Features and risk factors of peripheral neuropathy during treatment with bortezomib for advanced multiple myeloma.

BACKGROUND: Bortezomib is a first-in-class proteasome inhibitor with remarkable antitumor activity that is approved for the treatment of patients with multiple myeloma. Peripheral neuropathy (PN) is a frequent adverse event reported with bortezomib use. PATIENTS AND METHODS: The aim of this retrospective, single-center study was to determine the characteristics of bortezomib-associated PN in 100 patients with advanced myeloma. Peripheral neuropathy was evaluated by investigator's assessment. RESULTS: With a median follow-up of 8 months (range, 0.1-32 months) from bortezomib initiation, bortezomib-associated PN was observed in 38 patients (38%; 95% CI, 28%-47%), with grade 3 and 4 PN occurring in 5 patients and 1 patient, respectively. Median time to onset of bortezomib-associated PN was 53 days (range, 11-182 days). Of the 38 patients with bortezomib-associated PN, resolution or improvement occurred in 20 patients (53%) at a median of 3 months (range, 1-8 months). In multivariate analysis, the total number of cycles of bortezomib (< 4 cycles or > 4 cycles; P = .03; odds ratio [OR], 2.6; 95% CI, 1.1-6.1) and a previous history of thalidomide therapy (P = .02; OR, 3.9; 95% CI, 1.2-12.6) were significantly associated with an increased incidence of bortezomib-associated PN. CONCLUSION: We conclude that, though relatively frequent, bortezomib-associated PN is reversible in a majority of patients. However, bortezomib-associated PN seems to be dependent on previous therapy with thalidomide, suggesting that bortezomib followed by thalidomide could be an optimal sequence of administration of these drugs in the salvage setting.

Rearrangements involving 12q in myeloproliferative disorders: possible role of HMGA2 and SOCS2 genes.

We report two cases of translocation associated with deletion on derivative chromosomes in atypical myeloproliferative disorder (MPD). In a MPD with t(3;12)(q29;q14), the rearrangement targeted the HMGA2 locus at 12q14 and deleted a region of about 1.5 megabases (Mb) at 3q29. In an MPD with t(9;12)(q13 approximately q21;q22) and JAK2 V617F mutation, array comparative genomic hybridization delineated a deletion of about 3 Mb at 9q13 approximately q21 and a deletion of about 2 Mb at 12q22 containing SOCS2. These results show that close examination of translocations in hematopoietic diseases may reveal associated microdeletions. The role of these deletions is discussed.

Depression and clinical progression in HIV-infected drug users treated with highly active antiretroviral therapy.

OBJECTIVE: To disentangle the impact of adherence from that of injecting drug status and depressive syndrome on HIV clinical progression in a cohort of highly active antiretroviral therapy (HAART)-treated HIV patients infected through drug use. DESIGN: MANIF 2000 is a French cohort of HIV-infected drug users with scheduled medical visits every 6 months. Only patients enrolled in the MANIF 2000 cohort who had a CD4 cell count >200 cells/microl at HAART initiation were selected. The follow-up period included all post-HAART initiation visits. METHODS: HIV clinical progression was defined as either AIDS-related death or reaching a CD4 level <200 cells/microl. Adherence was assessed using a self-administered questionnaire and a structured face-to-face interview. Depressive symptoms were evaluated by a Center for Epidemiologic Studies Depression Scale (CES-D) score at each visit. Cox proportional hazards model was used to calculate crude and adjusted relative hazards and 95% confidence intervals and thus identify independent predictors of clinical progression. RESULTS: Of the 305 HAART-treated patients in the cohort, 243 had CD4 cell count >200 cells/microl at HAART initiation. At the first visit after HAART initiation, median CD4 cell count was 466 cells/microl and 45% had undetectable viral load. Injecting drug users accounted for 17% of the study group. Over the follow-up period, 32 patients experienced HIV clinical progression. Probable depression was encountered in 46% of patients and non-adherence in 31% of the sample. After adjustment on baseline CD4 cell count, predictors of clinical progression were: having a higher level of cumulative non-adherence over the follow-up period [HR (95% CI)=1.2 (1.1-1.3) per 10% increase] and having a high score of depressive symptoms following HAART initiation [HR (95% CI)=5.3 (2.21-3.0)]. CONCLUSIONS: Although depressive syndrome is known to influence non-adherence behaviours that are amongst the major reasons for clinical progression, it is also a predictor of clinical progression in HIV-infected intravenous drug users on HAART, independently of non-adherence behaviours. HIV care providers should be more sensitive to depressive symptoms in order to detect them early and supply HIV patients with specific care. Further research is needed to determine whether treating depressive symptoms may improve adherence and thus delay disease progression and mortality.

Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide.

Thalidomide (Thal) was shown to be a potent immunomodulating agent. Because of their central role in controlling immunity, we investigated the effects of Thal on monocyte-derived dendritic cells (Mo-DC). The addition of 10 micro g/ml or 20 micro g/ml Thal from the beginning of monocyte culture with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However, Thal exerted a modulation of Mo-DC functional properties. At 10 micro g/ml, Thal modified the allostimulatory capacity of DC little, whereas a dose of 20 micro g/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a dose-dependent manner between 10 and 20 micro g/ml (P=.001). Mo-DC generated with 10 micro g/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses (P=.01), but 20 micro g/ml was able to strengthen Th1 responses (P=.03). Also, Thal induced a significant reduction of IL-10 production in response to the maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor alpha production was significantly decreased when Mo-DC were exposed to 10 micro g/ml Thal, and a dose of 20 micro g/ml did not induce any significant changes. The effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1 responses might contribute to the antitumor effects of Thal. Thus, DC appear to be potential targets for the immunomodulatory capacity of Thal, defining a new mechanism of action of this drug.

Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen.

OBJECTIVE: Reduced-intensity conditioning regimens (RIC) and peripheral blood stem cells (PBSC) are increasingly used for allogeneic stem cell transplantation (allo-BMT). RIC has been shown to allow engraftment with minimal early transplant-related mortality (TRM). However, in the context of RIC, the use of bone marrow (BM) as stem cell source is still little evaluated. PATIENTS AND METHODS: In this report, we analyzed the outcome of 32 high-risk patients with hematological malignancies who received an HLA-identical sibling allo-BMT after RIC including fludarabine, busulfan, and anti-thymocyte globulin (ATG). RESULTS: Sustained neutrophil and platelet recovery occurred at a median of 13 days (range, 10-19) and 17 days (range, 0-45) respectively. Early and durable full donor chimerism could be established as soon as the first month after allo-BMT. Also, a sustained and early CD8(+) T-cell recovery was observed, but the CD4(+) T-cell compartment remained profoundly low. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 26% (95% CI, 11-41%) and 31% (95% CI, 15-47%) respectively. The overall cumulative incidence of TRM was 28% (95% CI, 12-44%) occurring mainly in patients aged over 50. In this setting, GVHD showed a protective effect on disease progression or relapse with better progression-free survival for patients with GVHD as compared to patients without GVHD (p=0.03). CONCLUSIONS: Collectively, these results confirm that the use of BM grafts for RIC is feasible with durable donor engraftment and no detrimental GVHD.

Effects of antiretroviral drug combinations on the differentiation of adipocytes.

OBJECTIVE: Preadipocyte cell lines present a cell model with which to understand the physiopathological mechanisms underlying lipodystrophy syndrome, a common complication observed in patients treated with highly active antiretroviral therapy (HAART) that, in general, is associated with the use of protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The aim of this study was to evaluate the effects of NRTI and of PI and NRTI combinations in this cell model. METHODS: The differentiation of 3T3-F442A cells was studied by monitoring the expression of specific genes in the presence of therapeutic concentrations of antiretroviral drugs. Messenger RNA (mRNA) was quantified by two reverse transcription-PCR-based methods. RESULTS: In the presence of 2 microM saquinavir, 30 microM ritonavir or 1 microM zidovudine preadipocytes delayed their differentiation, whereas the use of 10 microM nelfinavir led to cell death. Indinavir (10 microM) promoted lipoprotein lipase expression whereas 1 microM lamivudine or 1 microM stavudine enhanced slightly the expression of the malic enzyme gene. However, the combination of indinavir, lamivudine and stavudine led to a large increase in both lipoprotein lipase and malic enzyme mRNA transcription whereas the combination of indinavir, lamivudine and zidovudine led to a 2.5-fold increase in the expression of the lipogenic malic enzyme gene. Similar potentiating effects of NRTI and PI were observed on the expression of the fatty acid synthase gene. CONCLUSIONS: Our data suggest that, like PI (although to a lesser extent) NRTI interfere with the differentiation process of adipocytes. In addition, we demonstrate that the effects produced by combinations of NRTI and PI are different from those elicited by each drug separately. This point may be particularly relevant in understanding the physiopathological mechanisms underlying the lipodystrophic syndrome.

Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial.

BACKGROUND: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. METHODS: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 10(6) cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 10(6) IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. RESULTS: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 10(6) cells/l, respectively; P < 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P < 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P < 0.0001) and natural killer cells (P < 0.001). In a logistic regression analysis, odds of being responders to recall antigens was 8.5-fold higher in IL-2 recipients (P = 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01). CONCLUSIONS: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.

Natural killer cell-triggering receptors in patients with acute leukaemia.

Human natural killer (NK) cells are potent effectors involved in destruction of virus infected cells and tumours. Their cytolytic function is regulated by surface receptors that either inhibit or increase the NK-mediated cytotoxicity. Under physiological conditions, NK cells recognize major histocompatibility complex (MHC)-class I molecules through surface receptors delivering signals that inhibit NK cells function. Nonetheless, the "missing self hypothesis", i.e. the release of an inhibitory signal by the interaction between HLA I-specific inhibitory receptors and their ligands, is not sufficient to entirely explain the regulation of NK cytotoxicity. Activating and co-receptors also play a central role in NK cell activation. In the haematology field, several lines of evidence suggest that NKs participate to the anti-leukaemia immune response: (1) leukaemic cells have down-regulated HLA-class I molecule expression and putative allele loss, (2) several reports have indicated an inverse relationship between NK cell number or activity and prognosis in acute leukaemia, (3) NK-cell activity dependent immunodeficiency syndromes are associated with an increased frequency of lymphoid haematological malignancies, (4) recent data support a role for NK cells in the graft-versus-leukaemia effect observed in allogeneic bone marrow transplantation. All these data raise several questions. How NK cells kill leukaemic targets, and how can leukaemia escape from innate immunity surveillance? What are the therapeutic possibilities to manipulate NK receptor-ligand interaction in order to increase leukaemia cell destruction? The responses to these questions will contribute to immunotherapy advancements in leukaemia and more generally in cancer.

Drug injection cessation among HIV-infected injecting drug users.

This article reports findings from a cohort study that investigated drug injection cessation over an 18-month period among HIV-infected injecting drug users followed up in a clinical setting. At 18th month visit, individuals reporting persistent injection practices were compared with individuals who reported drug injection cessation for at least 12 months. Crude and adjusted odds ratios were used to assess the impact of change in addictive and sexual behaviors, contacts with the drug network, depression, negative life events, clinical status, HIV therapy, and drug maintenance treatment (DMT) on drug injection cessation. After multiple adjustment, a general decrease of addiction practices (alcohol and cannabis) and of unsafe sexual behaviors significantly accompanied injection cessation. Individuals with higher education level, still in contact with the drug network, and not yet treated for their HIV disease were significantly more likely to persist injecting behaviors. These results underscore the importance and the need of monitoring addiction practices and unsafe sexual behaviors among HIV-positive individuals to properly address primary and secondary prevention in the era of highly active antiretroviral treatments (HAART).

[The problems in France created by the HIV/AIDS epidemic at the onset of the third millenium]. / Les problèmes posés par l'épidémie VIH/sida à la société française à l'aube du troisième millénaire.

UNANSWERED QUESTIONS: The HIV/AIDS epidemic represented a medical, social and political challenge to our society. It raises numerous questions, to which some replies have been partially proposed. In the context of less attention paid to AIDS, the epidemic continues to create problems in France and has led to the debates on medical and sanitary questions and other political, social and economical issues. FROM A THERAPEUTIC POINT OF VIEW: Among the issues concerning health management, those related to treatment are first-line: progress in therapeutic indications, choice of antiretroviral molecules and their combinations, particular aspects of treatments delivered in certain circumstances (pregnant women or primary-infection), difficulties in the assessment of the benefit/risk progress. The problems of compliance that occasionally induce severe side effects, provoke therapeutic failure in some patients and for whom rapid access to new antiretroviral molecules and new therapeutic strategies is mandated. THE CROSS-LINK WITH POLITICAL, SOCIAL AND ECONOMIC PROBLEMS: The resulting debates partly depend on the progress made in therapeutics. The latter have led to expectations of HIV-infected patients, who would like to benefit fully from the promise of a return to normal life (access to insurance and medically-assisted procreation). HIV/AIDS has led to new ethical debates on the rights of patients, such as those related to screening, clinical research or confidential access of under-aged patients to treatment. Some of these aspects involve political decisions: prevention measures to be taken against the possibility of a new epidemic, the risks and damages related to the use of drugs and the guarantee of access to treatment of patients living in under-developed countries.

