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PubMed2003

Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals.

OBJECTIVES: Nucleoside analog reverse transcriptase inhibitors (NRTI) are used in virtually all anti-HIV regimens. Clinical response depends on the intracellular formation of the pharmacologically active triphosphate moiety. Our objective was to quantify the pharmacological characteristics of zidovudine and lamivudine triphosphate in HIV-infected individuals. METHODS: Peripheral blood mononuclear cells were obtained at multiple planned intervals from antiretroviral-naive adults participating in a study of zidovudine, lamivudine and indinavir, and triphosphate levels were determined by immunoassay and high-performance liquid chromatography/mass spectrometry. Plasma HIV-RNA, CD4 cell counts, and plasma drug concentrations were collected over 18 months. Data were analysed using non-parametric, regression and time-to-event methods. RESULTS: Thirty-three subjects were evaluated. The estimated half-lives of zidovudine and lamivudine triphosphate were 7 and 22 h, respectively. Triphosphate concentrations were elevated in individuals with low baseline CD4 cell counts. Triphosphate concentrations in women were higher than in men by 2.3 and 1.6-fold for zidovudine and lamivudine, respectively. Women reached an HIV-RNA level under 50 copies/ml twice as fast as men. Zidovudine triphosphate above 30 fmol/10(6) cells was independently predictive of the time to under 50 copies/ml. Lamivudine triphosphate above 7017 fmol/10(6) cells was independently predictive of a longer virological response. Indinavir concentrations were related to antiviral responses in univariate analyses. CONCLUSION: Zidovudine and lamivudine triphosphate concentration thresholds were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The significantly elevated triphosphate concentrations in women and individuals with low baseline CD4 cell counts, groups that historically experience high rates of serious NRTI toxicities, provide a hypothesis for the pathogenesis of these events.

Adult↗
PubMed2003

Clinical, immunological and virological response to different antiretroviral regimens in a cohort of HIV-2-infected patients.

OBJECTIVE: To assess the clinical, immunological and virological response and the emergence of resistance towards antiretroviral therapy (ART) in a cohort of HIV-2-infected patients. DESIGN: Observational study. PATIENTS: HIV-2-infected patients residing in the Netherlands. RESULTS: From 1995 to 2001 seven patients failed various ART regimens. The resistance mutations were analysed retrospectively. Development of mutations proved to be similar to that observed in HIV-1-infected patients, with the exception of a higher occurrence of the Q151M mutation within the reverse transcriptase gene. In a prospective study, comprising 13 consecutive naive HIV-2-infected patients, all patients achieved plasma HIV-2-RNA suppression below the detection limit (500 copies/ml). The antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and indinavir, with a boosting dose of ritonavir; the median follow-up was 91 weeks. Two patients experienced a temporary virological rebound, while at the same time therapeutic drug monitoring showed sub-therapeutic plasma levels of indinavir. CONCLUSION: Sustained viral suppression in HIV-2-infected patients can be achieved using an antiretroviral regimen of two NRTIs and boosted indinavir or lopinavir.

Adult↗
PubMed2001

Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection.

Published data suggest that therapeutic drug monitoring of human immunodeficiency virus protease inhibitors would improve the management of antiretroviral therapy. The authors have developed a high-pressure liquid chromatographic assay allowing simultaneous determination of six protease inhibitors (ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, and lopinavir), using carbamazepine as internal standard. Detection was based on a dual wavelength ultraviolet spectrophotometer and can be improved by the use of a photodiode array detector. Monitoring was performed 1 month after initiation of therapy or in instances of therapeutic failure, side effects, suspicion of noncompliance, drug interactions, or malabsorption. Trough concentrations were 0.15 to 13.6 mg/L for ritonavir, 0.06 to 9.7 mg/L for indinavir, 0.03 to 5.5 mg/L for saquinavir, and 0.15 to 4.15 mg/L for nelfinavir. Concentrations below the limit of quantification were observed in 63/438 (14%) of the patients. Target concentrations are not well established, and reported in vitro inhibitory concentrations may be of limited value. The authors therefore chose to compare observed concentrations with mean plasma concentrations reported in clinical trials. Observed saquinavir and indinavir concentrations were often below or close to these target concentrations, particularly when used as a single protease inhibitor. Concentration-controlled studies should now be used to select proper target concentrations for each protease inhibitor, either prescribed alone or in combination.

