Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma

Authors


Abstract

BACKGROUND

The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)-related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV-related, systemic, non-Hodgkin lymphoma (HIV-NHL), the authors compared retrospectively a group of 24 patients with HIV-NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP-like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy.

METHODS

All patients were enrolled in two sequential trials performed at the Aviano Cancer Center, Italy, from April 1988 to December 1998. HAART was included with combination therapy from January 1997. Antiretroviral regimens consisted of two reverse transcriptase inhibitors and one protease inhibitor.

RESULTS

The two treatment groups were well matched with regard to patient demographics, NHL characteristics, HIV status, and treatment, i.e., the number of cycles and chemotherapy dose. The response rates were similar between the two groups. Severe anemia (Grade 3–4 according to the World Health Organization criteria) was significantly greater in the patients who received CHOP-HAART compared with the patients who received CHOP alone (33% vs. 7%, respectively; P = 0.001). Leukopenia was similar between the two groups, but colony stimulating factor support was significantly greater in the CHOP-HAART group than in the control group (92% vs. 66%, respectively; P = 0.03). Seventeen percent of CHOP-HAART patients developed severe autonomic neurotoxicity, whereas none of the CHOP patients developed neurotoxicity (P = 0.002). At similar median follow-up, opportunistic infection (OI) rates and mortality were significantly lower in the CHOP-HAART patients than in the CHOP patients (18% vs. 52%, respectively; P = 0.05; and 38% vs. 85%, respectively; P = 0.001). The median survival for CHOP-HAART patients was not reached, whereas the medial survival of CHOP patients was 7 months (P = 0.03).

CONCLUSIONS

The combination of CHOP plus HAART is feasible and may reduce the morbidity from OIs in HIV-NHL patients. However, careful attention must be directed to cross toxicity and possible pharmacokinetic interactions between antiretroviral and antineoplastic drugs. The impact of the combined chemotherapy plus HAART treatment on patient survival needs urgently to be evaluated in prospective studies. Cancer 2001;91:155–63. © 2001 American Cancer Society.

Combination antiretroviral therapy that includes two reverse transcriptase inhibitors and a protease inhibitor or highly active antiretroviral therapy (HAART) is the treatment of choice for patients with human immunodeficiency (HIV) infection.1, 2 HAART results in an effective suppression of viral replication with consequent improvement of immune function and a dramatic reduction in the rates of opportunistic infections (OIs), hospitalization, and mortality among HIV-infected patients.3–6 Conversely, the morbidity and mortality rates for patients with non-Hodgkin lymphoma (NHL) are still increasing within the HIV-infected population.7–10 Although chemotherapy may be associated with a high risk of OIs, and the median survival is still less than 1 year in the majority of series, it remains the treatment of choice for patients with HIV-NHL, inducing complete remission in a significant fraction of patients.8, 9, 11–14

With the advent of HAART, the integration of antiretroviral therapy with antineoplastic chemotherapy should be now advisable. Moreover, the rapid development of resistant viruses, when adherence to antiretroviral drugs is poor, supports the need for concomitant chemotherapy and HAART in patients with HIV-NHL.1, 2, 15–17 However, the feasibility and the efficacy of combining antiretroviral and antineoplastic treatment remains unknown.

To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV-related NHL, we retrospectively compared a group of 24 patients with HIV and systemic NHL who were concomitantly treated with the CHOP regimen and HAART with a group of 80 patients who were treated only with CHOP or a CHOP-like regimen, (i.e., when HAART was not yet available).

MATERIALS AND METHODS

One hundred four patients with HIV and intermediate-high grade, systemic NHL were enrolled in two sequential prospective trials performed at the Aviano Cancer Center, Italy, from April 1988 to December 1998, as reported previously.11, 18, 19 HAART was introduced in the clinic at our institute in January 1997, and, since then, all patients were treated with concomitant chemotherapy and HAART. Twenty-four patients received the CHOP regimen (cyclophosphamide 750 mg/m2 intravenously [i.v.] on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, vincristine 1.4 mg/m2 [maximum, 2 mg] i.v. on Day 1, and prednisone 100 mg per os on Days 1–5) plus HAART. Antiretroviral regimens were selected based on patient prior therapy and consisted of azidothymidine (AZT)-lamivudine (3TC)-saquinavir (SQV), or indinavir (IDV), or ritonavir (RTV) in 14 patients (58%); stavudine (D4T)-3TC-SQV or IDV in 7 patients (29%); D4T-didanosine (DDI)-SQV or IDV in 2 patients (8%); and DDI-nevirapine-RTV in 1 patient (4%).

