Clinical Efficacy of the HIV Protease Inhibitor Indinavir in Combination with Chemotherapy for Advanced Classic Kaposi Sarcoma Treatment: A Single-Arm, Phase II Trial in the Elderly.

Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.

The antiretroviral protease inhibitor ritonavir accelerates glutathione export from cultured primary astrocytes.

Antiretroviral protease inhibitors are a class of important drugs that are used for the treatment of human immunodeficiency virus infections. Among those compounds, ritonavir is applied frequently in combination with other antiretroviral protease inhibitors, as it has been reported to boost their therapeutic efficiency. To test whether ritonavir affects the viability and the glutathione (GSH) metabolism of brain cells, we have exposed primary astrocyte cultures to this protease inhibitor. Application of ritonavir in low micromolar concentrations did not compromise cell viability, but caused a time- and concentration-dependent loss of GSH from the cells which was accompanied by a matching increase in the extracellular GSH content. Half-maximal effects were observed for ritonavir in a concentration of 3 µM. The ritonavir-induced stimulated GSH export from astrocytes was completely prevented by MK571, an inhibitor of the multidrug resistance protein 1. In addition, continuous presence of ritonavir was essential to maintain the stimulated GSH export, since removal of ritonavir terminated the stimulated GSH export. Ritonavir was more potent to stimulate GSH export from astrocytes than the antiretroviral protease inhibitors indinavir and nelfinavir, but combinations of ritonavir with indinavir or nelfinavir did not further stimulate astrocytic GSH export compared to a treatment with ritonavir alone. The strong effects of ritonavir and other antiretroviral protease inhibitors on the GSH metabolism of astrocytes suggest that a chronic treatment of patients with such compounds may affect their brain GSH metabolism.

Surface structured liposomes for site specific delivery of an antiviral agent-indinavir.

The present investigation was aimed at targeting indinavir, a protease inhibitor to cells of mononuclear phagocyte system (MPS) via mannosylated liposomes. ß-d-1-thiomannopyranoside residues were covalently coupled with dimyristoyl phosphatidylethanolamine (DMPE) to generate mannosylated-DMPE (Man-DMPE) conjugate which was further incorporated with disteroyl phosphatidyl choline and cholesterol to prepare mannosylated liposomes. The optimized mannosylated liposomes were nanometric in size (142 ± 2.8 nm) with optimum entrapment efficiency (88.7 ± 2.3%). Less than 20% cumulative drug release was observed from the prepared formulations in 24 h in phosphate buffer saline (pH 7.4). Cellular uptake studies performed on J774.A1 macrophage cell line via flow cytometric analysis depicted enhanced uptake of mannosylated liposomes as compared to plain liposomes. Annexin-V-fluorescein isothiocyanate/propidium iodide apoptosis assay delineated marginal cytotoxicity in macrophages from the developed formulation. Plasma and tissue distribution studies performed to assess the drug reach to macrophage rich regions depicted a significant level (P < 0.05) of indinavir in macrophage rich tissues like liver, spleen, and lungs from mannosylated liposomes as compared to plain liposomes and free drug. The conducted studies suggest the potential of indinavir loaded mannosylated liposomes for anti-human immunodeficiency virus therapy.

Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages.

Long-term antiretroviral therapy (ART) for human immunodeficiency virus type one (HIV-1) infection shows limitations in pharmacokinetics and biodistribution while inducing metabolic and cytotoxic aberrations. In turn, ART commonly requires complex dosing schedules and leads to the emergence of viral resistance and treatment failures. We posit that the development of nanoformulated ART could preclude such limitations and affect improved clinical outcomes. To this end, we wet-milled 20 nanoparticle formulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz, collectively referred to as "nanoART," then assessed their performance using a range of physicochemical and biological tests. These tests were based on cell-nanoparticle interactions using monocyte-derived macrophages and their abilities to uptake and release nanoformulated drugs and affect viral replication. We demonstrate that physical characteristics such as particle size, surfactant coating, surface charge, and most importantly shape are predictors of cell uptake and antiretroviral efficacy. These studies bring this line of research a step closer to developing nanoART that can be used in the clinic to affect the course of HIV-1 infection.

