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Impact of Concomitant Antiblastic Chemotherapy and Highly Active Antiretroviral Therapy on Human Immunodeficiency Virus (HIV) Viremia and Genotyping in HIV-Infected Patients with Non-Hodgkin Lymphoma

  1. Cecilia Simonelli1,
  2. Stefania Zanussi2,
  3. Roberta Cinelli1,
  4. Luigino Dal Maso3,
  5. Giampiero Di Gennaro1,
  6. Monica D'Andrea2,
  7. Guglielmo Nasti1,
  8. Michele Spina1,
  9. Emanuela Vaccher1,
  10. Paolo De Paoli2, and
  11. Umberto Tirelli1
  1. 1Division of Medical Oncology A, National Cancer Institute, Aviano, Italy
  2. 2Microbiology, National Cancer Institute, Aviano, Italy
  3. 3Epidemiology Units, National Cancer Institute, Aviano, Italy
  1. Reprints or correspondence: Prof. Umberto Tirelli, Div. of Medical Oncology A, National Cancer Institute, Via Pedemontana Occidentale 12, 33081 Aviano (PN), Italy (oma{at}cro.it).
 
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Abstract

We evaluated the replication and resistance patterns of human immunodeficiency virus (HIV) strains recovered from HIV-infected patients with non-Hodgkin lymphoma (NHL) who were receiving chemotherapy (CT) concomitant with highly active antiretroviral therapy (HAART). We analyzed virological response to HAART in 35 patients with HIV and NHL who were treated with a cyclophosphamide-doxorubicin-vincristine-prednisone chemotherapy regimen and HAART and the virological response in 26 HIV-infected patients with CD20 cell-positive NHL who were treated with rituximab and cyclophosphamide-doxorubin-etoposide therapy. Genotype and virtual phenotype analyses were performed at baseline and when virological failure occurred. Only 9 patients met the criteria for virological failure. Genotype and virtual phenotype analyses demonstrated that, during CT administration, new mutations might occur, but there were no significant changes in the preexisting resistance patterns. Our data show that combination therapy consisting of CT and HAART is feasible and that the virological response can be maintained in the majority of patients receiving this treatment.

Although it has been recently reported that HAART improves the survival rate among HIV-infected patients with non-Hodgkin lymphoma (NHL) [1–8], the prognosis for these patients is still poorer than that observed in HIV-negative patients affected by similar lymphomas [9–11]. It is well known that chemotherapy (CT) reduces both CD4 and CD8 cell counts in HIV-negative patients with cancer [12, 13]. In the pre-HAART era, our group showed that polychemotherapy, which includes regimens such as cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP), increases the virus load significantly and also enhances the rate of CD4 cell depletion considerably [14]. Recently, the effects of a combination of CT plus HAART on the immune parameters have been studied, and it has been reported that the CD4 cell count decreases 50% during CT [15].

Among patients with HIV and NHL who were treated with CHOP plus HAART, the incidence of myelosuppression and autonomic neurotoxicity was higher than that among patients who received CHOP alone. However, the combined treatment is feasible and tolerable, is not associated with any life-threatening toxicity, and has similar response and disease-free survival rates [11, 16]. Antinori et al. [17] treated HIV-positive patients who had recently received a diagnosis of NHL with various CT regimens and HAART. They demonstrated that effective use of HAART (reduction of HIV RNA plasma load of >2 log10 copies/mL) was associated with a statistically significant likelihood of complete remission, as well as with longer survival. Moreover, multivariate analysis revealed 3 independent prognostic factors for longer survival: a complete response to CT, an immune response to HAART, and use of a higher dose of CT [17]. These data suggest that optimal control of underlying HIV infection must be an integral part of AIDS-associated NHL treatment.

However, the effect of CT on HIV load is a matter of discussion. Durable suppression of HIV replication provides the strongest genetic barrier to the occurrence of viral resistance. The aim of this study was to investigate the impact of CT on HIV load and resistance in patients with HIV and NHL who received concomitant HAART.

