在 HIV-1 感染的抗逆转录病毒初治成人中，采用卡替拉韦加利匹韦林（每日 1 次）进行诱导治疗后，加用卡替拉韦加核苷逆转录酶抑制剂（LATTE）：一项随机、2b 期、剂量范围试验。
Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial.
机构信息
GlaxoSmithKline, Infectious Diseases, Research Triangle Park, NC, USA.
Central Texas Clinical Research, Austin, TX, USA.
出版信息
Lancet Infect Dis. 2015 Oct;15(10):1145-1155. doi: 10.1016/S1473-3099(15)00152-8. Epub 2015 Jul 19.
BACKGROUND
In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals.
METHODS
In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809.
FINDINGS
Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group.
INTERPRETATION
Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection.
FUNDING
ViiV Healthcare and Janssen Research and Development.
背景
在 I 期试验中，HIV-1 整合酶链转移抑制剂卡博特韦（GSK1265744）单独使用或与非核苷类逆转录酶抑制剂利匹韦林联合使用时，具有良好的耐受性。我们评估了卡博特韦加利匹韦林作为一种两药口服抗逆转录病毒方案，用于维持抗逆转录病毒初治的 HIV-1 感染者的病毒抑制。
方法
在加拿大和美国进行的多中心 2b 期长效抗逆转录病毒治疗使能（LATTE）试验中，将 181 例抗逆转录病毒初治的 HIV-1 感染成人（年龄≥18 岁）随机分为 1:1:1:1 比 10mg、30mg、60mg 每天口服一次卡博特韦或每天口服一次依非韦伦 600mg 加双重核苷逆转录酶抑制剂（NRTIs）24 周诱导期。在第 24 周时病毒学抑制的患者接受两药维持治疗方案，由随机分配的卡博特韦剂量加口服利匹韦林 25mg 或继续依非韦伦加 NRTIs 治疗 72 周。患者和研究人员对卡博特韦的剂量在 96 周时进行双盲，但对卡博特韦或依非韦伦的分配没有双盲。主要终点是第 48 周时 HIV-1 RNA 载量少于 50 拷贝/ml（美国食品和药物管理局快照算法）的患者比例。分析采用意向治疗。本研究在 ClinicalTrials.gov 注册，NCT01641809。
结果
在随机分配和治疗的 243 例患者中，156 例（86%）60mg、30mg、60mg 组（分别为 52[87%]、51[85%]和 53[87%]）和 46 例（74%）依非韦伦组在诱导治疗后 HIV-1 RNA 载量少于 50 拷贝/ml。卡博特韦组患者在第 24 周从双重 NRTIs 转为利匹韦林后，149 例（82%；77-88）患者病毒学抑制，卡博特韦组 48 例（80%；70-90）、48 例（80%；70-90）和 53 例（87%；78-95）患者在 10mg、30mg、60mg 组，依非韦伦组 44 例（71%；60-82）病毒学抑制，137 例（76%；69-82）接受卡博特韦（41[68%]、45[75%]和 51[84%]）患者在 10mg、30mg、60mg 组，依非韦伦组 39 例（63%；51-75）病毒学抑制。93 例（51%）卡博特韦治疗患者（28[47%]、32[53%]和 33[54%]）和 42 例（68%）依非韦伦治疗患者报告了与治疗相关的不良事件。卡博特韦组 6 例（3%）患者因治疗相关不良事件退出，依非韦伦组 9 例（15%）患者因治疗相关不良事件退出。
解释
卡博特韦加双重 NRTI 治疗在诱导期具有强大的抗病毒活性。作为一种两药维持治疗方案，卡博特韦加利匹韦林的抗病毒活性与依非韦伦加双重 NRTIs 相似，直到第 96 周。联合疗效和安全性结果支持我们选择每天口服 30mg 卡博特韦进行进一步评估。LATTE 之前的研究评估了长效注射制剂作为一种两药方案治疗 HIV-1 感染的效果。
资金
ViiV 医疗保健公司和杨森研究与开发公司。
Zotero 插件