Non-comparative Phase II Open Study Evaluating the Efficacy of a Reduced Dose Atazanavir / Ritonavir 200/100 mg + 2 NRTI in HIV-1-infected Patients With Virological Success With Atazanavir / Ritonavir 300/100 mg + 2 NRTI
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Measure of effectiveness assessed by maintaining undetectable plasma HIV viral load (viral load ≤ 50 copies / ml) during the all period of this study of treatment with ATV / r 200/100 mg + 2 NRTIs, for all patients.
研究概览
简要总结
The goal of antiretroviral therapy should be maintaining undetectable plasma viral load, only present condition to prevent the progression of the disease, improve immune restoration and prevent the emergence of viral resistance mutations. In addition to the individual benefit, antiretroviral treatment reduces the transmission of HIV from an infected person to sexual partners. There is to date no alternative strategy to antiretroviral treatment and antiretroviral therapy, even extended, does not allow viral eradication.
The need to maintain antiretroviral therapy for life raises the long-term safety concerns of it, even with the latest molecules. Also, one of the key issues in clinical research is whether after reaching undetectable viral load, antiretroviral treatment can be reduced in order to reduce exposure to molecules. Indeed, this treatment of "maintenance" could potentially need a smaller antiviral potency. On the other hand, reduction of antiretroviral treatment reduces costs, an important consideration in light of new global recommendations of treatment for all patients with T-cells CD4 below 500 / mm3.
The alleviation of antiretroviral therapy is to either reduce the number of molecules by making monotherapies or dual therapy, or to realize or intermittent treatment is to reduce the doses of molecules such as randomized ENCORE -1 showing the equivalence of a dose of Efavirenz 400mg instead of 600mg in naive patients.
Atalow study has the sense to lower the dose of Atazanavir / Ritonavir in combination with two NRTI to reduce exposure to this molecule and its cost while maintaining an undetectable viral load.
详细描述
Protease inhibitors (PIs) are key treatments in the current therapeutic strategy. They have major qualities such as their antiviral potency and high genetic barrier.
However, their long-term use is associated with gastrointestinal side effects, metabolic disorders (lipid, carbohydrate, lipohypertrophy) and cardiovascular comorbidities, renal and bone. The decrease in IP doses would reduce this predominantly concentration-dependent toxicity.
Atazanavir (Reyataz) was the first protease inhibitor once daily approved in 2003 for the treatment of HIV patients. Its favorable safety profile, ease of making and effectiveness have made treatment widely used and recommended first line. Atazanavir is recommended in Europe in naïve patient at the 300 mg dose once daily boosted with ritonavir 100 mg and in the pretreated patient at the 300 mg boosted with 100mg ritonavir or a dose of 400 no boosted mg in combination with two other antiretroviral drugs.
After oral administration, atazanavir is rapidly absorbed with improved variable bioavailability with food intake (40% increase in Cmin) and dependent on the gastric potential hydrogen (pH). Atazanavir is highly bound to plasma proteins (86%) and is largely metabolised by the isoform 3A4 (CYP3A4) cytochrome P450. There is great variability in the pharmacokinetics of atazanavir between patients due to inter-individual variability in the expression and function of CYP3A4. Co-administration of ritonavir increased 11.9 times Cmin and decreases the interindividual variability. The major effect of ritonavir is to decrease hepatic clearance of atazanavir. Its half-life of elimination is 8.6 hours when administered at 300 mg with 100 mg of ritonavir. 90% inhibitory concentration of atazanavir adjusted to the plasma protein binding (PBA EC90) is 14ng / ml. At the standard dose of 300 mg taken with 100 mg ritonavir once daily, the mean trough concentration at steady state is according to research from 526 ng / ml and 862 ng / ml in HIV patients. Residual therapeutic levels (Cmin) must be greater than 150 ng / ml. The relationship between the residual plasma concentrations and virologic response was demonstrated in the naive patient pharmacokinetic substudy BMS 089.
If the inhibitor atazanavir is best tolerated on lipid map protease is responsible for specific side effects such as hyperbilirubinemia and nephrolithiasis, concentration-dependent side effects. Indeed, atazanavir is responsible for a reversible elevation of unconjugated bilirubin, inhibiting glucuronide conjugation bilirubin by UGT1A1. This effect, not easily concealed by the patient, is an important and annoying side effects that may interfere with treatment adherence. This hyperbilirubinemia is concentration-dependent, with elevated bilirubin most common grade 3-4, atazanavir C min is greater than 760 ng / ml (600 to 850 ng / ml according to studies).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented HIV-1 infection.
- •Age ≥ 18 years
- •Plasma HIV-RNA level ≤ 50 copies/mL during the last 24 months prior to screening visit (W-4), documented by at least 4 time-points
- •Stable antiretroviral treatment with 2 NRTI + ATV/r 300/100 for at least 6 month
- •CD4+ lymphocytes > 300 cells/mm3
- •Negative urinary pregnancy test and use of efficient contraception for women of childbearing potential
- •Signed informed consent
- •Patient affiliated or beneficiary of a national insurance scheme (article L1121-11 of the Public health code) (the Medical aid of State or SOUL is not a national insurance scheme)
排除标准
- •HIV-2 infection.
- •Patient with resistant mutation for ATV and/or NRTI used on the available genotypic test
- •Concomitant treatment using one or more molecules interacting with hepatic cytochromes
- •Ongoing cancer. Patients with cancer considered cured for at least six months may be included.
- •Active viral hepatitis C requiring a specific treatment during the 48 weeks of the trial
- •hemodialysis patients
- •Pregnant women, breastfeeding women or women wishing to be pregnant during the study period
- •Patient with a history of non-compliance or irregular follow-up
- •Subjects under "Backup justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship
- •Subjects participating in another clinical trial evaluating different therapies and including an exclusion period that is still in force during the screening phase
- •All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol compliance, adherence and/or trial treatment tolerance
- •Non-attendance which could impede the trial participation (travel abroad, moving, impending transfer...)
研究组 & 干预措施
non comparative open study
In patients signed an informed consent and meeting all the eligibility criteria at the time of the run-in (S-4), switch of antiretroviral therapy Atazanavir 300 mg/ritonavir 100 mg once a day to Atazanavir 200 mg/ritonavir 100 mg once a day without changing the combination of 2 NRTIs associated.
The administration will be done once a day orally for 48 weeks.
干预措施: Atazanavir 200 mg/r (Drug)
结局指标
主要结局
Measure of effectiveness assessed by maintaining undetectable plasma HIV viral load (viral load ≤ 50 copies / ml) during the all period of this study of treatment with ATV / r 200/100 mg + 2 NRTIs, for all patients.
时间窗: one year
Measure of safety (adverse events)
时间窗: one year
Number of participant with adverse events
Measure of tolerability assessed by quantification of bilirubinemia
时间窗: one year
Measure of tolerability assessed by number of patient interrupting the study treatment for virological failure
时间窗: one year
Measure of effectiveness assessed by number of patient maintaining a target trough plasma concentration of atazanavir associated to efficacy:
时间窗: one year
Residual plasma concentrations of ATV / r (Dates and last dose of antiretroviral schedules and the association or not with food ) will be performed at day 0 before changing dose reduction of atazanavir, week 12 and week 24 for all patients.
Measure of effectiveness assessed in patient with virological failure number of patient dysplaing HIV strains with mutations associated to treatment resistance
时间窗: one year
Measure of tolerability assessed by number of patient interrupting the study treatment for in tolerance
时间窗: one year
Measure of tolerability assessed by quantification of creatininemia
时间窗: one year
次要结局
未报告次要终点