Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Indinavir”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 847 records · Page 47Linked to original sources
PubMed2005

Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S.

The crystal structures, dimer stabilities, and kinetics have been analyzed for wild-type human immunodeficiency virus type 1 (HIV-1) protease (PR) and resistant mutants PR(L24I), PR(I50V), and PR(G73S) to gain insight into the molecular basis of drug resistance. The mutations lie in different structural regions. Mutation I50V alters a residue in the flexible flap that interacts with the inhibitor, L24I alters a residue adjacent to the catalytic Asp25, and G73S lies at the protein surface far from the inhibitor-binding site. PR(L24I) and PR(I50V), showed a 4% and 18% lower k(cat)/K(m), respectively, relative to PR. The relative k(cat)/K(m) of PR(G73S) varied from 14% to 400% when assayed using different substrates. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom. Each mutant revealed distinct structural changes relative to PR. The mutated residues in PR(L24I) and PR(I50V) had reduced intersubunit contacts, consistent with the increased K(d) for dimer dissociation. Relative to PR, PR(I50V) had fewer interactions of Val50 with inhibitors, in agreement with the dramatically increased K(i). The distal mutation G73S introduced new hydrogen bond interactions that can transmit changes to the substrate-binding site and alter catalytic activity. Therefore, the structural alterations observed for drug-resistant mutations were in agreement with kinetic and stability changes.

Crystallography, X-Ray↗
PubMed2000

In vitro evaluation of the effect of temporary removal of HIV drug pressure.

We tried to establish whether MT-4 cells that were infected with HIV-1(HTLV-III(B)) at a high multiplicity of infection (m.o.i.=1), and subsequently treated with high concentrations of anti-HIV drugs for several days, would be able to resume virus production after the antivirals are washed away. The HIV inhibitors studied were the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and lamivudine, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and loviride, the acyclic nucleoside phosphonate RT inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (tenofovir) and the protease inhibitors (PIs) saquinavir, indinavir and ritonavir. The compounds, at 50 and 500 times their 50% inhibitory concentration (IC(50), determined at a m.o.i.=0.01), were added immediately after virus adsorption and removed after an incubation period of 0 (wash control), 24, 48 or 72 h. Virus breakthrough was monitored by microscopical examination of cytopathicity, viral infectivity (yield) and p24 levels in the supernatant. The presence of HIV-1(HTLV-III(B)) proviral DNA was determined after a 72-h incubation period. None of the antiviral drugs studied was able to prevent resumption of viral growth after removal of the compound. Tenofovir, lamivudine and the NNRTIs nevirapine, delavirdine and loviride, at 500 times their respective IC(50), were able to delay viral breakthrough for approximately 2-3 days. The NRTI zidovudine and the PIs saquinavir, indinavir and ritonavir, under the same conditions, were not able to delay viral breakthrough at all. Virus recovered upon treatment proved as sensitive to the anti-HIV drugs as wild-type virus. Our results suggest that viral replication at the cellular level was not completely inhibited by drug monotherapy. Consequently, virus rebounded when drug therapy stopped. In conclusion, our findings suggest that drug holidays would result in viral breakthrough, even after virus replication has been previously suppressed by adequate drug levels.

Anti-HIV Agents↗
PubMed2003

Elucidation of HIV-1 protease resistance by characterization of interaction kinetics between inhibitors and enzyme variants.

The kinetics of the interaction between drug-resistant variants of HIV-1 protease (G48V, V82A, L90M, I84V/L90M, and G48V/V82A/I84V/L90M) and clinically used inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) were determined using biosensor technology. The enzyme variants were immobilized on a biosensor chip and the association and dissociation rate constants (k(on) and k(off)) and affinities (K(D)) for interactions with inhibitors were determined. A unique interaction kinetic profile was observed for each variant/inhibitor combination. Substitution of single amino acids in the protease primarily resulted in reduced affinity through increased k(off) for the inhibitors. For inhibitors characterized by fast association rates to wild-type protease (ritonavir, amprenavir, and indinavir), additional substitutions resulted in a further reduction of affinity by a combination of decreased k(on) and increased k(off). For inhibitors characterized by slow dissociation rates to wild-type enzyme (saquinavir and nelfinavir), the decrease of affinity conferred by additional mutations was attributed to increased k(off) values. Development of resistance thus appears to be associated with a change of the distinctive kinetic parameter contributing to high affinity. Further inhibitor design should focus on improving the "weak point" of the lead compound, that being either k(on) or k(off).

