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PubMed1997

HIV-1 protease inhibitors. A review for clinicians.

OBJECTIVE: The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented. DATA SOURCES: A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996. STUDY SELECTION AND DATA EXTRACTION: Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care. DATA SYNTHESIS: Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs. CONCLUSIONS: The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

Anti-HIV Agents↗
PubMed1998

Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors.

Ritonavir, indinavir, and saquinavir, all human immunodeficiency virus-1 protease inhibitors with a potent antiviral effect during triple therapy, are extensively metabolized by liver cytochrome P450 3A4. As this P450 isoform is involved in the metabolism of about 50% of drugs, coadministration of protease inhibitors with other drugs may lead to serious effects due to enzyme inhibition. Among these drugs, methadone and buprenorphine, both metabolized by P450 3A4, are potential candidates to drug interactions. In this study, metabolic interactions between these protease inhibitors and methadone or buprenorphine were studied in vitro in a panel of 13 human liver microsomes. Ritonavir was the most potent competitive inhibitor with Ki about 50 and 20 nM for methadone and buprenorphine metabolisms, respectively. Indinavir and saquinavir also inhibited methadone N-demethylation (Ki about 3 and 15 microM, respectively) and buprenorphine N-dealkylation (Ki about 0.8 and 7 microM, respectively). The rank order of inhibition potency against metabolism of methadone and buprenorphine was ritonavir > indinavir > saquinavir. There is obvious potential for clinically significant drug interactions, particularly with ritonavir. In brief, caution should be advised if human immunodeficiency virus-1 protease inhibitors are coadministered with methadone and buprenorphine.

Alkylation↗
PubMed1998

[Anterior uveitis in HIV-infected patients. 3 cases in patients treated with an antiprotease].

OBJECTIVES: Uveitis is an ocular manifestation rarely observed in HIV-infected patients. We observed three cases of anterior uveitis without progressive retinitis in HIV patients receiving antiprotease treatment. CASE REPORT: The first patient developed a first episode of uveitis during ritonavir therapy. Two other episodes occurred with indinavir. The second patient developed uveitis when treated with indinavir. In the third patient, the first episode developed with indinavir and a second with a ritonavir-saquinavir combination. Uveitis was unilateral in 4 episodes. Clinical manifestations were red irritable eyes and, in 2 episodes, reduced visual acuity. The antiprotease was interrupted in 4 of the 6 episodes and clinical course was rapidly favorable. DISCUSSION: Pure anterior uveitis should suggest drug induction in HIV infected patients; rifabutin is often the cause. Infectious causes predominate in case of total uveitis associating choroid and retinal involvement. Cytomegalovirus, herpes zoster, syphilis, and toxoplasmosis have been incriminated. Antiproteases would appear to be a new cause of anterior uveitis in HIV-infected patients.

AIDS-Related Opportunistic Infections↗
PubMed1999

Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes.

Both indinavir and troleandomycin (CYP3A inhibitors) are incapable of completely inhibiting dextromethorphan metabolism to 3-methoxymorphinan in human liver microsomes. It is hypothesized that CYPs in addition to CYP3A4 and 3A5 contribute to this biotransformation. The effect of CYP-selective inhibitors on the residual 3-methoxymorphinan activity in human liver microsomes (i.e. in the presence of 30 microM indinavir, a selective CYP3A4 and 3A5 inhibitor) was measured to identify these enzymes. At this concentration, indinavir completely inhibited the formation of 3-methoxymorphinan by rCYP3A4 and rCYP3A5. In addition, the formation kinetics of 3-methoxymorphinan in rCYPs was measured. Only CYP2B6, 2C8 and 2C18 were considered likely candidates as contributors to residual 3-methoxymorphinan activity. The residual 3-methoxymorphinan activity was highly correlated with CYP2B6 activity as measured by CYP2B6 antibody (r(2)=0.90, p<0.001) and by orphenadrine (r(2)=0.97, p<0.001), but was not correlated (r(2)=0.12, p>0.05) with CYP2C8 activity. Collectively, these findings suggest that CYP2B6 is a major contributor towards residual 3-methoxymorphinan activity, while CYP2C8 and 2C18 are either minor contributors or do not contribute to this metabolic process.