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations.

Nanoformulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz were manufactured by wet milling, homogenization or sonication with a variety of excipients. The chemical, biological, immune, virological, and toxicological properties of these formulations were compared using an established monocyte-derived macrophage scoring indicator system. Measurements of drug uptake, retention, release, and antiretroviral activity demonstrated differences amongst preparation methods. Interestingly, for drug cell targeting and antiretroviral responses the most significant difference among the particles was the drug itself. We posit that the choice of drug and formulation composition may ultimately affect clinical utility.

NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery.

BACKGROUND: Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. METHODS: NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. RESULTS: Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. CONCLUSION: These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.

Less sensitive HIV-1 enzyme immunoassay as an adjuvant method for monitoring patients receiving antiretroviral therapy.

Viral suppression after antiretroviral therapy is monitored by determining plasma HIV-1 through viral load assays. However, such assays only provide HIV-1 replication rates at the moment samples are drawn and do not reflect any trend in viremia fluctuation preceding sample collection. The objective of this study was to correlate the optical density (OD) of the less sensitive HIV-1 enzyme immunoassay (EIA), used in the serologic testing algorithm for recent HIV seroconversion, with viral loads in a group of HIV-infected patients on antiretroviral therapy. We studied samples from 20 previously antiretroviral-naive subjects treated with the zidovudine-lamivudine combination plus indinavir for a 20-week period. Viral loads were assessed using the less sensitive HIV-1 EIA at baseline and at 4-week intervals. There was a strong correlation between lower OD and viral load after introduction of antiretroviral drugs (p < 0.01). The ODs tended to decrease in parallel with drops in viral loads and remain steady when viral loads did not change significantly. These results suggest that the less sensitive HIV-1 EIA may be used as a complementary method for monitoring the efficacy of antiretroviral therapy, with special appeal in resource-poor areas where health professionals have limited laboratory expertise.

Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery.

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 microM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4(+) T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.

Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073).

BACKGROUND: Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs. OBJECTIVE: To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure. METHODS: Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples. RESULTS: At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations. CONCLUSIONS: In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.

Co-treatment with grapefruit juice inhibits while chronic administration activates intestinal P-glycoprotein-mediated drug efflux.

P-Glycoprotein (P-gp) mediated efflux is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp-mediated drug efflux, in which GFJ has been shown both to inhibit and activate it. Hence, the present study adopted a two-way approach, involving both co-treatment and chronic administration. Bi-directional transport of paclitaxel (PCL) was carried out in the absence and presence of GFJ extract, in rat everted ileum sac. Further, the effect of chronic administration of GFJ to rats was characterized by permeability studies with indinavir (INDI). Co-treatment of GFJ extract at 100% concentration reduced the asymmetric transport of PCL (efflux ratio = 20.8) by increasing absorptive (A --> B) transport by 921% and reducing secretory (B --> A) transport by 41%. Further, GFJ showed a concentration dependent effect on PCL permeability. Imipramine, a passive permeability marker with absorptive permeability of 15.33 +/- 4.26 x 10(-6) cm/s showed no asymmetric transport and also no significant (P < 0.05) change in permeability in the presence of GFJ. Chronic administration of GFJ resulted in a significant decrease in absorptive transport of indinavir, which was even greater than that produced by rifampicin pretreatment. No change in permeability of propranolol, a passive permeability marker, was observed. Further, the decrease in absorptive transport of INDI was reversed by the P-gp inhibitor verapamil. In conclusion, GFJ extract inhibited P-gp-mediated efflux in co-treatment, whereas chronic administration led to increased levels of P-gp expression, thus having a profound effect on intestinal absorption and GFJ-drug interactions in vivo.

HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants.

Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients but is associated with significant side effects such as diabetes, atherosclerosis, and cardiovascular complications. Oxidative stress can disrupt endothelial homeostasis by dysregulating the balance between pro- and antiatherogenic factors. We hypothesized that chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cell recruitment, an early event in atherosclerosis. We studied the effects of HAART drug combinations, consisting of zidovudine, a nucleoside reverse transcriptase inhibitor; efavirenz, a nonnucleoside reverse transcriptase inhibitor; and either of the two protease inhibitors (PIs), indinavir or nelfinavir, on human aortic endothelial cells (HAECs) by monitoring the following parameters: (1) generation of reactive oxygen species (ROS), (2) mono-nuclear cell (Jurkat or U-937) adhesion, and (3) expression of cell adhesion molecules (CAMs). HAART exposure increased ROS formation in HAECs. Exposure to PIs alone and in HAART combinations increased mononuclear cell adhesion to HAECs in a concentration-dependent manner. Mononuclear cell adhesion to HAART-exposed HAECs was significantly enhanced following acute (24-h) exposure to the inflammatory cytokines, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and was suppressed by the antioxidants N-ace-tylcysteine and glutathione. Exposure to HAART increased intercellular adhesion molecule-1 (ICAM-1) gene expression and concomitant exposure to TNF-alpha further increased ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule cell surface protein levels. These studies indicate that chronic HAART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, which may eventually precipitate the cardiovascular diseases observed in HIV-1+ individuals on antiretroviral therapy.

In vitro and in vivo prevention of HIV protease inhibitor-induced insulin resistance by a novel small molecule insulin receptor activator.

Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non-peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin-stimulated GLUT4 at the plasma membrane, and enhanced insulin-stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.

Virological and immunological outcomes in HIV-1-infected Chinese patients treated with a combination of Efavirenz and Indinavir for 48 weeks.

BACKGROUND: The incidence of HIV-1-related infection diseases and the mortality of AIDS have dramatically decreased since highly active antiretroviral therapy began to be used clinically in China in 1999. And we initiated a second clinical trial using a combination of Efavirenz and Indinavir to observe the effects of the immunoreaction. METHODS: Twenty patients with laboratory-confirmed chronic HIV-1 infection were recruited. Blood samples were collected initially and during the weeks after initiation of treatment. Within 48 hours of blood sampling, peripheral blood plasma and mononuclear cells were separated using routine methods. HIV-1 viral load was measured in thawed plasma samples. Within 48 hours of peripheral blood sampling, CD4(+) and CD8(+) T cell subsets were enumerated. RESULTS: The drug regimen was efficient in reducing HIV-1 plasma viral load and increasing total CD4(+) T cell counts. The percentage of CD4(+) and CD8(+) T cell subsets expressing CD38 and HLA-DR activation markers was positively correlated with plasma viral load and tended to normalize. CONCLUSIONS: The combination of Efavirenz and Indinavir was generally well tolerated and efficient at reducing HIV-1 RNA. Furthermore, the treatment improved the immunological function.

Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir.

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in HIV-infected adults failing a protease inhibitor regimen.

