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PubMed2002

Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter.

We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 10(7) fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of >or=500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of >or=500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load.

Adult↗

PubMed2001

Switch of protease inhibitor-containing HAART in routine clinical practice: a four-year prospective observational study.

An evaluation was made of the frequency of outcomes, the features, and one-year outcomes of the substitution, carried out because of failure or toxicity, of protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART). Nine hundred and seventy-two HIV-infected patients were prospectively followed up since 1996, with the condition that they had a minimum 80% adherence to prescribed regimens. Four hundred and fifty-two changes occurred in 397 of the 876 evaluable patients (45.3%). Virological and/or immunological failure was of concern in 245 cases (54.2%). Interest in saquinavir had the greatest incidence and earliest occurrence (although the subsequent switch had a significantly better outcome than that of patients failing with other PIs); nelfinavir benefited from a shorter time to change and a worse long-term outcome (probably attributable to its predominant use in indinavir- and ritonavir-experienced patients); while indinavir showed the lowest overall frequency of substitution. Intolerance occurred in the remaining 207 cases (45.8%); with saquinavir being better tolerated than other PIs. A favourable outcome was obtained more frequently when poor tolerability was of concern, compared with therapeutic failure (P<0.008), while no significant differences were found according to prior antiretroviral experience and the subsequently selected HAART regimen. The overall one-year outcome per single substituted compound proved significantly better for patients who stopped using saquinavir and ritonavir, by contrast with those who stopped using indinavir and nelfinavir (P<0.0008). A significantly shorter mean time to substitution was recognized for nelfinavir and saquinavir than with ritonavir and indinavir (P<0.0001). When analysing the subset of patients experiencing HAART failure, a highly significant reverse relationship was demonstrated between mean time to failure, and rate of subsequent response to a modified antiretroviral regimen (P<0.0001). When considering the different patterns of efficacy, durability, resistance induction, expected adherence, and safety of each antiretroviral drug, initial and subsequent therapeutic choices should be carefully balanced against expected benefits and risks.

Antiretroviral Therapy, Highly Active↗

PubMed2006

Acid suppressive therapy and the effects on protease inhibitors.

OBJECTIVE: To review the literature associated with the pharmacokinetic interaction between protease inhibitors (PIs) and acid suppressive therapies and to characterize the impact of this interaction on virologic and immunologic outcomes. DATA SOURCES: A MEDLINE search (1966-October 2006) was conducted using the names of the 10 PIs and specific acid suppressive therapies including antacids, histamine(2)-receptor antagonists, and proton pump inhibitors. Abstracts and poster presentations from recent HIV/AIDS meetings were reviewed for relevance. References from retrieved articles, as well as product packaging and manufacturer information, were evaluated. STUDY SELECTION AND DATA EXTRACTION: Pertinent pharmacokinetic, immunologic, and virologic studies, in healthy and HIV-infected patients, evaluating the use of a PI and acid suppressive therapy were reviewed. DATA SYNTHESIS: Potential interactions between concomitant acid suppressive therapy and PIs were evaluated. Available information indicates that indinavir and atazanavir require an acidic gastric medium for adequate absorption. Indinavir pharmacokinetic parameters are variable with acid suppressive therapy but primarily result in decreased oral absorption. This interaction abates with concurrent ritonavir use. No immunologic or virologic data are available regarding the concomitant use of indinavir and acid suppressive therapy. The minimum concentration of atazanavir, area under the concentration-time curve, and maximum concentration are significantly reduced when used concurrently with acid suppressive therapy. Atazanavir 300 or 400 mg boosted with ritonavir 100 mg increases plasma concentrations when used with acid suppressive drugs. Virologic and immunologic outcomes appear stable when boosted atazanavir is used in HIV-positive patients. Atazanavir therapeutic monitoring should be considered when used in combination with acid suppressive therapy. CONCLUSIONS: Of the PIs reviewed, significant pharmacokinetic interactions exist between acid suppressive therapy and indinavir or atazanavir. These PIs should be used with low-dose ritonavir if acid suppressive therapy is necessary.

