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 Blood, 1 November 2004, Vol. 104, No. 9, pp. 2943-2946.
Prepublished online as a Blood First Edition Paper on July 6, 2004; DOI 10.1182/blood-2004-05-1747.

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NEOPLASIA
Brief report

Protease inhibitors potentiate chemotherapy-induced neutropenia

Mark Bower, Neil McCall-Peat, Natalie Ryan, Liz Davies, Anne Marie Young, Srirupa Gupta, Mark Nelson, Brian Gazzard, and Justin Stebbing

From The Chelsea and Westminster Hospital, London, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Study design
 Results and discussion
 References
 
Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (Mann-Whitney U test; P = .012) and day-14 (P = .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colony-stimulating factor (G-CSF) administered between groups (P = .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART ({chi}2 test; P = .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.


   Introduction
Top
 Abstract
 Introduction
Study design
 Results and discussion
 References
 
HIV-1 infection is associated with a greatly increased risk for cerebral and systemic non-Hodgkin lymphoma (NHL), and the incidence of each increases with decreasing CD4 cell counts and progressive immunodeficiency. Effective highly active antiretroviral therapy (HAART) has reduced this incidence, though NHL remains a common cause of morbidity and mortality during the course of infection with HIV-1 and the second most common tumor observed in HIV-1 patients.1-6

Treatment of AIDS-related non-Hodgkin lymphoma (ARL) first involved standard conventional chemotherapy schedules. Recently, infusional treatment has been advocated and adopted by many larger treatment centers.7,8 Infusional chemotherapy for systemic NHL was first reported in the pre-HAART era using cyclophosphamide-doxorubicin-etoposide (CDE) administered as a 96-hour continuous infusion for up to 6 courses, together with granulocyte colony-stimulating factor (G-CSF).9 However, additional studies have suggested interactions between HAART and chemotherapy. When CDE was combined with the protease inhibitor (PI) saquinavir, mucositis was observed in 67% of patients.10 When it was given with the nucleoside analog didanosine, mucositis was observed in 12% of patients.11

A multicenter phase-2 trial, conducted by the Eastern Cooperative Oncology Group, of infusional CDE in 48 patients with ARL not receiving HAART demonstrated less impressive results (complete remission rate [CR], 46%; median survival, 8 months).12 This particular schedule has been used with concomitant HAART, and we have previously demonstrated the effects on lymphocyte subsets and HIV viral load.13 At the National Cancer Institute, etoposide-prednisolone-vincristine-cyclophosphamide-doxorubicin (EPOCH), a dose-adjusted infusional chemotherapy schedule, has been developed, and it, too, omits all HAART for the duration of the chemotherapy.14 Initial reports have been encouraging, with a CR rate of 79%. However, there was a dramatic decrease in the CD4 cell count during chemotherapy; even with the reinstitution of HAART at the end of chemotherapy, baseline levels were not recovered for another 12 months.15 This study has been expanded to 39 selected patients (CR rate, 74%)16 and is under investigation in a multicenter study under the auspices of the AIDS Malignancy Consortium.

Although initial studies demonstrating the efficacy of HAART were performed with PI-based therapies,17 recent data have indicated that non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART is at least as effective at controlling immunologic and viral load parameters, has a lower pill burden, and is better tolerated than PI-based HAART.5,18-20 Much of the controversy surrounding the concomitant use of HAART with chemotherapy centers on the potential for drug interactions.21 Both major categories of HAART, NNRTIs and PIs, are extensively metabolized by the cytochrome P450 system; hence, there may be competitive drug interactions when they are administered concomitantly with other drugs metabolized through this pathway.22,23 PIs may modify the metabolism of cytotoxic drugs by inhibiting the CYP3A4 enzyme. Indeed, pharmacokinetic studies have demonstrated a modest delay in the clearance of cyclophosphamide in patients receiving indinavir compared with historical controls, though no increase in hematologic toxicity was observed.24 Another potential interaction occurs because protease inhibitors are substrates and inhibitors of the drug transporter P-glycoprotein, an efflux pump that transports a wide range of structurally unrelated drugs, such as PIs and anthracyclines.25-29 One application of these interactions now used in HIV therapy is pharmacokinetic boosting, whereby metabolic interactions are exploited to reduce peaks and troughs.30

To investigate further the interactions between the 2 major categories of HAART and chemotherapy, we compared PI- and non-PI-containing HAART regimens on the incidence of neutropenia in a cohort of patients with ARL. The finding of significantly increased neutropenia in patients receiving CDE and PIs supports previous findings of interactions between these drugs and underscores the need for caution and regular monitoring when prescribing them together.


