using whole blood stained with murine antihuman monoclonal antibodies to CD4 (T helper cells), CD8 (a cytotoxic T-cell marker), CD19 (B-cells) and CD16/56 (natural-killer cells; TetraOne, Beckman Coulter, High Wycombe, UK) and were evaluated on an Epics XL-MCL (Beckman Coulter) multiparametric four color flow cytometer.
Univariate Analysis Clinical information on a total of 9,621 HIV-seropositive patients has been prospectively collected since 1983. Two hundred eighty patients have been diagnosed with lymphoma, including 206 with systemic NHL, 55 with primary cerebral lymphoma, and 19 with Hodgkin's disease. During the HAART era, 5,832 individuals have been identified as being at risk of systemic NHL, representing a total of 34,133 patient-years of follow-up. Of these, 102 patients have been diagnosed with systemic AIDS-related NHL, a total of 682 years at risk. The lymphomas were high-grade B-cell NHL in 98 patients; 20 of these 98 patients were diagnosed with Burkitt's lymphoma. Three patients had high-grade T-cell lymphomas and one had a natural killer/T-cell lymphoma. A previous study that compared pre- and post-HAART outcomes (no survival differences were found; log-rank P = .15) included 15 of the 206 individuals.10 The male:female ratio was approximately 12:1 with no significant differences in the RR and incidence of NHL between genders (in the entire cohort of HIV-positive individuals, 88% are male). There were also no significant differences between ethnic origin groups (Table 1; P = .88). Patient age at entry to the cohort was, however, found to be significant, and for each year of patient age over 39 years old, the RR for the development of NHL was 1.07 (P < .001).
Immune Parameters In the univariate analysis, we observed that lower T-cell lymphocyte counts (CD4 and CD8, adaptive immune markers) and the CD16/56 natural killer counts (innate markers) significantly predisposed HIV-infected individuals to systemic NHL. This difference was most marked for the T-lymphocyte counts (P < .001 for lymphocytes v P = .042 for natural-killer cells; Table 1). For nadir CD19 counts, we observed that the highest incidence of NHL between the 25th and 50th quartiles, a pattern not observed with other immune parameters (Table 1). This may reflect peripheral (blood) detection of increased proliferation of B-cells in such individuals.
Antiretroviral Treatment
Multivariate Analysis The multivariate analysis, adjusting for ethnic origin, sex, and nadir CD19 and CD16/56 counts demonstrated the following: 1) age at entry to cohort was significantly associated with protection from NHL, with ages > 39 years having an increase in rate per year of increase in age (RR, 1.02; 95% CI, 1.01 to 1.03; P < .001); 2) CD4 counts of less than 200 cells/mm3 (P = .01) and CD8 counts of less than 595 cells/mm3 (P = .02) were associated with an increased risk of NHL; and 3) a significant trend in the incidence of NHL was observed with antiretroviral therapy exposure (Fig 2).
The data from CD4 counts in quartiles demonstrated statistical significance for the lowest counts (P = .02) and the 25th to 50th percentile (P = .01). Against the reference category (CD4 count > 289 cells/µL), a CD4 count of 144 to 289 cells/µL did not demonstrate significantly greater protection (P = .291). The rate ratios here also provide significant evidence of a time dependent effect, with those individuals with lower nadir CD4 counts (RR = 1.3) developing NHL more rapidly than those with increased nadir CD4 counts (RR = 1.0).
As both CD4 and CD8 counts were observed to be independent predictors of risk of NHL, we investigated the incidence of NHL and risk, stratified for both of these immune parameters together. Interestingly, at CD4 counts
Exposure to NNRTI-based therapy (RR, 0.4; 95% CI, 0.3 to 0.5) was found to have identical protective effects to PI-based regimens. Exposure ever to both a PI and an NNRTI showed the same effect (RR, 0.3; 95% CI, 0.3 to 0.4). PI- and NNRTI-based HAART together conferred significantly greater protection against NHL than nucleoside analogue–only therapy (RR, 0.5; 95% CI, 0.4 to 0.7). There were no statistically significant differences between PI- and NNRTI-based HAART regimens at the time of diagnosis of NHL. Figure 3 demonstrates the probability of NHL in individuals who had been exposed to different antiretroviral regimens since the HAART era commenced. The graph demonstrates that by 18 months exposure to no antiretroviral treatment or nucleoside analogs, there is an increased probability of NHL compared with any HAART regimen. NHL probability remains low in patients exposed to PI and/or NNRTI containing HAART. This also applies to the antiretroviral regimen at diagnosis of NHL.