Antacids↗

PubMed2004

Effect of mycophenolate mofetil on the pharmacokinetics of antiretroviral drugs and on intracellular nucleoside triphosphate pools.

OBJECTIVE: To study the effect of mycophenolate mofetil therapy on the pharmacokinetic parameters of a number of antiretroviral drugs, on intracellular pools of deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP), and on intracellular concentrations of the triphosphate of lamivudine (3TCTP). DESIGN: Randomised pharmacokinetic study. PARTICIPANTS: Nineteen HIV-1-infected patients. METHODS: Antiretroviral-naive men starting treatment with didanosine 400 mg once daily, lamivudine 150 mg twice daily, abacavir 300 mg twice daily, indinavir 800 mg twice daily, ritonavir 100 mg twice daily and nevirapine 200 mg twice daily were randomised to a group with or without mycophenolate mofetil 500 mg twice daily. After 8 weeks of therapy, the plasma pharmacokinetic profiles of mycophenolic acid (the active metabolite of mycophenolate mofetil), abacavir, indinavir and nevirapine, and triphosphate concentrations (dCTP, dGTP and 3TCTP) in peripheral blood mononuclear cells, were determined. RESULTS: Nine of the 19 patients received mycophenolate mofetil. There was no difference in plasma clearance of indinavir or abacavir between the two groups. The clearance of nevirapine was higher in patients using mycophenolate mofetil (p = 0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. CONCLUSION: In this small cohort of patients, mycophenolate mofetil therapy reduced the plasma concentration of nevirapine but had no effect on plasma concentrations of indinavir and abacavir. There were no consistent effects of mycophenolic acid on the intracellular concentrations of dCTP, dGTP or 3TCTP.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Saquinavir: a review of its use in boosted regimens for treating HIV infection.

UNLABELLED: Protease inhibitor boosting involves concurrent administration of a protease inhibitor, such as saquinavir, plus a potent inhibitor of cytochrome P450 (CYP) 3A4, usually ritonavir in subtherapeutic doses. Since protease inhibitors are extensively metabolised by CYP3A4, this results in a marked increase in systemic exposure of saquinavir or other protease inhibitors boosted by ritonavir. As with traditional protease inhibitor regimens, boosted regimens are typically used in combination with nucleoside reverse transcriptase inhibitors (NRTIs). In protease inhibitor-experienced and -naive patients with HIV infection, twice-daily and once-daily boosted saquinavir regimens achieved good rates of viral suppression, improved CD4+ cell counts and were generally well tolerated in clinical trials. Encouraging results have also been reported in a number of small studies in heavily pretreated HIV-infected patients who received salvage therapy comprising double-boosted regimens of saquinavir plus lopinavir with subtherapeutic doses of ritonavir, along with other agents. The largest clinical trials have been multicentre, randomised comparisons of twice-daily boosted saquinavir versus twice-daily boosted indinavir (MaxCmin1) or lopinavir (MaxCmin2) regimens. In the MaxCmin1 study, >90% of patients in both groups had an undetectable viral load (<400 copies/mL) after 48 weeks of therapy in the on-treatment analysis. However, viral suppression was achieved in significantly more saquinavir than indinavir recipients in the intention-to-treat analysis, which appeared to be due to the significantly greater percentage of patients in the indinavir group who switched from randomised therapy because of adverse events. Interim 24-week results of the MaxCmin2 trial indicate that 90% of patients in both groups combined had plasma HIV RNA levels <400 copies/mL; final results at 48 weeks will report data separately for the boosted regimens of saquinavir and lopinavir. CONCLUSION: Boosted protease inhibitor regimens (including two NRTIs) are recommended as a first-line option in current HIV treatment guidelines and are used extensively in clinical practice. The convenient administration schedule and good pharmacokinetic profile associated with boosted saquinavir regimens have the potential to increase adherence to therapy and improve antiretroviral effects through increased drug exposure. Twice-daily boosted saquinavir is one of the most extensively evaluated boosted protease inhibitor regimens and has been shown to have good efficacy on surrogate markers of HIV disease as well as significant tolerability advantages over boosted indinavir. Once-daily boosted saquinavir regimens may be most suitable for HIV-infected patients with busy lifestyles and those who would benefit from directly observed therapy.