Amino Acid Substitution↗
PubMed2000

[Renal colic and lithiasis in HIV(+)-patients treated with protease inhibitors].

INTRODUCTION: Protease inhibitors, mainly Indinavir, are widely used drugs for the treatment of patients infected by the human immunodeficiency virus (HIV) and are related to renal colic and urinary obstruction. These conditions are the result of urine excretion of these drugs which favours the formation of small calculi (crystalluria and lithiasis). MATERIAL AND METHODS: Five PI treated HIV(+) patients; four males, one female, have recently been seen for renal colic at the Lithiasis Unit, Fundación Jiménez Díaz (FJD). All five patients had renal colic, one bilateral and one renal obstruction and fever. Small lithiasic concretions of null or minor radiological calcium density were identified by urinary X-ray and UIV. The patients had haematuria, crystalluria and urinary pH 5.0-6.0. Treatment was symptomatic, pharmacologic, emergency in situ extracorporeal shock-wave lithotrity (ESWL), or ureteral catheterisation, as appropriate. RESULTS: Patients had been treated with these antiviral agents for several months. They all required urologic care: pharmacologic, ureteral catheterisation, or ESWL, with good results. No stones were obtained for mineralogic analysis, but crystalluria was identified as being due to Indinavir and calcium oxalate. CONCLUSIONS: Renal excretion and urinary elimination of PIs (or their metabolites) results in asymptomatic crystalluria in HIV(+) patients treated with this class of drugs. Other cases present genuine calcium oxalate calculi with sings of renal colic and urinary obstruction requiring urologic care.

Adult↗
PubMed2003

Use of HIV protease inhibitors to block Kaposi's sarcoma and tumour growth.

HIV protease inhibitors are antiretroviral drugs that block the enzyme required for production of infectious viral particles. Although these agents have been designed to selectively bind to the catalytic site of HIV protease, evidence indicates that other cellular and microbial enzymes and pathways are also affected. It has been reported that patients treated with highly active anti-retroviral therapy (HAART) containing a protease inhibitor may be at reduced risk of Kaposi's sarcoma (KS) and some types of non-Hodgkin lymphomas; some disease regressions have also been described. Here we review recent data showing that several widely used protease inhibitors, including indinavir, saquinavir, ritonavir, and nelfinavir, can affect important cellular and tissue processes such as angiogenesis, tumour growth and invasion, inflammation, antigen processing and presentation, cell survival, and tissue remodelling. Most of these non-HIV-related effects of protease inhibitors are due to inhibition of cell invasion and matrix metalloprotease activity, or modulation of the cell proteasome and NFkappaB. These elements are required for development of most tumours. Thus, by direct and indirect activities, protease inhibitors can simultaneously block several pathways involved in tumour growth, invasion, and metastasis. These findings indicate that protease inhibitors can be exploited for the therapy of KS and other tumours that occur in both HIV-infected and non-infected individuals. A multicentre phase II clinical trial with indinavir in non-HIV-associated KS is about to start in Italy.

Animals↗
PubMed2002

In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible contribution to lipodystrophy syndrome.

Highly active antiretroviral therapy has been associated with the emergence of lipodystrophy syndromes that have clinical features commonly seen in patients with mitochondrial dysfunction. The effect of therapeutic protease inhibitors (PIs) on mitochondrial function is unknown. Mitochondrial matrix space proteins possess an amino-terminal leader peptide that is removed by the mitochondrial processing protease (MPP). Lack of cleavage could result in non- or dysfunctional mitochondrial proteins. The effects of different PIs on protease processing using pure MPP or yeast mitochondria, recognized models for mammalian counterparts, were examined in vitro. Multiple PIs were found to inhibit MPP, evidenced by accumulation of immature pALDH and decreased levels of processed ALDH. Both indinavir and amprenavir at 5.0 mg/ml resulted in significant inhibition of MPP. Although inhibition of MPP was also observed with ritonavir and saquinavir, the inhibition was difficult to quantify due to background inhibition of MPP by DMSO that was required to solubilize the drugs for the in vitro studies. Indinavir was also shown to inhibit MPP within yeast mitochondria. Lack of processing may impair mitochondrial function and contribute to the observed mitochondrial dysfunctions in patients receiving HAART and implicated in antiretroviral-associated lipodystrophy.

