The Immunological Impact of Adding Hydroxychloroquine in Patients With Discordant CD4+ Cell Responses to Suppressive HAART: A Phase I Pilot Study.
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in CD4 from baseline
研究概览
简要总结
The purpose of the study is to examine the effects of adding a drug called hydroxychloroquine, usually used to treat rheumatoid arthritis, to patients' usual antiretroviral combination. HIV causes activation of some parts of the immune system and this immune activation may persist despite effective antiretroviral therapy. Ongoing activation may be responsible for poor CD4 rise on antiretroviral therapy and for some HIV-related complications. Drugs like hydroxychloroquine work by inhibiting immune activation.
The study will primarily investigate the effect of adding this medication on immunological parameters (particularly CD4 count), on other safety parameters (such as cholesterol), patients' side effects and viral load.
If you decide to take part, the duration of your involvement in the study will be 24 weeks plus two screening visits up to 84 days prior to the start of the study and a follow up visit.
详细描述
Studies exploring changes in antiretrovirals or addition of antiretrovirals from new classes in patients with discordant immune response to suppressive HAART have, in general, yielded disappointing results.
The addition of the antiretroviral maraviroc (a CCR5 antagonist) in patients who had been on suppressive HAART for at least a year but with a CD4 count less than 250 (and not rising) yielded no improvement in CD4 counts in 6 individuals after approximately 5 months.
A small study investigating the benefit of switching to lopinavir/ritonavir (predominantly from NNRTI-based therapy) showed a significant improvement in CD4 cell count with a reduction in cell apoptosis at 6 months.However, data for other switches are lacking and lopinavir/ritonavir may not be a preferred switch option due to gastrointestinal tolerability and an increased risk of myocardial infarction in cohort analyses.
Chronic HIV infection is characterised by gradual loss of CD4 T-cells by direct (virus mediated CD4 death) and indirect mechanisms. Increased immune activation is an indirect mechanism that is central to CD4 T-cell loss. In observational studies, the level of immune activation is associated with the rate of CD4 decline and in patients taking antiretroviral therapy (with or without complete viral suppression) the extent of CD4 recovery is associated with the degree of immune activation.
Immune activation has also been shown to correlate with disease progression and survival. The causes of generalized immune activation in HIV are not fully understood but may be related to nef or gp120.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Documented HIV infection
- •Age 18 to 65 years.
- •On stable antiretroviral therapy for at least 96 weeks
- •CD4 count less than 350 on screening blood test and on one other test performed within 4 months prior to screening and less than 150 cell rise in CD4 count in last 3 years
- •Expression of CD38 on CD8+ T cells >10%
- •Plasma HIV RNA viral load less than 50 copies/ml on screening blood test and for at least 72 weeks prior to screening (blips defined as a single viral load >50 and <500 copies/ml preceded and followed by an undetectable result will be permitted)
- •Willing and able to provide written informed consent
- •Females of child-bearing potential will need to use effective contraception
- •Satisfactory ophthalmological assessment including:
- •visual acuity
- •careful ophthalmoscopy
- •fundoscopy
- •central visual field testing with a red target
- •colour vision.
排除标准
- •History of psoriasis, porphyria cutanea tarda, epilepsy, myasthenia gravis, myopathy, cardiac arrhythmias or glucose 6-phosphate dehydrogenase (G6PD) deficiency.
- •Insulin-dependent or non-insulin-dependent diabetes mellitus.
- •Chronic liver disease of any cause or alcoholism (investigator defined)
- •Pneumonia, meningitis, septicaemia or any other serious infection in the 2 months prior to screening.
- •Any acute infection with fever and systemic symptoms in the last 24 hours.
- •Any vaccinations in the 2 months prior to screening.
- •Active malignancy (patients are eligible if treatment for the malignancy was completed more than 2 years prior to screening and there has been no subsequent clinical evidence of active disease or localised completely excised cutaneous cancers and low volume Kaposi's sarcoma) or any active immune-mediated or inflammatory disease.
- •Any known suicide attempts (at any time in the past) or current or past history of depression requiring treatment within the 2 years prior to screening.
- •A woman who is currently pregnant or breastfeeding.
- •Use of systemic corticosteroids or other immunomodulatory drugs within the 12 months prior to screening.
- •Current use of medication with known serious hepatotoxic effects or known interaction with hydroxychloroquine (section 5.2)
- •Evidence of cardiac conduction defects or cardiac arrhythmia on screening ECG.
- •Hepatitis B surface antigen (HBsAg) positive or Hepatitis C PCR positive (patients who are Hepatitis C antibody positive are allowed to enter if PCR is negative).
- •Any of the following laboratory abnormalities on screening blood test:
- •Haemoglobin less than 10.5g/dl
- •Absolute neutrophil count less than 1.0x109/L
- •Platelet count less than 100 X 109/L
- •ALT or AST, or alkaline phosphatase above 2.5 x upper limit of normal (ULN) Template V 2.0, 06 April 2008 SSAT039 Page 23 of 73 Version 6.0, 17 October 2011
- •Serum creatinine greater than 1.5xULN
- •Estimated creatinine clearance (MDRD equation*) below 60ml/min
- •Inability to attend or comply with treatment or follow-up scheduling.
- •Current participation in any other clinical intervention trial.
研究组 & 干预措施
Delayed
Delayed addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART
干预措施: Hydroxychloroquine (Drug)
Immediate
Immediate addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART
干预措施: Hydroxychloroquine (Drug)
结局指标
主要结局
Change in CD4 from baseline
时间窗: 12 weeks
To measure the change in CD4 from baseline after 12 weeks of hydroxychloroquine therapy
次要结局
未报告次要终点