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Patients and Methods

Patients. HIV-infected patients with systemic, intermediate, or high-grade NHL who received a diagnosis of NHL and were treated at the Aviano Cancer Center (Aviano, Italy) were enrolled in a study to evaluate HIV replication and resistance profiles during concomitant receipt of antiblastic drugs and HAART. From January 1997 through June 1998, HIV-infected patients affected by NHL were treated with a regimen of CHOP (cyclophosphamide, 750 mg/m2 iv, on day 1; doxorubicin, 50 mg/m2 iv, on day 1; vincristine, 1.2 mg/m2 iv, on day 1; and prednisone, 100 mg po, on days 1–5, for a total of 4–6 cycles of CHOP every 21 days) plus HAART.

From June 1998 through the time of this writing, patients with CD20 cell-positive NHL were treated with the following therapeutic regimen: rituximab (anti-CD20 monoclonal antibody, 375 mg/m2 iv) plus cyclophosphamide-doxorubicin-etoposide (CDE; cyclophosphamide, 200 mg/m2/day; doxorubicin, 12.5 mg/m2/day; and etoposide, 60 mg/m2/day, by 4-day continuous infusion every 4 weeks for ⩽6 cycles). Granulocyte colony-stimulating factor was given as primary prophylaxis (5 µg/kg/day on days 6–12 of each CT cycle). Antiretroviral regimens were selected on the basis of each patient's therapy history.

Eligible patients. Patients were considered eligible for HIV load determination and resistance-profile analysis if they had received at least 3 cycles of CT plus HAART. Patients were considered naive to HAART if they had not received triple therapy that included 1 protease inhibitor (PI) or 1 nonnucleoside reverse-transcriptase inhibitor (NNRTI) 4 weeks before CT initiation.

Criteria for HIV virological failure. Virological failure was defined as follows: (1) a decrease of ⩽1 log10 copies/mL in the baseline HIV load in patients who were naive to HAART at the initiation of CT; (2) an increase of ⩾0.5 log10 copies/mL in the baseline load in patients who had received HAART before initiating CT (i.e., HAART-experienced patients); (3) an increase of ⩾0.5 log10 copies/mL in the nadir load reached during receipt of treatment with CT plus HAART; (4) a positive HIV load (i.e., >50 copies/mL) if the baseline or nadir levels were negative (i.e., <50 copies/mL). Patients who met these criteria were called “nonresponders” (i.e., patients who did not respond to HIV therapy), whereas patients who did not meet these criteria were called “responders” (i.e., patients who responded to HIV therapy).

HIV load analysis. HIV RNA analysis was performed by Quantiplex HIV-1 RNA (bDNA) assay (version 2.0; Bayer) at baseline, the beginning of every CT cycle, and 1 month after the end of CT.

HIV genotyping. HIV genotyping was performed for patients with an HIV load of >1000 copies/mL who met the HIV virological failure criteria at baseline and when a virological failure was documented. For patients enrolled before November 2000, the assay was performed retrospectively when samples were available. The HIV pol region was sequenced with the ViroSeq HIV-1 genotyping system, version 2 (PE Biosystems) [18]. The adjusted sequence was then analyzed online by the Stanford HIV-SEQ program (updated in June 2001) [19] and electronically submitted to Virco for VircoNET analysis (version 1.6.1).

Statistical evaluation. Data analysis was performed according to the CT regimen for subsets of patients of the same sex and age distribution. The patients' baseline characteristics and the differences in the relevant outcomes were compared using Fisher's exact test and the Wilcoxon 2-sample test. Correlation between different variables was computed with Spearman's correlation coefficient.

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Results

HIV Load Analysis

CHOP plus HAART group. Thirty-five patients were enrolled in the study. Nineteen (54%) of 35 patients, 16 of whom were male, were considered evaluable for virological and resistance-pattern analysis. Of the 19 evaluable patients, 10 were naive to HAART, and 4 were naive to antiretroviral therapy. Ten were receiving HAART at CT initiation, and 7 had an undetectable HIV load. Among the patients with a detectable HIV load, the median value was 63,825 copies/mL (range, 550–466,000 copies/mL); the baseline median CD4 cell count was 148 cells/mm3 (range, 16–839 cells/mm3) (table 1).