This group of patients was compared retrospectively with a group of the remaining 80 patients who were treated with CHOP (39 patients) or with a CHOP-like regimen CHVmp-VCR-BLM (cyclophosphamide 600 mg/m2 i.v. on Day 1, doxorubicin 50 mg/m2 i.v. on Day 1, teniposide 60 mg/m2 i.v. on Day 1, prednisone 40 mg/m2 per os on Days 1–5, vincristine 1.4 mg/m2 [maximum, 2 mg] i.v. on Day 15, and bleomycin 10 mg/m2 i.v. on Day 15)20, 21 (n = 41 patients) without antiretroviral therapy (n = 74 patients) or with AZT monotherapy (n = 6 patients).18 Informed consent was obtained for all patients according to institutional guidelines.

All patients received central nervous system prophylaxis, consisting of intrathecal methotrexate 12 mg on Day 1. Supportive care included Pneumocysistis carinii pneumonia prophylaxis (160 mg trimethoprim plus 800 mg sulfamethoxazole three times per week) for all patients or inhaled pentamidine (300 mg monthly) for patients with sulfa intolerance. Prophylaxis for mycobacterium avium, cytomegalovirus, or fungal disease was not administered. Granulocyte macrophage-colony stimulating factor (GM-CSF) was given as primary or secondary prophylaxis to 2 patients, and granulocyte-colony stimulating factor (G-CSF) to was given 55 patients since it became available, in agreement with protocol guidelines. Erithropoietin prophylaxis was not administered. Two patients who were on HAART pre-CHOP therapy did not receive antiretroviral drugs during or after the chemotherapy for refusal. Six patients who received AZT monotherapy concomitantly with CHOP stopped antiretroviral therapy after chemotherapy due to NHL progression (n = 4 patients) or refusal (2 = patients). Seven patients who received CHOP alone in the immediate pre-HAART era did not receive antiretroviral drugs after they completed chemotherapy because of intercurrent OIs (n = 4 patients) or lymphoma progression (n = 3 patients).

For all patients, the initial staging procedure included a detailed history, physical examination, routine biochemistry studies, HIV serology, CD4 cell count, chest radiographs, computed tomography scan of the abdomen, bone marrow aspiration and biopsy, and lumbar puncture for spinal fluid cytology. Other examinations were performed as clinically indicated.

HIV serology was performed by enzyme-linked immunoadsorbent assay and was reconfirmed by Western blot (immunoblot) analysis in all patients. HIV RNA analysis was performed by branch DNA assay from March 1997 (n = 20 patients).

The Working Formulation for clinical usage was adopted for pathologic classification of NHL.22 Stages of lymphoma were assigned according to the Ann Arbor staging system.23 The revised Centers of Disease Control (CDC) classification system for HIV infection was used. For the AIDS diagnosis, according to the World Health Organization (WHO), only CDC clinical criteria were adopted.24 Performance status (PS) was based on the Eastern Cooperative Oncology Group scale (0–4). Diagnosis of chronic hepatitis C was performed by liver biopsy and serum hepatitis C virus (HCV) RNA (polymerase chain reaction) assay.25 Arbitrarily, we defined any pathologically chronic hepatitis in patients with negative or unknown HCV-RNA assay as unspecified chronic hepatitis.

A complete response (CR) was defined as the complete disappearance of all lesions for at least 4 weeks. A partial response (PR) was defined as a 50% reduction in the sum of the products of the cross-sectional greatest dimensions of all known lesions for at least 4 weeks. No response (NR) was defined as less than a PR or the occurrence of disease progression. Only patients who received at least two cycles of chemotherapy were considered assessable for response. Toxicity was evaluated according to WHO criteria.26