Area Under Curve↗

PubMed1997

Cost-effectiveness of chemoprophylaxis after occupational exposure to HIV.

OBJECTIVES: To assess the economic efficiency of recent US Public Health Service recommendations for chemoprophylaxis with a combination of antiretroviral drugs following high-risk occupational exposure to human immunodeficiency virus (HIV). To provide a framework for evaluating the relative effectiveness and costs associated with candidate postexposure prophylaxis (PEP) regimens. METHODS: Standard techniques of cost-effectiveness and cost-utility analysis were used. The analysis compares the costs and consequences of a hypothetical, voluntary combination-drug PEP program consisting of counseling for all HIV-exposed health care workers, followed by chemoprophylaxis for those who elect it vs an alternative in which PEP is not offered. A societal perspective was adopted and a 5% discount rate was used. Hospital costs of recommended treatment regimens (zidovudine alone or in combination with lamivudine and indinavir) were used, following the dosing schedules recommended by the US Public Health Service. Estimates of lifetime treatment costs for HIV and acquired immunodeficiency syndrome were obtained from the literature. Because the effectiveness of combination PEP has not been established, the effectiveness of zidovudine PEP was used in the base-case analyses. MAIN OUTCOME MEASURES: Net PEP program costs, number of HIV infections averted, cost per HIV infection averted, and cost-utility ratio (net cost per discounted quality-adjusted life-year saved) for zidovudine, lamivudine, and indinavir combination PEP. Lower bounds on the effectiveness required for combination regimens to be considered incrementally cost saving, relative to zidovudine PEP alone, were calculated. Multiple sensitivity and threshold analyses were performed to assess the impact of uncertainty in key parameters. RESULTS: Under base-case assumptions, the net cost of a combination PEP program for a hypothetical cohort of 10,000 HIV-exposed health care workers is about $4.8 million. Nearly 18 HIV infections are prevented. The net cost per averted infection is just less than $400,000, which exceeds estimated lifetime HIV and acquired immunodeficiency syndrome treatment costs. Although combination PEP is not cost saving, the cost-utility ratio (about $37,000 per quality-adjusted life-year in the base case) is within the range conventionally considered cost-effective, provided that chemoprophylaxis is delivered in accordance with Public Health Service guidelines. Small incremental improvements in the effectiveness of PEP are associated with large overall societal savings. CONCLUSIONS: Under most reasonable assumptions, chemoprophylaxis with zidovudine, lamivudine, and indinavir following moderate- to high-risk occupational exposures is cost-effective for society. If combination PEP is minimally more effective than zidovudine PEP, then the added expense of including lamivudine and indinavir in the drug regimen is clearly justified.

Adult↗

PubMedDate not supplied

Analysis of the pH-dependencies of the association and dissociation kinetics of HIV-1 protease inhibitors.

The kinetic constants for the interactions between HIV-1 protease and a selection of inhibitors were determined at different pH-values using a biosensor based interaction assay. Since this technique does not involve a substrate, it was possible to determine the pH-dependencies of the association and dissociation rates of an inhibitor, without the complication of a pH-dependent enzyme-substrate/product equilibrium. The importance of these interactions was evaluated by correlating the free energy changes upon association and dissociation of inhibitors with the predicted change in electrostatic properties of the interacting groups as a result of altered pH. It was found that the kinetic parameters varied with pH in a unique manner for all inhibitors, demonstrating that the kinetic features were associated with the specific structure of each inhibitor. Association and dissociation had different pH-profiles, indicating that the two processes proceeded by different pathways/mechanisms. The energy barrier for dissociation of the enzyme-indinavir complex increased with pH from 4.1 to 7.4, while it was generally reduced for the other inhibitors as the pH was increased from 5.1 to 7.4. The pH-dependent interactions involved in the recognition/binding of inhibitors and in the stabilization of the complex were identified by analysing three-dimensional structures of enzyme-inhibitor complexes. The interaction between the pyridine nitrogen of indinavir with Arg-8 was hypothesized to be responsible for the unique pH-dependency of indinavir. The analysis revealed features of interactions that are significant for understanding enzyme function and for optimization of new drug leads. It also highlighted the importance of environmental conditions on interactions.

