Peter J. Piliero

Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects.

Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (−2.57 to −2.33 log10 copies/mL), the proportion of subjects with HIV RNA <400 copies/mL (56%–64%) and <50 copies/mL (28%–42%), and mean increases in CD4 cell count (185–221 cells/mm3) were comparable across treatment groups. Diarrhea was two to three times more common in the nelfinavir group (61% of subjects) than in the atazanavir groups (23%–30% of subjects, p < .0001 versus nelfinavir), and jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) (p < .03 for all atazanavir regimens vs. nelfinavir). Mean percent change from baseline in fasting low-density lipoprotein (LDL) cholesterol was significantly less in the atazanavir groups (−7% to 4%) than in the nelfinavir group (31%) (p < .0001). In conclusion, once-daily atazanavir is a potent, safe, and well tolerated PI that rapidly and durably suppresses HIV RNA and durably increases CD4 cell count in antiretroviral-naive subjects. Through 48 weeks, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglycerides. In comparison, nelfinavir was associated with prompt, marked, and sustained elevations in these parameters of a magnitude that suggests they are clinically relevant.

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

Background:The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. Methods:The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. Results:A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level ≥1.0 log10 change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. Conclusion:These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults.

Objective:873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults. Design:Double-blind, randomized, placebo-controlled multi-center trial. Methods:Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 × 106 cells/l, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24. Results:Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus. Median baseline HIV RNA ranged from 4.26log10 to 4.46 log10. 873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1–3 days on therapy. No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters. Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log10 decrease were −0.12 (0%) for placebo, −0.46 (17%) for 200 mg once daily, −1.23 (75%) for 200 mg twice daily, −1.03 (63%) for 400 mg once daily, and −1.66 (100%) for 600 mg twice daily. An Emax relationship was observed between the area under the 873140 plasma concentration–time curve and change in HIV RNA. Conclusions:873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.

Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers.

ObjectiveTo evaluate the safety and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV). MethodsThree open-label, randomized, two-sequence, multiple-dose studies having the same design (7 days of APV or RTV alone followed by 7 days of both drugs together) used 450 or 900 mg APV with 100 or 300 mg RTV every 12 h with pharmacokinetic assessments on days 7 and 14. Safety was monitored as clinical adverse events (AEs) and laboratory abnormalities. ResultsRelative to APV alone, RTV co-administration resulted in a 3.3- to 4-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration–time curve (AUCτ,ss) and minimum concentration (Cmin,ss), respectively. APV 900 mg with RTV 100 mg resulted in a 2.09-fold and 6.85-fold increase in the GLS mean AUCτ,ss and Cmin,ss, respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUCτ,ss (μg • h/mL) was 23.49 (19.32–28.57) with 300 mg RTV and 35.42 (30.46–44.42) with 100 μg RTV, and for the 900 mg APV with 100 mg RTV 47.11 (39.47–61.24). The 450 mg APV Cmin,ss (μg/ml) were 1.32 (1.05–1.67) and 2.01 (1.70–2.61), and 2.47 (2.08–3.32) for 900 mg APV. The most common AEs were mild and included diarrhea, nausea/vomiting, oral parasthesias, and rash. The triglyceride and cholesterol increased significantly from RTV exposure. ConclusionAdding RTV to APV resulted in clinically and statistically significant increases in APV AUC and Cmin with variable effects on maximum concentration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg RTV.

Safety of Enfuvirtide in Combination With an Optimized Background of Antiretrovirals in Treatment-Experienced HIV-1-Infected Adults Over 48 Weeks

Background:Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. Methods:A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. Results:In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. Conclusion:The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors.

Options for antiretroviral therapy in patients infected with HIV continue to expand as new drugs are integrated into treatment regimens. Nonetheless, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) remain the backbone of highly active antiretroviral therapy (HAART). With the approval of emtricitabine in 2003, there are now 8 Food and Drug Administration (FDA)-approved NRTIs/NtRTIs. Several of these agents are effective as once-daily therapy, including didanosine, lamivudine, extended-release stavudine (FDA approved, but not currently available), tenofovir DF, and emtricitabine. Recent results from pharmacokinetic and clinical trials indicate that another NRTI, abacavir, may also be effective as a once-daily therapy, and FDA approval of once-daily dosing is anticipated. NRTIs are inactive as administered, requiring anabolic phosphorylation within target cells to achieve their antiretroviral effects. All NRTIs are converted to nucleoside triphosphates, which serve as the active metabolites (the NtRTI, tenofovir DF, only requires conversion to the diphosphate form). Frequency of drug administration is closely related to the pharmacokinetic properties of a drug. The key parameter is the half-life; however, the plasma elimination half-life of the NRTIs/NtRTIs as administered is of little use in developing a dosing schedule. Rather, the intracellular half-life of the nucleoside triphosphate is the relevant parameter. This article reviews the pharmacokinetic properties, particularly those of the various phosphorylation steps, of the NRTIs/NtRTIs.

Guillain-Barré Syndrome Associated with Immune Reconstitution

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.

Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers

ABSTRACT To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.

Atazanavir: a novel HIV-1 protease inhibitor.

The introduction of HIV-1 protease inhibitors in 1995 ushered in the era of highly active antiretroviral therapy. For the first time, inhibition of two key enzymes responsible for HIV replication, reverse transcriptase and protease, was possible. The combination of two nucleoside reverse transcriptase inhibitors with a single protease inhibitor proved highly effective at reducing viral burden. In resource-rich countries where such combination therapy is readily available, dramatic reductions in HIV-related morbidity and mortality have been seen. However, long-term use of highly active antiretroviral therapy has led to several issues, including development of drug resistance and metabolic complications. Atazanavir (formerly BMS-232632), a novel azapeptide protease inhibitor, is a potent protease inhibitor that is not associated with significant dyslipidaemia as seen with other protease inhibitors. In this review, the current standard approach to the treatment of HIV in the US will be discussed as background to understand the potential utility of this new antiretroviral agent.