Prediction of the Liver Safety Profile of a First-in-Class Myeloperoxidase Inhibitor Using Quantitative Systems Toxicology Modeling.

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modeling to predict the liver safety profile of novel therapeutics.

A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results.

BACKGROUND: Nucleoside and ritonavir (RTV) toxicities have led to increased interest in nucleoside reverse transcriptase inhibitors (NRTIs) and RTV-sparing antiretroviral regimens. SPARTAN was a multicenter, randomized, open-label, noncomparative pilot study evaluating the efficacy, safety, and resistance profile of an investigational NRTI- and RTV-sparing regimen (experimental atazanavir [ATV] dose 300 mg bid + raltegravir [RAL] 400 mg bid [ATV+RAL]). The reference regimen consisted of ATV 300 mg/RTV 100 mg qd + tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg qd (ATV/r+TDF/FTC). METHODS: Treatment-naïve HIV-infected patients with HIV-RNA ≥5,000 copies/mL were randomized 2:1 to receive twice-daily ATV+RAL (n=63) or once-daily ATV/r+TDF/FTC (n=31). Efficacy at 24 weeks was determined by confirmed virologic response (CVR; HIV-RNA <50 copies/mL) with noncom-pleters counted as failures based on all treated subjects. RESULTS: The proportion of patients with CVR HIV RNA <50 copies/mL at week 24 was 74.6% (47/63) in the ATV+RAL arm and 63.3% (19/30) in the ATV/r+TDF/FTC arm. Systemic exposure to ATV in the ATV+RAL regimen was higher than historically observed with ATV/r+TDF/ FTC. Incidence of Grade 4 hyperbilirubinemia was higher on ATV+RAL (20.6%; 13/63) than on ATV/r+TDF/FTC (0%). The criteria for resistance testing (virologic failure [VF]: HIV-RNA ≥400 copies/mL) was met in 6/63 patients on ATV+RAL, and 1/30 on ATV/r+TDF/FTC; 4 VFs on ATV+RAL developed RAL resistance. CONCLUSIONS: ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.

Semisynthetic Glycoconjugate Vaccine Candidates against Escherichia coli O25B Induce Functional IgG Antibodies in Mice.

Extraintestinal pathogenic Escherichia coli (ExPEC) is a major health concern due to emerging antibiotic resistance. Along with O1A, O2, and O6A, E. coli O25B is a major serotype within the ExPEC group, which expresses a unique O-antigen. Clinical studies with a glycoconjugate vaccine of the above-mentioned O-types revealed O25B as the least immunogenic component, inducing relatively weak IgG titers. To evaluate the immunological properties of semisynthetic glycoconjugate vaccine candidates against E. coli O25B, we here report the chemical synthesis of an initial set of five O25B glycan antigens differing in length, from one to three repeat units, and frameshifts of the repeat unit. The oligosaccharide antigens were conjugated to the carrier protein CRM197. The resulting semisynthetic glycoconjugates induced functional IgG antibodies in mice with opsonophagocytic activity against E. coli O25B. Three of the oligosaccharide-CRM197 conjugates elicited functional IgGs in the same order of magnitude as a conventional CRM197 glycoconjugate prepared with native O25B O-antigen and therefore represent promising vaccine candidates for further investigation. Binding studies with two monoclonal antibodies (mAbs) revealed nanomolar anti-O25B IgG responses with nanomolar K D values and with varying binding epitopes. The immunogenicity and mAb binding data now allow for the rational design of additional synthetic antigens for future preclinical studies, with expected further improvements in the functional antibody responses. Moreover, acetylation of a rhamnose residue was shown to be likely dispensable for immunogenicity, as a deacylated antigen was able to elicit strong functional IgG responses. Our findings strongly support the feasibility of a semisynthetic glycoconjugate vaccine against E. coli O25B.

Treatment of advanced HIV disease in antiretroviral-naïve HIV-1-infected patients receiving once-daily atazanavir/ritonavir or twice-daily lopinavir/ritonavir, each in combination with tenofovir disoproxil fumarate and emtricitabine.