Arbitrarily, we defined all patients who were treated with CHOP or CHVmP-VCR-BLM as the CHOP group because of the similar toxicity of the two chemotherapy regimens in HIV negative21 as well as in HIV positive patients. Survival duration was calculated from the date of diagnosis of lymphoma to death or to the last known date of examination. Disease free survival (DFS) was calculated for patients who achieved a CR from the time of documentation of the CR until disease recurrence, death, or the last known date of examination. Survival curves were estimated by using the Kaplan–Meyer method.27 Differences between groups were assessed by means of the log rank test. The relative dose intensity (RDI) was computed as the percentage of the total dose actually received by the patient compared with the scheduled dose, according to the method reported by Hryniuk.28

RESULTS

Patient Characteristics

General patient characteristics, laboratory investigations, and clinicopathologic features are listed in Tables 1 and 2, which present the data for both groups: the CHOP-HAART group (24 patients) and the CHOP group (80 patients). The two patient groups were similar with respect to age, gender, risk factors for HIV infection, prior AIDS, prior antiretroviral therapy, severe (C1 according to the CDC criteria) and active OIs at the time of diagnosis, and comorbidity (i.e., chronic hepatitis and peripheral neuropathy). Among patients with chronic hepatitis, an increase in serum aminotransferase levels ranging from 1.5 to 2.5 times the upper limit of normal levels occurred in 5 patients (33%) in the CHOP-HAART group and in 10 patients (32%) in the CHOP group (P = 0.6). The pattern of prior antiretroviral treatment differed significantly between the two groups: Patients who underwent prior HAART were more numerous in the CHOP-HAART group than in the CHOP group (46% vs. 3%, respectively; P = 0.0001). Among the CHOP-HAART patients, the median duration of prior HAART was 4 months (range 0.5–20.0).

Table 1. Patient Characteristics and Laboratory Investigations by Treatment Group
CharacteristicCHOP-HAART no. (%)CHOP no. (%)P value
  • CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; HAART: highy active antiretroviral therapy; SD: standard deviation; IVDUs: intravenous drug users; AIDS: acquired immunodeficiency syndrome; OI: opportunistic infection; C1: severe, active OI according to the Centers for Disease Control criteria; HIV: human immunodeficiency virus; NS: not significant.

  • a

    Fisher exact test.

  • b

    Mann–Whitney test.

  • c

    Heterosexual, 4 patients; unknown, 3 patients.

  • d

    Heterosexual, 12 patients; IVDU-heterosexual, 2 patients; unknown, 9 patients.

  • e

    Chronic hepatitis (CH) C, 12 patients; unspecified CH, 3 patients.

  • f

    CHC, 20 patients; unspecified CH, 11 patients.

Total2480
Gender (male/female)20/4 (83/17)68/12 (85/15)NSa
Age in yrs: Mean (± SD)38 (± 8.6)37 (± 10)NSb
Risk group
 IVDUs12 (50)40 (50)
 Homosexuals5 (21)17 (21)
 Others7 (29)c23 (29)dNSa
Prior AIDS8 (33)21 (27)NSa
Prior antiretr. therapy13 (54)43 (61)NSa
 Prior HAART11 (46)2 (3)0.0001a
 Active OI (C1) at diagnosis2 (8)15 (19)NSa
Comorbidity
 Chronic hepatitis15 (71)e31 (51)f
 Neuropathy3 (4)NSa
Leukocyte count (μL): Mean (± SD)7007 (± 3988)4430 (± 2942)0.001b
Hemoglobin (g/dL): Mean (± SD)11.2 (± 11.8)10.5 (± 11.9)NSb
Platelet count (μL): Mean (± SD)210 (± 119.9)184 (± 104.9)NSb
CD4 cell count (μL): Mean (± SD)190 (± 205.8)146 (± 167.6)NSb
HIV-RNA (range)
 Undetectable6 (30)
 Detectable14 (70)
 Median viremia (cp/mL)5800 (197–800,000+)
Table 2. Clinicopathologic Features by Treatment Group
FeatureCHOP-HAART no. (%)CHOP no. (%)P value
  • CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; HAART: highly active antiretroviral therapy; PS: performance status; ECOG: Eastern Cooperative Oncology Group.

  • a

    Fisher exact test.