Area Under Curve↗
PubMed2004

Automated, fast, and sensitive quantification of drugs in human plasma by LC/LC-MS: quantification of 6 protease inhibitors and 3 nonnucleoside transcriptase inhibitors.

An analytic assay based on automated sample preparation and liquid chromatography (LC) coupled with electrospray mass spectrometry (ESI-MS) was developed for the quantification of 6 protease inhibitors (PIs) and 3 nonnucleoside reverse transcriptase inhibitors (NNRTIs). The 6 PIs, amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, and saquinavir, as well as the three NNRTIs, nevirapine, efavirenz, and delavirdine, require a succinct analysis technique for therapeutic drug monitoring in HIV/AIDS patients. After protein precipitation, samples were loaded on a C8, 10 x 4-mm extraction column, washed, and, after activation of the column-switching valve, backflushed onto the 30 x 2.1 mm C8 analytic column. [M+H] ions were detected in the selected ion mode. A nonlinear fit (y(-1) = a + b/x, all r2 > 0.999) for amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, and saquinavir and a linear fit (y = ax + b, all r2 > 0.999) for nevirapine, efavirenz, and delavirdine led to best regression. Absolute recoveries were as follows: PIs > 81%; NNRTIs > 76%. Interday and intraday precision were <12.5% for the PIs and <11.7% for the NNRTIs. Interday and intraday accuracy were <12.2% for the PIs and <14.9% for the NNRTIs. Limits of quantification were 20, 40, 50, 40, 40, 20, and 100 microg/L for amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, saquinavir, and the NNRTIs, respectively. The assay allows fast analysis of patient samples for therapeutic drug monitoring (TDM) and has successfully been used for TDM and pharmacokinetic drug-drug interactions studies.

Anti-HIV Agents↗
PubMed2004

Mechanism-based inactivation of CYP3A by HIV protease inhibitors.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are inhibitors of CYP3A enzymes, but the mechanism is poorly defined. In this study, time- and concentration-dependent decreases in activity as defined by maximum rate of inactivation (k(inact)) and inhibitor concentration that gives 50% maximal inactivation (K(I)) of CYP3A by amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir were quantified using testosterone 6beta-hydroxylation as a marker for CYP3A activity with recombinant CYP3A4(+b(5)), recombinant CYP3A5, and pooled human liver microsomes (HLMs). All the PIs, except indinavir, displayed inactivation with CYP3A4(+b(5)) and HLMs. Ritonavir was the most potent (K(I) = 0.10 and 0.17 microM) and demonstrated high k(inact) values (0.32 and 0.40 min(-1)) with both CYP3A4(+b(5)) and HLMs. Ritonavir was not significantly depleted by high-affinity binding with CYP3A4(+b(5)) and confirmed that estimation of reversible inhibition was confounded with irreversible inhibition. For CYP3A5, nelfinavir exhibited the highest k(inact) (0.47 min(-1)), but ritonavir was the most potent (K(I) = 0.12 microM). Saquinavir and indinavir did not show time- and concentration-dependent decreases in activity with CYP3A5. Spectrophototmetrically determined metabolic intermediate complex formation was observed for all of the PIs with CYP3A4(+b(5)), except for lopinavir and saquinavir. The addition of nucleophilic and free aldehyde trapping agents and free iron and reactive oxygen species scavengers did not prevent inactivation of CYP3A4(+b(5)) by ritonavir, amprenavir, or nelfinavir, but glutathione decreased the inactivation by saquinavir (17%) and catalase decreased the inactivation by lopinavir (39%). In conclusion, all the PIs exhibited mechanism-based inactivation, and predictions of the extent and time course of drug interactions with PIs could be underestimated if based solely on reversible inhibition.

Aldehydes↗
PubMed2003

Kinetics of lymphocyte proliferation during primary immune response in macaques infected with pathogenic simian immunodeficiency virus SIVmac251: preliminary report of the effect of early antiviral therapy.