HIV Protease↗

PubMed2000

The pharmacokinetics of liposomal encapsulated daunorubicin are not modified by HAART in patients with HIV-associated Kaposi's sarcoma.

PURPOSE: To investigate the pharmacokinetics of liposomal daunorubicin (DaunoXome) administered alone or in combination with antiviral therapy including protease inhibitors (PI) to HIV-positive patients affected by Kaposi's sarcoma (KS). PATIENTS AND METHODS: A group of 18 patients with extensive or rapidly progressing AIDS-related KS received DaunoXome at a dose of 40 mg/m2 alone or in association with a triple combination therapy consisting of one PI plus two nucleoside reverse transcriptase inhibitors (NRTI). Daunorubicin pharmacokinetics were determined in a total of 23 cycles, 6 with DaunoXome alone, 9 in combination with indinavir, 6 with ritonavir and 2 with saquinavir. Plasma samples were obtained at different times during the 72 h after DaunoXome administration. Daunorubicin and daunorubicinol plasma levels were determined by high-performance liquid chromatography. RESULTS: After the DaunoXome infusion, daunorubicin was rapidly cleared from the body following, in most cases, a one-compartment open kinetic model. The daunorubicin peak concentrations, clearances and elimination half-lives were (means +/- SD): 16.3 +/- 2.8 microg/ml, 0.3 +/- 0.1 l/h per m2 and 5.6 +/- 2.6 h after DaunoXome alone; 15.1 +/- 4.9 microg/ml, 0.5 +/- 0.3 l/ h per m2 and 5.8 +/- 2.1 h after the combination with indinavir; and 14.5 +/- 2.8 microg/ml, 0.4 +/- 0.2 l/h per m2 and 6.5 +/- 3.9 h after the combination with ritonavir. In all groups, daunorubicinol plasma levels were approximately 25-30 times lower than those of the parent drug. CONCLUSION: Our data show that there are no significant differences in the pharmacokinetic parameters of daunorubicin in patients receiving DaunoXome in combination with indinavir and ritonavir compared with those in patients not receiving PIs. Therefore in patients affected by AIDS-related KS treated with Highly Active AntiRetroviral Therapy (HAART) there is no pharmacokinetic justification for reducing the doses of DaunoXome.

AIDS-Related Opportunistic Infections↗

PubMed2006

Absorption of poorly water soluble drugs subject to apical efflux using phospholipids as solubilizers in the Caco-2 cell model.

The purpose of this work was to determine the influence of liposomal solubilization of poorly water soluble drugs exhibiting apical efflux on permeation kinetics and cell toxicity in Caco-2 cells. The HIV-protease inhibitors indinavir and saquinavir were incorporated in phosphatidylcholine liposomes at maximal drug-to-lipid mass ratios and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using purely aqueous drug solutions as reference. A novel mathematical model was developed to quantitatively delineate the contribution of passive membrane permeation and carrier mediated efflux to transport across the cell monolayer and passive permeability coefficient and maximal efflux rate and affinity constant of the transporter system were determined. Cell toxicity of phospholipids was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and the lactate dehydrogenase (LDH) assay. Cell integrity was not significantly affected by phospholipid concentrations of up to 150 mg/ml with respect to the used standard tests. Maximum drug concentration was increased 10- and 750-fold for indinavir and saquinavir, respectively, by the use of liposomes. The passive membrane permeability coefficient differed between the two drugs in accordance with their lipophilicity and the affinity for apical efflux transporters was on average 4-fold greater for saquinavir than for indinavir. Liposomal solubilization diminished the passive permeability coefficient of both drugs but the passive apical-to-basal delivery rate was increased by the liposomes compared to the purely aqueous solutions at maximal donor concentrations for at least one of the two drugs. Efflux rate reached a maximum for the liposomal formulations reflecting transporter saturation. Hence, liposomal solubilization considerably increased drug concentration in the media and altered absorption behavior by affecting both the passive diffusion and the carrier mediated efflux components of cell monolayer permeation.

