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PubMed2006

N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.

Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the co-occurrence of D30N and L90M. Third, D30N+N88D+L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N-->D30N+N88D-->D30N+N88D+L90M-->D30N+N88D+L90M+(L33F+/-I84V or M46I/L+/-I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.

Base Sequence↗
PubMed1999

Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children.

OBJECTIVE: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HIV-infected previously treatment-naive children taking triple therapy. METHODS: sixteen HIV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. RESULTS: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log10 (range, 1.4-4.2 log10) was achieved over a period of 12 months in both groups. Viral load < 500 copies/ml was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 x 10(6) to 850 x 10(6) cells/l after 3 months and was maintained at 813 x 10(6) cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. CONCLUSION: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HIV-infected children compared with studies combining two nucleoside analogues.

Anti-HIV Agents↗
PubMed2000

Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and hepatitis C virus (HCV).

A 49-year old male patient with severe hemophilia A, coinfected with HIV and HCV, who underwent orthoptic liver transplantation because of hepatitis C cirrhosis is presented. We describe a strong interaction between nelfinavir and tacrolimus postoperatively, that caused a reduction of the dose of tacrolimus by a factor 70 compared with normal, to achieve therapeutic blood concentrations and to avoid toxic side effects. We suggest that nelfinavir inhibits the metabolism of tacrolimus because both compounds are well-known substrates for the cytochrome P450 isoenzyme CYP 3A4. The nelfinavir serum concentrations were not affected by the institution of tacrolimus. Although the interaction dramatically changed the tacrolimus dose-concentration relationship, the situation was manageable by frequent monitoring of blood concentrations of tacrolimus.

Drug Interactions↗
PubMed2001

The effect of nevirapine in combination with nelfinavir in heavily pretreated HIV-1-infected patients: a prospective, open-label, controlled, randomized study.

The purpose of the current study was to determine the efficacy and safety of nevirapine combined with nelfinavir and two nucleoside reverse transcriptase inhibitors (NRTIs) in patients previously exposed to highly active antiretroviral therapy (HAART). In a prospective, open-label, randomized study, 56 HIV-infected adults who had received HAART, including saquinavir hard gel capsule, ritonavir, or indinavir, were randomly assigned to receive nevirapine in addition to nelfinavir and two NRTIs. The proportion of patients who achieved an undetectable viral load (plasma HIV-RNA <200 copies/ml) at weeks 24 and 36 was significantly higher in the nevirapine group than in the control group (55% and 52% vs. 22% and 22%; p =.015 and p =.047). No differences in CD4 cell count or clinical outcome were observed. In the nevirapine group, 17% of patients discontinued treatment because of rashes. We conclude that the addition of nevirapine, when switching from one protease inhibitor-containing regimen to one containing nelfinavir, has a substantial effect on viral suppression.

Adult↗
PubMed2005

Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors.

Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

Alkynes↗
PubMedDate not supplied

Effectiveness of step-wise intervention plan for managing nelfinavir-associated diarrhea: a pilot study.

PURPOSE: Pilot study to evaluate the effectiveness of a step-wise diarrhea management strategy for nelfinavir-associated diarrhea. METHOD: HIV-infected adults (CD4 count > 100 cells/mm3, and no evidence of enteric pathogens) developing symptoms of diarrhea after initiation of nelfinavir for a duration of > or = 1 month were enrolled into this 9-week prospective pilot study. Step-wise interventions, reviewed and adjusted additively at 2-week intervals, included nutritional counseling (+/- lactase and/or psyllium), calcium carbonate, and loperamide. Outcome measure included stool-form consistency, bowel movement frequency, and incidents of associated morbidity (urgency, incontinence) daily. Patient quality of life was also assessed. RESULTS: Eighteen patients completed the study. Mean daily bowel movement frequency decreased by 32%, from 2.98 to 2.03 (p = .005). Mean daily stool form shifted from a rating of 4.24 to 2.37 (p = .0001), representing a shift to firmer stools. Period prevalence of incontinence (28%) and urgency (33%) decreased to 6% each, respectively. Quality of life ratings relating to gastrointestinal disturbance and overall physical/psychosocial function were improved. CONCLUSION: The results of this pilot study demonstrated that a step-wise intensified approach may be successful in managing nelfinavir-associated diarrhea and will need to be validated in a larger scale, randomized controlled trial.