The aim of this study was to evaluate the kinetics of lymphocyte proliferation during primary infection of macaques with pathogenic simian immunodeficiency virus (SIV) and to study the impact of short-term postexposure highly active antiretroviral therapy (HAART) prophylaxis. Twelve macaques were infected by intravenous route with SIVmac251 and given treatment for 28 days starting 4 h postexposure. Group 1 received a placebo, and groups 2 and 3 received combinations of zidovudine (AZT), lamivudine (3TC), and indinavir. Macaques in group 2 received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route whereas macaques in group 3 were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs, and a higher dose of indinavir (60 mg/kg). The kinetics of lymphocyte proliferation were analyzed by monitoring 5-bromo-2'-deoxyuridine (BrdU) uptake ex vivo and by fluorescence-activated cell sorting analysis. HAART did not protect against SIV infection but did strongly impact on virus loads: viremia was delayed and lowered during antiviral therapy in group 2, with better control after treatment was stopped, and in group 3, viremia was maintained at lower levels during treatment, with virus even undetectable in the blood of some macaques, but there was no evidence of improved control of the virus after treatment. We provide direct evidence that dividing NK cells are detected earlier than dividing T cells in the blood (mostly in CD45RA(-) T cells), mirroring plasma viremia. Dividing CD8(+) T cells were detected earlier than dividing CD4(+) T cells, and the highest percentages of proliferating T cells coincided with the first evidence of partial control of peak viremia and with an increase in the percentage of circulating gamma interferon-positive CD8(+) T cells. The level of cell proliferation in the blood during SIV primary infection was clearly associated with viral replication levels because the inhibition of viral replication by postexposure HAART strongly reduced lymphocyte proliferation. The results and conclusions in this study are based on experiments in a small numbers of animals and are thus preliminary.

Animals↗
PubMed1999

Rifapentine: its role in the treatment of tuberculosis.

OBJECTIVE: To review the pharmacokinetics, efficacy, adverse effects, and cost of the newest antitubercular drug, rifapentine. DATA SOURCES: A MEDLINE search using key terms such as rifapentine, rifampin, isoniazid, Mycobacterium tuberculosis, and pyrazinamide was conducted for the time period 1966-November 1998. STUDY SELECTION: Animal data were used for basic information and human studies were selected for inclusion if they were randomized, controlled studies assessing efficacy, or if they were single- or multiple-dose studies assessing the pharmacokinetics of rifapentine. Background articles on the pathophysiology of tuberculosis and cost of care and noncontrolled studies assessing drug interactions were also included. DATA SYNTHESIS: Compared with an oral solution, the relative bioavailability of rifapentine is 70% following oral admninistration of tablets. Food increased bioavailability by 55%. Rifapentine accumulated significantly in human macrophages and its elimination half-life was longer than that of rifampin. Comparative studies of rifapentine and rifampin in humans during intensive- and continuation-phase treatment of tuberculosis suggest that at currently accepted doses, rifapentine was slightly less effective than rifampin. The most significant drug interaction with rifapentine involves indinavir: the maximum concentration and AUC of indinavir are reduced by 55% and 70%, respectively, when rifapentine is coadministered with indinavir. Adverse events of rifapentine may occur less frequently at the currently recommended 600-mg dose as compared with rifampin; however, the difference was not statistically significant. If only drug costs were evaluated during the six-month treatment of tuberculosis, rifapentine is more expensive than rifampin. CONCLUSIONS: Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. This may improve patient adherence over some other treatments and possibly reduce costs of treatment by preventing development of resistant tubercular strains due to nonadherence. Rifapentine is well tolerated, with most patients experiencing adverse effects at a similar rate as rifampin. Rifapentine induces cytochrome P450 somewhat less than rifampin, although few drug interaction studies have been done with rifapentine. Its efficacy at the currently approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy can be achieved with higher doses of rifapentine. Rifampin is less expensive than rifapentine. Further pharmacoeconomic studies are needed to evaluate costs of relapse and failure in patients receiving these agents.

Abnormalities, Drug-Induced↗
PubMed1998

Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents.

Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha 1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600 mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h. In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent and sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.

Animals↗
PubMed1996

Current knowledge and future prospects for the use of HIV protease inhibitors.