Antibodies, Blocking↗
PubMed2006

Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity.

OBJECTIVE: Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common and disabling disorder, often associated with antiretroviral therapy (ART) use. We investigated the clinical features and associated pathogenic determinants of HIV-SN in a neurological cohort of HIV-infected patients, together with a novel model of HIV-SN. METHODS: HIV-infected patients with neurological disease were investigated in terms of clinical and laboratory aspects together with ART exposure focusing on symptomatic HIV-SN. Rat-derived dorsal root ganglion (DRG) cultures, transgenic for human CD4 and CCR5 treated with ARTs or HIV infected, or both, were studied with respect to quantitative neuronal injury. RESULTS: Among 221 patients assessed from 1998 to 2004, 120 had no sensory neuropathy, whereas 101 displayed HIV-SN, including 64 with distal sensory neuropathy and 37 with antiretroviral toxic neuropathy. HIV-SN patients exhibited significantly greater mean age, peak plasma viral loads, and exposure to neurotoxic dideoxynucleosides and protease inhibitors, including indinavir, saquinavir, or ritonavir. HIV-infected DRG cultures exposed to indinavir or didanosine showed significant neuronal atrophy, neurite retraction, and process loss, compared with controls. Indinavir was selectively cytotoxic to DRG macrophages compared with other ARTs. INTERPRETATION: Protease inhibitor exposure is an unrecognized risk factor for the development of HIV-SN, which may potentiate neuronal damage in HIV-infected DRGs, possibly through the loss of macrophage-derived trophic factors.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Rapid quantification of HIV protease inhibitors in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

HIV protease inhibitors are important antiretroviral drugs which have substantially reduced the morbidity and mortality associated with HIV-1 infection. Recent data have shown relationships between plasma concentrations of the protease inhibitors and clinical response, which makes therapeutic drug monitoring valuable. We have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of the six licensed protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and the pharmacologically active nelfinavir metabolite M8 in plasma. The sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using only 100 microl of plasma. Chromatographic separation was performed on an Inertsil ODS3 column (50 x 2.0 mm i.d., particle size 5 microm), with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.5 ml min(-1). The analytical run time was 5.5 min. The use of a 96-well plate autosampler allowed batch sizes up to 150 patient samples. The triple-quadrupole mass spectrometer was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 0.01-10 microg ml(-1) for indinavir and saquinavir, 0.1-10 microg ml(-1) for amprenavir, 0.05-10 microg ml(-1) for nelfinavir and ritonavir, 0.1-20 microg ml(-1) for lopinavir and 0.01-5 microg ml(-1) for M8. Saquinavir-d(5) and indinavir-d(6) were used as internal standards. The coefficients of variation were always <10% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (+/-15%). The validated concentration ranges proved to be adequate in daily practice. This robust and fast LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring and pharmacokinetic studies in our hospital.

Chromatography, High Pressure Liquid↗
PubMed2005

Lymphoid tissue targeting of anti-HIV drugs using liposomes.

