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© 2001 American Society for Clinical Oncology Chemotherapy for Human Immunodeficiency Virus–Associated Non-Hodgkin’s Lymphoma in Combination With Highly Active Antiretroviral TherapyFrom the AIDS Malignancy Consortium Operation Center, University of Alabama, Birmingham, AL. Address reprint requests to Lee Ratner, MD, PhD, Washington University, Box 8069, 660 S. Euclid, St Louis, MO 63110; email: lratner{at}imgate.wust1.edu
PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin’s lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.
MORE THAN 1 million individuals in the United States have been infected with human immunodeficiency virus type 1 (HIV-1). Their lifespans have been markedly lengthened by the introduction of highly active antiretroviral therapy (HAART), which resulted in a dramatic reduction of opportunistic infections.1 However, the incidence of non-Hodgkin’s lymphoma (NHL), which is 100- to 200-fold higher in HIV-infected than uninfected individuals, has not been altered by the introduction of HAART.2-6 All groups at risk for HIV can develop NHL, and the clinical course appears to be similar among these different groups.7 Most HIV-NHL are B-cell intermediate-grade large-cell, high-grade immunoblastic, or small noncleaved Burkitt’s-like lymphomas.8,9 A majority of patients present with widespread disease and B symptoms, and the risk of CNS involvement is increased compared with HIV-negative individuals. Factors associated with underlying immunosuppression, such as depressed CD4 count, prior opportunistic infections, and poor performance status, have been found to be important predictors of poor outcome.9,10 The presence of extranodal disease, particularly bone marrow involvement,9,10 advanced stage of disease,11 and elevated serum lactate dehydrogenase (LDH) levels, are also associated with a poor clinical outcome.12 Other studies have suggested that older age,12 immunoblastic subtype,13,14 and monoclonality represent additional adverse prognostic factors.15 Initial trials of dose-intensive regimens were associated with increased mortality due to opportunistic infections.9,16 A randomized study of modified-dose compared with full-dose therapy with methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (M-BACOD) demonstrated equivalent efficacy, but increased toxicity with the full-dose arm.17 Many previous trials using combination chemotherapy for HIV-NHL precluded the use of concurrent antiretroviral therapy. We sought to determine if HAART can be given with combination chemotherapy in order to obviate complications of HIV infection that could compromise or delay the delivery of antineoplastics for lymphoma. The objectives of the current study were to determine (1) the toxicity of combining cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with HAART; (2) the effects of CHOP with HAART on viral load, CD4 counts, and opportunistic infections; (3) pharmacokinetic interactions of CHOP with HAART; and (4) the response of HIV-NHL to CHOP combined with HAART.
Patient Characteristics Patients were enrolled if they were HIV seropositive, between the ages of 18 and 70, with Karnofsky performance scores (KPS) of at least 70%, biopsy-proven intermediate or high-grade B-cell lymphoma and adequate baseline organ functions as defined by hemoglobin greater than 8 g/dL, absolute neutrophil count greater than 1,000/mm3, platelet count greater than 75,000/mm3, creatinine less than 1.5 mg/dL or creatinine clearance greater than 50 mL/min, transaminases and alkaline phosphatase levels less than 3 times normal, and bilirubin less than 2.0 mg/dL. Patients were excluded if there was meningeal lymphoma or primary CNS lymphoma; active opportunistic infections other than Mycobacterium avium complex or other serious medical disorders requiring treatment within 14 days of enrollment; presence of a concurrent malignancy requiring treatment; patients receiving immunomodulating agents within 2 weeks of the study; any prior systemic chemotherapy except for Kaposi’s sarcoma; or intolerance to indinavir, lamivudine, or stavudine. Prestudy evaluation included a medical history, physical examination, hematology and blood chemistry tests, CD4 count, viral load, urinalysis, ECG, chest radiographs, computed tomographic scans (of the chest, abdomen, pelvis, and brain), as well as unilateral bone marrow biopsy and lumbar puncture, and a pregnancy test for women of child-bearing age. Pathologic slides were reviewed centrally by a single pathologist.