PS (ECOG)
 0–123 (96)50 (63)
 2–4130 (38)0.002a
Histology
 DLCL14 (58)44 (55)
 SNCC5 (21)19 (24)
 Other5 (21)17 (21)NSa
B symptoms9 (38)40 (50)NSa
Stage
 I–II7 (29)20 (25)
 III–IV17 (71)60 (75)NSa
Adenopathy16 (67)50 (63)NSa
Extranodal disease23 (96)74 (93)NSa
Bone marrow involvement6 (25)14 (18)NSa
Liver involvement6 (25)16 (20)NSa

The mean ± standard deviation (SD) leukocyte count was significantly higher in the CHOP-HAART group than in the CHOP group (P = 0.001). The other laboratory investigations (hemoglobin, platelet, and CD4 cell count) were similar for the two groups. At the time of presentation, detectable plasma HIV-RNA was found in 14 of 20 evaluable patients (70%) in the CHOP-HAART group, with viral load ranging from 197 cp/mL to > 800,000 cp/mL (median, 5800 cp/mL). No data on HIV-viremia were available for patients who were treated with CHOP alone.

Table 2 shows that more patients with a good PS were present in the CHOP- HAART group compared with the CHOP group (P = 0.002). Histology distribution, B symptoms, stage, adenopathy, extralymph node disease, and bone marrow and liver involvement were similar for the CHOP-HAART and CHOP patients.

No statistically significant differences in dose, number of cycles of chemotherapy, or mean RDI were observed between the two groups. Full doses of chemotherapy were employed in 17 patients (71%) in the CHOP-HAART group compared with 53 patients (66%) in the CHOP group, and low doses (50% reduced dose) were employed in 7 patients (29%) compared with 27 patients (34%) in the same respective groups (P = 0.7). The median number of cycles of chemotherapy was 3 (range, 1–4 cycles) in both groups. The mean RDI (± SD) was 91% (± 10%) in the CHOP-HAART group compared with 87% (± 16%) in the CHOP group (P = 0.7).

The response rates were similar between the two treatment groups. A CR was achieved in 12 of 24 patients (50%) in the CHOP-HAART group and in 27 of 75 evaluable patients (36%) in the CHOP group (P = 0.2).

During treatment, a significant (2 log) decrease in plasma HIV-RNA levels was found in 9 of 10 evaluable patients (90%) in the CHOP-HAART group, and persistent suppression of viral replication was achieved in all 6 patients with initial undetectable plasma viremia. At the end of chemotherapy, the mean CD4 cell count (± SD) was similar between the two evaluable patient groups: 84.6 cells/μL (± 64.2 cells/μL) in the 10 CHOP-HAART patients and 86.6 cells/μL (± 72.8 cells/μL) in the 30 CHOP patients (P = 0.9). There were no available data on CD4 cell count and HIV-RNA viremia during follow-up.

Toxicity

Significant differences in the distribution of toxicity were detected between the two treatment groups. Grade 3 or higher anemia occurred in 8 of 24 patients (33%) in the CHOP-HAART group compared with 5 of 67 evaluable patients (7%) in the CHOP group (P = 0.001). Patients who developed severe anemia received AZT-3TC-IDV in four cases, AZT-3TC-RTV or SQV in two cases, and D4T-DDI or 3TC-SQV in two cases concomitant with CHOP. Grade 3 or higher leukopenia was similar between the two groups, occurring in 12 patients (50%) in the CHOP-HAART group and in 35 evaluable patients (51%) in the CHOP group. Grade 3 or higher thrombocytopenia developed in 10 patients (43%) in the CHOP-HAART group compared with 15 evaluable patients (21%) in the CHOP group, although the difference was of borderline significance (P = 0.09).

Four of 24 patients (17%) in the CHOP-HAART group developed Grade 3 or higher autonomic neurotoxicity, including abdominal cramps and severe constipation or paralytic ileus, whereas none of 65 evaluable patients in the CHOP group had severe neurotoxicity (P = 0.002). Among the patients who developed autonomic neurotoxicity, HAART consisted of D4T-3TC-SQV in two patients and AZT-3TC-SQV or IDV in the other two patients. In all patients, neurotoxicity disappeared after HAART interruption and symptomatic treatment. All patients had normal liver function. In three patients, autonomic neurotoxicity occurred during the first cycle of the combined CHOP-HAART treatment and in one patient during the third cycle of the combined CHOP-HAART treatment. Intermittent interruption of HAART during subsequent chemotherapy infusions was performed in these patients without neurotoxicity recurrence. The dose of vincristine was the same in all cycles of chemotherapy.