   Study design
Top
 Abstract
 Introduction
 Study design
Results and discussion
 References
 
Patients

The Chelsea and Westminster cohort of HIV-positive patients is one of the largest in Europe, and we prospectively collect data on the patients who enter the study. We investigated patients in whom ARL was diagnosed during the HAART era, from 1999 to 2003. During this time, 46 patients with newly diagnosed ARL were treated with concomitant HAART and infusional cyclophosphamide (200 mg/m2 per day on days 1-4), doxorubicin (12.5 mg/m2 per day on days 1-4), and etoposide (60 mg/m2 per day on days 1-4) chemotherapy (CDE at 4 weekly cycles through a Hickman line for 6 cycles). All patients received prophylaxis with 960 mg co-trimoxazole daily, 1250 mg azithromycin once a week, and either 200 mg itraconazole or 50 mg fluconazole daily. Three hundred micrograms G-CSF administered subcutaneously once a day was initiated 24 hours after the completion of the 96-hour infusion of chemotherapy and continued until a neutrophil count of more than 1.5 x 106/L was recorded. This study was performed with appropriate ethical approval (from the Chelsea and Westminster Hospital) and informed consent in accordance with the Declaration of Helsinki.

Concomitant HAART therapy was prescribed in accordance with current published guidelines.31-33 Total leukocyte and neutrophil counts were measured on days 1, 7, 10, and 14 of each cycle, and the number of days of G-CSF was recorded for each cycle. CD4 lymphocyte subset analysis was performed using whole blood stained with murine anti-human monoclonal antibodies (TetraOne; Beckman Coulter, High Wycombe, United Kingdom). Response rates were recorded according to standard criteria,34 as were International Prognostic Index (IPI) scores35 and toxicity to chemotherapy.

Statistical methods

Variables between groups were compared using the {chi}2 test for nominal variables and the Mann-Whitney U test for non-parametric variables. Survival was calculated from the day of diagnosis until death or the date of last follow-up. Overall survival duration curves were plotted according to the method of Kaplan and Meier.36 The log rank method was used to test for the significance of differences in survival distributions.37


   Results and discussion
Top
 Abstract
 Introduction
 Study design
 Results and discussion
References
 
Patient demographics

Demographic details of the cohort of 46 patients with ARL are shown in Table 1. Most (93%) of these patients were men, and they underwent a total of 190 cycles of CDE, 48 with PI HAART regimens (11 patients) and 142 (35 patients) with PI-sparing HAART regimens. The concomitant HAART treatment was triple nucleoside therapy (n = 3), NNRTI with dual nucleoside (n = 32), PI with dual nucleoside (n = 9), and both NNRTI and PI with nucleosides (n = 2). Twelve patients received zidovudine as part of HAART (1 with a PI regimen and 11 with a PI-sparing regimen {chi}2 test; P = .14).


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  		Table 1.. Clinicopathologic details of patients

 

Patients receiving a PI (n = 11) were compared with patients on HAART regimens that did not contain PIs (n = 35). There were no statistically significant differences in CD4 cell count (Mann-Whitney U test; P = .41) or in HIV-1 viral load (Mann-Whitney U test; P = .38) at NHL diagnosis between the 2 groups. There was also no significant difference in histologic subtype of NHL ({chi}2 test; P = .56), NHL stage distribution ({chi}2 test; P = .37), bone marrow infiltration ({chi}2 test; P = .76), meningeal disease at presentation ({chi}2 test; P = .32), or IPI38 group ({chi}2 test; P = .55).

