Center for Global Health and Division of Infectious Diseases, Northwestern University, Chicago, IL, USA.
INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France.
Lancet HIV. 2015 Mar;2(3):e82-91. doi: 10.1016/S2352-3018(15)00026-0. Epub 2015 Feb 17.
Achievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine.
In this multicentre, randomised, open-label, non-comparative, phase 2 clinical trial, we enrolled eligible adults 18-70 years of age with chronic HIV-1 infection on suppressive antiretroviral therapy with current CD4 count of at least 350 cells per μL and HIV DNA between 10 and 1000 copies per 10(6) peripheral blood mononuclear cells. After an 8 week lead-in of antiretroviral intensification therapy (standard dose raltegravir and dose-adjusted maraviroc based on baseline antiretroviral therapy), patients were randomly assigned (1:1) to receive antiretroviral therapy intensification alone or intensification plus injections of HIV DNA prime vaccine (4 mg VRC-HIVDNA016-00-VP) at weeks 8, 12, and 16, followed by HIV rAd5 boost vaccine (10(10) particle units of VRC-HIVADV014-00-VP) at week 32. Randomisation was computer generated in permuted blocks of six and was stratified by study site. The primary endpoint was a 0·5 log10 or greater decrease in HIV DNA in peripheral blood mononuclear cells at week 56. This study is registered with ClinicalTrials.gov, number NCT00976404.
Between Nov 29, 2010, and Oct 28, 2011, we enrolled 28 eligible patients from three academic HIV clinics in the USA. After the 8 week lead-in of antiretroviral intensification therapy, 14 patients were randomly assigned to continue antiretroviral therapy intensification alone and 14 to intensification plus vaccine. Enrolled participants had median CD4 count of 636 cells per μL, median HIV DNA 170 copies per 10(6) peripheral blood mononuclear cells, and duration of antiretroviral therapy of 13 years. The median amount of HIV DNA did not change significantly between baseline and week 56 in the antiretroviral therapy intensification plus vaccine group. One participant in the antiretroviral therapy intensification alone group reached the primary endpoint, with 0·55 log10 decrease in HIV DNA in peripheral blood mononuclear cells. Both treatments were well tolerated. No severe or systemic reactions to vaccination occurred, and five serious adverse events were recorded during the study, most of which resolved spontaneously or were judged unrelated to study treatments.
Antiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir. A multifaceted approach that includes stronger activators of HIV expression and novel immune modulators will probably be needed to reduce the latent HIV reservoir and allow for long-term control in patients off antiretroviral therapy.
Objectif Recherche Vaccin SIDA (ORVACS).
实现艾滋病病毒感染的治愈可能需要重新激活潜伏的病毒并改善艾滋病特异性免疫。作为初步步骤，在这项试验中，我们评估了强化抗逆转录病毒治疗和使用 DNA 初免和重组腺病毒 5（rAd5）加强疫苗进行免疫调节的效果。
在这项多中心、随机、开放标签、非对照、2 期临床研究中，我们招募了年龄在 18-70 岁之间、有慢性 HIV-1 感染、正在接受抑制性抗逆转录病毒治疗、目前 CD4 计数至少为 350 个细胞/μL 且 HIV DNA 为每 10(6)个外周血单核细胞 10-1000 拷贝的合格成年人。在 8 周的强化抗逆转录病毒治疗导入期（基于基线抗逆转录病毒治疗的标准剂量雷替格韦和剂量调整的马拉维若）后，患者被随机分配（1:1）接受强化抗逆转录病毒治疗或强化治疗加 HIV DNA 初免疫苗（4mg VRC-HIVDNA016-00-VP）在第 8、12 和 16 周，然后在第 32 周接受 HIV rAd5 加强疫苗（10(10)个病毒颗粒单位的 VRC-HIVADV014-00-VP）。随机分配由计算机生成，以 6 个为一组的置换块进行，并按研究地点分层。主要终点是外周血单核细胞中 HIV DNA 减少 0.5log10 或更多，时间为第 56 周。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00976404。
在 2010 年 11 月 29 日至 2011 年 10 月 28 日期间，我们从美国的三个学术性 HIV 诊所招募了 28 名符合条件的患者。在 8 周的强化抗逆转录病毒治疗导入期后，14 名患者被随机分配继续接受强化抗逆转录病毒治疗，14 名患者接受强化治疗加疫苗。纳入的参与者中位 CD4 计数为 636 个细胞/μL，中位 HIV DNA 为每 10(6)个外周血单核细胞 170 个拷贝，抗逆转录病毒治疗持续时间为 13 年。在强化抗逆转录病毒治疗加疫苗组中，从基线到第 56 周，HIV DNA 的中位数没有明显变化。强化抗逆转录病毒治疗组中有 1 名参与者达到了主要终点，外周血单核细胞中 HIV DNA 减少了 0.55log10。两种治疗均耐受良好。疫苗接种没有发生严重或全身性反应，研究期间记录了 5 例严重不良事件，大多数自行缓解或被认为与研究治疗无关。
强化抗逆转录病毒治疗后再给予 DNA 初免和 rAd5 加强疫苗并不能显著增加 HIV 的表达或减少潜伏的 HIV 储存库。可能需要一种多方面的方法，包括更强的 HIV 表达激活剂和新型免疫调节剂，以减少潜伏的 HIV 储存库，并允许患者在停止抗逆转录病毒治疗后长期控制。
Objectif Recherche Vaccin SIDA（ORVACS）。