Table 1
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Table 1

Baseline demographic and clinical characteristics of eligible patients, by treatment group.

Only 3 (15.7%) of 19 patients met the HIV virological failure criteria. Two of the 3 nonresponders died. The causes of death were opportunistic infection (OI) and NHL progression. The third patient was still alive and was showing a complete response to NHL treatment with good control of his HIV load at the time of writing. This patient was receiving HAART at baseline and had had an undetectable HIV load. His virus load had become detectable after 3 treatment cycles, but, after the last cycle, it was undetectable again without any treatment adjustments. Only 1 of 3 nonresponders was naive to HAART (table 2).

Table 2
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Table 2

Data for patients who did not respond to chemotherapy and HAART (nonresponders).

The majority of the patients (16 [84.4%] of 19) maintained a virological response during CT. As for patients with HIV viremia, the 6 cases of baseline undetectable HIV loads remained undetectable, whereas in the other 7 patients, the HIV load became undetectable.

Six of 16 responders died. Five deaths were caused by NHL (table 3). The sixth patient was still completely responding to NHL treatment and had an undetectable HIV load at death.

Table 3
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Table 3

Data for patients who responded to chemotherapy and HAART (responders).

Rituximab-CDE plus HAART group. Twenty-six patients were enrolled in the study. Nineteen of 26 patients (73%)—15 male and 4 female—were considered evaluable for virological and resistance-profile analyses. Thirteen were naive to HAART, and 10 were naive to antiretroviral therapy. Eleven were receiving HAART at CT initiation, and 2 had an undetectable HIV load. Among patients with a detectable HIV load, the median value was 30,980 copies/mL (range, 49–295,488 copies/mL), and the baseline median CD4 cell count was 146 cells/mm3 (range, 3–588 cells/mm3) (table 1).

Six of 19 patients (31.6%) met the HIV virological failure criteria. Two died as a result of NHL progression and OI. Four of the 6 nonresponders were still alive and were completely responding to NHL treatment at the time of writing, 4 were naive to HAART, and 4 were receiving HAART at baseline (table 2).

The majority of the patients (13 [68.4%] of 19) maintained a virological response during CT. Compared with baseline levels, the HIV load was still undetectable in 2 cases, had become undetectable in 6 of 10 detectable cases, and had decreased significantly in 5 of 10 detectable cases. Eleven of 13 patients were naive to HAART. Four of 13 responders died, 3 because of NHL progression and 1 because of OI. Nine were still alive at the time of writing (table 3).

The baseline characteristics of both groups were not statistically significantly different; however, the group receiving CHOP plus HAART had a higher percentage of patients with an undetectable HIV load (37%) than did the group receiving rituximab-CDE plus HAART (11%). The group that received rituximab-CDE plus HAART had a slightly higher number of nonresponders, compared with the group that received CHOP plus HAART (6 [31.6%] vs. 3 [15.7%]), but no statistically significant differences were observed (P = .27). No significant differences were seen between the groups with regard to CT-related hematological and gastrointestinal toxicity and the onset of OI (data not shown). Moreover, no correlations were observed between the occurrence of virological failure and the CD4 cell count at baseline, the CD4 cell count at the time of failure, and the onset of OI during follow-up (data not shown).

HIV Resistance Pattern

HIV genotyping was performed at baseline and at the time of virological failure in nonresponders. Mutations associated with clinical resistance to HIV-1, on the basis of a recent review of the International Aids Society—USA [20] are reported in table 4, and the results of the drug resistance interpretation (performed with Stanford University beta test software) and the virtual phenotype relative to reverse-transcriptase (RT) inhibitors and PIs are shown in tables 5 and 6, respectively.