Treatment
Statistics
Sixty-five patients were enrolled on this study at 17 different medical centers. One patient was ineligible because of active meningeal disease. One patient was unevaluable because of early patient withdrawal. Neither patients received the study drugs. Ninety-two percent of the study participants were men, and the percentages of white, black, and Hispanic men were 45%, 21%, and 32%, respectively. The mean age of study participants was 41 years (range, 28 to 58 years). Thirty-six previously untreated patients with AIDS-NHL were enrolled onto the mCHOP arm of this study between March 1997 and March 1998. In addition, two patients previously treated with radiation therapy or small bowel resection were enrolled onto this arm of the study. Two other patients had received prior systemic chemotherapy for another malignancy. Because of a lack of severe toxicity, an additional 25 previously untreated patients with AIDS-NHL were then enrolled onto the full-dose CHOP arm between March 1998 and March 1999. Pretreatment characteristics of individuals in each group are similar, as listed in Table 1. The median CD4 count was 138 cells/mm3 among study entrants (range, 12 to 965 cells/mm3), 138 cells/mm3 among patients on the mCHOP arm, and 122 cells/mm3 among patients on the full-dose CHOP arm. The median Karnofsky performance score was 80% among patients enrolled on the mCHOP arm and 90% among those enrolled on the full-dose CHOP arm. Thirty-seven patients had a prior opportunistic infection and two patients had another malignancy. Sixty-three percent of the patients on the mCHOP arm had stage IV lymphoma, which was significantly higher compared with 35% of patients treated with full-dose CHOP arm (P = .03).
Central pathologic review was performed on slides available from 51 of the patients, and these results are listed in Table 1. A similar proportion of patients with intermediate- and high-grade lymphomas were enrolled onto each arm of the study. The majority of patients had diffuse large-cell lymphomas, but small-cell noncleaved lymphomas were diagnosed in 16% of patients on each arm of the study. Thirty percent of patients on the mCHOP arm achieved complete response (CR) and an additional 30% of patients achieved partial response (PR) ( Table 2). In contrast, 48% of subjects treated with full-dose CHOP achieved CR and 9% achieved PR. Relapse occurred in 33% of those achieving a CR with mCHOP and 9% of those treated with full-dose CHOP. Figure 1 shows the proportion of responders and complete responders who remained free of disease during the follow-up period. The median CR duration for patients on the mCHOP arm was 9 months, and the median response duration on the full-dose CHOP arm has not yet been reached. The overall response rates for mCHOP and full-dose CHOP arms were 60% (95% CI, 45% to 75%) and 57% (95% CI, 38% to 77%), respectively. No differences were detected between the two response rates (P = .79) or response durations (P = .73) on each arm of the study.