Adolescent↗
PubMedDate not supplied

L-glutamine supplementation improves nelfinavir-associated diarrhea in HIV-infected individuals.

PURPOSE: To determine whether L-glutamine decreases the severity of nelfinavir-associated diarrhea in HIV-infected individuals. Other endpoints include the effect on quality of life, muscle-wasting syndrome, CD4 counts, and viral load. METHOD: HIV-infected patients with nelfinavir-associated diarrhea for >1 month were randomized to receive L-glutamine 30 g/day or placebo for 10 days in a prospective, double-blind, crossover study. Diarrhea was measured on a scale ranging from grade 0 (no diarrhea) to grade 4 (severe diarrhea, > 7 stools/day). Quality of life was assessed by the Medical Outcome Study (MOS) HIV questionnaire. RESULTS: Twenty-five participants completed the study. There was a significant difference between the L-glutamine and placebo arms on the mean grade of diarrhea (0.762 vs. 1.850, p <.01) when placebo was administered first. When L-glutamine was administered first, there was a significant crossover effect (p <.02), with similar mean grades of diarrhea in the two groups. There was also a significant difference between L-glutamine and placebo in the mean change in MOS scores from baseline (1.48 vs. -2.19, p <.017). There were no significant differences between treatment groups for the other endpoints. CONCLUSIONS: In this population of HIV-positive participants, L-glutamine 30 g/day significantly (p <.01) reduced the severity of nelfinavir-associated diarrhea and produced improved quality of life compared with placebo.

Administration, Oral↗
PubMedDate not supplied

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Anti-HIV Agents↗
PubMedDate not supplied

Efficacy of nelfinavir in patients switched from ritonavir/saquinavir combination antiretroviral therapy.

UNLABELLED: Based on available data and expert opinion, the IAS-USA treatment guidelines recommend "selective substitution" of the medication thought most likely to be causing a side effect for one that should have a different side effect profile. PURPOSE: This study evaluates the short-term virological efficacy of selective substitution with nelfinavir-nucleoside combination therapy in individuals with plasma viral RNA below 400 copies/mL. METHOD: This study involved a retrospective chart review at five large urban HIV Clinical practice settings and included 19 patients taking combination therapy including ritonavir with saquinavir. We performed selective substitution with a nelfinavir combination. Our main outcome measure was plasma HIV-1 RNA (Amplicor) obtained during the period between weeks 12 to 18. RESULTS: We identified 19 HIV-1-infected individuals with evidence of viral suppression as defined by a viral load below 400 copies/mL while taking dual nucleoside reverse transcriptase inhibitors with ritonavir/saquinavir. Reasons for switching included adverse effects (37%) or preference for nelfinavir due to the possibility of a better defined salvage regimen (63%). We defined a composite viral endpoint indicative of continued viral suppression using the first 12 to 18 weeks following the medication change. We found that 73% maintained undetectable viral loads (plasma HIV RNA below 400 copies/mL) during this period. CONCLUSION: These data suggest that any medication adjustment should be made cautiously, as there may be some potential risk in a substitution. Selective substitution of a medication that has undesirable side effects or other characteristics should be considered when the possible risks of the loss of viral suppression are outweighed by the potential benefits of that substitution.

Anti-HIV Agents↗
PubMed2006

Carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir.