Current guidelines for HIV therapy recommend initiating treatment at a CD4 cell count of 500 cells/mm(3). However, a large proportion of patients with HIV infection begin antiretroviral treatment at a more advanced stage. In the CASTLE study, patients with the most advanced HIV disease (CD4 cell count <50 cells/mm(3)) showed that 78% (45/58) vs. 58% (28/48) of the patients achieved HIV RNA <50 copies/mL in the intent-to-treat analysis at week 96 for atazanavir/ritonavir and lopinavir/ritonavir, respectively. This current sub-analysis of the CASTLE study describes demographics, virologic failure, discontinuations, safety, tolerability, immunologic response, and clinical outcomes for the following baseline strata: CD4 cell count (cells/mm(3)) <50, 50 to <100, 100 to <200, and ≥200 and HIV RNA (copies/mL) <100,000, 100,000 to <500,000, and ≥500,000. In the lowest CD4 cell count stratum (<50 cells/mm(3)), the proportion of discontinuations was 2-fold greater for the lopinavir/ritonavir arm (33%) than for the atazanavir/ritonavir arm (16%) with a similar rate of virologic failure between the two groups. Also in this CD4 cell count stratum, grades 2-4 treatment-related adverse events occurred in 25% in the atazanavir/ritonavir group and in 43% of lopinavir/ritonavir group, and the rate was also higher than in the higher CD4 cell count strata within the lopinavir/ritonavir treatment group (range: 29-34%). Grades 2-4 treatment-related diarrhea and nausea occurred in more patients receiving lopinavir/ritonavir than atazanavir/ritonavir in all strata. The atazanavir/ritonavir group had more grades 2-4 treatment-related jaundice than in the lopinavir/ritonavir group. These results highlight the importance of tolerability of antiretroviral therapy (ART) in the patients at greatest risk of morbidity and mortality when using regimens of similar potency.

Gastrointestinal tolerability and quality of life in antiretroviral-naive HIV-1-infected patients: data from the CASTLE study.

Most ritonavir-boosted protease inhibitor (PI)-based antiretroviral regimens offer comparable levels of virological efficacy. Thus, the tolerability of the regimen becomes a distinguishing factor with implications for patient quality of life (QoL), treatment adherence, and clinical outcome. This article describes results from the CASTLE study (comparing once-daily atazanavir/ritonavir [ATV/RTV] with twice-daily lopinavir/ritonavir [LPV/RTV], both in combination with fixed-dose tenofovir/emtricitabine, in treatment-naive HIV-infected patients) and an evaluation of the impact of gastrointestinal (GI) complications of treatment on patient QoL, as measured by the irritable bowel syndrome (IBS) QoL questionnaire (IBS-QoL). Changes in IBS-QoL from baseline over time (to week 24) were classified as: "Improvement" (> or =2-point positive change from baseline), "No change" (<2-point change), or "Worsening" (> or =2-point negative change). Data were collected on GI adverse events (AEs) and use of GI medications. Of the 599 patients with IBS-QoL-evaluable data through week 24, fewer patients in the ATV/RTV group than in the LPV/RTV group experienced grade 2-4 treatment-related GI AEs including diarrhea (3% versus 10%), nausea (5% versus 7%), and vomiting (<1% on both arms). Nearly three times as many patients receiving LPV/RTV used GI medications. ATV/RTV was associated with an increase in overall IBS-QoL scores and more patients receiving ATV/RTV than LPV/RTV experienced improvement in IBS-QoL through week 24. In contrast to LPV/RTV, ATV/RTV treatment was associated with earlier and more positive improvements in QoL scores across CD4 sub-groups. Differences in the health-related QoL profile between ATV/RTV and LPV/RTV may be important when selecting PI-based antiretroviral regimens.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV-0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC0-t (91.2%; CI, 88.1-94.3%), and AUC0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets.

Changes in body composition with ritonavir-boosted and unboosted atazanavir treatment in combination with Lamivudine and Stavudine: a 96-week randomized, controlled study.

This 96-week, open-label, randomized study assessed changes in body composition in treatment-naive patients infected with human immunodeficiency virus type 1 who were treated with either atazanavir or ritonavir-boosted atazanavir, in combination with stavudine and lamivudine. Both treatment groups had similar increases in trunk fat, but patients treated with ritonavir-boosted atazanavir had a significantly lower incidence of lipoatrophy.

Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN Study (AI424-097) 48-week results.