Eight patients were not evaluable for response, including six patients on the mCHOP arm and two patients on the full-dose CHOP arm. This included one patient with an adverse event (ileus) during the first 4 weeks of therapy; three deaths within the first 8 weeks of the study because of cardiopulmonary failure, encephalopathy after intrathecal chemotherapy, and pulmonary embolus; one patient with disease progression within the first week of therapy; one patient who withdrew from the study; and the two patients who received prior therapy before entering the study. The median duration of therapy for 63 patients was 11 weeks. One patient (2%) terminated therapy because of an adverse event, and 22 patients (34%) discontinued treatment because of disease progression. The median time to response was 6 weeks (range, 1 to 26 weeks). Logistic regression analysis was used to identify variables that correlated with likelihood of CR. In order to find variables that affected response duration, the Cox proportional hazards model was used to model the response duration time. The following variables were considered in these analyses: baseline CD4 count, prior opportunistic infection, performance status, age greater than or less than 40 years, bone marrow involvement, stage I or II versus III or IV disease, A versus B disease, normal or increased LDH, and small-cell histology versus other histologies. Small-cell histology was associated with a lower likelihood of achieving CR (P = .03), whereas full-dose CHOP compared to mCHOP was associated with a higher likelihood of CR (P = .04). The other variables were not correlated to the likelihood of CR. Of note, the CR rates on the mCHOP arm were 36% for those individuals with baseline CD4 count less than 100 cells/mm3 and 28% for those with baseline CD4 count greater than or equal to 100 cells/mm3. The CR rates on the full-dose CHOP arm were 45% for those with baseline CD4 count less than 100 cells/mm3 and 58% for those with baseline CD4 count greater than or equal to 100 cells/mm3. None of these variables was significantly related to response duration. Grade 3 or 4 toxicities occurring among these patients are listed in Tables 3 and 4. Grade 3 or 4 neutropenia occurred among patients on both the mCHOP arm (25%) and full-dose CHOP arm with G-CSF (13%, P = .34), the latter administered together with G-CSF. Only one patient had febrile neutropenia, occurring on two different occasions on the mCHOP arm. Other toxicities, including hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), transaminase elevation (48% and 52%), and nausea or vomiting (3% and 9%) occurred at similar rates among patients on the modified and full-dose CHOP arms, respectively. Hyperglycemia occurred in 10% of patients on the mCHOP arm, but in none of the patients on the full-dose arm (P = .29). This was presumed to be a complication of the use of indinavir and dexamethasone, although one of these patients had involvement of the pancreas by lymphoma. Other grade 3 or 4 toxicities included headache or anemia in four patients each; thrombocytopenia in three patients; infection, chills, diarrhea, or generalized pain in two patients each; and peripheral neuropathy, dyspnea, deep vein thrombosis, pneumonia, fatigue, fever, malaise, hypokalemia, elevated alkaline phosphatase, dehydration, erythema, syncope, neuralgia, arthralgia, melena, pruritus, proctalgia, nephrolithiasis, sepsis, wound dehiscence, prolonged prothrombin time, seizures, genital herpes, or small bowel obstruction in one patient each. Four patients died of treatment-related complications, one on the mCHOP arm and three on the full-dose CHOP arm.
Pharmacokinetics were performed in 18 patients on the mCHOP arm and 11 patients on the full-dose CHOP arm. The mean cyclophosphamide clearances were 41 and 46 mL/min/m2 on the mCHOP and full-dose CHOP arms, respectively, compared with historical controls of 70 mL/min/m2. Doxorubicin clearance rates were 594 and 607 mL/min/m2 on the modified and full-dose CHOP arms, respectively, compared with historical controls of 500 mL/min/m2. The concentration curves for indinavir showed values of 28 and 25 µM/h for the mCHOP and full-dose CHOP arms, respectively, compared with 32 µM/h in historical controls. The median viral load at study entry was 29,000 copies/mL (mean, 209,000; range, < 500 to 1,895,000 copies/mL). Thirty-eight patients (60%) had received prior protease inhibitor therapy, and the percentages of patients receiving prior therapy with zidovudine, didanosine, zalcitabine, stavudine, or lamivudine, were 37%, 11%, 2%, 41%, and 57%, respectively. Thirty-one patients (49%) had received prior three-drug regimens. The median minimum HIV viral load on study was 500 copies/mL. There were no significant differences in levels of viral load or their declines on the two arms of the study. There were also no significant differences in levels of baseline (28,900 and 35,300 copies/mL, respectively) and minimum viral loads on study for responders and nonresponders (500 copies/mL for both). During the study, the median CD4 count increased significantly from baseline values (P = .0001 for modified CHOP and P = .0039 for full-dose CHOP arms). The median maximum CD4 count was 216 cells/mm3. There was no significant difference between the two study arms with respect to baseline CD4 counts (Table 1), maximum CD4 count, or change in CD4 counts.