OBJECTIVE: To present a case of carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir. CASE SUMMARY: A 50-year-old HIV-positive male developed excessive drowsiness secondary to carbamazepine when an antiretroviral regimen containing lopinavir/ritonavir was introduced. The carbamazepine serum concentration increased 46%. Subsequently, the patient developed a possible adverse skin reaction to his antiretrovirals and was hospitalized. The protease inhibitor was changed to nelfinavir. Within 3 days, the patient again developed excessive drowsiness and became unsteady on his feet. This time, the carbamazepine serum concentration had increased by 53%. In both instances, the carbamazepine dosage was decreased by 33%, which resulted in resolution of symptoms. DISCUSSION: Carbamazepine undergoes extensive hepatic metabolism. The major metabolic pathway involves oxidation of carbamazepine via CYP3A4 to an active metabolite, carbamazepine-10,11-epoxide. Protease inhibitors are well-known CYP3A4 inhibitors. Other cases of carbamazepine toxicity secondary to protease inhibitors are reviewed. A MEDLINE search (1966-May 2006) revealed 4 cases of carbamazepine toxicity secondary to antiretrovirals. Carbamazepine serum concentrations increased two- to threefold from baseline. Vertigo, drowsiness, disorientation, ataxia, and vomiting occurred within 12 hours to 2 months, which resolved with reduction of the carbamazepine dosage. CONCLUSIONS: An objective causality assessment suggests that our patient became drowsy and unsteady on his feet secondary to a carbamazepine-protease inhibitor interaction. Lopinavir/ritonavir and nelfinavir may decrease carbamazepine metabolism, causing an elevation in carbamazepine serum concentrations. Carbamazepine toxicity may be prevented by reducing the carbamazepine dosage by 25-50% when protease inhibitors are introduced. A carbamazepine serum concentration should be repeated 3-5 days after the protease inhibitors are started.

Anticonvulsants↗
PubMed1998

Simultaneous quantitative determination of the HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir in human plasma by ion-pair high-performance liquid chromatography with ultraviolet detection.

A reversed-phase high-performance liquid chromatographic assay for the simultaneous quantitative determination of five HIV protease inhibitors (i.e. amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) in human plasma is described. Sample pretreatment consisted of solid-phase extraction prior to ion-pair, reversed-phase high-performance liquid chromatography with ultraviolet detection at 210 nm (amprenavir, indinavir and nelfinavir) and 239 nm (saquinavir and ritonavir). For amprenavir, indinavir and saquinavir the method has been validated over the range of 25 ng/ml to 25 microg/ml using a 0.6 ml sample volume. For nelfinavir and ritonavir the method has been validated over the range of 50 ng/ml to 25 microg/ml. The method proved to be accurate, with an average accuracy at four concentrations ranging from 90.6 to 109.2%, and precise, with the within-day and between-day precision ranging from 1.8 to 6.7%, and 0.7 to 7.6%, respectively. The protease inhibitors which can be quantified by using this assay proved to be stable under various conditions. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of these protease inhibitors.

Anti-HIV Agents↗
PubMed2003

Therapeutic drug monitoring of the HIV/AIDS drugs abacavir, zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir.

Combination therapy with antiretroviral drugs is used for the treatment of patients infected with the human immunodeficiency virus. To achieve optimal drug concentrations for viral suppression and avoidance of drug toxicity, monitoring of drug levels has been considered essential. We set up an analytical procedure for monitoring the plasma concentrations of a total of seven drugs: abacavir, zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir. The plasma samples were liquid/liquid extracted and subjected to high-performance liquid chromatography (HPLC) analysis. The compounds were monitored by ultraviolet detection: indinavir, lopinavir, and nelfinavir at 215 nm; efavirenz at 254 nm, and abacavir, zidovudine, and nevirapine at 266 nm. Two different extraction procedures and two different HPLC eluents on a C(8) reversed-phase HPLC column were used to monitor all seven compounds. Under steady state conditions, the plasma concentrations of antiviral drugs in 175 patients were correlated with the time after the last dosing to define the peak or trough levels. Due to the short plasma elimination half-life of abacavir and zidovudine, only peak levels could be determined for these compounds, whereas both peak and trough levels could be assessed for the other compounds because of a longer plasma elimination half-life. The mean peak concentrations (microg/ml) were 0.69 for abacavir and 0.57 for zidovudine; the mean peak/trough concentrations (microg/ml) were 2.07/1.32 for efavirenz, 2.43/2.23 for nevirapine, 5.48/1.08 for indinavir, 4.69/3.51 for lopinavir, and 3.54/1.45 for nelfinavir. The described analytical method offers a broad-spectrum monitoring of plasma levels of antiretroviral drugs.

Anti-HIV Agents↗
PubMed2006

Cooperative contribution of gag substitutions to nelfinavir-dependent enhancement of precursor cleavage and replication of human immunodeficiency virus type-1.