BACKGROUND: Atazanavir is a once-daily protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infection that has previously been studied in cohorts of treatment-naive and treatment-experienced patients. Limited data are available on the usefulness of switching from a PI-based regimen to a regimen based on a different PI, such as atazanavir, in HIV-infected patients experiencing virologic suppression but seeking regimen simplification. METHODS: The Switch to Another Protease Inhibitor (SWAN) study was a 48-week, open-label trial involving HIV-positive patients with virologic suppression who were receiving stable PI-based regimens (with or without ritonavir). Patients were randomized 2 : 1 to switch to atazanavir (400 mg per day)--or, if they were receiving tenofovir, to atazanavir-ritonavir (300/100 mg per day)--or to continue to receive their existing PI. The proportion of patients who experienced virologic rebound (defined as an HIV RNA load >or=50 copies/mL) was compared through study week 48. RESULTS: Patients either received an atazanavir-containing regimen (278 patients) or continued to receive a comparator PI-containing regimen (141 patients). The proportion of patients who experienced virologic rebound was significantly lower among those who switched to an atazanavir-containing regimen (19 [7%] of 278) than it was among those who continued to receive a comparator PI regimen (22 [16%] of 141; P=.004). Patients who switched to atazanavir therapy experienced significantly fewer total cholesterol, fasting triglyceride, and non-high density lipoprotein cholesterol elevations than did patients in the comparator PI group (P<.001); patients receiving atazanavir had comparable rates of adverse event-related discontinuation and serious adverse events. CONCLUSIONS: In patients with virologic suppression who were receiving other PIs, switching to a once-per-day regimen containing atazanavir provided better maintenance of virologic suppression (as demonstrated by significantly lower rates of virologic rebound and treatment failure than those observed with continued unmodified therapy), a comparable safety profile, and improved lipid parameters, compared with those for patients who continued their prior PI-based regimen through 48 weeks.

96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures.

BACKGROUND: In BMS Study 045, once-daily (QD) atazanavir/ritonavir (ATV/RTV) demonstrated comparable efficacy and safety to twice-daily (BID) lopinavir/ritonavir (LPV/RTV) over 48 weeks in treatment-experienced patients. Results of extended follow-up to 96 weeks are presented. METHODS: BMS Study 045 was an open-label, randomized, multi-national trial of HIV-infected patients with virologic failure on two or more prior HAART regimens designed to evaluate the efficacy and safety of ATV/RTV (300/100 mg) QD and LPV/RTV (400/100 mg) BID, each with tenofovir (300 mg) QD and one nucleoside reverse transcriptase inhibitor. The primary efficacy measure was the time-averaged difference (TAD) in reduction in HIV RNA from baseline. Secondary objectives included evaluation of safety and plasma lipid levels through week 96. RESULTS: Over 96 weeks, the ATV/RTV regimen demonstrated similar virologic efficacy to the LPV/RTV regimen. Mean reductions from baseline in HIV RNA were -2.29 and -2.08 log10 copies/ml, respectively [TAD (97.5% confidence interval): 0.14 log10 copies/ml (-0.13, 0.41)]. The LPV/RTV regimen resulted in significant increases in total cholesterol (+9%) and fasting triglycerides (+30%) in comparison with the ATV/RTV regimen, which demonstrated decreases in these parameters [-7 and -2%, respectively, (P < 0.0001)]. Grade 2-4 diarrhoea occurred less frequently in ATV/RTV patients (3%) in comparison with LPV/RTV patients (13%) (P < 0.01). Grade 3-4 elevations in bilirubin were more common in ATV/RTV patients (53%) than LPV/RTV patients (< 1%) (P < 0.0001), with no resulting discontinuations. CONCLUSIONS: Regimens containing once-daily ATV/RTV demonstrated comparable efficacy and safety, with significant reductions in total cholesterol and fasting triglycerides and improved gastrointestinal-tolerability in comparison with twice-daily regimens containing LPV/RTV over 96 weeks in treatment-experienced patients.

Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study.

CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.

Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naïve subjects in the CASTLE study.

BACKGROUND: CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents. OBJECTIVES: Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE. METHODS: A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology. RESULTS: Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores. CONCLUSION: Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.

Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study.