Considering that HIV-1 accumulates and replicates actively within lymphoid tissues, any strategy that will decrease viral stores in these tissues might be beneficial to the infected host. Follicular dendritic cells (FDC), B lymphocytes, antigen-presenting cells like macrophages, and activated CD4(+) T cells are abundant in lymphoid tissues, and all express substantial levels of the HLA-DR determinant of the major histocompatibility complex class II (MHC-II). Monocyte-derived macrophages, which are also CD4(+) and express HLA-DR, are considered to be the most frequent hosts of HIV-1 in tissues of infected individuals. This chapter describes a method for the generation of sterically stabilized immunoliposomes grafted with anti-HLA-DR antibodies that allows efficient delivery of drugs to lymphoid tissues. The method first involves the production of murine HLA-DR (clone Y-17, IgG(2b)) and human HLA-DR (clone 2.06, IgG(1)) antibodies from hybridomas in mice and their purification from ascites fluids. This step is followed by the production of Fab' fragments of antibodies 2.06 and Y-17 that are grafted at the surface of sterically stabilized immunoliposomes instead of the complete IgG to reduce their immunogenicity. The preparation of sterically stabilized liposomes, the composition of which allows an efficient entrapment and retention of several drugs, by the method of thin lipid film hydratation followed by extrusion through polycarbonate membranes is then described. This step is followed by the removal of unencapsulated drug, when present, by low-speed centrifugation of the liposomal preparation through a Sephadex G-50 column. These liposomes contain a fixed amount of poly(ethylene glycol) chain terminated by a maleimide reactive group for the coupling of Fab' fragments. The procedure for the coupling of Fab' fragments at the surface of sterically stabilized liposomes and the removal of uncoupled fragments of antibodies is described. In vitro binding studies of sterically stabilized immunoliposomes to cell lines expressing different surface levels of the mouse or human HLA-DR determinant of MHC-II demonstrate that these liposomes are very specific. When compared with conventional liposomes, the subcutaneous administration in the upper back, below the neck, of mice of anti-HLA-DR immunoliposomes resulted in a 2.9 and 1.6 times greater accumulation in the cervical and brachial lymph nodes, respectively. The use of sterically stabilized immunoliposomes increases 2 to 4.6 times the concentration of liposomes in all tissues, with a peak accumulation at 240 h in brachial, inguinal, and popliteal lymph nodes and at 360 h or greater in cervical lymph nodes. A single bolus injection of indinavir given subcutaneously to mice results in no significant drug levels in lymphoid organs. Most of the injected drug accumulates in the liver and is totally cleared within 24 h postadministration. In contrast, sterically stabilized immunoliposomes are very efficient in delivering high concentrations of indinavir to lymphoid tissues for at least 15 days postinjection. The drug accumulation in all tissues leads to a 21- to 126-fold increased accumulation when compared with the free agent. Anti-HLA-DR immunoliposomes containing indinavir are as efficient as the free agent in inhibiting HIV-1 replication in PM1 cells that express high levels of cell surface HLA-DR. Sterically stabilized anti-HLA-DR immunoliposomes mostly accumulate in the cortex in which follicles (B cells and FDCs) are located, and in parafollicular areas in which T cells, interdigitating dendritic cells, and other accessory cells are abundant. The delivery of drugs in this area of the lymph nodes could represent a convenient strategy to inhibit more efficiently HIV-1 replication. Although the method described in this chapter is specific to the coupling of anti-HLA-DR antibodies, any antibody fragment or peptide specific for an antigen present in relatively large quantities at the surface of lymphoid cells, that is anchored to the surface of sterically stabilized liposomes with an appropriate coupling method, can be used to concentrate drugs within target tissues and improve the therapeutic effect of drugs.

Animals↗
PubMed1997

Human immunodeficiency virus protease inhibitors. From drug design to clinical studies.

The discovery of human immunodeficiency virus (HIV) protease inhibitors is an example in which pharmacokinetic evaluation was implemented early in the discovery phase to obtain optimal pharmacological and pharmacokinetic properties. Currently, three HIV protease inhibitors, saquinavir, indinavir and ritonavir are clinically available. As a family, these HIV protease inhibitors are characterized pharmacologically by their ability to inhibit the viral protease enzyme. Pharmacokinetically, they are quite different due to their dissimilarity in physicochemical properties. Bioavailability appears to be limited with saquinavir, but not with indinavir and ritonavir. Although all three drugs are metabolized extensively by cytochrome P-450, saquinavir and indinavir are high clearance drugs while ritonavir is a low clearance drug. Despite their significant differences in elimination clearance, all three HIV proteases are given at high oral doses (600-800 mg) either twice or three times daily. These HIV protease inhibitors show superior therapeutic activity and a more favorable safety profile than those reported for the established reverse transcriptase inhibitors. However, the potential for interactions with other drugs metabolized by the CYP 3A4 isoform appears to be considerable. In addition, repeated administration of enzyme inducers results in a substantial decrease of plasma concentrations of protease inhibitors. Therefore, co-administration of drugs, such as rifampicin and rifabutin, must be avoided. HIV protease inhibitors are promising in the treatment of AIDS. Although they are not a cure, they can significantly inhibit that viral replication and improve the quality of life for people who have HIV infection.