This clinical trial demonstrates that highly active antiretroviral therapy can be delivered safely and effectively with combination chemotherapy to patients with HIV-NHL. In this study, a specific HAART regimen was chosen in order to clarify interactions between HAART and CHOP. However, it is likely that any HAART regimen may be useful in this setting, excluding the use of zidovudine, which has significant effects on hematopoiesis.18 Several previous trials of combination chemotherapy for HIV-NHL have been published ( Table 5). Chemotherapy trials of HIV-NHL performed in the 1980s using CHOP or other regimens resulted in response rates of 8% to 72% (median, 33%), with median survivals of 3 to 15 months (median, 6 months).19,20 The conclusions of the authors of these trials was that intensive therapy for HIV-NHL resulted in excessive toxicity and poor response rates.
A trial from the AIDS Clinical Trials Group (ACTG) included 42 patients, treated with modified doses of M-BACOD, resulting in a 46% CR rate.21 Antiretroviral therapy was discontinued during the treatment, and zidovudine was instituted upon completion of chemotherapy. Despite the use of prophylaxis, PCP developed in 21% of the patients. The same group of investigators performed a randomized trial of modified-dose versus full-dose M-BACOD, the latter with granulocyte-macrophage colony-stimulating factor (GM-CSF). This resulted in CR rates of 41% and 52%, respectively (P = .56).17 Median survivals were 35 and 31 weeks for patients on the modified-dose and full-dose M-BACOD arms, respectively (P = .25). However, the full-dose arm was associated with more grade 3 toxicity (70% v 51%, P = .008), and thus modified-dose M-BACOD was recommended. A trial from the Eastern Cooperative Oncology Group included 25 patients treated with a combination of cyclophosphamide, doxorubicin, and etoposide, resulting in a 46% CR rate.24 Patients received PCP and Candida prophylaxis, G-CSF, and didanosine but no protease inhibitors. Grade 3 or 4 neutropenia developed in 75% of the participants, thrombocytopenia in 55%, and infection in 18%. A European intergroup trial stratified AIDS-NHL according to the presence or absence of prior AIDS diagnosis, CD4 count of less than or equal to or more than 100 cells/mm3, and performance status less than or equal to 1 or more than 1.25 One hundred fifty-nine patients lacking all three adverse characteristics were randomized to an intensive regimen with doxorubicin, cyclophosphamide, vindesine, and bleomycin or CHOP with G-CSF, resulting in complete responses of 66% and 60%, respectively. One hundred ten intermediate-risk patients with only one poor prognostic factor were randomized to receive modified or full-dose CHOP, resulting in CRs of 39% and 63%, respectively (P = .001) A trial of EPOCH chemotherapy, a combination of etoposide, vincristine, doxorubicin, and prednisone, given with G-CSF to 24 AIDS-NHL patients, resulted in a 79% CR rate.26 Grade 4 neutropenia developed during 29% of the chemotherapy cycles, and febrile neutropenia in 12%. Viral load increased by 1,000-fold over baseline values, but returned to baseline or lower levels 3 months later after discontinuation of EPOCH. The response rates on the current trial are similar to those reported in previous trials. Although a somewhat higher CR rate was observed in the present trial with full-dose CHOP compared with mCHOP, this was not a randomized study. Protease inhibitors can block the metabolism of drugs by cytochrome P-450 pathways, especially by inhibiting the CYP3A4 isoform. Pharmacokinetic studies performed in the current study showed retarded clearance of cyclophosphamide compared with historical controls, consistent with an effect of indinavir. However, clearance was only decreased 1.5-fold compared with historical controls, and excessive hematologic toxicity in comparison with previous studies was not seen. No significant effects on doxorubicin clearance were seen. The modest effects of HAART on cyclophosphamide clearance seen in the current study suggests that careful monitoring should be incorporated into trials