BACKGROUND: Once-daily atazanavir/ritonavir demonstrated similar antiviral efficacy to twice-daily lopinavir/ritonavir over 48 weeks, with less gastrointestinal disturbance and a better lipid profile, in treatment-naive patients. METHODS: International, multicenter, open-label, 96-week noninferiority randomized trial of atazanavir/ritonavir 300/100 mg once daily vs lopinavir/ritonavir 400/100 mg twice daily, each in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily, in antiretroviral-naive, HIV-1-infected patients. The primary end point was the proportion of patients with HIV RNA <50 copies/mL at 48 weeks. Results through 96 weeks are reported. RESULTS: Of 883 patients enrolled, 440 were randomized to atazanavir/ritonavir and 443 to lopinavir/ritonavir. At week 96, more patients receiving atazanavir/ritonavir achieved HIV RNA <50 copies/mL (74% vs 68%, P < 0.05) in the intent-to-treat analysis. On both regimens, 7% of subjects were virologic failures by 96 weeks. Bilirubin-associated disorders were greater in patients taking atazanavir/ritonavir. Treatment-related gastrointestinal adverse events were greater in patients taking lopinavir/ritonavir. Mean changes from baseline in fasting total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides at week 96 were significantly higher with lopinavir/ritonavir (P < 0.0001). CONCLUSIONS: Noninferiority of atazanavir/ritonavir to lopinavir/ritonavir was confirmed at 96 weeks. Atazanavir/ritonavir had a better lipid profile and fewer gastrointestinal adverse events than lopinavir/ritonavir.

Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients.

BACKGROUND: Atazanavir (ATV), the first once-daily protease inhibitor approved for the treatment of HIV-1 infection, is recommended for use in antiretroviral (ARV) treatment-naive and -experienced patients. Study AI424-089 was a prospective, randomized, open-label, 96-week study comparing 2 ATV-based treatment regimens in ARV-naive HIV-infected patients. METHODS: Adults with HIV RNA levels > or =2000 copies/mL were randomized (1:1) to once-daily ATV at a dose of 300 mg with ritonavir at a dose of 100 mg (ATV300/RTV) or ATV at a dose of 400 mg (ATV400); both regimens included lamivudine and an investigational extended-release formulation of stavudine. The primary endpoint for this noninferiority study was the proportion of patients (response rate) with an HIV RNA load <400 copies/mL at week 48. RESULTS: Response rates at week 48 were 86% and 85% on the ATV300/RTV and ATV400 regimens, respectively (difference estimate [95% confidence interval] = 1.5 [-8.2 to 11.1]). There were 3 and 10 patients with virologic failure in the ATV300/RTV and ATV400 groups, respectively. One patient (ATV400) developed phenotypic resistance to ATV associated with an I50L substitution. Adverse event-related discontinuations were 8% among ATV300/RTV-treated patients and <1% among ATV400-treated patients. Plasma lipid elevations were low with both regimens. Both regimens were well tolerated. CONCLUSIONS: These findings demonstrate the safety and efficacy of the ATV300/RTV regimen and confirm the safety and efficacy of ATV400 in an ARV-naive patient population.

Efficacy and tolerability of long-term efavirenz plus nucleoside reverse transcriptase inhibitors for HIV-1 infection.

OBJECTIVE: To compare the long-term efficacy and tolerability of two efavirenz-containing regimens with those of an indinavir-containing regimen in the initial use of HAART. METHOD: HIV-1-infected patients (N = 1266) were randomly assigned to receive one of three regimens: efavirenz, zidovudine plus lamivudine, n = 422; efavirenz plus indinavir, n = 429; or indinavir, zidovudine plus lamivudine, n = 415. Entrance criteria included baseline viral load greater than 10 000 copies/ml HIV-1 RNA, CD4 cell count 50 cells/mul or greater, and no previous use of lamivudine, any non-nucleoside reverse-transcriptase inhibitor or protease inhibitor. The primary endpoint was the proportion of patients (response rate) in each regimen with a viral load under 400 copies/ml at 168 weeks of treatment. RESULTS: Response rates at 168 weeks were 30% in the indinavir, zidovudine, lamivudine group, 48% in the efavirenz, zidovudine, lamivudine group (P < 0.0001, difference estimate; 97.5% confidence interval (CI) 18.5; 10.9, 26), and 40% in the efavirenz plus indinavir group (P = 0.0018, difference estimate; 97.5% CI 10.2; 2.9, 17.6). Median CD4 cell counts increased above respective baselines by 292 cells/mul (efavirenz, zidovudine, lamivudine and indinavir, zidovudine, lamivudine) and 300 cells/mul (efavirenz plus indinavir). Total discontinuations were 54% (efavirenz, zidovudine, lamivudine), 63% (efavirenz plus indinavir), and 69% (indinavir, zidovudine, lamivudine) of which 13, 12 and 26%, respectively, were caused by adverse events. No new or unexpected increases in the rates or severity of adverse events occurred from long-term treatment with efavirenz-containing regimens. CONCLUSION: Long-term HIV therapy with efavirenz-containing regimens, particularly efavirenz, zidovudine, lamivudine, provides significantly greater antiviral activity and tolerability than a regimen of indinavir, zidovudine plus lamivudine.