[Perception of hepatitis C infection and its management in women infected by HIV following intravenous use of drugs]. / Perception de la co-infection par le VHC et de sa prise en charge chez les femmes infectées par le VIH après usage intraveineux de drogues.

OBJECTIVE: To describe perception and knowledge of hepatitis C infection, related care and treatment, among women included in the Manif 2000 cohort, a study that enrolled patients HIV-infected through intravenous drug use (IVDU). METHOD: A qualitative survey among women who had been pregnant, conducted in the form of semi-direct interviews, between October 2000 and March 2001, in the PACA area (South Eastern) of France. Twenty-two out of the 32 eligible women agreed to participate. RESULTS: 21/22 women were HCV co-infected. In 13 cases, HCV screening was done during HIV infection follow-up. Although, for interviewed women, hepatitis C infection was of minor importance compared with HIV infection, the majority of them considered that they were well informed on HCV infection and its risks. Nevertheless, four women declared regular alcohol consumption and 8 women did not know how HCV was transmitted. None of them mentioned the risk of vertical transmission of the virus. For these women, their physician in charge of HIV was the master piece in the care of HCV infection and the main provider of information about this disease. Liver biopsy was offered to 11 women (9 agreed). Three women had already been treated for their HCV infection and 5 others were about to start treatment. CONCLUSION: With the improvement in life span of HIV-infected persons, the protection of liver functions has become an important medical challenge. It is of particular importance that the physicians in charge of HIV should provide more counselling to IVDU or ex-IVDU patients, in order to increase their awareness on the risks related to co-infections, the use of drugs and consumption of alcohol.

Age at transplantation and outcome after autologous stem cell transplantation in elderly patients with multiple myeloma.

BACKGROUND AND OBJECTIVE: The optimal treatment of patients with multiple myeloma (MM) is not well defined, in part because these patients are underrepresented in clinical studies. Autologous stem cell transplantation (auto-SCT) after high-dose melphalan chemotherapy can result in a prolonged response duration and survival in patients under 65 years of age. DESIGN AND SETTING: Single-center, retrospective study of patients treated at Paoli-Calmettes Institute Cancer Centre, between January 1994 and January 2007 (96 months) PATIENTS AND METHODS: We compared the outcome of elderly (age >65 years) patients with younger patients aged between 60 and 65 years with MM. RESULTS: We compared 82 elderly patients with 104 younger patients. Except for age, both groups had comparable demographic features, disease characteristics, and prognostic factors. Induction VAD chemotherapy was comparable between the elderly (87%) and younger (94%) group. Prior to auto-SCT, the calculated hematopoietic cell transplantation-specific co-morbidity index was also comparable. With a median follow-up of 41 months (range, 5-227 months) after auto-SCT, 120 patients were still alive. Disease progression (n=40; 61%) was the main cause of death, and it was comparable in the two groups. Auto-SCT-related mortality was 3.8% (n=4/104) in younger and 3.7% (n=3/82) in older patients. Comparing younger/older subjects, progression-free survival was significantly higher in the younger group (P<.0001). However, disease response rates after the first auto-SCT was comparable and overall survival (OS) was also comparable (57% vs. 54% at 5 years, P=NS; 32% vs. 24% at 10 years, P=NS). In a Cox multivariate analysis model, none of the relevant characteristics was shown to be a critical prognostic feature for OS. CONCLUSIONS: Age was insignificant for both OS and transplant-related mortality. We conclude that there is no biological justification for an age-discriminate policy for MM therapy. Physiologic aging is likely more important than chronologic aging.

Family nutritional support improves survival, immune restoration and adherence in HIV patients receiving ART in developing country.

In developing countries, access to antiretroviral treatment for persons living with HIV is still in progress. Malnutrition represents another cause of acquired immunodeficiency and premature death. This evaluation program estimated the impact of family nutritional support during the first year of antiretroviral treatment in West Africa's sub-Sahara region. Family nutritional support was proposed to patients with CD-4 cell count <200 /mm3 and/or developing a WHO stage III/IV or with body mass index <18.5 kg/m2 and receiving antiretroviral treatment. Follow-up of 62 patients receiving support was compared to 118 patients who had only received antiretroviral treatment the year before. Average body mass index, CD-4 cell count were 20.7 and 20.5, 217 and 191/mm3 respectively in supported and control groups (NS). Twenty-two (36%) and 56 (48%) were WHO stage III/IV (NS) respectively in supported and control groups. One patient who received support and twelve controls died (Mortality Ratio=0.19; p<0.05). Increase in CD-4 cell count was around 1.7 times higher (+ 114 vs. + 68 CD-4 cells/mm3 respectively in supported and control groups; p<0.05) and observance was improved in supported group (p<0.005). The evolutions of WHO stage and body mass index were not different but the study period was short. Family nutritional support for persons living with HIV initiating antiretroviral treatment in a developing country showed a positive impact after six months. This family intervention could be integrated into AIDS interventions as an effective and comprehensive community-based primary care.

