Detrimental clinical interaction between ritonavir-boosted protease inhibitors and vinblastine in HIV-infected patients with Hodgkin's lymphoma
Cingolani, Antonellaa; Torti, Lorenzab; Pinnetti, Carmelaa; Donati, Katleen de Gaetanoa; Murri, Ritaa; Tacconelli, Evelinaa; Larocca, Luigi Mariac; Teofili, Lucianab
aInstitute of Infectious Diseases, Italy
bInstitute of Hematology, Italy
cInstitute of Histopathology, Catholic University, Rome, Italy.
Received 24 March, 2010
Revised 24 June, 2010
Accepted 29 June, 2010
Correspondence to Antonella Cingolani, MD, Institute of Infectious Diseases, Catholic University, Rome, Italy. Tel: +39 06 30155385; fax: +39 06 3054519; e-mail: email@example.com
In order to analyze the clinical relevance of the pharmacokinetic interactions between vinblastine and antiretrovirals described in literature, we evaluated all HIV-infected patients with Hodgkin's lymphoma treated with vinblastine-containing regimens and combination antiretroviral therapy, in a single clinical center. The use of protease inhibitors was independently associated with WHO grade III–IV neutropenia. Moreover, an inverse correlation between dosage of ritonavir and mean nadir neutrophil count was found. The concomitant administration of vinblastine-containing chemotherapy regimens with protease inhibitors can lead to higher levels of neutropenia than those of different classes of drugs such as nonnucleoside reverse transcriptase inhibitors or integrase inhibitors.
HIV-infected people exhibit a higher risk to develop Hodgkin's lymphoma than the general population . Although combined antiretroviral therapy (cART) introduction deeply modified the epidemiology of several malignancies in HIV-infected population , the incidence of Hodgkin's lymphoma appears to be rising [3,4]. As it has been widely demonstrated that cART strongly improves the survival of HIV-infected people with lymphomas [5,6], the combined therapeutic approach of cART and chemotherapy represents the gold standard for the treatment of HIV-related lymphomas. Unfortunately, no standard therapy for Hodgkin's lymphoma in this set of patients has been identified . Initial experience with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), the internationally accepted standard regimen for Hodgkin's lymphoma , reported a significant incidence of infectious fatal complications in HIV individuals . The immune reconstitution achieved by adding cART to chemotherapy positively impacted on survival, reduced infectious complications and improved the tolerability of chemotherapy . Nevertheless, in a more recent retrospective study on HIV patients with Hodgkin's lymphoma treated by ABVD and cART combination between 1996 and 2005, a significant percentage of deaths were reported . The incidence of infectious complications in this setting of patients is surprisingly high if compared with that of the general population and suggests that, at least in some cases, severe and prolonged neutropenia might result from dangerous interactions between antiretroviral and chemotherapy. Actually, the cases of four patients receiving vinblastine and lopinavir/ritonavir who experienced life-threatening infectious complications have been recently described [12–14].
Ritonavir-boosted protease inhibitor (PI/r) represents a widely used component of cART regimens in naive as well as in experienced HIV-infected patients [15,16], due to its strong efficacy and high genetic barrier to development of resistance. Nevertheless, the coformulation with ritonavir is likely to increase plasma concentrations of several other drugs metabolized through the CYP3A pathway, including Vinca alkaloids .
Vinblastine is mainly metabolized by the cytochrome P4503A4 isoenzymes, and potent inhibitors of this isoenzyme, like ritonavir, may result in decreasing vinblastine metabolism and consequently increasing vinblastine-related myelosuppression .
In order to better define the interaction between cART regimens and vinblastine, we reviewed clinical charts of all HIV-infected patients followed at our center who received a diagnosis of Hodgkin's lymphoma. Differences in group proportions were assessed using χ2 test. One-way analysis of variance (ANOVA) test was used to test for differences among independent groups. The precision of the odds ratio (OR) was determined by calculating a 95% confidence interval (95%CI). Potential risk factors for WHO III–IV neutropenia were analyzed by step forward logistic regression analysis. A two-tailed P value less than 0.05 was considered statistically significant. Results are presented as multivariate (adjusted) odd ratios. The Hosmer and Lemeshow goodness-of-fit test was used to assess model fit. Statistical analysis was performed using the software program Intercooled Stata (version 8.0; Stata Corporation, College Station, Texas, USA).
From June 2002 to July 2009, 16 patients with Hodgkin's lymphoma were concomitantly treated with vinblastine-containing regimens (ABVD or Stanford V)  and cART, supported by granulocyte colony-stimulating factor (G-CSF) administration. Five out of 16 patients were on PI/r-based regimens during polychemotherapy (PCT) cycles and continued the same PI/r all PCT long; two out of 16 patients switched from PI/r regimen to non-PI/r regimens during PCT cycles (one patient switched to efavirenz and the other to raltegravir); two patients were on unboosted protease inhibitor regimens (both on indinavir); seven out of 16 patients were prescribed nonprotease inhibitor-based regimens [seven on nonnucleoside reverse transcriptase inhibitor (NNRTI) and one on raltegravir].