Lymphoma outcome

Three patients (1 on PI-based HAART) were not evaluable for response to CDE because they died before completing 2 courses of chemotherapy. The overall response rate for the cohort was 74%: 50% CRs (5 of 11 patients on PIs, 18 of 35 patients on non-PIs) and 24% partial responses (PRs) (4 of 11 patients on PIs, 7 of 35 patients on non-PIs). The median survival for the cohort was 26 months, and the 2-year overall survival rate is 61% (95% confidence interval [CI], 47-76). There was no statistically significant difference in the overall survival rate or the CR rate between patients receiving a PI and those not (CR, 18 of 35 and 5 of 11; PR, 7 of 35 and 4 of 11). There were no significant differences in overall survival (P = .28; Figure 1A) or in disease-free survival (P = .74; Figure 1B) between those receiving either category of HAART. The trend toward an increased overall survival is likely a consequence of the small sample size at the ends of the Kaplan-Meier curves.



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  		Figure 1.. Survival after HAART. (A) Kaplan-Meier overall survival duration curves comparing patients treated with and without a PI as part of concomitant HAART therapy. {chi}2 = 1.176; DF = 1; P = .2781. (B) Kaplan-Meier disease-free survival curves comparing patients treated with or treated without a PI as part of concomitant HAART therapy. {chi}2 = .108; DF = 1; P = .7426.

 

Treatment-related toxicity

Cancer Toxicity Criteria (CTC) grade 3 or 4 infections necessitating hospitalization were recorded for 58 (31%) of 190 cycles of CDE; 23 (48%) of 48 patients were prescribed PIs, and 35 (25%) of 142 were prescribed concomitant PI-sparing HAART ({chi}2 test; P = .0025). CTC grade 4 neutropenia was recorded for 79 (42%) of 190 cycles; 26 (54%) of 48 patients were prescribed PIs, and 53 (38%) of 138 were prescribed concomitant PI-sparing HAART ({chi}2 test; P = .05).

The median neutrophil counts at days 1, 7, and 10 for all cycles were 3.5 x 106/L (range, 0.3-31 x 106/L), 4.7 x 106/L (range, 0-28 x 106/L), and 0.6 x 106/L (range, 0-24 x 106/L). Values for patients receiving either a PI-based or a PI-sparing HAART regimen are shown in Table 2. Day-10 and -14 neutrophil counts were significantly lower in patients receiving concomitant protease inhibitors. Altogether, 20 (10%) of 190 cycles of chemotherapy were delayed, 7 (16%) of 48 of those when a PI-based schedule was administered and 13 (9%) of 142 when a PI-sparing schedule was used ({chi}2 test; P = .29). One patient who had stage Ib ethmoidal diffuse large B-cell lymphoma and who was receiving a PI-based regimen (nelfinavir, didanosine, and stavudine) died of neutropenic sepsis after his third cycle of chemotherapy. At the time of his death, he had achieved PR to treatment.


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  		Table 2.. Neutrophil counts and G-CSF use in patients receiving PI-based or PI-sparing HAART

 

In those for whom data are available, PI- and NNRTI-based HAART has reduced morbidity and mortality associated with HIV, mainly by reducing the incidence of opportunistic infections.17 Its protective effects have also been shown to result in a decreased incidence of AIDS-defining malignancies, such as NHL39 and Kaposi sarcoma,20 with PI- and NNRTI-based HAART demonstrating equivalent efficacies. Here, we observed that protease inhibitors significantly enhanced neutropenia induced by infusional CDE chemotherapy in patients with ARL, evidenced by statistically significant decreases in day-10 and day-14 neutrophil counts in patients receiving PI-containing HAART compared with those who received HAART that did not contain PIs. Importantly, grade 3 or 4 infections necessitating hospitalization occurred in significantly more patients receiving PIs than in those not receiving PIs (48% vs 25%; {chi}2 test; P = .0025). Other between-group comparisons, however, were not statistically significant.

Previously, the concomitant use of antiretroviral agents with chemotherapy had been considered standard clinical practice, with the possible exception of zidovudine, which significantly added to the myelosuppression of combination chemotherapy, and didanosine, which may worsen the peripheral neuropathy caused by taxones and vinca alkaloids.40,41 There are few data regarding the pharmacokinetic interactions of PIs and NNRTIs with chemotherapy, though the inhibition of cytochrome p450/CYP3A enzyme system by certain PIs22,42,43x may reduce hepatic metabolism of cyclophosphamide and anthracycline. Such inhibition and subsequent increased levels of cytotoxics may explain the significantly increased neutropenia observed here with PIs.