using higher doses of cyclophosphamide, for example, in the transplant setting. In the current study, several previously described prognostic factors (age, LDH, stage, baseline CD4 count, prior opportunistic infection, performance status, and bone marrow involvement) were not predictive of response. These results may be because of limitations related to the sample size in the current study, or to the use of concurrent HAART with combination chemotherapy. Only small-cell versus large-cell histology was predictive of a poor response, suggesting that CHOP might not provide adequate treatment for this aggressive lymphoma. Viral load is the strongest predictor of prognosis in HIV-1–infected patients without malignancy.27-29 The current trial is novel in that it used HAART, and initiated or continued antiretroviral therapy from the time of initiation of chemotherapy. Pharmacokinetic studies demonstrated no effects of chemotherapy on indinavir levels. Moreover, viral loads declined and CD4 counts significantly increased despite the concurrent use of chemotherapy, similar to that reported for HIV-infected patients without malignancies.30 The increase in CD4 counts during chemotherapy resulted from the institution or continuation of HAART, indicating its effectiveness. Moreover, only a single opportunistic infection (Cryptococcus) was reported during this trial or during the follow-up period. The very limited number of opportunistic infections in the current trial contrasts sharply with previous trials, and points to the efficacy of HAART therapy in this setting.9,16,17,19 Treatment of HIV-NHL with myelotoxic drugs frequently causes profound neutropenia.19 Low CD4 counts were associated with neutropenia in a prior ACTG study, and possibly poor immune function correlates with poor bone marrow function, both caused by HIV.17 This may be related to synergistic toxicity of these drugs with the effects of HIV-1 in suppressing hematopoiesis.31 In addition, frequent bone marrow involvement with lymphoma in HIV-1–infected patients further compromises hematopoiesis.19 Although the use of colony-stimulating factors can lessen these sequelae, they are not completely successful.17 Moreover, GM-CSF, although not G-CSF, has the potential risk of enhancing HIV replication in macrophages.32 Thus, improved immune function because of HAART may also result in improved bone marrow function. The current trial suggests that the concurrent use of HAART may be important for the delivery of full doses of chemotherapy without undue toxicity.
APPENDIX
Supported by National Cancer Institute grant nos. U01 CA70079, U01 CA70081, U01 CA70078, U01 CA70058, U01 CA70047, U01 CA70054, U01 CA70072, U01 CA70080, U01 CA71375, U01 CA70062, and U01 CA70019. We thank W. Powderly for helpful advice in the design of the study.
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Ledergerber B, Telenti A, Egger M: Risk of HIV related Kaposi’s sarcoma and non-Hodgkin’s lymphoma with potent antiretroviral therapy: Prospective cohort study. BMJ 319: 23-24, 1999 7. Serraino D, Salamina G, Franceshi S, et al: The epidemiology of AIDS-associated non-Hodgkin’s lymphoma in the World Health Organization European Region. Br J Cancer 66: 912-916, 1992[Medline] 8. Knowles DM, Chamulak GA, Subar M, et al: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS): The New York University experience with 105 patients (1981-1986). Ann Intern Med 108: 744-753, 1988
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Kaplan LD, Abrams DI, Feigel E, et al: AIDS-associated non-Hodgkin’s lymphoma in San Francisco. JAMA 261: 719-724, 1989 10. Levine AM, Sullivan-Halley J, Pike MC, et al: Human immunodeficiency virus-related lymphoma: Prognostic factors predictive of survival. Cancer 68: 2466-2472, 1991[Medline] 11. Straus D, Huang J, Testa M, et al: Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: Analysis of AIDS Clinical Trials Group protocol 142—low-dose versus standard-dose mBACOD plus granulocyte-macrophage colony-stimulating factor. J Clin Oncol 16: 3601-3606, 1998[Abstract] 12. Vaccher E, Tirelli U, Spina M, et al: Age and serum lactate dehydrogenase level are independent prognostic factors in human immunodeficiency virus-related non-Hodgkin’s lymphomas: A single institute study of 96 patients. J Clin Oncol 14: 2217-2223, 1996[Abstract] 13. Lowenthal DA, Straus DJ, Campbell SW, et al: AIDS-related lymphoid neoplasia: The Memorial Hospital experience. Cancer 61: 2325-2337, 1988[Medline] 14. Gisselbrecht C, Oksenhendler E, Tirelli U, et al: Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. Am J Med 95: 188-196, 1993[Medline]