Absorption↗

PubMed2003

Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain.

Treatment with drugs designed to inhibit the HIV protease ameliorates immune functions in AIDS patients, reducing cell deletion by apoptosis even in the absence of inhibition of viral spread. This suggests that they interact with the intrinsic apoptotic signaling. We found that caspases, the main executioner of the apoptotic process, are not directly inhibited. In search for the mechanism responsible for their anti-apoptotic effect, we have found that indinavir and ritonavir are able to inhibit apoptosis only in those cell systems where apoptosis involves the activation of calpains. They directly inhibit a calpain-like activity expressed in lysates from apoptotic cells, to the same extent as commercially available calpain inhibitor 1. In in vitro assays with purified calpains, indinavir and ritonavir strongly inhibit m-calpain, and moderately mu-calpain. These results have great therapeutic implications, going beyond AIDS treatment, since many degenerative disorders involve abnormal calpain activation, indicating calpain as an ideal pharmacological target. Indinavir and ritonavir, potent m-calpain inhibitors, largely used since several years on humans without important negative side effects, may become powerful tools against those pathologies.

Apoptosis↗

PubMed1999

Human immunodeficiency virus type 1 protease inhibitor attenuates Candida albicans virulence properties in vitro.

The putative virulence factor secreted aspartyl proteinase (SAP) of Candida albicans and the human immunodeficiency virus type 1 (HIV-1) protease both belong to the aspartyl proteinase family. The present study demonstrates that the HIV-1 protease inhibitor Indinavir is a weak but specific inhibitor of SAP. In addition, Indinavir reduces the amount of cell bound as well as released SAP antigen from C. albicans. Furthermore, viability and growth of C. albicans are markedly reduced by Indinavir. These findings indicate that HIV-1 protease inhibitors may possess antifungal activity and we speculate that in vivo SAP inhibition may add to the resolution of mucosal candidiasis in HIV-1 infected subjects.

Amino Acid Sequence↗

PubMed2002

Rapid phenotypic assay for human immunodeficiency virus type 1 protease using in vitro translation.

A rapid in vitro phenotyping method for human immunodeficiency virus type 1 (HIV-1) protease was developed. In this system, both HIV-1 protease and substrates are prepared using a rabbit reticulocyte based coupled in vitro transcription/translation system. The activity of protease is evaluated by the amount of cleaved substrate measured by ELISA. In this system, wild-type protease derived from strain HXB2 was specifically inhibited in a dose-dependent manner by the protease inhibitors, indinavir and nelfinavir. Three drug-resistant proteases carrying a single mutation, D30N, L90M, and V82F, were analyzed in the absence of the inhibitors. Reflecting their impaired fitness, they exhibited decreased protease activity compared with the wild type. The apparent protease activity was greater for a Gag-Pol substrate encompassing the Gag-protease-reverse transcriptase junctions than for a substrate only covering the Gag region. Using the Gag-Pol substrate as the target, the indinavir-resistant mutant V82F was evaluated further. V82F showed 9-fold resistance to its cognitive protease inhibitor, indinavir; however, it manifested only moderate (2-fold) resistance to a non-cognitive inhibitor, nelfinavir. This simple and rapid method may be useful for phenotyping of drug-resistant HIV-1 protease as well as for screening new inhibitors of HIV-1 protease.

Animals↗

PubMedDate not supplied

Evaluation of the origins of the selectivity of polymers imprinted with a HIV protease inhibitor using infrared spectroscopy and high performance liquid chromatography.

This work investigates the origins of enantioselectivity of polymers imprinted with the HIV protease inhibitor, Indinavir. For the preparation of imprints of the drug, the critical interactions between the functional monomer, methacrylic acid, and Indinavir were characterized by infrared (IR) spectroscopy to explore the optimum functional monomer concentration for the polymerization. It was shown that a polymer with high selectivity and minimum non-selective binding for Indinavir was obtained when prepared with enough functional monomer to hydrogen bond with all of the functional groups of the drug without using an excess of monomer. This observation is explained in terms of a balance that is achieved in the monomer-template equilibrium during the polymerization that yields a polymer with highly selective sites and minimal non-selective sites. This paper further demonstrates that IR spectroscopy can be a valuable tool in the design and syntheses of molecular imprinted polymers.