The other adverse events, including mucositis and nausea-emesis, were similar for the two treatment groups (Table 3). GM/G-CSF support was significantly greater in the CHOP-HAART group than in the CHOP group, occurring in 22 patients (92%) and 53 patients (63%), respectively (P = 0.03).

Table 3. Toxicity and Granulocyte Macrophage/Granulocyte-Colony Stimulating Factor Support by Treatment Group
Hematologic toxicity (grade)CHOP-HARRT no. (%)CHOP no. (%)P value
  • CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; HAART: highly active antiretroviral therapy; NS: not significant.

  • a

    Fisher exact test.

Leukopenia
 06 (25)9 (13)
 1–26 (25)24 (35)
 3–412 (50)35 (51)NSa
Anemia
 09 (38)17 (25)
 1–27 (29)45 (67)
 3–48 (33)5 (7)0.001a
Thrombocytopenia
 09 (39)31 (42)
 1–24 (17)24 (34)
 3–410 (43)15 (21)0.09a
Gastrointestinal toxicity oral
 018 (75)47 (75)
 1–24 (17)10 (16)
 3–426 (10)NSa
Nausea and emesis
 018 (75)52 (84)
 1–25 (20)7 (11)
 3–413NSa
Neurotoxicity
 016 (67)58 (88)
 1–24 (17)8 (12)
 3–44 (17)0.002a

Overall, 5 of 23 evaluable patients (22%) in the CHOP-HAART group reported intermittent adherence to the antiretroviral therapy because of toxicity, i.e., autonomic neurotoxicity (four patients) and mucositis (one patient). Toxicity comparisons between CHOP-HAART patients and CHOP patients who had received AZT concomitant with chemotherapy were not performed because of the small simple size of the last group and the different dose chemotherapy distribution between the two groups.

Survival and Cause of Death

During follow-up, only 4 of 22 patients (18%) in the CHOP-HAART group developed AIDS-defining OIs compared with 38 of 73 evaluable patients (52%) in the CHOP group (P = 0.005). The length of follow-up was similar in the two groups, with a median of 8.5 months (range, 1–25 months) in the CHOP-HAART group and a median of 7 months (range, 1–68 months) in the CHOP group.

Mortality differed between the two groups: It was significantly lower in the CHOP-HAART group compared with the CHOP group (9 of 24 patients [38%] vs. 68 of 80 patients [85%], respectively; P = 0.001). Among the patients who died, progression of NHL was the most common cause of death for all 9 patients in the CHOP-HAART group and for 38 of 50 evaluable patients (66%) in the CHOP group (P = 0.5).

Significant differences in the overall survival rate were found in the two treatment groups (Fig. 1). The median survival for patients who received combined CHOP-HAART was not reached, whereas the median survival of patients who received CHOP alone was 7 months. An analysis of prognostic factors for survival between the two treatment groups was not performed because of the inadequate sample size of the series and the retrospective nature of the study. The median DFS for both patient groups was not reached (P = 0.98).

Figure 1.

Overall survival in 104 patients (pts) with human immunodeficiency virus-related non-Hodgkin lymphoma according to treatment group. Solid line, CHOP-HAART group; dashed line, CHOP group).

Among the patients who achieved a CR, the disease recurrence rate was similar in the two groups, occurring in 3 of 12 evaluable patients (25%) in the CHOP-HAART group and in 6 of 25 patients (24%) in the CHOP group (P = 0.9), whereas mortality differed significantly between the two groups. Two patients (17%) who achieved a CR in the CHOP-HAART group died compared with 19 patients (70%) who achieved a CR in the CHOP group (P = 0.002). Both patients who achieved a CR in the CHOP-HAART group died of lymphoma progression, and all 19 patients who achieved a CR in the CHOP group died of OI, although the difference was not statistically significant (P = 0.2) (Table 4).

Table 4. Outcome of Patients who Achieved a Complete Response by Treatment Group
CharacteristicCHOP-HAART no. (%)CHOP no. (%)P value
  • CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; HAART: highly active antiretroviral therapy; CR: complete response; NS: not significant; NHL: non-Hodgkin lymphoma; OI: opportunistic infection.

  • a

    Fisher exact test.

  • b

    Twenty-five patients were evaluable.