Table 4
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Table 4

Genotyping analysis in patients who did not respond to therapy for HIV infection.

Table 5
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Table 5

Results of testing for resistance to reverse-transcriptase inhibitors.

Table 6
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Table 6

Results of testing for resistance to protease inhibitors.

CHOP plus HAART group. In the group receiving CHOP plus HAART, HIV genotyping was performed at baseline and at the time of virological failure for 2 of 3 nonresponders. In the third nonresponder, the genotyping procedures could be completed only when a virological failure occurred, because the baseline HIV load was <500 copies/mL.

Patient 1 was treated with zidovudine, lamivudine, and indinavir; his baseline HIV load was <500 copies/mL, and, after the third CT cycle, his HIV load was 13,003 copies/mL. Two mutations appeared in the RT gene (K70R, M184V) and 4 in the protease (P) gene (table 4). The drug resistance interpretation revealed only a high level of resistance (HLR) to lamivudine and a low level of resistance (LLR) to didanosine, zalcitabine, and abacavir (table 5); among the PIs, drug resistance interpretation revealed an HLR to nelfinavir, an intermediate level of resistance to indinavir, ritonavir, and saquinavir, and an LLR to amprenavir (table 6). Virtual phenotype analysis in this patient confirmed the resistance to lamivudine, nelfinavir, and ritonavir (tables 5 and 6). Patient 1, despite virological failure, adhered to the same antiretroviral therapy regimen during the study, and his HIV load was undetectable again after CT cessation.

Patient 14 was treated with zalcitabine, nevirapine, and nelfinavir. At the time of virological failure, the K103 mutation was lost in the RT gene, but the G190A mutation appeared (table 4). Both mutations are associated with NNRTI resistance, and, in fact, the drug resistance interpretation and the virtual phenotype analysis at baseline and at the time of virological failure did not show any differences in the patterns of resistance to RT inhibitors (table 5). Almost the same situation was observed for PIs. In fact, the same major mutations were present in the P gene at baseline and at the time of virological failure (table 4), and, consequently, no differences in results of the drug resistance interpretation and the virtual phenotype analysis were seen at the 2 different time points (table 6).

Patient 31 was treated with didanosine, stavudine, and saquinavir. Only 2 mutations were present in the P gene, and the strain recovered from this patient was susceptible to all drugs in the 3 different classes at baseline and at virological failure (tables 5 and 6).

Rituximab-CDE plus HAART group. HIV genotyping was performed at baseline and at the time of virological failure for 6 of 6 nonresponders in the group that received rituximab-CDE plus HAART. Mutations in the P and RT genes of each patient are shown in table 4.

Three patients (patient 5R, who was treated with zidovudine, zalcitabine, and saquinavir; 11R, treated with stavudine, didanosine, and ritonavir; and 26R, treated with zidovudine, lamivudine, and nelfinavir; table 4) had no mutations in the RT gene and ⩽2 mutations in the P gene in the HIV strains recovered from them. The drug resistance interpretation and the virtual phenotype analysis at baseline and at the time of virological failure did not show any differences in the resistance patterns. The HIV strains from these patients were susceptible to all drugs in the 3 different classes at baseline and at the time of virological failure.

Patient 21R was treated with stavudine, didanosine, ritonavir, and nelfinavir, and several mutations were present in the RT and P genes; the only differences observed between values at baseline and the time of virological failure were the disappearance of the E44D and V771 mutations in the RT and P genes, respectively, and the appearance of the K20M and M361 mutations in the P gene (table 4). However, the drug resistance interpretation and the virtual phenotype analysis did not reveal any significant changes in the resistance profile between values at baseline and the time of virological failure.