Chromatography, High Pressure Liquid↗

PubMed1999

Prolonged suppression of human immunodeficiency virus type 1 (HIV-1) viremia in persons with advanced disease results in enhancement of CD4 T cell reactivity to microbial antigens but not to HIV-1 antigens.

CD4 T cell responses were studied for >2 years in 27 zidovudine-experienced patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who received triple combination drug therapy with indinavir, zidovudine and lamivudine or zidovudine plus lamivudine or zidovudine alone for 24-42 weeks before switching to the three-drug therapy. Subjects initially given the three drugs had viremia suppressed to undetectable levels and increases in T cell proliferative and cytokine responses to microbial antigens through 2 years of follow-up. Patients receiving the triple-drug therapy after either indinavir or zidovudine-lamivudine treatment had similar increases in T cell responses only if they also had suppression of virus load. CD4 T cell reactivity to HIV-1 antigens was not restored. Prolonged indinavir-zidovudine-lamivudine treatment has significant but incomplete enhancing effects on CD4 T cell reactivity, which could be important in host control of microbial and persistent HIV-1 infections.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients.

OBJECTIVES: We have investigated whether chemotherapy for HIV-related systemic non-Hodgkin's lymphoma (NHL) affects the pharmacokinetics of protease inhibitors. PATIENTS AND METHODS: This was a prospective, open-label, non-randomized, two-way crossover trial in HIV-1-infected patients treated with highly active antiretroviral therapy and chemotherapy for NHL. Seven patients received indinavir at a dosage of 800 mg three times daily and three patients received nelfinavir at a dosage of 750 mg three times daily. Chemotherapy consisted of adriamycin, cyclophosphamide, vincristine and prednisolone (CHOP). Each patient had blood samples for protease inhibitor pharmacokinetics drawn concomitantly with or independently of the CHOP cycle. RESULTS: When indinavir was given concomitantly with CHOP, the AUC(0-8) increased by 38% (20.5 +/- 9.0 versus 14.9 +/- 9.5 mg.h/L; P=0.03), and was comparable to historical controls. By contrast, the AUC(0-8) of indinavir administered without CHOP was lower than expected. A similar trend was observed with nelfinavir. Likewise, we observed a significant number of patients with C(0) and C(8) below the IC(50) for the wild-type virus (0.1 mg/L) when the drug was administered without CHOP. CONCLUSIONS: Therapeutic drug monitoring of protease inhibitors should be part of the work-up in HIV-infected patients receiving chemotherapy for NHL.

Adult↗

PubMed1997

Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients.

OBJECTIVE: To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors. DESIGN AND SETTING: Retrospective study in two German tertiary care treatment centres. PATIENTS: A total of 198 HIV-infected patients treated with protease inhibitors in 1996. MAIN OUTCOME MEASURES: Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures. RESULTS: A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001). CONCLUSION: An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.

Adult↗

PubMed1998

Clinical experience with adding delavirdine to combination therapy in patients in whom multiple antiretroviral treatment including protease inhibitors has failed.