As we embark well into the third decade of the HIV pandemic, AIDS-related NHL remains a major cause of morbidity and mortality, not only in the United States, but also in sub-Saharan Africa.7,30–32 The relative efficacies of PI and NNRTI containing HAART regimens in protecting against the development of systemic AIDS-related NHL have not been previously evaluated, although it is now appreciated that both are similarly effective at reducing HIV viremia and maintaining CD4 counts.33,34 The multivariate analysis of our single center prospective cohort study demonstrates that HAART has clinically significant preventive effects and NNRTI-based regimens are able to protect against this tumor. Previously, only PI-based regimens have been shown to protect against ADIs. Here, NNRTI- or PI-based HAART regimens (and both in combination) appear equally effective at protecting from NHL, and the combination of two antiretroviral classes conferred significantly more protection than nucleoside analogs alone. We also confirmed as independent risk factors increased age and low T-lymphocyte counts; both CD4 and CD8 led to an increased incidence of NHL. Markers of the innate (CD16/56) and humoral (CD19) immune systems did not demonstrate significance when adjustments were made for other factors. The role of the immune system in the control of AIDS-related NHL is only now being established. Epstein-Barr virus (EBV) has been implicated in the aetiopathogenesis of B-cell transformation for many years, and both CD4 and CD8 positive T cells play significant roles in preventing viral replication.35 We observed that at higher CD4 counts, the rate ratio of NHL was not increased at different quartiles of CD8 counts (Table 2), lending credence to the importance of CD4 T-cell help in the CD8 response to EBV.36,37 The incidence and rate ratio of NHL appears greatest at lower CD4 and CD8 counts, with CD4 counts exerting the greatest influence on risk, although we did not observe specific differences within cases that had Burkitt's lymphoma. By mimicking B-cell antigen-activation pathways, EBV enters the long-lived memory B lymphocyte pool where it evades immune elimination by severely restricting its own gene expression.38 Higher EBV viral loads have recently been found associated with lower CD4 counts and in HIV-1 positive individuals versus controls.39–41 In a study of HIV-1 infected children, high EBV viral burden was significantly associated with the development of malignancy, an effect modified by higher CD4 cell counts.42 Also consistent with our data, zidovudine nucleoside analog antiretroviral therapy alone did not confer a significant protective effect for either the high (odds ratio, 0.81; 95% CI, 0.22 to 3.09; P = .77) or the low CD4 cell count groups (odds ratio, 0.27; 95% CI, 0.04 to 1.46; P = .16). Effective HAART appears a prerequisite for prevention of both NHL and KS, and sub-group analysis of specific effects of the PI ritonavir for KS25 and NHL patients do not show additional benefits. As the analyses here were adjusted for time since diagnosis, it is notable that age is an independent risk factor for the development of systemic AIDS-related NHL, although the association became weaker though still significant (P < .001) in the multivariate analysis (adjusted rate ratio, 1.07 in univariate analysis v 1.02 in multivariate). HAART may be able to decelerate age-related thymic atrophy,43 and mechanisms dependent on interleukin-7 are postulated to play a role.44 As the majority of cancers are more common with age, a feature interestingly observed in large studies examining seropositivity rates of chronic infections,45,46 this was perhaps unsurprising. Since the introduction of HAART, while a declining incidence of KS was noted within a few years, a concomitant decrease in NHL was not observed for a longer period and some studies reported no decline.10 In one prospective European study, the incidence of AIDS-defining illnesses decreased from 30.7 per 100 patient-years in 1994 to 2.5 per 100 patient-years in 1998.47 Only NHL increased as an AIDS-defining condition during this time; 4% of patients had lymphoma as an ADI in 1994 compared with 16% in 1998. In an analysis of 23 prospective cohort studies (n = 47,936) from patients living in established market economies, a decline in the incidence of NHL was reported for the first time, from 6.2 cases per 1,000 person-years in 1992 to 3.6 cases per 1,000 patient-years in 1999.13 The differences in KS and NHL epidemiologic features may be explained by an improvement in immune function on HAART, preventing KS in the short term, with an increased duration of therapy required to prevent NHL. Supporting this hypothesis, we observed that increased B-cell counts protect from KS19 and KS lesions may resolve with HAART alone,17 unlike the situation with NHL. In addition, natural-killer cells, first identified by their ability to lyse lymphoma cells,48,49 did not appear to have a significant role here in the multivariate analysis, suggesting that their role may be limited to early events in tumorigenesis. For the developing world, long-term HAART appears a necessity to prevent this particular ADI. It appears that the treatment of HIV is at least as important, if not more important than the selection of any subsequent chemotherapy itself.50 Available clinical trial data should be used to encourage the development of long-term anti-HIV strategies to manage AIDS-related lymphoma in parts of the world where the burden is greatest.51–53 Significantly, we show that a wide range of HAART appears protective against NHL and that this is probably achieved by maintaining adequate CD4 and CD8 T-lymphocyte counts. Thus, the choice of antiretrovirals as chemoprophylaxis for common neoplastic ADIs is diverse and can be considered to be any effective HAART regimen.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
200 cells/µL, any CD8 count of greater than 846 cells/µL (50th percentile), was associated with protection from NHL. For the lowest CD8 counts (< 25th percentile), a rate ratio of 1.0 was the lower limit of the 95% CI. In those with CD4 counts > 200 cells/µL, higher CD8 counts did not confer significantly increased protection (