Rank ligand stimulation induces a partial but functional maturation of human monocyte-derived dendritic cells.

Mature dendritic cells (DC) are efficient, antigen-presenting cells required for the stimulation of naive T lymphocytes. Many members of the tumour necrosis factor (TNF) receptor family are involved in DC maturation, such as Fas, CD40, OX40L, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) or RANK (receptor activator of NFkappaB), with different, but often overlapping effects. We focused our attention on RANK DC stimulation, since RANK ligand (RL) is expressed on activated T lymphocytes with different kinetic and expression patterns from the other members of TNF family previously cited. After culture with RL-transfected cells, a significant percentage of immature DC generated from monocytes (Mo-DC) acquired a typical, mature DC morphology and phenotype characterised by up-regulation of CD83, DC-LAMP (lysosome-associated membrane glycoprotein), HLA class I, CD86 and CD54. The functional RL-mediated maturation was demonstrated by a decrease in DC macropinocytosis and acquisition of the capacity to stimulate allogenic T-cells. Among the various cytokines tested, we detected only a weak up-regulation of IL-12p40. Our results show that ligation of RANK on DC cell surfaces is not only a survival stimulus, but also induces a partial and specific mature DC phenotype, the physiological significance of which is under investigation.

Baseline CD4 cell count and outcome of pegylated interferon plus ribavirin therapy in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: When to start hepatitis C treatment in HIV/hepatitis C virus (HCV)-coinfected patients remains unresolved. Our objective was to determine if a baseline CD4 count >/=350 cells/mm predicts a sustained HCV response to pegylated interferon plus ribavirin. METHODS: We conducted a multicenter cohort study of HIV/HCV-coinfected patients treated for HIV in hospitals in Nice, Tourcoing, and Marseille (France). Sustained viral response (SVR) was defined as undetectable HCV RNA 24 weeks after treatment. The relation between CD4 cell count and SVR was examined separately for patients with HCV genotype 1 or non-1. RESULTS: One hundred seventy-five patients were included. In patients with HCV genotype 1, the rate of SVR was 13% and was not related to baseline CD4 cell count (odds ratio [OR] = 1.0, 95% confidence interval [CI]: 0.1 to 9.3). In patients with HCV genotype non-1, the rate of SVR was 46% and was not significantly increased by a baseline CD4 count >/=350 cells/mm (OR = 1.8, 95% CI: 0.6 to 5.9). CONCLUSIONS: Higher CD4 cell count at treatment initiation with pegylated interferon plus ribavirin did not improve treatment success probability, regardless of HCV genotype.

Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia.

BACKGROUND: : Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, which is explained by the disease itself and by host-related factors. The objective of this study was to determine the prognostic role of comorbidities in this population. METHODS: : For this single-center, retrospective study, the authors analyzed the outcome of 133 patients aged >/=70 years who received induction chemotherapy for nonpromyelocytic AML between 1995 and 2004. Comorbidities were evaluated by using an adapted form of the Charlson comorbidity index (CCI). RESULTS: : The median patient age was 73 years. The CCI score was 0 for 83 patients (68%), 1 for 16 patients (13%), and >1 for 23 patients (19%). The complete remission (CR) rate was 56%, and the median overall survival was 9 months. In multivariate analysis, 4 adverse prognostic factors for CR were identified: unfavorable karyotype, leukocytosis >/=30 g/L, CD34 expression on leukemic cells, and CCI >1. A score could be generated to allow the stratification of patients into low-, intermediate-, and high-risk groups with CR rates of 87%, 63%, and 37%, respectively. The risk of early mortality and the probability of survival also were different in the 3 risk groups (P = .02 and P = .01, respectively). CONCLUSIONS: : The results from this study indicated that associated comorbidities are independent factors that may influence achievement of CR in elderly patients with AML. Such a scoring system may be useful in the prognostic staging systems that are used to identify patients with AML who can benefit from induction chemotherapy.

Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients.

AIMS: The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients. METHODS: Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5. RESULTS: The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P