We previously described a clinical human immunodeficiency virus type-1 (HIV-1) isolate, CL-4, which showed nelfinavir (NFV)-dependent enhancement of replication (Matsuoka-Aizawa, S., Sato, H., Hachiya, A., Tsuchiya, K., Takebe, Y., Gatanaga, H., Kimura, S., Oka, S, 2003. Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication. J. Virol. 77, 318-327.). To identify the responsible region(s) of HIV-1 proteins for such replication enhancement, we constructed a panel of recombinant HIV-1 clones harboring portions of the Gag and protease of CL-4 and analyzed their replication capabilities and Gag processing patterns. Our data suggested that the substitutions in the matrix and N-terminal half of capsid of CL-4 were indispensable for the NFV-dependent enhancement of replication and that NFV facilitated the cleavage between the matrix and capsid of the Gag precursor harboring these substitutions. The substitutions in C-terminal half of capsid rather decreased the cleavability of Gag precursor and NFV counteracted such negative impact. Efficient replication enhancement with NFV can be observed only in the presence of the substitutions in entire Gag and protease of CL-4.

Amino Acid Sequence↗
PubMed2006

Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate.

The selective pressure of the competitive protease inhibitors causes both HIV-1 protease and occasionally its substrates to evolve drug resistance. We hypothesize that this occurs particularly in substrates that protrude beyond the substrate envelope and contact residues that mutate in response to a particular protease inhibitor. To validate this hypothesis, we analyzed substrate and protease sequences for covariation. Using the chi2 test, we show a positive correlation between the nelfinavir-resistant D30N/N88D protease mutations and mutations at the p1-p6 cleavage site as compared to the other cleavage sites. Both nelfinavir and the substrate p1-p6 protrude beyond the substrate envelope and contact residue 30, thus possibly making the p1-p6 cleavage site more vulnerable to co-evolution.

Drug Resistance, Viral↗
PubMed2001

Synthesis and anti-HIV activity of glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir.

With the aim at improving the transport of the current HIV protease inhibitors across the intestinal and blood brain barriers and their penetration into the central nervous system, the synthesis of various acyl and carbamatoyl glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir, their in vitro stability with respect to hydrolysis, and their anti-HIV activity have been investigated. D-Glucose, which is actively transported across these barriers, was connected through its 3-hydroxyl to these antiproteases via a linker. The liberation of the active free drug during the incubation time of the prodrugs with the cells was found to be crucial for HIV inhibition. The labile ester linking of the glucose-containing moiety to the peptidomimetic hydroxyl of saquinavir or to the indinavir C-8 hydroxyl, which is not part of the transition state isostere, is not an obstacle for anti-HIV activity. This is not the case for its stable carbamate linking to the peptidomimetic hydroxyl of saquinavir, indinavir and nelfinavir. The chemical stability with respect to hydrolysis of some of the saquinavir and indinavir prodrugs reported here, the liberation rate of the active free drug and the HIV inhibitory potency are acceptable for an in vivo use of these prodrugs. These glucose-linked ester and carbamate prodrugs display a promising therapeutic potential provided that their bioavailability, penetration into the HIV sanctuaries, and/or the liberation of the active free drug from the carbamate prodrugs are improved. Furthermore, no cytotoxicity was detected for the prodrugs for concentrations as high as 10 or even 100 microM, thus indicating an encouraging therapeutic index.

Carbamates↗
PubMed2000

Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir, nelfinavir and the non-nucleoside reverse transcriptase inhibitor efavirenz by high-performance liquid chromatography after solid-phase extraction.