Journal Article↗
PubMed2003

HIV protease inhibitors as new treatment options for Kaposi's sarcoma.

A reduced incidence and regression of Kaposi's sarcoma (KS) and other tumours has been reported in Acquired Immune Deficiency Syndrome (AIDS) patients treated with antiretroviral combination therapies containing Human Immunodeficiency Virus (HIV) protease inhibitors (PIs) such as indinavir or saquinavir. Indeed, evidence indicates that although PIs were designed to selectively inhibit the HIV protease activity, they can interfere with several cellular pathways and can inhibit tumour growth. In particular, our recent results indicate that doses of indinavir or saquinavir similar to those employed to treat AIDS patients can induce regression of experimental KS by directly blocking two fundamental steps of KS initiation and progression: new blood vessel formation (angiogenesis) and KS tumour cell invasion. This is because indinavir or saquinavir inhibit the activation of matrix metalloproteinase-2 (MMP-2), a basement membrane-degrading enzyme, which is required for the progression of most tumours. Based on these results, a multicentre clinical trial is now starting in Italy, which will assess PI effects on the progression of KS in HIV-uninfected individuals (classical KS).

Animals↗
PubMedDate not supplied

Synthesis and in vitro biological evaluation of mannose-containing prodrugs derived from clinically used HIV-protease inhibitors with improved transepithelial transport.

In an approach to improve the pharmacological properties, safety and pharmacokinetic profiles, and their penetration into HIV reservoirs or sanctuaries, and consequently, the therapeutic potential of the current protease inhibitors (PIs) used in clinics, we investigated the synthesis of various mannose-substituted saquinavir, nelfinavir, and indinavir prodrugs, their in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity, and permeation through a monolayer of Caco-2 cells used as a model of the intestinal barrier. Mannose-derived conjugates were prepared in two steps, in good yields, by condensing an acid derivative of a protected mannose with the PIs, followed by deprotection of the sugar protecting group. With respect to hydrolysis, these PI prodrugs are chemically stable with half-life times in the 50-60 h range that are compatible with an in vivo utilization aimed at improving the absorption/penetration or accumulation of the prodrug in specific cells/tissues and liberation of the active free drug inside HIV-infected cells. These stabilities correlate closely with the low in vitro anti-HIV activity measured for those prodrugs wherein the coupling of mannose to the PIs was performed through the peptidomimetic PI's hydroxyl. Importantly, mannose conjugation to the PIs was further found to improve the absorptive transepithelial transport of saquinavir and indinavir but not of nelfinavir across Caco-2 cell monolayers, by contrast to glucose conjugation which had the opposite effect. The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability, penetration into the HIV infected macrophages, and HIV-reservoirs of these PIs are improved.

Caco-2 Cells↗
PubMed1998

Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions.

Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The Ki value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 microM. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.

Anti-HIV Agents↗
PubMed2001

"In vitro" antifungal activity of protease inhibitors.