Because modification of the p-glycoprotein efflux pump is an important underlying mechanism of drug interaction,44,45 another possibility is that the well-described inhibition of this transporter by PIs46,47 leads to increased intracellular levels of cytotoxics. Interestingly, PI-containing HAART, non-PI (NNRTI-containing)-based HAART, and cytotoxics such as doxorubicin can increase the levels of expression of p-glycoprotein48-50 though the functional consequences of increased expression are unclear.

A study of concomitant HAART and chemotherapy in patients with ARL has demonstrated that the CD4 cell count declines by 50% during chemotherapy but recovers rapidly within 1 month of the completion of chemotherapy.51 These findings support the use of concomitant HAART during chemotherapy to maintain immune function and during chemotherapy when patients are at high risk for infection. Recent work has highlighted the fact that PIs may have clinically important antitumor effects. These experiments, conducted more than 3 decades after Folkman's, showed that tumor growth was dependent on the formation of new blood vessels52 and that systemic administration of the PIs saquinavir and indinavir to nude mice induced regression of proliferative lesions promoted by angiogenic cytokines,53 with a potency similar to that of paclitaxel. Ritonavir has also been observed to have specific antitumor effects in vitro and in mouse xenotransplantation models.54 However, data from large cohort studies has found that NNRTI-based HAART is as effective as PI-based regimens at preventing NHL and Kaposi sarcoma during the course of HIV-1 infection.5,20,55

The potentiation of myelosuppression by PIs that we observed is likely caused by a pharmacokinetic interaction with the p450 microsomal enzyme system or inhibition of the P-glycoprotein efflux pump. However, there is no observed increase in response rate with PI-based HAART, suggesting that there is no significant dose-response gradient at this threshold even if there is a statistically significant dose-toxicity relationship. Patients with ARL have increased susceptibility to the consequences of immunosuppression, and our data suggest that physicians prescribing infusional chemotherapy to patients with ARL may want to consider alternative antiretroviral regimens to PIs. Recent data indicating the potency and durability of NNRTI-based HAART should provide reassurance to clinicians in this setting.


   Footnotes
 
Submitted May 11, 2004; accepted June 17, 2004.

Prepublished online as Blood First Edition Paper, July 6, 2004; DOI 10.1182/blood-2004-05-1747.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.

Reprints: Mark Bower, Department of Oncology, The Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10 9NH, United Kingdom; e-mail: m.bower{at}imperial.ac.uk.


   References
Top
 Abstract
 Introduction
 Study design
 Results and discussion
 References
 

  1. Jacobson LP, Yamashita TE, Detels R, et al. Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals: Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1999;21(Suppl 1): S34-S41.

  2. Bower M, Matthews G, Powles T, Mandalia S, Nelson M, Gazzard B. Changes in AIDS related lymphoma (ARL) in the era of highly active antiretroviral therapy (HAART) [abstract]. Proc ASCO. 2000;19: 17.

  3. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst. 2000;92: 1823-1830.[Abstract/Free Full Text]

  4. Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR, Gazzard BG. Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood. 2000;96: 2730-2734.[Abstract/Free Full Text]

  5. Stebbing J, Gazzard B, Mandalia S, et al. Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol. 2004;22: 2177-2183.[Abstract/Free Full Text]

  6. Stebbing J, Marvin V, Bower M. The evidence-based treatment of AIDS-related non-Hodgkin's lymphoma. Cancer Treat Rev. 2004;30: 249-253.[CrossRef][Medline] [Order article via Infotrieve]

  7. Sparano JA, Lee S, Henry DH, Ambinder RF, von Roenn J, Tirelli U. Infusional cyclophosphamide, doxorubicin and etoposide in HIV associated non-Hodgkin's lymphoma: a review of the Einstein, Aviano and ECOG experience in 182 patients [abstract]. J AIDS. 2000;23: 11.[CrossRef]