Despite the prophylactic administration of G-CSF, the mean nadir neutrophil count (+SD) for all cycles of PCT on the same cART regimens were 0.218 + 0.343 × 106/l for patients taking regimens containing PI/r, 0.375 + 0.078 × 106/l in patients taking protease inhibitor-unboosted and 1560 + 715 × 106/l in patients on nonprotease inhibitor-based regimens (P < 0.001).
Table 1 summarizes detailed characteristics of the population. Two patients taking lopinavir/r-containing cART regimens died of a Gram-negative bacterial sepsis during the first ABVD cycle. After controlling for CD4 cell count less than 200 cells/μl, use of zidovudine and bone marrow involvement, the use of protease inhibitors were more likely to be associated with severe grade III–IV neutropenia (OR 34.3, 95%CI 1.9–602.4; P = 0.02; McFadden R2 = 0.50). Therefore, the role of boosting ritonavir in developing III–IV neutropenia was further analyzed. An inverse correlation between dosage of ritonavir and mean nadir neutrophil count was found. The mean nadir neutrophil count was 1.350 × 106/l (+SD 0.800) in patients not taking ritonavir, 0.850 × 106/l (+SD 0.091) in patients taking 100 mg of ritonavir and 0.047 × 106/l (+SD 0.050) in those taking 200 mg of ritonavir as boosting, respectively.
Our study demonstrated that the concomitant administration of vinblastine-containing chemotherapy regimens with protease inhibitors can lead to higher levels of neutropenia and that in this set of patients, cART regimens containing different classes of drugs (NNRTI, integrase inhibitors) are more advisable.
There are some limits to our analysis. First, the study is a retrospective one. It is possible that significant confounders were not addressed. Second, the study was performed in a single center and the generalization of results might not be ensured. Third, the small number of patients and the lack of pharmacokinetic data do not allow us to evaluate the causative role of ritonavir boosting in developing neutropenia in patients taking protease inhibitor; nevertheless, the fact that only two patients were taking nonboosted protease inhibitor (indinavir) and that higher doses of ritonavir lead to an increased risk of WHO III–IV neutropenia allowed us to assume this hypothesis. Moreover, as protease inhibitor-unboosted cART regimens are no longer recommended [15,16], in all available guidelines, the more stringent question of whether a lower dose of ritonavir (100 mg) could safely be assumed in patients concomitantly treated with vinblastine-PCT regimens appears crucial and it must be evaluated in larger studies.
Notwithstanding the clinically relevant interactions reported in the literature and confirmed in our study, recommendations are very poor. Two strategies aiming to avoid the detrimental effects of drug interactions have been proposed [12,13]. The first one consists of a temporary interruption of PI/r around chemotherapy administration, which results in a prompt and stable recovery from neutropenia. Nevertheless, although boosted protease inhibitor showed a very high genetic barrier, the potential occurrence of drug-resistance-associated mutations either in protease gene and in reverse transcriptase for the concomitant interruption of nucleoside reverse transcriptase inhibitor backbone must be taken into account. The other strategy consists of the reduction of vinblastine dose. It sounds to be a feasible approach, even though the dose intensity has been demonstrated to be associated with a better prognosis of lymphomas either in general or in HIV-infected population [19,20].
Unfortunately, as per our knowledge, vinblastine plasma concentration is not routinely assessed as therapeutic drug monitoring, even though it should be taken into consideration in the management of patients assuming concomitant PI/r.
In our study, no clinically relevant interaction has been found between the NNRTI-based or the raltegravir-based regimens and vinblastine. Also the NNRTIs, and the mixed inducer and inhibitor efavirenz in particular, are substrates of CYP3A4. Nevertheless, interaction between efavirenz and commonly used antineoplastic drugs, particularly vinblastine, has not been studied, even though it could be predicted based on the pharmacokinetic profile of both drugs . The HIV-1 integrase strand transfer inhibitor raltegravir shows a potent activity against HIV-1 and HIV-2 and a good safety profile in experienced as well as in naive patients [22,23]. Differently from ritonavir-boosted protease inhibitors, raltegravir is not a substrate of CYP450, being eliminated mainly via UGT1A1-mediated glucuronidation pathway metabolism . Very limited published data are available regarding the use of raltegravir in combination with chemotherapy regimens in HIV-infected people, whereas the concomitant administration of raltegravir and immunosuppressive drugs such as cyclosporine and tacrolimus, both metabolized via the cytochrome P450 family, proved to be safe and efficacious in HIV-infected transplant patients [25,26].