The HIV protease (or proteinase) enzyme is an essential component of the replicative cycle of HIV, performing the post-transitional processing of the gag and gag-pol gene products into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to production of immature noninfectious viral progeny, and hence prevention of further rounds of infection. Structurally, the enzyme is a homodimer consisting of two identical 99 amino acid chains. HIV protease is a member of the aspartic protease family but is structurally dissimilar to human aspartic proteases such as renin, gastricsin and cathepsin D and E, suggesting the possibility of creating inhibitors with a wide therapeutic index. At least 6 inhibitors of HIV protease are currently in clinical development: saquinavir, indinavir, ritonavir, nelfinavir (AG-1343), KNI-272 and VX-478, the first four of which have shown antiretroviral activity and acceptable tolerability in initial phase I/II clinical trials. Resistance or reduced sensitivity to the leading protease inhibitors has been reported in vivo and appears to be associated with loss of therapeutic effect. However, resistance patterns appear to be distinct. Treatment for 1 year with indinavir has been reported to lead to selection of virus in 4 patients, which was cross-resistant to all other leading protease inhibitors. On the other hand, a larger series of clinical isolates from patients receiving saquinavir alone or in combination with zidovudine for up to 3 years did not lead to virus cross-resistant to either indinavir or ritonavir. This suggests that care should be exercised in designing the sequence of protease usage. Additionally, differing resistance patterns may be used to select combinations of protease inhibitors in future trials. Data from studies combining protease inhibitors with nucleoside analogues suggest value in terms of larger and more prolonged virological and immunological marker responses than are observed with single agent therapy, and this is likely to be the primary role for protease inhibitors; both in initial combinations for patients commencing therapy and as add-in therapies for patients previously treated with antiretrovirals. However, in vitro and animal pharmacokinetic studies also give evidence of the possibility of combining protease inhibitors, potentially leading to improved bioavailability, antiviral synergy and delay in emergence of viral resistance.

Anti-HIV Agents↗
PubMed1998

Efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.

Administration, Oral↗
PubMed1999

Didanosine: an updated review of its use in HIV infection.

UNLABELLED: Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is converted to its active moiety, dideoxyadenosine-5'-triphosphate (ddATP), which inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now well established that didanosine therapy produces beneficial effects on virological and immunological markers of HIV disease and improves clinical outcome in adults or children with HIV infection. In numerous clinical trials, pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+ cell counts occurred in previously untreated or antiretroviral therapy-experienced patients treated with didanosine in combination with at least 1 other antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in combination with didanosine. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. In double-blind, placebo-controlled trials, triple therapy with didanosine, zidovudine and nevirapine was significantly more effective than dual therapy with various combinations of these agents in improving surrogate disease markers in treatment-naive patients and in delaying disease progression or death in treatment-experienced patients with advanced disease. Improvements in virological and immunological markers were greater with didanosine-containing triple regimens than with dual therapy or monotherapy in comparative trials. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine and nevirapine. Combination therapy with didanosine plus hydroxyurea as dual therapy or with a third agent produced marked and sustained decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy with didanosine and zidovudine delays disease progression and prolongs survival in patients with intermediate or advanced HIV infection. In large, randomised, double-blind, clinical trials, dual therapy with didanosine plus zidovudine was significantly more effective than zidovudine monotherapy in preventing disease progression and prolonging survival in previously untreated or antiretroviral therapy-experienced patients with intermediate or advanced HIV infection. Pancreatitis and peripheral neuropathy are serious adverse effects of didanosine. These effects are dose-related and usually reversible after discontinuation of treatment. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported in patients receiving treatment with the drug. CONCLUSIONS: Didanosine is an effective and generally well tolerated drug in previously untreated and antiretroviral therapy-experienced patients with HIV infection. Given once or twice daily, it has an important role as a component of triple combination regimens for the treatment of patients with symptomatic or asymptomatic HIV infection.

Adult↗
PubMed2000

Saquinavir soft-gel capsule: an updated review of its use in the management of HIV infection.