In the last five years, as HAART has become standard therapy in HIV seropositive or AIDS patients, changes have been noted in the numbers and types of opportunistic fungal infections in these cohorts of patients. Particularly, oropharyngeal candidiasis have become rare in HIV infected patients since the introduction of new anti-HIV drugs of the protease inhibitors type. At the Immunology Institute of the Universidad Central de Venezuela the most frequent protease inhibitors (PIs) used for the treatment of these patients have been: Nelfinavir (Viracept, Roche), Indinavir (Crixivan Merck), Ritonavir (Norvir, Abbott), Saquinavir (Fortovase, Roche). Recently, we observed that recurrent candidiasis was less frequent and no Candida could be isolated in our patients. A direct relation to the PIs was suspected. In order to assess the "in vitro" antifungal activity of the afore mentioned protease inhibitors on Candida sp., we used both the well diffusion test and the NCCLS broth microdilution test to assay 100 Candida sp. isolates from HIV seropositive or AIDS patients with syntomatic oropharyngeal Candida infection. In general, the data obtained with the well diffusion test were in agreement with those obtained by the broth microdilution test. All 100 isolates were susceptible to Saquinavir and 32 were susceptible to Indinavir using the NCCLS microdilution test, while 97 were susceptible to Saquinavir and 52 to Indinavir by the well diffusion test. From 17 C. albicans resistant to fluconazole, all were susceptible to Saquinavir by the NCCLS micromethod and 16 by the well diffusion test. Our results showed anticandidal activity "in vitro" of PIs, mainly Saquinavir.

AIDS-Related Opportunistic Infections↗
PubMed2002

The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients.

Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants.

Adult↗
PubMed2003

Effect of protease inhibitor-containing regimens on lymphocyte multidrug resistance transporter expression.

BACKGROUND: Increased expression of multidrug resistance transporters, such as P-glycoprotein (P-gp), has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites and tissue compartments. OBJECTIVES: To investigate the effect of PIs on the surface lymphocyte expression of P-gp in vitro and in vivo. PATIENTS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy subjects (n = 15) and incubated (72 h) with 10 microM of each PI studied (saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir), or dimethyl sulphoxide (DMSO) control. PBMCs were also isolated from HIV-infected subjects (n = 50; viral load <50 copies/mL) on a PI- or a non-PI-containing combination antiretroviral regimen. P-gp expression was analysed by flow cytometry. RESULTS: No differences in surface P-gp expression on lymphocytes, CD4+ or CD8+ lymphocyte subsets were observed following incubation with 10 microM saquinavir, ritonavir, indinavir, amprenavir or lopinavir in vitro. Nelfinavir, however, increased P-gp expression. In vivo, no difference in P-gp expression on total lymphocytes was observed between patients receiving a PI-containing regimen [saquinavir n = 9, ritonavir n = 6, nelfinavir n = 7, indinavir n = 7 and lopinavir/ritonavir n = 13, and two nucleoside reverse transcriptase inhibitors (NRTIs)] and patients receiving a control regimen of three NRTIs alone (n = 8). CONCLUSION: This study suggests that, of the PIs, only nelfinavir increases P-gp expression in vitro, and in vivo the PI class of antiretrovirals do not increase P-gp expression on lymphocytes. It is clear that factors other than PI induction are important in the inter-individual variability in the lymphocyte expression of P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Considerations in the choice of protease inhibitor-sparing regimens in initial therapy for HIV-1 infection.

The current standard of care for initial antiretroviral therapy is a combination of 2 nucleoside analogues with a third agent, a protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor or a third nucleoside analogue. Recent data heralding the arrival of potent PI-sparing regimens for initial anti-retroviral therapy and concerns regarding PI-related metabolic disturbances have led to significant shifts in treatment practices. Protease inhibitor-sparing regimens with optimal antiviral activity may have several advantages over PI-based therapy for initial or prolonged therapy. These advantages include more convenient, non-food dependent dosing regimens, lower tablet volume, fewer drug interactions, central nervous system penetration and the maintenance of PIs as an option for second line therapy. However, no data currently exist directly comparing triple therapy regimens based on the three leading PI-sparing agents, efavirenz, nevirapine or abacavir. All these agents have been compared in randomized controlled studies in treatment naïve patients to triple therapy with the PI indinavir. In these studies, similar responses to indinavir were observed with nevirapine or abacavir regimens, whereas superiority was observed with efavirenz. Limited data in high viral load patients treated with nevirapine based regimens currently exist. However, the superiority of efavirenz over indinavir based regimens was also observed in comparative data in this patient subset. PI-sparing approaches appear generally well tolerated with few individuals discontinuing in clinical studies due to adverse drug events. The majority of adverse events with efavirenz and nevirapine occur within the first month, are predictable and are manageable without therapy interruption. Similarly, apart from a rare (3%) hypersensitivity reaction, which requires therapy cessation without rechallenge, adverse effects with abacavir are uncommon.