In conclusion, randomized studies aimed to evaluate the impact of different classes of antiretrovirals on tolerability and response to chemotherapy protocols are lacking and it should be warranted that all possible pharmacokinetic interactions between chemotherapy and antiretrovirals be accurately considered in the design of the studies.
1. Beral V, Peterman T, Berkelman R, Jaffe H. AIDS associated non-Hodgkin's lymphoma. Lancet 1991; 337:805–809.
2. Bonnet F, Chêne G. Evolving epidemiology of malignancies in HIV. Curr Opin Oncol 2008; 20:534–540.
3. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al
, Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med 2008; 148:728–736.
4. Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, et al
. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol 2009; 27:884–890. Epub 2008 Dec 29.
5. Navarro JT, Ribera JM, Oriol A, Vaquero M, Romeu J, Batlle M, et al
. Influence of highly active antiretroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin lymphoma treated with cyclophosphamide, hydroxydoxorubicine, vincristine and prednisone. Br J Haematol 2001; 112:909–915.
6. Hoffmann C, Wolf E, Fätkenheuer G, Buhk T, Stoehr A, Plettenberg A, et al
. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS related lymphoma. AIDS 2003; 17:1521–1529.
7. Spano JP, Costagliola D, Katlama C, Mounier N, Oksenhendler E, Khayat D. AIDS-related malignancies: state of the art and therapeutic challenges. J Clin Oncol 2008; 26:4834–4842. Epub 2008 June 30 [review].
8. Levine AM, Li P, Cheung T, Tulpule A, Von Roenn J, Nathwani BN, Ratner L. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin's disease: a prospective, multiinstitutional AIDS clinical trials group study (ACTG 149). J Acquir Immune Defic Syndr 2000; 24:444–450.
9. Evens AM, Hutchings M, Diehl V. Treatment of Hodgkin lymphoma: the past, present, and future. Nat Clin Pract Oncol 2008; 5:543–556. Review.
10. Hoffmann C, Chow KU, Wolf E, Faetkenheuer G, Stellbrink HJ, van Lunzen J, et al
. Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin's disease. Br J Haematol 2004; 125:455–462.
11. Xicoy B, Ribera JM, Miralles P, Berenguer J, Rubio R, Mahillo B, et al
, GESIDA Group; GELCAB Group. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral therapy in advanced stage, human immunodeficiency virus-related Hodgkin's lymphoma. Haematologica 2007; 92:191–198.
12. Kotb R, Vincent I, Dulioust A, Peretti D, Taburet AM, Delfraissy JF, Goujard C. Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman's disease. Eur J Haematol 2006; 76:269–271.
13. Makinson A, Martelli N, Peyrière H, Turriere C, Le Moing V, Reynes J. Profound neutropenia resulting from interaction between antiretroviral therapy and vinblastine in a patient with HIV-associated Hodgkin's disease. Eur J Haematol 2007; 78:358–360.
14. Martin P, Leonard JP, Coleman M, Furman RR. Durable complete remissions in HIV-associated Hodgkin lymphoma after treatment with only one cycle of chemotherapy complicated by sepsis. Clin Lymphoma Myeloma 2009; 9:247–249.
15. DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
1 December 2009.
16. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs
17. Antoniou T, Tseng AL. Interactions between antiretroviral and antineoplastic drug therapy. Clin Pharmacokinet 2005; 44:111–145.
18. Spina M, Gabarre J, Rossi G, Fasan M, Schiantarelli C, Nigra E, et al
. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 2002; 100:1984–1988.
19. Schmitz N, Kloess M, Reiser M, Berdel WE, Metzner B, Dorken B, et al
, German High-Grade Non Hodgkin's Lymphoma Study Group (DSHNHL). Four versus six courses of a dose-escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus etoposide (megaCHOEP) and autologous stem cell transplantation: early dose intensity is crucial in treating younger patients with poor prognosis aggressive lymphoma. Cancer 2006; 106:136–145.
20. Antinori A, Cingolani A, Alba L, Ammassari A, Serraino D, Ciancio BC, et al
. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 2001; 15:1483–1491.
21. Kappelhoff BS, van Leth F, MacGregor TR, Lange J, Beijnen JH, Huitema AD. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir Ther 2005; 10:145–155.
22. Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, et al
, BENCHMRK Study Teamsa. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis 2010; 50:605–612.
23. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al
, STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naïve patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374:796–806, 2009.
24. Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al
. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus integrase enzyme. Drug Metab Dispos 2007; 35:1657–1663.
25. Tricot L, Teicher E, Peytavin G, Zucman D, Conti F, Calmus Y, et al
. Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. Am J Transplant 2009; 9:1–7.
26. Fulco PP, Hynicka L, Rackley D. Raltegravir-based HAART regimen in a patient with large B-cell lymphoma. Ann Pharmacother 2010; 44:377–382.
© 2010 Lippincott Williams & Wilkins, Inc.