UNLABELLED: Saquinavir is a potent and highly selective HIV protease inhibitor. Initially formulated as a hard-gel capsule (HGC), saquinavir was the first protease inhibitor available commercially for the treatment of patients with HIV infection. The limited oral bioavailability of saquinavir HGC has been improved significantly with the introduction of a soft-gel capsule (SGC) formulation. Saquinavir SGC displays greater than dose-proportional pharmacokinetics and mean area under the plasma concentration-time curve (AUC) values are 8- to 10-fold higher with saquinavir SGC 1200 mg 3 times daily than with the HGC formulation 600 mg 3 times daily, the recommended dosages of the 2 formulations. In combination with other protease inhibitors (particularly "low dose" ritonavir), the oral bioavailability of saquinavir (as either the HGC or SGC formulation) is markedly increased, allowing for reduced dosing frequency and/or dosage. The efficacy and tolerability of once- or twice-daily saquinavir SGC/"low dose" ritonavir combinations are currently being evaluated in patients with HIV infection. Data (up to 48 weeks) from noncomparative and comparative clinical trials evaluating saquinavir SGC-containing combination regimens in adult patients with HIV infection, support and strengthen the clinical efficacy profile of the drug that was demonstrated in initial trials. In antiretroviral therapy-naive and -experienced patients, saquinavir SGC combined with > or =2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or nelfinavir plus 2 NRTIs or nonnucleoside reverse transcriptase inhibitors (NNRTIs), markedly improved immunological and virological surrogate markers (increased mean CD4+ cell counts and decreased mean plasma HIV RNA levels) of HIV infection. Saquinavir SGC demonstrated a trend to greater antiviral efficacy (measured by improvements in surrogate markers) than the HGC formulation (not statistically significant); a significantly greater proportion of patients treated with saquinavir SGC had plasma HIV RNA levels <400 copies/ml than patients receiving the HGC formulation. In the first direct comparison of 2 protease inhibitors, saquinavir SGC plus 2 NRTIs demonstrated similar antiviral efficacy to indinavir plus 2 NRTIs in patients with HIV infection (almost all of whom were antiretroviral therapy-naive); at 24 weeks, a significantly greater increase in CD4+ cell count from baseline was obtained in the saquinavir SGC group compared with the indinavir group, although this difference was not apparent at week 32. Triple therapy with saquinavir SGC plus 2 NRTIs was as effective as nelfinavir-containing triple therapy, or quadruple therapy (saquinavir SGC plus 2 NRTIs plus nelfinavir) in markedly suppressing HIV RNA levels in antiretroviral therapy-experienced or -naive patients. Saquinavir SGC is generally well tolerated. Gastrointestinal disturbances (generally nausea, diarrhoea, abdominal pain, vomiting and dyspepsia of moderate or greater intensity) are the most common adverse events associated with saquinavir SGC-containing therapy. In comparative trials, saquinavir SGC-containing therapy was as well tolerated as indinavir- and nelfinavir-containing therapy; although there were no statistical differences between treatment groups, the incidence of diarrhoea was lower in patients receiving saquinavir SGC compared with nelfinavir, saquinavir SGC plus nelfinavir (all combined with 2 NRTIs) or saquinavir SGC plus nelfinavir without additional therapy. Compared with the HGC formulation, saquinavir SGC appears to be associated with a higher overall incidence of adverse events. CONCLUSIONS: Clinical trial data have shown that as part of triple or quadruple combination therapy, saquinavir SGC is an effective and generally well tolerated protease inhibitor in antiretroviral therapy-naive or -experienced patients with HIV infection. (ABSTRACT TRUNCATED)

Animals↗
PubMed1999

[Clinical and immuno-virologic efficacy of the expanded access use of protease inhibitors for HIV-1 advanced disease].

OBJECTIVE: To compare the efficacy and tolerance of additive therapy with protease inhibitors (PI) in patients with advanced HIV infection previously treated with retro-transcriptase inhibitors (RTI). METHODS: Eighty patients with prior antiretroviral therapy with RTI (zidovudine, ddI or ddc) for more than 6 months were included. Fifteen patients received indinavir, 42 ritonavir and 23 saquinavir. Data were collected at 4, 12 and 24 weeks and included clinical events, tolerability, plasma HIV-1 RNA viral load and CD4+ cell counts. Virologic response was defined if a viral load reduction > 1 log was achieved. RESULTS: Virological response was observed in 45 patients (56.5%) at 4 weeks and was maintained in most of them at 24 weeks. Viral load below limit of detection was achieved in 11 (15%) patients at 12 weeks. Adverse effects were not uncommon, specially with ritonavir, and 10 patients (12.5%) discontinued treatment. Indinavir was the most efficient drug and statistical differences in decreasing viral load were reached in pairwaise comparison with saquinavir at any time and with ritonavir at 12 and 24 weeks. CD4+ cell counts increased with all three drugs parallel with the decrease of viral load. Four patients died and 12 had opportunistic infections. Proportion of patients without infections in the follow-up was associated with virological response over treatment (p < 0.01). CONCLUSIONS: The additive therapy with PI in advanced HIV patients can achieve a sustained reduction of viral load and a persistent recovery of CD4+ cell counts with clinical benefits. Within the limits of this study, indinavir seems more interesting in this group of patients in terms of probability pursuit of treatment because of better efficiency and fewer adverse effects.