OBJECTIVE: To determine the effectiveness and safety of adding delavirdine mesylate to a treatment regimen that included indinavir and nucleoside analog reverse transcriptase inhibitors in patients in whom combination therapy had failed. DESIGN: Observational study. SETTING: Private practice. PATIENTS: HIV-1-positive patients with peripheral blood CD4+ lymphocyte counts < 300 x 10(6)/l in whom antiretroviral therapy had failed or whose condition was deteriorating. Of the 53 patients who were eligible for the study, 47 took part; for the majority of these patients indinavir combination therapy had been unsuccessful. the majority of the patients were male (98%), white (92%) and homo/bisexuals (96%). INTERVENTIONS: Delavirdine added to current therapy (usually zidovudine, indinavir and lamivudine); in approximately half of the patients zidovudine was replaced with stavudine. MAIN OUTCOME MEASURES: Plasma HIV-1 RNA levels; peripheral blood CD4+ and CD8+ lymphocyte counts. Safety of the therapy was assessed by monitoring side-effects. RESULTS: Mean baseline CD4+ lymphocyte count was 127 x 10(6)/l and mean baseline HIV-1 plasma RNA was 5 log10 copies/ml. Adding delavirdine to the therapeutic regimen produced a rapid and sustained decrease in the mean plasma HIV-1 RNA of 1.1 log10 copies/ml over 6 months; 18-21% of patients showed decreases of 2-3 log10 copies/ml. Viral burden in 33% of subjects declined below the assay's limit of detection (2.6 log10 copies/ml) after 6 months. CD4+ lymphocyte counts increased by 66-90% in each group between 1 and 9 months (mean increase approximately 60 x 10(6)/l after 6 months). Adding delavirdine to current therapy was well tolerated. Side-effects reported were: skin rash, 28%; nausea, 9%; kidney stones, 9%; diarrhea, 6%; flank pain, 2%; proteinuria, 2%. Three patients reported serious medical events all of which resolved and none of which were attributed to delavirdine. CONCLUSIONS: Adding delavirdine to the combination regimen of patients in whom protease inhibitor therapy had failed often resulted in a rapid and remarkable decrease in viral load, sustained improvement in CD4+ lymphocyte counts and viral load, and clinical improvement with minimal toxicity.

Adult↗

PubMed1998

An open randomized controlled trial of zidovudine plus lamivudine versus stavudine plus lamivudine.

OBJECTIVE: To compare the antiretroviral effect and safety of zidovudine (ZDV)-lamivudine (3TC) with that of stavudine (d4T)-3TC. METHODS: In an open randomized controlled trial antiretroviral therapy-naive patients who had CD4+ counts > or = 200 x 10(6)/l and plasma HIV RNA load > or = 10000 copies/ml were randomized to receive ZDV-3TC (200 mg three times daily and 150 mg twice daily, respectively) or d4T-3TC (40 mg and 150 mg, both twice daily). If the plasma HIV RNA level at week 8 or thereafter was > 500 copes/ml, indinavir was added at the next scheduled visit. Genotypic resistance analysis of the reverse transcriptase gene was performed at week 0 and 12. Results over 24 weeks were reported. RESULTS: Forty-seven patients were treated (24 took ZDV-3TC; 23 took d4T-3TC). Plasma HIV RNA levels decreased from median 4.80 to 3.15 log10 copies/ml (ZDV-3TC, P < 0.0001) and from 4.98 to 3.03 log10 copies/ml (d4T-3TC, P < 0.0001) after 12 weeks of treatment. Indinavir was added at week 12 in 11 out of 21 patients with ZDV-3TC and in 10 out of 22 patients with d4T-3TC. Median virus load at week 24 was 2.41 log10 and 2.29 log10 copies/ml (P=0.14), respectively. Seventy-five per cent (15 out of 20; ZDV-3TC) and 95% (18 out of 19; d4T-3TC) of patients had a virus load of < 500 copies/ml. Genomic evidence for 3TC resistance was found in all patients tested (11/11 ZDV-3TC and 12/12 d4T-3TC). At week 12, CD4 cell counts had increased with a median of 110 x 10(6)/l in the ZDV-3TC group (baseline, 315 x 10(6)/l) and a median of 115 x 10(6)/l in the d4T-3TC group (baseline 290 x 10(6)/l). At week 24, the median increases were 90 and 120 x 10(6)/l, respectively. Overall the increase of CD4+ cells was higher in the d4T-3TC group (P=0.02). CONCLUSION: d4T-3TC is at least as effective as ZDV-3TC, but 3TC resistance emerged in all patients investigated. The virological response of the dual nucleoside combination is of short duration. However, after addition of indinavir the virus load could be reduced to < 500 copies/ml in the majority of patients. The increase in CD4+ cell count was significantly greater in the d4T-3TC group. To prevent 3TC resistance, the drug should not be used in regimens containing only two nucleosides, irrespective the virus load at baseline.

Adult↗