Journal Article↗
PubMed2000

Epidemiology of thrombosis in HIV-infected individuals. The Adult/Adolescent Spectrum of HIV Disease Project.

OBJECTIVE: To describe the incidence of clinically recognized thrombosis and associated factors among individuals infected with HIV. DESIGN: A longitudinal medical record review. SETTING: Over 100 medical clinics in nine US cities. PATIENTS: A total of 42 935 individuals aged 13 years or older with HIV infection, observed for an average of 2.4 years. MAIN OUTCOME MEASURES: The incidence of thrombosis among HIV-infected individuals; adjusted odds ratios for factors associated with thrombosis. RESULTS: The incidence of thrombosis among HIV-infected individuals was 2.6/1000 person-years (PY). Factors significantly associated with thrombosis included: age of 45 or more years (adjusted odds ratio [AOR], 1.9; 95% confidence interval [CI], 1.4-2.7); a diagnosis of cytomegalovirus disease or retinitis (AOR, 1.9; CI, 1.2-2.9), or other AIDS-defining opportunistic illness (AOR, 1.5; CI, 1.1-2.2); hospitalization (AOR, 3.3; CI, 2.5-4.4); and the prescription of megestrol acetate (AOR, 2.0; CI 1.3-2.9) or indinavir (AOR, 2.4; CI 1.4-4.3). The prescription of other protease inhibitors, sex, race, and mode of HIV exposure were not associated with thrombosis. CONCLUSION: Among HIV-infected individuals, clinically detected thrombosis is more common in those who have opportunistic illnesses, for whom megestrol acetate or indinavir have been prescribed, who have been hospitalized, and who are aged 45 years or older. Physicians should be aware of the risks of thrombosis in order to promote the early identification and appropriate treatment or prophylaxis. Further study is needed to characterize the association between indinavir and thrombosis.

Adolescent↗
PubMed2001

Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile.

BACKGROUND: Protease inhibitor-containing antiretroviral therapy for the treatment of HIV-1 infection is associated with elevated triglyceride and low-density lipoprotein (LDL)-cholesterol levels which may expose patients to an increased risk of coronary artery disease (CAD). We report the lipid and lipoprotein profiles of a representative subset of treatment-naive patients included in the Atlantic Study. This study compares patients treated with stavudine and didanosine plus the random addition of either the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), the protease inhibitor indinavir or the nucleoside reverse transcriptase inhibitor lamivudine. METHODS: Lipids and lipoproteins were quantified from prospectively collected and cryopreserved plasma samples obtained at weeks 0, 6 and 24. RESULTS: We observed a striking increase in high-density lipoprotein (HDL)-cholesterol (49%), apolipoprotein AI (19%), lipoprotein AI (38%) and HDL particle size (3%) in the NVP-treated patients (n = 34) at week 24. Much less pronounced changes in these parameters were seen to a similar extent both in patients receiving lamivudine (n = 39) and indinavir (n = 41). LDL-cholesterol also increased significantly both in the NVP and indinavir arms, but only in the NVP arm was this offset by a significant reduction (14%) in total over HDL-cholesterol ratio. Using a multivariate linear regression model, adjusting for CD4 cell count and plasma HIV RNA both at baseline and during treatment, randomization to the NVP-containing arm remained significant in explaining the observed changes in HDL-cholesterol and other HDL-related parameters. CONCLUSIONS: In HIV-1 infected patients treated with a regimen of stavudine, didanosine and NVP we found changes in lipids and lipoproteins which are associated with a sharp decrease in risk for CAD in other settings. If confirmed in larger studies, these findings both may influence the initial choice of therapy for HIV-1 infection, and might lead to novel approaches targeted at raising HDL-cholesterol for CAD prevention.

Adult↗
PubMed2002

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.

3T3 Cells↗