Switching Treatment-Experienced, Integrase Inhibitor-Naïve, Virally Suppressed HIV-1 Infected Adults From Ritonavir Boosted Protease Inhibitors to Dolutegravir: An Open-Label Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 795
- 试验地点
- 4
- 主要终点
- Virologic failure
研究概览
简要总结
Kenya has the 4th largest HIV burden in the world with about 1.6 million people living with HIV. Of these, just over 1 million are on antiretroviral therapy (ART). Current national guidelines recommend a first line regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTI) plus an integrase strand transfer inhibitor (INSTI) or a non-nucleoside reverse transcriptase inhibitor(NNRTI). Second line regimens are composed of 2 NRTI plus a ritonavir boosted protease inhibitor(PIr). This is based on evidence showing good clinical outcomes on this regimen. PIr are associated with side effects including an increase in cardiovascular disease risk and, have significant drug to drug interactions that complicate management of other conditions such as tuberculosis. INSTIs have been shown in one study to be an alternative to PIr in second line regimens when combined with fully active NRTIs. It is not clear if this would still be the case if the activity of the NRTIs was not known. The investigators will evaluate the efficacy of switching from a PIr to a dolutegravir based second line ART regimen.
Hypothesis: switching virologically suppressed patients from a PIr based second line to a dolutegravir based second line is non-inferior to continuing on a PIr based second line.
Objectives: The primary objective will be to evaluate the non-inferiority of switching to a DTG containing regimen relative to maintaining a PI/r containing second-line regimen in virologically suppressed, INSTI-naive HIV-1 positive adults (≥ 18 years old) as determined by having HIV-1 RNA ≥ 50 copies/ml at week 48. Secondary objectives will be to assess the impact of such a switch on CD4 count, safety and tolerability.
Methods: Open-label, randomized, non-inferiority, multisite trial over 48 weeks, describing the efficacy and safety of switching from a second-line ARV regimen containing a ritonavir-boosted protease inhibitor (PI/r) plus 2 NRTIs to DTG plus 2 NRTIs in patients with virological suppression (HIV-1 RNA < 50 copies/ml) for at least 12 weeks and with no prior INSTI exposure. Adult participants will be randomized at baseline to remain on their pre-enrollment PI/r or switch to DTG. Participants will continue the NRTIs from their pre-enrollment regimen in both arms. A total of 766 participants(388 per arm) will be recruited from 4 sites in Kenya Conclusion: This study seeks to inform guidelines around the efficacy and safety of alternative second line regimens.
详细描述
Background and Purpose of Research:
Current Kenya National Antiretroviral(ARV) Guidelines recommend that after failing an NNRTI-based first-line regimen, patients should move to a ritonavir-boosted protease inhibitor (PI/r) + 2 nucleoside reverse transcript inhibitors second-line regimen. Several randomised trials support this sequencing, even without drug resistance testing results to guide the choice of second-line NRTIs. The Kenya guidelines have recommended PI/r-based second-line regimens for over a decade and essentially all second-line patients in Kenya are currently on PI/r-based regimens with approximately 75% of these patients currently virally suppressed.
The pill burden, long-term toxicities, tolerability challenges, drug-drug interactions and higher cost of PI/r containing regimens are considerable disadvantages of the current second-line regimens in Kenya and much of sub-Saharan Africa. In contexts with high Tuberculosis (TB) prevalence, the impact of potential drug-drug interactions is considerable, requiring either super boosting of the PI with ritonavir which is toxic and poorly tolerated and only found to result in adequate drug levels for LPV/r but not for ATV/r or DRV/r or, use of rifabutin which is not co-formulated with other anti-mycobacterial agents and leads to a high pill burden affecting adherence. The supply of rifabutin has been unreliable in Kenya.
No study has evaluated a switch strategy from PI/r to DTG for virally suppressed treatment experienced patients who have failed a prior first line regimen consisting of a NNRTI + NRTIs. If such a strategy is found to be non-inferior to the current standard of care it would have major implications for the current regimens distribution in Kenya and similar settings, allowing a transition of almost 75% of current second-line patients from PI/r-based to DTG-based second line with lower cost, improved tolerability, decreased risk of toxicity, reduced risk of drug-drug interactions, and lower pill burden.
Summary of Previous Studies
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to understand and comply with the protocol requirements, instructions and restrictions
- •Able and willing to give informed consent
- •Age 18 years or above
- •Documented HIV-1 infection as confirmed by HIV-antibody testing as per the Kenya National Guidelines
- •Has been receiving a second-line ARV regimen containing a PI/r (DRV/r, ATV/r or LPV/r) and 2 NRTIs for at least 24 weeks
- •Documented HIV-1 RNA viral load < 50 copies/ml at least 12 weeks prior to enrollment and no viral rebound between the first viral load < 50 copies/ml and the screening viral load
- •HIV-1 RNA viral load < 50 copies/ml at screening (within 28 days prior to enrollment)
- •If female and of childbearing potential, is using effective contraception and is willing to continue using effective contraception throughout the study period (as defined in Appendix 5). Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and age of 45 years or above) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy
排除标准
- •Any prior use of integrase inhibitor
- •Documented HIV-2 infection
- •Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
- •Has AST and/or ALT at least 5-times greater than the upper limit of normal in conjunction with hepatitis B virus infection (HBV) or hepatitis C virus infection (HCV). Note: patients can enter the study with chronic HBV or HCV if AST and ALT are less than 5-times greater than the upper limit of normal and, in the investigators opinion, their medical status will not interfere with assessments or completion of the study
- •Is both HBsAg positive and has a CrCl below 50 ml/min (as estimated using the Cockcroft-Gault estimate for glomerular filtration rate)
- •Advanced renal insufficiency requiring dialysis
- •If female, currently pregnant or breastfeeding, or intending to become pregnant during the study period
- •Documented opportunistic infection within 4 weeks prior to the study enrolment
- •Investigator opinion that the patient should switch from PI/r to DTG immediately for clinical reasons (including Grade 3 or 4 lipid abnormalities at screening or enrollment)
- •Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the study
- •History or presence of allergy to the study drugs or their components
研究组 & 干预措施
Dolutegravir
Participants in this arm will have a switch from a protease inhibitor based second line regimen to Dolutegravir maintaining the same NRTI backbone
干预措施: Dolutegravir (Drug)
Protease Inhibitor
Participants in this arm will be maintained on their protease inhibitor based second line regimen
干预措施: Dolutegravir (Drug)
结局指标
主要结局
Virologic failure
时间窗: 48 weeks
Proportion of participants with HIV-1 RNA ≥ 50 copies/ml at week 48 (by US Food and Drug Administration snapshot algorithm, modified to allow for changes in NRTIs for clinical reasons)
次要结局
- Blood sugar(24 and 48 weeks)
- CD4 count(24 and 48 weeks)
- Patient satisfaction: HIV Treatment Satisfaction Questionnaire scores(Baseline, week 24 and week 48)
- Treatment success(24 and 48 weeks)
- Total cholesterol:HDL ratio(24 and 48 weeks)
- Virologic failure(24 weeks)
- Body mass index(24 and 48 weeks)
- Waist-hip ratio(24 and 48 weeks)
- Waist circumference(24 and 48 weeks)
- Low density lipoprotein(24 and 48 weeks)
- Weight(24 and 48 weeks)
- Total cholesterol(24 and 48 weeks)
- Triglyceride(24 and 48 weeks)
- Percentage of participants experiencing an adverse event(24 and 48 weeks)
- Resistance(48 weeks)
研究者
Loice Achieng
Principal Investigator
University of Nairobi