In 2 patients (patient 8R, who was treated with saquinavir, nelfinavir, and nevirapine; and 17R, treated with stavudine, lamivudine, and ritonavir), at the time of virological failure, the Y188L and K103N mutations occurred in the RT gene. Both mutations are associated with NNRTI resistance, and, in fact, the drug resistance interpretation and the virtual phenotype analysis clearly demonstrated the onset of resistance to the 3 NNRTIs (table 5). Patient 8R had 4 mutations in the P gene, and no additional mutations appeared at the time of virological failure (table 4); no differences were seen in the drug resistance interpretation and the virtual phenotype analysis associated with the PI (table 6). Patient 17R had 3 mutations in the P gene, and, similar to patient 8R, no changes in the drug resistance profile were observed at the time of virological failure (tables 4 and 6).

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Discussion

Currently, most evidence suggests that the combination of CT and HAART has acceptable toxicity limits and that CT maintains the same response rate when combined with HAART [11, 16]. However, the effects of CT on HIV replication are not well described. Investigators at the US National Cancer Institute (Bethesda, MD) reported that virus load had a median increase of 0.83 log10 copies in HIV-infected patients affected by NHL who were treated with a 96-h infusion of etoposide vincristine, doxorubicin, and dose-adjusted cyclophosphamide (EPOCH) in the absence of HAART. Despite the observed increase of the virus load during therapy, a return to baseline within 3 months after the initiation of EPOCH was observed in all patients after the resumption of HAART [21]. Our study demonstrated that HAART can maintain the virological response in the majority of the patients during the period of CT administration, when the maximum decrease in CD4 cell count is expected. In fact, of 37 evaluable patients, only 9 (24.3%) were considered nonresponders. The rate of virological failure we observed is within the range of failures (8%–49.9%) observed in several other studies [22–24]. It is worth mentioning that, until recently, there were no standardized criteria for determining virological failure and that, therefore, a large variability in the failure rate has been reported because of the variety of adopted criteria.

Even if the difference was not statistically significant, we observed a different percentage of nonresponders in the 2 groups: 15.7% in the group that received CHOP plus HAART versus 31.6% in the group that received rituximab-CDE plus HAART. On the contrary, no differences in the rate of CT-related toxicity were observed. However, the lack of pharmacokinetic data and the small size of the sample prevent us at present from completely ruling out the assumption that the 2 different CT regimens (bolus intravenous administration of CHOP vs. continuous infusion of CDE and intravenous immunotherapy with rituximab) might have had some effects on HIV replication. Currently, no data are available on the effect of rituximab on HIV replication. Prospective clinical trials that study both HIV dynamics and pharmacokinetic interactions between antiretroviral and antiblastic drugs are required.

HIV genotype and virtual phenotype analyses were performed for all 9 nonresponders; the 2 analyses demonstrated that, between baseline and the time of virological failure, different mutations might be present in the RT and P genes, but no significant changes in the resistance profile were observed in the majority of the nonresponders. Actually, 6 of 9 patients maintained the same resistance profile, even though a virological failure had occurred. Two patients showed different resistance patterns between baseline and the time of failure, but it should be pointed out that they developed resistance to NNRTI, the antiretroviral therapies with the weakest genetic barrier to the occurrence of viral resistance. One patient was studied only when failure occurred, because the HIV load was undetectable at baseline. In this particular case, we know from the drug resistance interpretation that HIV became highly resistant to 3TC and intermediately resistant to Idv (2 of 3 drugs in the patient's regimen), although the virtual phenotype analysis confirmed only the resistance to 3TC. Taken together, these data could explain why the HIV load decreased in 3 weeks and was undetectable again after CT cessation, even if the same HAART regimen was administered to the patient.

In conclusion, our data show that HAART can control HIV replication during CT administration in patients affected by AIDS-related NHL. Moreover, the data suggest that CT does not significantly increase the occurrence of new resistance patterns.

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acknowledgments

We thank Ms. Daniela Furlan for her valuable assistance in the layout of the manuscript.

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Footnotes

  • Financial support: Italian Ministry of Health (grants F.S.N. 2000 [contract no. ICS 060.2/RF00-55] and AIRC 2002).

  • Received January 29, 2003.
  • Accepted May 6, 2003.
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  1. Clin Infect Dis. (2003) 37 (6): 820-827. doi: 10.1086/377204
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