Journal Article↗
PubMed2003

Sensitive and specific determination of eight antiretroviral agents in plasma by high-performance liquid chromatography-mass spectrometry.

Therapeutic drug monitoring of antiretroviral drugs has become more and more important. Therefore, a highly specific method is presented, which is capable of quantifying the different proteinase inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) and non-nucleoside reverse transcriptase inhibitors (efavirenz, nelfinavir). The antiretroviral agents were separated and detected using LC-MS and atmospheric pressure chemical ionization. After solid-phase extraction, the antiretrovirals were separated within 21 min using gradient elution. The calibration range of each drug was linear including the expected minimum and maximum concentrations measured in plasma after the administration of the different drugs. All within-day and between-day coefficients of variation were below 10% and the recovery rates were between 34.8 and 124%. The respective quantification limits were 1 microg/l (indinavir), 10 microg/l (amprenavir, efavirenz), 50 microg/l (saquinavir), 90 microg/l (nelfinavir), 200 microg/l (nevirapine, ritonavir) and 250 microg/l (lopinavir).

Chromatography, High Pressure Liquid↗
PubMed2000

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Anti-HIV Agents↗
PubMed2003

Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors.

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold is described. Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts. The most potent inhibitor (-)-7 displayed 13% oral bioavailability in dogs. X-ray structure analysis of the monopyrrolinone compounds cocrystallized with the wild-type HIV-1 protease provided valuable information on the interactions between the inhibitors and the HIV-1 enzyme. In each case, the inhibitors assumed similar orientations for the P2'-P1 substituents, along with an unexpected hydrogen bond of the pyrrolinone NH with Asp225. Interactions with the S2 pocket, however, were not optimal, as illustrated by the inclusion of a water molecule in two of the three inhibitor-enzyme complexes. Efforts to increase affinity by displacing the water molecule with second and third generation inhibitors did not prove successful. Lack of success with this venture is a testament to the difficulty of accurately predicting the many variables that influence and build binding affinity. Comparison of the inhibitor positions in three complexes with that of Indinavir revealed displacements of the protease backbones in the enzyme flap region, accompanied by variations in hydrogen bonding to accommodate the monopyrrolinone ring. The binding orientation of the pyrrolinone-based inhibitors may explain their sustained efficacy against mutant strains of the HIV-1 protease enzyme as compared to Indinavir.

Animals↗
PubMed2000

Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

Animals↗
PubMed1998

In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents.

To combat infection and inhibit viral replication of HIV in the brain, antiretroviral agents must cross the blood-brain barrier (BBB). An in vitro BBB model consisting of bovine brain microvessel endothelial cells grown on porous filters was used to study and compare the transport of nevirapine, a potent and selective nonnucleoside reverse transcriptase inhibitor, with other HIV antiretroviral agents currently in use for the treatment of HIV infection. These included nucleoside reverse transcriptase inhibitors (didanosine, stavudine, zalcitabine, zidovudine), a nonnucleoside reverse transcriptase (delaviridine), and protease inhibitors (indinavir, saquinavir, VX-478). Nevirapine was the most permeable antiretroviral agent studied in the BBB model. The order of in vitro BBB permeability was nevirapine >> VX-478 > didanosine, stavudine, zalcitabine, zidovudine > indinavir > saquinavir. There was an apparent bell-shaped relationship between in vitro BBB permeability and octanol/phosphate-buffered saline distribution coefficient (D) where all lipophilic (log D > 2.5) as well as hydrophilic (log D < -0.5) antiretrovirals were less permeable than nevirapine (log D = 1.8). There were no significant effects on the in vitro BBB permeability of nevirapine in combination with other antiretroviral agents. Saquinavir was the only drug shown to have an affinity for the P-glycoprotein efflux pump, which may have contributed to its very low permeability. The apparent ability of nevirapine to readily permeate the BBB and enter the brain, where it may inhibit replication of HIV, potentially increases its therapeutic value.

