Jane Yeo

The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks : a randomised non-inferiority trial

BACKGROUND Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients. METHODS This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943. FINDINGS At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir. INTERPRETATION Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

Background. Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1–infected subjects with genotypic evidence of RAL resistance. Methods. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log10 copies/mL from baseline or was <400 copies/mL. Results. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Conclusion. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.

Emergence of Resistance to Protease Inhibitor Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients: Selection of Four Alternative Viral Protease Genotypes and Influence of Viral Susceptibility to Coadministered Reverse Transcriptase Nucleoside Inhibitors

ABSTRACT Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I+I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P = 0.014 and P = 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.

Six-Week Randomized Controlled Trial To Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients

ABSTRACT This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (τ), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUCτ,ss versus the AUC from 0 h to ∞ was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA (∼2 log10 copies/ml) and increased CD4+ cell counts (∼100 cells/mm3) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.

Abacavir and the potential risk of myocardial infarction

The D:A:D Study Group describe results from their international observa tional cohort of 33 347 HIV-1infected individuals, which suggest an unexpected increased risk of myo cardial infarction associated with abacavir therapy (relative rate 1·9, 95% CI 1·47–2·45; p=0·0001). We summarised data from our HIV data repository, which includes information from 54 clinical trials sponsored by GlaxoSmithKline (GSK) designed for 24 or 48 weeks of combina tion anti retroviral therapy. Data were assessed from 14 683 HIV-infected patients who received abacavir (n=9639; 7845 person-years) or no abacavir (n=5044; 4653 person-years). Base line demographic and HIV disease characteristics, including lipids and glucose values, were similar. Incidences of coronary/myocardial events were similar between the groups; no higher risk for these events was identifi ed with respect to abacavir (table). A supporting analysis with the 13 studies designed with an experimental control for abacavir was consistent. The fi ndings of the D:A:D study were unexpected. Like the D:A:D investigators, we are unaware of a potential biological mechanism that might explain their results. In the summary described here, we did not fi nd a result consistent with that of D:A:D. Analyses of relevant spon tan eous reports from the GSK and US Food and Drug Administration adverse event reporting system data bases did not identify increased risk of myocardial ischaemic events associated with abacavir. Nonetheless, GSK takes the D:A:D fi nding seriously and is committed to understanding these data more fully and to com municating openly with treating physicians and regulatory agencies globally. As with all medications, physicians and patients must weigh the risks of HIV disease against the overall benefi ts and risks of the antiretroviral medicines available.

Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3

VIKING‐3 aimed to examine efficacy and safety of dolutegravir (DTG) 50 mg twice daily in patients with resistance to multiple ARV classes, including integrase inhibitors (INI).

Safety profile and tolerability of amprenavir in the treatment of adult and pediatric patients with HIV infection.

BACKGROUND Amprenavir (APV) is a new HIV-I protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-1 infection. OBJECTIVE The aim of this study was to assess the safety profile and tolerability of APV. METHODS A review of data from 358 adults enrolled in 2 phase III, randomized, 48-week, controlled studies and from 268 children enrolled in 1 phase II and 1 phase III study was conducted. The adult data were collected between February 25, 1997, and April 1, 1999. Data were collected in children from September 10, 1997, to January 15, 1999; these data were collected before completion of either study. Adults and children who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, APV was used in combination with 2 nucleoside reverse transcriptase inhibitors. RESULTS The most common drug-related adverse events in patients receiving APV were gastrointestinal events and oral/perioral paresthesia. The majority of adverse events were mild or moderate in intensity, early in onset, and transient. Nausea (27/358 patients, 8%), vomiting (15/358, 4%), rash (11/358, 3%), and diarrhea/loose stools (9/358, 3%) were the most common adverse events associated with treatment discontinuation. Severe laboratory abnormalities possibly related to APV were rare. In children, the nature and frequency of adverse events were similar to those in adults. Metabolic complications were infrequent in APV studies to date; symptoms related to fat redistribution were reported in <3% of patients treated with APV. Lipid or glucose laboratory abnormalities were reported with similar frequency in the APV and control groups in both studies in adults. CONCLUSIONS In the clinical trials reviewed, APV was generally well tolerated when administered with other antiretroviral agents in adult and pediatric patients with HIV infection.

Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961)

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

A 42-Week Open-Label Study to Assess the Pharmacokinetics, Antiretroviral Activity, and Safety of Amprenavir or Amprenavir plus Ritonavir in Combination with Abacavir and Lamivudine for Treatment of HIV-Infected Patients

The pharmacokinetics, antiviral activity, and safety of an amprenavir-ritonavir (APV-RTV) 600/100 mg b.i.d. regimen and an APV-RTV 1200/200 mg q.d. regimen were studied in a human immunodeficiency virus (HIV)-infected population. The geometric least-square mean ratio (90% confidence interval) of steady-state trough concentrations, compared with that of the amprenavir 1200 mg b.i.d. regimen, was 6.08 (4.94-7.49) for the twice-daily APV-RTV regimen, and it was 4.19 (2.90-6.08) for the daily APV-RTV regimen. The regimens were well tolerated, which supports APV-RTV as an option for twice-daily or daily therapy for HIV.

Fosamprenavir/ritonavir in advanced HIV disease (TRIAD): a randomized study of high-dose, dual-boosted or standard dose fosamprenavir/ritonavir in HIV-1-infected patients with antiretroviral resistance

BACKGROUND APV102002 was an open-label study comparing a dual-boosted HIV-1 protease inhibitor (PI) [fosamprenavir/lopinavir/ritonavir (FPV/LPV/RTV; 1400 mg/533 mg/133 mg twice daily)] and a high dose of FPV/RTV 1400 mg/100 mg twice daily (HD-FPV/RTV) versus the standard FPV/RTV 700 mg/100 mg twice-daily (STD-FPV/RTV) regimen for 24 weeks. METHODS Adult patients with prior failure to two or more PI-based regimens and on a failing PI regimen were randomized to STD-FPV/RTV (n = 24), HD-FPV/RTV (n = 25) or FPV/LPV/RTV (n = 25). The primary aim was to test week 24 superiority of HD-FPV/RTV and FPV/LPV/RTV over STD-FPV/RTV as measured by plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB). RESULTS There was no difference in the week 24 AAUCMB between the regimens. The proportion of patients with <50 copies/mL of plasma HIV RNA was 21%, 24% and 20%, respectively, by time to loss of virological response (TLOVR) analysis. High baseline drug resistance provided some explanation for the low efficacy. A lower baseline background drug resistance and higher fosamprenavir genotypic inhibitory quotient led to better antiviral responses. The plasma amprenavir trough concentartion (C(tau)) was 49% higher in the HD-FPV/RTV arm than in the STD-FPV/RTV arm and similar in the FPV/LPV/RTV and STD-FPV/RTV arms. The plasma lopinavir C(tau) was similar to historical data with standard LPV/RTV 400 mg/100 mg twice daily. All regimens were relatively well tolerated, although diarrhoea was more frequent in the HD-FPV/RTV and FPV/LPV/RTV arms, and hypertriglyceridaemia and increased total cholesterol were more common in the FPV/LPV/RTV arm. CONCLUSIONS While the strategies of higher dose FPV/RTV and dual FPV/LPV/RTV were relevant at the time of study initiation, new therapies for antiretroviral-experienced patients make such strategies of limited interest. In addition, this study failed to demonstrate antiviral superiority of the HD-FPV/RTV or FPV/LPV/RTV regimen over the STD-FPV/RTV twice-daily regimen in highly treatment-experienced patients.