Total CR patients12 (50)27 (36)NSa
Recurrence3 (25)6 (24)bNSa
Mortality2 (17)19 (70)0.002a
Cause of death
 NHL progression2 (100)
 OI19 (100)NSa

DISCUSSION

The use of combined antineoplastic and antiretroviral treatment remains a matter of concern.8, 9, 29 The current data show that myelosuppression and autonomic neurotoxicity are significantly more frequent in patients who are treated with CHOP-HAART than in patients who are treated with CHOP alone. However, the combined treatment is feasible and tolerable, and it is not associated with life-threatening toxicity.

Severe anemia was significantly greater in the CHOP-HAART group than in the CHOP group (33% vs. 7%, respectively; P = 0.001). Leukopenia was similar between the two groups, but the lack of differences may be related to the significantly higher colony stimulating factor support in the CHOP-HAART group than in the CHOP group. It is noteworthy that, at baseline, patients in the CHOP-HAART group had a significantly better PS and bone marrow reserve compared with control patients, probably due to the prior HAART.

The majority of patients who developed anemia had received AZT. Anemia is the prominent toxicity of AZT therapy in HIV-infected patients,30 and an overlapping bone marrow toxicity may occur when combining AZT with chemotherapy.8, 18, 29–31 In this setting, anemia is usually a later toxicity than leukopenia from combination therapy that includes AZT without colony stimulating factor support.31

In the current study, parasympathetic neuropathy, but not peripheral neuropathy, developed more frequently in the CHOP-HAART patients than in the CHOP patients (P = 0.002). Peripheral sensimotor neuropathy occurs frequently in patients taking DDI, D4T, or zalcitabine as well as vincristine.32, 33 To date, no gastrointestinal autonomic neuropathy has been reported in HIV-infected patients who were treated with reverse transcriptase and protease inhibitors alone, whereas acute and severe autonomic neuropathy may arise as a consequence of high dose vincristine therapy (> 2 mg/m2) or in patients who are treated with normal dose of vinka alkaloids but with altered hepatic functions.33 It is noteworthy that the prevalence of chronic hepatitis and lymphomatous liver involvement were similar between the two treatment groups. Moreover, no patients had received a high dose of vincristine.

Theoretically, drug-drug interactions may be significant when antiviral agents are combined with the various antineoplastic agents used in the treatment of patients with HIV-related malignancy. The protease inhibitors have a high affinity for the hepatic cytochrome P450 3A enzyme family, especially RTV and IDV.2, 34 Anthracyclines, the vinka alkaloids, taxanes, cyclophosphamide, and etoposides are metabolized by the liver through the same pathway.33 Pharmacokinetic interactions between protease inhibitors and chemotherapy may affect the toxicity as well as the efficacy of both classes of drugs. Moreover, an interaction of the protease inhibitors with the multidrug transporter P-glycoprotein (P-gp), a plasma membrane efflux pump, has been found recently in human cultured cells. Saquinavir, RTV, and NFV (but not IDV) significantly inhibited the efflux of paclitaxel and vinblastine in P-gp positive cells in vitro, resulting in increase in intracellular accumulation of these agents.35 It is noteworthy that P-gp transports a broad range of drugs in vivo, including anticancer agents (i.e., anthacyclines, vinca alkaloids, and taxanes).36

However, there are only scant preliminary data published in abstract form with regard to the use of combined treatment with antiretroviral therapy, including protease inhibitors or HAART, and chemotherapy. Sparano et al.37 reported on a combination of SQV-DDI and/or D4T plus infusional cyclophosphamide, doxorubicin, and etoposide (CDE). In logistic regression analysis, SQV use was the only factor associated with a significantly greater risk of severe mucositis (relative risk, 7.9; P = 0.03), suggesting that protease inhibitors may alter the metabolism of one or more of the cytotoxic agents in the CDE regimen. In an AIDS Malignancy Consortium study, only small differences in doxorubicin and IDV pharmacokinetic parameters were found in patients who were treated with a combination of low dose or full dose CHOP and HAART, including D4T-3TC-IDV, compared with the literature and/or historic controls. In this study, cyclophosphamide clearance rates were 39 mL per minute/m2 in both arms compared with the literature mean of 70 mL per minute/m2.38 In our experience at our institution, no significant differences in doxorubicin pharmacokinetic parameters have been found in a comparative study between doxorubicin plus miscellaneous protease inhibitors compared with doxorubicin alone in 17 patients with HIV-related NHL (data not published).