Animals↗
PubMed2002

St Johns wort increases expression of P-glycoprotein: implications for drug interactions.

AIMS: St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug-drug interactions. METHODS: Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n = 15) or placebo (n = 7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, fixed and permeabilized. Cells were stained with a P-glycoprotein specific antibody, quantified by flow cytometry and median fluorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was confirmed by RT-PCR. P-glycoprotein mediated drug efflux was determined as a function of rhodamine efflux in the absence and presence of ritonavir. Data are expressed as mean +/- s.d. and were subjected to nonparametric analysis. RESULTS: P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0 +/- 1.9 vs 29.5 +/- 14.3 (MFI); P < 0.05). There was no effect with placebo (5.1 +/- 1.3 vs 6.0 +/- 1.9 MFI). SJW increased P-glycoprotein mediated rhodamine efflux (reduced ratio) compared with baseline (0.12 +/- 0.04 vs 0.24 +/- 0.18 P < 0.05). There was no change with placebo. Ritonavir (5 microm) inhibited P-glycoprotein mediated efflux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9 +/- 15.3% vs 75.4 +/- 16.4% P < 0.05). CONCLUSIONS: SJW increased expression and enhanced the drug efflux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug-herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically significant drug interactions may occur.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

HIV-Protease inhibitors reduce cell adherence of Candida albicans strains by inhibition of yeast secreted aspartic proteases.

Since the introduction of new anti-retroviral agents such as human immunodeficiency virus (HIV) protease inhibitors, oropharyngeal candidiasis is less often observed in acquired immune deficiency syndrome patients. Secretory aspartic proteases of Candida albicans, which have similarities to the HIV aspartic proteases, are pathogenicity factors that have been intensively investigated in recent years. The inhibitory effect of four different HIV aspartic protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), on the activity of different Candida albicans secretory aspartic proteases was demonstrated. These anti-retroviral agents were able to inhibit Candida albicans secretory aspartic proteases 1, 2, and 3 which are involved in Candida adherence. As a consequence of these results we used selected HIV protease inhibitors in an adherence assay of Candida cells to epithelial cells. Ritonavir and saquinavir inhibited adherence of Candida albicans under the chosen experimental conditions similarly to the in vitro results, whereas indinavir had no effect. This inhibition was shown to be concentration dependent. The specificity of these effects with respect to the secretory aspartic proteases was demonstrated by competitive binding experiments using purified recombinant secretory aspartic proteases. On the basis of these studies we conclude that lower rates of oropharyngeal candidiasis in individuals receiving potent anti-retroviral therapy could reflect not only an improvement in the immune system but also direct inhibition of Candida secretory aspartic proteases by HIV protease inhibitors.

Aspartic Acid Endopeptidases↗
PubMed1999

The effect of increasing alpha1-acid glycoprotein concentration on the antiviral efficacy of human immunodeficiency virus protease inhibitors.

The effect of a 4-fold increase in alpha1-acid glycoprotein (AGP) on the antiviral efficacy of 5 human immunodeficiency virus (HIV) protease inhibitors (PIs) was examined by the effect of HIV PIs on p24 production in peripheral blood mononuclear cells infected with protease wild-type and PI-resistant HIV isolates. For wild-type virus, the efficacy of the PIs at trough concentrations was unaffected by a 4-fold increase in AGP. With the partially HIV PI-resistant isolate, a 4-fold increase in AGP resulted in 2%, 30%, 37%, 37%, and 42% loss of activity for indinavir, saquinavir, nelfinavir, ritonavir, and amprenavir, respectively. The high-level HIV PI-resistant isolate had a greater loss in activity. The change in IC50 secondary to the addition of AGP was the greatest for ritonavir, nelfinavir, and amprenavir and lowest for indinavir. These data suggest that the target plasma concentration for the highly bound HIV PIs may need to be raised in subjects with elevated AGP who harbor partially PI-resistant isolates.

