Impact of Raltegravir Intensification on HIV-1-infected Subjects With Complete Viral Suppression Under Monotherapy With Protease Inhibitors. A 24-week Open-label, Proof-of-concept Pilot Clinical Trial.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Change from week -8 in Integrated viral HIV-1 DNA in A peripheral blood mononuclear cells (PBMCs) at 8 months.
研究概览
简要总结
This is a pilot, proof of concept, open-label clinical trial, to assess the extend of persistent viral reservoir and the level of immune activation in patients receiving suppressive treatment with protease inhibitors.
40 Chronically HIV-1 infected subjects, receiving monotherapy with ritonavir-boosted lopinavir or darunavir for at least 12 months with plasma viremia below 50 copies HIV RNA per ml, and CD4 T-cell counts greater than 500 cells/mm3 will be included.
The total duration of the study will be 48 weeks: 12 weeks for patients' inclusion, 24 weeks of follow-up once the last patient is included, and 12 weeks for data analysis.
详细描述
AIDS continues to be a major global health priority. Although important progress has been achieved in preventing new HIV infections and in lowering the annual number of AIDS-related deaths, the number of people living with HIV worldwide continued to grow in 2008, reaching an estimated 33.4 million. AIDS-related illnesses remain one of the leading causes of death globally and are projected to continue as a significant global cause of premature mortality in the coming decades: an estimated 3 million new HIV infections and 2 million deaths due to AIDS-related illnesses occurred worldwide in 2008 (UNAIDS, report 2009).
In contrast to the failed attempts at developing a vaccine against HIV, efforts to provide drug therapies stand as a great success. More than 25 agents have been approved thus far, and the right combinations can suppress replication of the virus, often keeping blood levels so low as to be undetectable by standard tests. These powerful drug combinations, collectively termed highly active antiretroviral therapy, HAART, have prolonged life and health in countless infected individuals.
Although life expectancy of HAART-treated people in developed countries has significantly improved, treatment has to be carefully observed to avoid virus rebound, what will happen in only in a few days after treatment withdrawal (13). Moreover, long-term treatment is not exempt from complications, including the continuous likelihood of developing drug resistance and the induction of significant metabolic disturbances as a consequence of drug toxicities, which will clinically impact on the future health of the HIV-infected patient, including hyperlipidaemia, lipodystrophy, metabolic syndrome, cardiovascular disease and type 2 diabetes. Finally, the cost of full HIV-1 treatment implementation should not be disregarded. Only in Catalunya, the annual cost in antiretroviral approaches the 300 million Euros.
Guidelines for the use of antiretrovirals for HIV-1 infection recommend combining at least three agents. However, toxicities, cost, and the complexity of such regimens warrant the search for other options. Boosted protease inhibitor monotherapy is one of the appealing options being investigated.
Different clinical trials have evaluated the efficacy of boosted protease inhibitor monotherapy in several clinical settings: maintenance therapy of HAART-suppressed subjects (1-3, 12), salvage regimens (10) and first-line treatment (4, 7-9). Monotherapies with boosted lopinavir or darunavir have been largely investigated in maintenance and induction-maintenance strategies, showing that they are able to maintain viral suppression in a high proportion of patients. Thus, both Darunavir/ritonavir DRV/r and Lopinavir/ritonavir LPV/r are accepted options for monotherapy regimens when triple therapy is not possible.
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
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 infected adults (≥18 years old).
- •Absence of prior virological failure with protease inhibitors (PIs).
- •No mono or dual protease inhibitor therapy previous to HAART initiation.
- •Patients had to be on monotherapy with ritonavir-boosted lopinavir (LPV/r 400/100 mg every 12 hours) or darunavir (DRV/r 800/100 mg every 24 hours) for ≥ 12 months. Switching from standard HAART to protease inhibitor monotherapy had to happen with undetectable plasma viremia.
- •Complete virological suppression (<50 copies/mL) for ≥12 months, including at least 2 times during the last year.
- •CD4 cell count ≥500 cells/µL.
- •Availability (if possible, not mandatory) of a genotype prior to the start of HAART, with absence of any major drug-related mutations.
- •Voluntary written informed consent.
排除标准
- •Lactating, pregnancy, or fertile women willing to be pregnant.
- •Active substance abuse or major psychiatric disease.
- •Presence of any polymorphism or mutation associated to raltegravir resistance at baseline (prior to first HAART).
研究组 & 干预措施
Monotherapy with IPs+ Raltegravir 400 mg
Lopinavir/r 400/100 mg every 12 hours + Raltegravir 400 mg every 12 hours or Darunavir/rit 800/100 mg every 24 hours + Raltegravir 400 mg every 12 hours
干预措施: Isentress® (Raltegravir, 400 mg every 12 hours) (Drug)
Monotherapy with IPs+ Raltegravir 400 mg
Lopinavir/r 400/100 mg every 12 hours + Raltegravir 400 mg every 12 hours or Darunavir/rit 800/100 mg every 24 hours + Raltegravir 400 mg every 12 hours
干预措施: Isentress® (Raltegravir, 400 every 12 hours) (Drug)
结局指标
主要结局
Change from week -8 in Integrated viral HIV-1 DNA in A peripheral blood mononuclear cells (PBMCs) at 8 months.
时间窗: week -8, -4, Baseline, week 4, 12 and 24
Change from week -8 in Unintegrated viral HIV-1 DNA in PBMCs at 8 months.
时间窗: week -8, -4, Baseline, week 1, 2, 4, 8, 12 and 24
Change from week -8 in lymphocyte activation markers in PBMCs at 8 months.
时间窗: week -8, -4, Baseline, week 4, 8, 12 and 24
次要结局
- ultrasensitive HIV-1 viral load(week -8, -4, Baseline, week 1, 2, 4, 8, 12 and 24)
- viral load >50 copies/mL(week -8, -4, Baseline, week 1, 2, 4, 8, 12 and 24)
- Change in the lymphocyte activation markers(week -8, -4, Baseline, week 1, 2, 4, 8, 12, and 24 and 48.)
- HIV-1 RNA below 50 copies/mL.(week 24 and 48)
- Change in the inflammation markers (soluble CD14, IL-6, D-Dimer, vCam, C Reactive Protein)(week -8, -4, Baseline, week 4, 8, 12, and 24 and 48)