The response and DFS rates were similar between the two treatment groups, suggesting that there was no influence on the efficacy of chemotherapy by HAART. These data, however, should be confirmed prospectively in studies. Similarly, further investigations regarding the potential pharmacokinetic interactions between the two classes of drugs are needed. Until more data are available, antiretroviral use during chemotherapy should be guided by toxicity and possible pharmacokinetic interactions with chemotherapy agents. AZT, due to its myelosuppressive effects, may not be the best antiretroviral agent to be used in the combined chemotherapy-HAART treatment.

Chemotherapy produces a significant decrease in CD4 lymphocytes and significantly increases the risk of OIs in patients with HIV-related malignancies. Some 20–80% of patients with HIV-related NHL who are treated with a variety of chemotherapy agents developed OIs, with a median survival of 4–7 months.11–14, 18, 39 The risk of infection is a function of the intensity of the chemotherapy regimen and the degree of HIV-related immunosuppression.39 At similar median follow-up, patients who were treated with CHOP plus HAART were found to have significantly lower OI rates than patients who were treated with CHOP alone (18% vs. 52%; P = 0.05). Moreover, mortality was significantly lower in the combining treatment group than in the control group (38% vs. 85%; P = 0.001), probably due to the lower prevalence of OIs. At the time of presentation, CD4 cell counts were similar between the two groups, probably due to the short duration of HAART pretherapy (4 months) in the combined treatment group. At the end of chemotherapy, as expected, the rates of antineoplastic-induced CD4 lymphocytopenia were similar between the two treatment groups (P = 0.9). The mechanism whereby HAART decreases the OI incidence in HIV-infected patients probably is related to its recovery of immune function, i.e., increase of the CD4 cell count and/or restoration of the functional T-cell activity.2, 32, 34 Recently, Little et al.40 reported that temporary suspension of HAART during 16 treatment weeks with dose-adjusted EPOCH did not prevent postchemotherapy immunorecovery or HIV control in 13 patients who achieved a CR. At 6 months postchemotherapy follow-up, the median CD4 cell count and median HIV-viremia were not different from baseline values, i.e., 303/μL (baseline, 320/μL; P = 0.92) and 3300 cp/mL (baseline, 3601 cp/μL; P = 0.16), respectively. However, no data on infection rates or on CD4 cell functional activity in vitro have been reported in this series of patients with a good prognosis. For immune recovery evaluation, both numeric and functional immunologic responses are essential. Moreover, a late improvement in T-cell functional activity derived from HAART may occur in patients with advanced HIV infection or in patients with a poor prognosis.41–43 Thus, discontinuation of antiretroviral therapy during chemotherapy should be avoided in these patients.

The effect of chemotherapy on HIV pathogenesis and viral load is a matter of controversy.8, 29 Conversely, durable suppression of HIV replication provides the strongest genetic barrier possible to the emergency of viral resistance.15, 16 Recently, as little as 1 week of withdrawal from HAART has been reported to result in a rapid plasma HIV-RNA rebound (median increase, 0.2 log per day) in HIV-infected patients without chemotherapy.44 Thus, the long term effectiveness of HAART may be compromised by the intermittent use as well as the poor adherence to antiretroviral drugs during chemotherapy. Prospective trials within our group are currently investigating the impact of combined chemotherapy-HAART treatment on the immune system and HIV viral load in patients with HIV-related NHL.

CHOP-HAART patients have a better survival than the CHOP patients, suggesting that the reduction of OI morbidity by HAART, other than the good PS8, 11 of these patients, may improve the overall outcome of the patients who undergo combined treatment. However, the impact of combined chemotherapy plus HAART on the survival of patients with HIV-related tumors needs to be evaluated in prospective studies.

In conclusion, the findings in the current study have important implications for the management of patients with HIV-related NHL. The combination of CHOP plus HAART is feasible, and it may reduce the morbidity rate for OIs in HIV-related NHL patients. However, careful attention must be directed toward the cross toxicity and the possible pharmacokinetic interactions of antiretroviral and antineoplastic drugs.

Acknowledgements

The authors thank Maddalena Mosconi for the expert assistance in the preparation of the article.

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