Cell Line↗
PubMed2001

Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo.

The human immunodeficiency virus type 1 protease mutation N88S, which is occasionally selected by treatment with nelfinavir or indinavir, confers hypersusceptibility to amprenavir in vitro. The clinical relevance of this observation is unclear. We report a case of N88S developing after virologic failure of both indinavir- and nelfinavir-containing regimens that was managed successfully with a regimen that contained amprenavir.

Adult↗
PubMed2002

Durability of response to treatment among antiretroviral-experienced subjects: 48-week results from AIDS Clinical Trials Group Protocol 359.

The 24-week extension of AIDS Clinical Trials Group Protocol 359, a study of human immunodeficiency virus (HIV)-infected, indinavir-experienced patients, was designed to study the durability of "salvage" treatment regimens. Patients received saquinavir in combination with either ritonavir or nelfinavir and, in addition, delavirdine, adefovir, or both. Patients who demonstrated a virologic response at weeks 12-16 were eligible to continue therapy in the extension through week 48. Of the 105 eligible subjects who were enrolled in the extension, 86 (82%) completed 48 weeks, and 49 (57%) of those 86 had HIV RNA levels <or=500 copies/mL at week 48. For these 86 subjects who completed 48 weeks, the median change in CD4 cell count from baseline was +72 cells/mm(3). Greater body weight, higher CD4 cell count, and greater degree of phenotypic susceptibility to indinavir and saquinavir at baseline were significantly associated with durable virologic suppression. These results show that some patients who experience treatment failure can demonstrate durable virologic and immunologic responses with salvage antiretroviral regimens.

Antiviral Agents↗
PubMed2002

Mechanisms of early virologic failure in antiretroviral-naive patients starting protease inhibitor-containing regimens: the APROVIR Study.

The virologic and pharmacologic mechanisms of virologic failure (VF) were studied in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)-containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220 patients with follow-up data, VF occurred in 35 (16%) during the first year of follow-up. A higher baseline virus load and poorer adherence to therapy were associated with VF. At the time of VF, key PI-resistance mutations were detected in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6 patients with indinavir treatment failure. PI plasma levels were more often below the range of active concentrations in VF with wild-type viruses (74%) than in VF with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of selection of PI-resistant viruses differed by type of PI and were dependent on PI plasma levels.

Adult↗
PubMed2003

Clinical and immunologic outcome in patients with human immunodeficiency virus infection, according to virologic efficacy in the year after virus undetectability, during antiretroviral therapy.

To evaluate factors associated with durable viral suppression (DVS), low viral rebound (virus load of 500-5000 copies/mL), and high viral rebound (virus load above 5000 copies/mL), we studied 3736 patients who achieved an undetectable virus load (i.e., <500 copies/mL) while receiving an initial highly active antiretroviral therapy regimen containing a protease inhibitor (PI). A total of 2636 patients (71%) had DVS, 387 (10%) had low viral rebound, and 713 (19%) had high viral rebound. Factors associated with DVS were antiretroviral-naive status, choice of PI (indinavir or boosted PI), lower virus load and higher CD4+ cell count, shorter duration of therapy (<6 months), and larger CD4+ cell increment until an undetectable virus load was attained. These factors (except for receipt of indinavir) were also associated with low versus high viral rebound. Compared with patients with DVS, patients with high viral rebound were more likely to experience clinical failure (adjusted hazard ratio [aHR], 1.71; 95% confidence interval [CI], 0.97-3.02) and immunologic failure (aHR, 1.57; 95% CI, 1.34-1.83), and patients with low viral rebound were as likely to experience these types of failure (aHR for clinical failure, 1.18 [95% CI, 0.48-2.92]; aHR for immunologic failure, 1.07 [95% CI, 0.87-1.32]), suggesting that a low viral rebound while receiving HAART that contains a PI has no significant consequence on midterm clinical outcome.

Adult↗