As part of an on-going study on the suitability of a formal therapeutic drug monitoring (TDM) of antiviral drugs for improving the management of HIV infection, a high-performance liquid chromatography method has been developed to quantify simultaneously in plasma five HIV protease inhibitors (PIs) (i.e., indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and the novel non-nucleoside reverse transcriptase inhibitor efavirenz. After viral inactivation by heat (60 degrees C for 60 min), plasma (600 microl), with clozapine added as internal standard, is diluted 1:1 with phosphate buffer, pH 7 and subjected to a solid-phase extraction on a C18 cartridge. Matrix components are eliminated with 2 x 500 microl of a solution of 0.1% H3PO4 neutralised with NaOH to pH 7. PIs and efavirenz are eluted with 3 x 500 microl MeOH. The resulting eluate is evaporated under nitrogen at room temperature and is reconstituted in 100 microl 50% MeOH. A 40-microl volume is subjected to HPLC analysis onto a Nucleosil 100, 5 microm C18 AB column, using a gradient elution of MeCN and phosphate buffer adjusted to pH 5.15 and containing 0.02% sodium heptanesulfonate: 15:85 at 0 min-->30:70 at 2 min-->32:68 at 8 min-->42:58 at 18 min-->46:54 at 34 min, followed by column cleaning with MeCN-buffer, pH 5.15 (90:10), onto which 0.3% AcOH is added. Clozapine, indinavir, amprenavir, saquinavir, ritonavir, efavirenz and nelfinavir are detected by UV at 201 nm at a retention time of 8.2, 13.0, 16.3, 21.5, 26.5, 28.7 and 31.9 min, respectively. The total run time for a single analysis is 47 min, including the washing-out and reequilibration steps. The calibration curves are linear over the range 100-10,000 ng/ml. The absolute recovery of PIs/efavirenz is always higher than 88%. The method is precise with mean inter-day relative standard deviations within 2.5-9.8% and accurate (range of inter-day deviations -4.6 to +4.3%). The in vitro stability of plasma spiked with PIs/efavirenz at 750, 3000 and 9000 ng/ml has been studied at room temperature, -20 degrees C and +60 degrees C. The method has been validated and is currently applied to the monitoring of PIs and efavirenz in HIV patients. This HPLC assay may help clinicians confronted to questionable compliance, side effects or treatment failure in elucidating whether patients are exposed to adequate circulating drug levels. The availability of such an assay represents an essential step in elucidating the utility of a formal TDM for the optimal follow-up of HIV patients.

Alkynes↗
PubMed2004

Prodrugs of HIV protease inhibitors-saquinavir, indinavir and nelfinavir-derived from diglycerides or amino acids: synthesis, stability and anti-HIV activity.

With the aim of improving the pharmacological properties of current protease inhibitors (PIs), the synthesis of various acyl and carbamate amino acid- or diglyceride-containing prodrugs derived from saquinavir, indinavir and nelfinavir, their in vitro stability with respect to hydrolysis and their anti-HIV activity in CEM-SS and MT4 cells have been investigated. l-Leucine (Leu) and l-phenylalanine (Phe) were connected through their carboxyl to the PIs while l-tyrosine (Tyr) was conjugated through its aromatic hydroxyl via various spacer units. Hydrolysis of the prodrug with liberation of the active free drug was crucial for antiviral activity. The Leu- and Phe-PI prodrugs released the active free drug very rapidly (half-lives of hydrolysis in buffer at 37 degree C of 3-4 h). The Tyr-PI conjugates with a -C(O)(CH(2))(4)- linker exhibited half-lives in the 40-70 h range and antiviral activities in the 21-325 nM range (from 2 to 22 nM for the free PIs). The chemically very stable carbamate "peptidomimetic" Tyr-PI prodrugs (no hydrolysis detected after 7 days in buffer) displayed a very low anti-HIV activity or were even inactive (EC(50) from 2300 nM to >10 microM). A very low antiviral activity was measured for the diglyceride-substituted saquinavir and for all of the disubstituted indinavir and nelfinavir prodrugs. All these prodrugs probably released the active parent PI too slowly under the antiviral assay conditions. These results combined with those from transepithelial transport studies (Rouquayrol et al., Pharm. Res., 2002, 19, 1704-1712) indicate that conjugation of amino acids (through their carboxyl) to the PIs constitutes a most appealing alternative which could improve the intestinal absorption of the PIs and reduce their recognition by efflux carriers.

Anti-HIV Agents↗
PubMed2000

Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359.

This study compared antiretroviral activity among 6 "salvage" therapy regimens. The study was a prospective, randomized, 2x3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with delavirdine and/or adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had </=500 HIV RNA copies/mL. Virologic response did not differ significantly between pooled ritonavir and nelfinavir groups (28% vs. 33%; P=.50) or between pooled delavirdine and delavirdine/adefovir groups (40% vs. 33%; P=.42). Pooled delavirdine groups had a greater virologic response rate than did adefovir groups (40% vs. 18%; P=.002). Overall, one-third of patients who experienced virologic failure on an indinavir-containing regimen suppressed virus load levels while they were taking a new salvage regimen.

Adenine↗