  8. Tirelli U, Spina M, Jaeger U, et al. Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: preliminary results of a phase I/II study. Recent Results Cancer Res. 2002;159: 149-153.[Medline] [Order article via Infotrieve]

  9. Sparano JA, Wiernik PH, Leaf A, Dutcher JP. Infusional cyclophosphamide, doxorubicin, and etoposide in relapsed and resistant non-Hodgkin's lymphoma: evidence for a schedule-dependent effect favoring infusional administration of chemotherapy. J Clin Oncol. 1993;11: 1071-1079.[Abstract/Free Full Text]

  10. Sparano JA, Wiernik PH, Hu X, Sarta H, Henry DH, Ratech H. Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin and etoposide in patients with HIV-associated non-Hodgkin's lymphoma. Med Oncol. 1998;15: 50-57.[Medline] [Order article via Infotrieve]

  11. Sparano JA, Wiernik PH, Hu X, et al. Pilot trial of infusional cyclophosphamide, doxorubicin and etoposide plus didanosine and filgrastim in patients with HIV associated non-Hodgkin's lymphoma. J Clin Oncol. 1996;14: 3026-3035.[Abstract]

  12. Sparano JA, Weller E, Nazeer T, et al. Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493). Blood. 2002;100: 1634-1640.[Abstract/Free Full Text]

  13. Powles T, Imami N, Nelson M, Gazzard BG, Bower M. Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS. 2002;16: 531-536.[CrossRef][Medline] [Order article via Infotrieve]

  14. Wilson WH, Grossbard ML, Pittaluga S, et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002; 99: 2685-2693.[Abstract/Free Full Text]

  15. Little R, Pearson D, Steinberg S, Elwood P, Yarchoan R, Wilson W. Dose-adjusted EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin's lymphoma [abstract]. Proc ASCO. 1999;18: 10.

  16. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003;101: 4653-4659.[Abstract/Free Full Text]

  17. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med. 1998;338: 853-860.[Abstract/Free Full Text]

  18. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults: Study 006 Team. N Engl J Med. 1999;341: 1865-1873.[Abstract/Free Full Text]

  19. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. Clin Infect Dis. 2002;34: 504-510.[CrossRef][Medline] [Order article via Infotrieve]

  20. Portsmouth S, Stebbing J, Gill J, et al. A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS. 2003; 17: 17-22.

  21. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002;41: 1195-1211.[CrossRef][Medline] [Order article via Infotrieve]

  22. Chiba M, Nishime JA, Lin JH. Potent and selective inactivation of human liver microsomal cytochrome P-450 isoforms by L-754,394, an investigational human immune deficiency virus protease inhibitor. J Pharmacol Exp Ther. 1995;275: 1527-1534.[Abstract/Free Full Text]

  23. Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet. 2001;40: 893-905.[CrossRef][Medline] [Order article via Infotrieve]

  24. Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol. 2001; 19: 2171-2178.[Abstract/Free Full Text]

  25. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet. 2002;359: 30-36.[CrossRef][Medline] [Order article via Infotrieve]

  26. Hochman JH, Chiba M, Nishime J, Yamazaki M, Lin JH. Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther. 2000;292: 310-318.[Abstract/Free Full Text]

  27. Hochman JH, Chiba M, Yamazaki M, Tang C, Lin JH. P-glycoprotein-mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome P450 3A4. J Pharmacol Exp Ther. 2001; 298: 323-330.[Abstract/Free Full Text]

  28. Hochman JH, Yamazaki M, Ohe T, Lin JH. Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein. Curr Drug Metab. 2002;3: 257-273.[CrossRef][Medline] [Order article via Infotrieve]

  29. Stebbing J, Bower M. What can oncologists learn from HIV? Lancet Oncol. 2003;4: 438-445.[CrossRef][Medline] [Order article via Infotrieve]

  30. Rathbun RC, Rossi DR. Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement. Ann Pharmacother. 2002;36: 702-706.[Abstract]

  31. BHIVA Guidelines Co-ordinating Committee. British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet. 1997;349: 1086-1092.[CrossRef][Medline] [Order article via Infotrieve]

  32. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002; 288: 222-235.[Abstract/Free Full Text]

  33. Pozniak A, Gazzard B, Anderson J, et al. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med. 2003;(suppl 1): 1-41.