There is no standard treatment of HIV-infected patients who fail protease inhibitor (PI)-containing antiretroviral therapy. This open-label, noncomparative 24-week study with a 24-week extension evaluated the efficacy, safety, and tolerability of twice-daily indinavir/ritonavir 800/200 mg plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) in this population. Presented here are the results of the 24-week study. Patients were HIV-infected adults who had prior viral RNA (vRNA) suppression (<400 copies/mL), subsequent failure (> or =400 and < or =100,000 copies/mL) on antiretroviral therapy, and at least one new NRTI available for treatment. The proportions of patients achieving plasma vRNA <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat (ITT) models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Mean changes from baseline in vRNA and CD4 cell count were evaluated using DAO and an ITT mixed-model approach. Sixty-three patients (87% male) with a mean age of 42 years and mean baseline vRNA and CD4 cell counts of 3.8 log(10) copies/mL and 360 cells/mm(3), respectively, were enrolled. The proportion (95% confidence interval) of patients achieving vRNA <400 and <50 copies/mL at week 24 were 76% (61%, 87%) and 50% (35%, 65%) for DAO, 64% (50%, 75%) and 43% (30%, 56%) for GEE, and 56% (43%, 68%) and 37% (25%, 50%) for NC = F, respectively. At Week 24, baseline vRNA decreased by >1.0 log(10) copies/mL and CD4 cell counts increased by approximately 90 cells/mm(3). Three patients (5%) experienced serious drug-related adverse events. Seven patients (11%) discontinued treatment due to clinical or laboratory adverse events. In this study, the enhanced, twice-daily regimen of indinavir/ritonavir 800/200 mg plus 2 NRTIs provided suppression of HIV in many patients who had failed a PI-containing regimen and was generally well tolerated.

Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in protease inhibitor-naive HIV-infected adults.

Low-dose ritonavir can boost plasma levels of indinavir, thereby enhancing its antiretroviral activity despite less frequent dosing. In this open-label, noncomparative, 24-week trial with a 24-week extension phase, HIV-infected protease inhibitor (PI)- and lamivudine-naive adults received indinavir/ritonavir 800 mg/100 mg plus stavudine and lamivudine every 12 hours. The proportions of patients achieving plasma HIV RNA (vRNA) <400 and <50 copies/mL were analyzed with data as observed (DAO) and intention-to-treat models using generalized estimating equations (GEE) or counting noncompleters as failures (NC = F). Eighty-nine patients (80% men) with a median age of 36 years and mean baseline vRNA levels and CD4 counts of 5.01 log(10) copies/mL and 269 cells/mm(3) were enrolled. The proportions (95% confidence interval [CI]) of patients achieving vRNA <400 copies/mL were 93% (84%, 98%), 78% (67%, 86%), and 68% (57%, 78%) at week 24 for DAO, GEE, and NC = F analyses, respectively; the corresponding results at week 48 were 95% (84%, 99%), 65% (53%, 76%), and 45% (35%, 57%). Most patients with vRNA <400 had <50 copies/mL. At week 48, baseline vRNA decreased by >2 log(10) copies/mL and CD4 counts increased by approximately 200 cells/mm(3). Five patients (6%) experienced serious drug-related adverse experiences. Twenty patients (23%) discontinued therapy due to adverse experiences. In this study, twice-daily indinavir 800 mg/ritonavir 100 mg with two nucleoside reverse transcriptase inhibitors provided potent viral suppression and immunologic reconstitution in many PI-naive patients.

Type B lactic acidosis: a rare complication of antiretroviral therapy after cardiac surgery.

This report describes a 47-year-old woman with human immunodeficiency virus (HIV) and end-stage renal disease on hemodialysis, treated with combination antiretroviral drug therapy, who developed an acute, severe type B lactic acidosis 24 hours after homograft root replacement for endocarditis. She fully recovered after HIV medication was discontinued, along with administration of riboflavin and supportive measures including hemodialysis. The timing of this complication and previous reports suggest that open heart surgery may be a risk factor for nonischemic (type B) lactic acidosis in patients taking nucleoside analogue reverse transcriptase inhibitors.

Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains.

Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.

AIDS-related primary central nervous system lymphoma: prolonged remission associated with highly active antiretroviral therapy.

A 36-year-old HIV-seropositive man developed progressive confusion and unilateral tremor of the hand. His medical history included cryptococcal meningitis and CMV colitis. CT scan revealed a single hyperdense mass with minimal peripheral enhancement at the region of the cerebral peduncle and pons, causing obstructive hydrocephalus. He was treated with ventriculo-peritoneal shunt and cranial radiotherapy. He also received treatment with highly active antiretroviral therapy (HAART). A CD4+ cell count was increased from 2 to 345 cells/mm3. He returned to normal function for about 32 months after treatment.