Adult↗
PubMed2001

Antiretroviral activity and safety of abacavir in combination with selected HIV-1 protease inhibitors in therapy-naive HIV-1-infected adults.

OBJECTIVE: To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors. DESIGN: A 48-week, open-label study. MATERIALS AND METHODS: Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count > or = 100 cells/mm3, plasma HIV-1 RNA > or = 5,000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA < or = 400 and < or = 50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities. RESULTS: At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA < or = 400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA < or = 50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups. CONCLUSIONS: Abacavir is safe and effective when used in combination with a protease inhibitor.

Administration, Oral↗
PubMed2003

Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy.

Familial partial lipodystrophy (FPL) and lipodystrophy observed in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) share multiple clinical and metabolic features. Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes. Moreover, the cellular retinoic acid binding protein (CRABP) has been suggested to be involved in HAART associated lipodystrophy. In this study, we excluded mutations within the complete coding region and the promoter of LMNA and the CRABP II gene in HIV-1 infected patients with lipodystrophy and also any correlation of the nucleotide polymorphism at codon 566 in exon 10 of LMNA with metabolic abnormalities. Protease inhibitors including indinavir have been shown to reduce adipocyte cell differentiation and increase apoptosis of adipocytes in vitro. Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP. Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter. This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART.

Amino Acid Sequence↗
PubMed2003

Intracellular disposition and metabolic effects of zidovudine, stavudine and four protease inhibitors in cultured adipocytes.

OBJECTIVE: The pathogenesis of lipodystrophy caused by the HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is unclear. We have investigated the disposition of these drugs in adipocytes and the consequent effect on adipocyte metabolism and viability. DESIGN: Laboratory study utilizing two murine cell lines, 3T3-L1 and 3T3-F442A. METHODS: Intracellular NRTI phosphate and PI concentrations were determined by HPLC and HPLC-MS/MS, respectively. The cytotoxicity of the drugs was examined on the different adipogenic stages together with their effects on glucose uptake plus or minus insulin, and on glycerol and triglyceride levels. RESULTS: There was rapid intracellular accumulation and phosphorylation of [3H]-zidovudine and -stavudine to their phosphate metabolites in adipocytes. The NRTIs were not cytotoxic, did not affect preadipocyte protein synthesis and did not inhibit adipogenesis or induce lipolysis. PIs accumulated in adipocytes (nelfinavir>saquinavir>ritonavir>indinavir). All PIs, except indinavir, were cytotoxic and inhibited adipogenesis, increased lipolysis and impaired preadipocyte protein synthesis. PIs inhibited glucose uptake in the rank order: indinavir>saquinavir>ritonavir>nelfinavir. CONCLUSION: These data demonstrate that PIs may play a role in the insulin resistance observed in lipodystrophy by affecting glucose uptake, adipogenesis and lipolysis. NRTIs alone do not seem to have any effect on adipocyte metabolism despite undergoing phosphorylation to their triphosphorylated anabolites, although their effects in combination with PIs in perturbing adipocyte metabolism warrants further investigation.

Adipocytes↗
PubMed2001

Prevalence and predictive value of intermittent viremia with combination hiv therapy.

CONTEXT: In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown. OBJECTIVE: To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL). DESIGN AND SETTING: Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995). PATIENTS: Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine. MAIN OUTCOME MEASURES: Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up. RESULTS: Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance. CONCLUSIONS: Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Anti-HIV Agents↗
PubMed2002

Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial.

CONTEXT: Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge. OBJECTIVE: To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen. DESIGN: Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks. SETTING: Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States. PARTICIPANTS: A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL. INTERVENTION: Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil. MAIN OUTCOME MEASURES: Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility. RESULTS: Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03). CONCLUSIONS: In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.

Adenine↗