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Kaplan LD, Straus DJ, Testa MA, et al: Randomized trial of standard-dose vs low-dose mBACOD chemotherapy for HIV-associated non-Hodgkin’s lymphoma. N Engl J Med 336: 1641-1648, 1997 18. Groopman JE: Antiretroviral therapy and immunomodulators in patients with AIDS. Am J Med 90: 18S-21S, 1991[Medline]
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Levine AM: Acquired immunodeficiency syndrome-related lymphoma. Blood 80: 8-20, 1992 20. Levine AM, Sullivan-Halley J, Pike MC, et al: Human immunodeficiency virus-related lymphoma: Prognostic factors predictive of survival. Cancer 68: 2466-2472, 1991
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Levine AM, Wernz JC, Kaplan L, et al: Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma: A prospective multi-institutional trial. JAMA 266: 84-88, 1999
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Kersten MJ, Veduyn TJ, Reiss P, et al: Treatment of AIDS-related non-Hodgkin’s lymphoma with chemotherapy (CNOP) and rhu-G-CSF: clinical outcome and effect on HIV-1 viral load. Ann Oncol 9: 1135-1138, 1998 23. Davis AJ, Goldstein D, Milliken S: Long-term follow-up of CEOP in the treatment of HIV related non-Hodgkin’s lymphoma. Aust N Z J Med 28: 28-32, 1998[Medline] 24. Sparano JA, Lee S, Chen M, et al: Phase II trial of infusion cyclophosphamide, doxorubicin, and etoposide (CDE) in HIV-associated non-Hodgkin’s lymphoma: An Eastern Cooperative Oncology Group Trial. Proc Am Soc Clin Oncol 18: 12a, 1999 (abstr 41) 25. Gisselbrecht C, Gabarre J, Spina M, et al: Treatment of HIV-related non-Hodgkin’s lymphoma adapted to prognostic factors. Proc Am Soc Clin Oncol 18: 16a, 1999 (abstr 55) 26. Little RF, Pearson D, Franchini G, et al: Dose adjusted EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin’s lymphoma: Preliminary report of efficacy, immune reconstitution, and HIV control following therapy. Paper presented at: 3rd National AIDS Malignancy Conference; May, 1999; Bethesda, MD (abstr 93) 27. Saag MS, Holodniy M, Kuritzkes DR, et al: HIV viral load markers in clinical practice. Nat Med 2: 625-629, 1996[Medline] 28. O’Brien WA, Hartigan PM, Martin D, et al: Change in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 334: 425-431, 1996
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Mellors JW, Kingsley LA, Rinaldo CR, et al: Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 122: 573-579, 1995 30. Deeks SG, Hecht FM, Swanson M, et al: HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: Response to both initial and salvage therapy. AIDS 13: F35-F43, 1999[Medline]
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Louache F, Henri A, Bettaieb A, et al: Role of human immunodeficiency virus replication in defective in vitro growth of hematopoietic progenitors. Blood 80: 2991-2999, 1992
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher’s exact test was used to test response rate differences between treatment arms. The response duration was evaluated using the Kaplan-Meier method. The log-rank test was used to compare response duration between the two study arms. The Wilcoxon signed rank test was used to evaluate changes from baseline in HIV viral load. The Wilcoxon two-sample test (rank sum test) was used to detect differences between responders and nonresponders with respect to HIV viral load levels. Logistic regression analysis was used to identify variables that correlated with the likelihood of complete response. In order to find variables that affected response duration, the Cox proportional hazards regression model was used. 