  34. Therasse P, Arbuck S, Eisenhauer E, et al. New guidelines to evaluate the response to treatment in solid tumors (RECIST guidelines). J Natl Cancer Inst. 2000;92: 205-216.[Abstract/Free Full Text]

  35. Rossi G, Donisi A, Casari S, Re A, Cadeo G-P, Carosi G. The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer. 1999; 86: 2391-2397.[CrossRef][Medline] [Order article via Infotrieve]

  36. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: 457-481.[CrossRef]

  37. Peto R, Pike M, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient, II: analysis and examples. Br J Cancer. 1977;35: 1-39.[Medline] [Order article via Infotrieve]

  38. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329: 987-994.[Abstract/Free Full Text]

  39. Stebbing J, Gazzard B, Patterson S, et al. Antibody-targeted MHC complex-directed expansion of HIV-1- and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination. Blood. 2004;103: 1791-1795.[Abstract/Free Full Text]

  40. Gabarre J, Lepage E, Thyss A, et al. Chemotherapy combined with zidovudine and GM-CSF in human immunodeficiency virus-related non-Hodgkin's lymphoma. Ann Oncol. 1995;6: 1025-1032.[Abstract/Free Full Text]

  41. Lebbe C, Blum L, Pellet C, et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma. AIDS. 1998;12: 45-49.

  42. Chiba I, Sakakibara A, Iwata TH, et al. Hepatic microsomal cytochrome p450s and chlorinated hydrocarbons in largha and ribbon seals from Hokkaido, Japan: differential response of seal species to Ah receptor agonist exposure. Environ Toxicol Chem. 2002;21: 794-806.[CrossRef][Medline] [Order article via Infotrieve]

  43. Echizen H, Tanizaki M, Tatsuno J, et al. Identification of CYP3A4 as the enzyme involved in the mono-N-dealkylation of disopyramide enantiomers in humans. Drug Metab Dispos. 2000;28: 937-944.[Abstract/Free Full Text]

  44. Huisman MT, Smit JW, Crommentuyn KM, et al. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS. 2002;16: 2295-2301.[CrossRef][Medline] [Order article via Infotrieve]

  45. Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther. 2002;300: 1036-1045.[Abstract/Free Full Text]

  46. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol. 1999;57: 1147-1152.[CrossRef][Medline] [Order article via Infotrieve]

  47. Perloff MD, von Moltke LL, Fahey JM, Daily JP, Greenblatt DJ. Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture. AIDS. 2000;14: 1287-1289.[CrossRef][Medline] [Order article via Infotrieve]

  48. Haas DW, Wu H, Li H, et al. MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study. J Acquir Immune Defic Syndr. 2003;34: 295-298.[Medline] [Order article via Infotrieve]

  49. Ford J, Meaden ER, Hoggard PG, et al. Effect of protease inhibitor-containing regimens on lymphocyte multidrug resistance transporter expression. J Antimicrob Chemother. 2003;52: 354-358.[Abstract/Free Full Text]

  50. Lucia MB, Rutella S, Leone G, Larocca LM, Vella S, Cauda R. In vitro and in vivo modulation of MDR1/P-glycoprotein in HIV-infected patients administered highly active antiretroviral therapy and liposomal doxorubicin. J Acquir Immune Defic Syndr. 2002;30: 369-378.[Medline] [Order article via Infotrieve]

  51. Powles T, Imami N, Nelson M, Gazzard BG, Bower M. Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS. 2002;16: 531-536.[CrossRef][Medline] [Order article via Infotrieve]

  52. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285: 1182-1186.[Medline] [Order article via Infotrieve]

  53. Sgadari C, Barillari G, Toschi E, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med. 2002;8: 225-232.[CrossRef][Medline] [Order article via Infotrieve]

  54. Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS Jr, Weichold FF. Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood. 2002;99: 3771-3779.[Abstract/Free Full Text]

  55. Stebbing J, Portsmouth S, Nelson M, et al. The efficacy of ritonavir in the prevention of AIDS-related Kaposi's sarcoma. Int J Cancer. 2004; 108: 631-633.[CrossRef][Medline] [Order article via Infotrieve]


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