Virologic Outcomes of Lamivudine/Dolutegravir in Virologically Suppressed Subjects With Expected or Confirmed Resistance to Lamivudine.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 167
- 试验地点
- 19
- 主要终点
- The efficacy of a switch to DTG/3TC for maintenance of virologic suppression, in persons with past confirmed or suspected 3TC resistance, when proviral DNA population sequencing does not detect 3TC resistance-associated mutations at baseline.
研究概览
简要总结
Dolutegravir (DTG) plus lamivudine (3TC) is a dual regimen combination recommended for both naïve and suppressed persons with HIV-1 infection1. However, data regarding the efficacy of this regimen in suppressed persons with history of past resistance or virologic failures is currently insufficient. This is a phase IIa, open-label, single arm, multicentric study.
The hypothesis is that therapy with DTG/3TC would be able to maintain viral control in HIV infected participants with prior history of 3TC resistance but without evidence of M184V/I resistance mutation in proviral DNA population sequencing at baseline. The investigators also hypothesize that archived minority 3TC resistance associated mutations detected by next-generation (NGS) sequencing prior to the switch would not have a significant impact on the efficacy of DTG/3TC.
详细描述
This is a multicentre study, and it will be conducted at different healthcare centres in Spain. 117 participants will be recruited. A minimum of 30%-50% of the study population would be required to have historical RNA population genotype with confirmed M184V/I mutation.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults (>=18 years old) with HIV-1 infection able to understand and give informed written consent.
- •Stable ART in the 12 weeks prior to screening visit.
- •- Only switch for tolerability/convenience/access reasons to generic drugs or switch from ritonavir to cobicistat or TDF to TAF would be allowed in the 12-week window and as long as the components of the regimen are unchanged.
- •Viral load <50 copies/mL at screening and in the year prior to study entry.
- •- A blip (50-500 copies/ml) would be allowed within 48 weeks prior to inclusion in the study, if preceded and followed by an undetectable VL determination.
- •CD4 count > 200 cel/μL at screening.
- •History of 3TC resistance: either confirmed historical 3TC resistance (historical RNA Sanger or RNA NGS>20% threshold genotype with M184V/I mutation) OR suspected historical 3TC resistance.
- •Suspicion of past 3TC resistance is defined as any of the following:
- •i. Previous treatment with only 2 NRTIs (1 of them being emtricitabine or 3TC [XTC]).
- •ii. Two consecutive VL > 200 cp/mL while on treatment including XTC. iii. One VL > 200 cp/mL while on treatment including XTC PLUS change of ART as consequence of that elevated VL.
排除标准
- •Participants with M184V/I or K65R in screening visit proviral DNA Sanger genotype.
- •Prior virologic failure (VF) under integrase inhibitor (INSTI)- based regimen. defined as two consecutive VL > 200 copies/mL while receiving INSTI regardless of genotypic test results
- •INSTI resistance mutations in historical RNA genotype.
- •Positive Surface Hepatitis B Ag (HBAgS) OR negative HBAgS and negative hepatitis B surface antibody (anti-HBs) with positive anti-core antibody (anti-HBc) and positive HBV DNA.
- •Pregnant, breastfeeding women, women with a positive pregnancy test at the time of screening, sexually active fertile women wishing to conceive or unwilling to commit to contraceptive methods (see Appendix 1 for the accepted list of the highly effective methods for avoiding pregnancy), for the duration of the study and until 4 weeks after the last dose of study medication. All women are considered fertile unless they have undergone a sterilizing surgery or are over the age of 50 with spontaneous amenorrhea for over 12 months prior to study entry.
- •Patients with active opportunistic infections or cancer requiring intravenous treatment and/or chemotherapy at screening.
- •Any comorbidities or treatment with experimental drugs that according to the investigator could bias study results or entail additional risks for the participant.
- •Participants receiving other medications that according to study drug label are contraindicated.
- •Severe hepatic impairment (Class C) as determined by Child-Pugh classification.
- •Alanine aminotransferase (ALT) over 5 times the upper limit of normal (ULN) or ALT over 3xULN and bilirubin over 1.5xULN.
- •Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or jaundice due to Gilbert's syndrome or asymptomatic gallstones);
- •Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method.
- •Any verified Grade 4 laboratory abnormality that to the investigators criteria would affect the safety of the participant if included in the study.
- •History or presence of allergy to dolutegravir or lamivudine.
研究组 & 干预措施
Dovato (Dolutegravir+lamivudine)
Treatment: Dolutegravir 50 mg/Lamivudine 300 mg, one film coated-tablet once daily during 96 weeks
干预措施: Dolutegravir 50 MG / Lamivudine 300 MG Oral Tablet [Dovato] (Drug)
结局指标
主要结局
The efficacy of a switch to DTG/3TC for maintenance of virologic suppression, in persons with past confirmed or suspected 3TC resistance, when proviral DNA population sequencing does not detect 3TC resistance-associated mutations at baseline.
时间窗: Week 48
Proportion of virologic failure (VF) defined as HIV-1 RNA viral load (VL) ≥ 50 copies per mL (in the intention-to-treatexposed population (ITT-e) using the US Food and Drug Administration (FDA) snapshot algorithm).
The Efficacy of a Switch to DTG/3TC for Maintenance of Virologic Suppression, in Persons With Past Confirmed or Suspected 3TC Resistance, When Proviral DNA Population Sequencing Does Not Detect 3TC Resistance-associated Mutations at Baseline.
时间窗: Week 48
There were eight participants with no data at week 48: one LTFU, one protocol deviation (M184V at screening), two investigator decision (1 lung cancer, 1 M184V mutation detected in plasma RNA population genotyping at transient rebound, suppressed with dolutegravir/lamivudine not fulfilling criteria for virologic withdrawal), one consent withdrawal and three withdrawals for AEs. It was pre-specified to report all participants who discontinued with last available HIV-1 RNA ≥50 copies/mL in "Number of Participants with HIV-1 RNA ≥50 copies/mL" category at week 48.
次要结局
- Estimations of virological control(Week 48 and week 96)
- Viral resistance in persons experiencing VF.(Throughout all the study, an average of 96 weeks)
- Proportion of participants with VF with baseline 3TC or INSTI resistanceassociated mutations detected at baseline by NGS with 1, 5, and 20% threshold.(Throughout all the study, an average of 96 weeks)
- Type of resistance mutations (RT and integrase) in proviral DNA measured by NGS.(Throughout all the study, an average of 96 weeks)
- Frequency of resistance mutations (RT and integrase) in proviral DNA measured by NGS.(Throughout all the study, an average of 96 weeks)
- Change in CD4+/CD8+ cell counts ratio(Basal, Week 48 and week 96)
- Proportion of VF in subgroups: Confirmed historical M184V/I vs No resistance mutations(Throughout all the study, an average of 96 weeks)
- Proportion of VF in subgroups: INSTI exposure vs No prior INSTI exposure(Throughout all the study, an average of 96 weeks)
- Time virologically suppressed(Throughout all the study, an average of 96 weeks)
- Proportion of VF in subgroup: Time on 3TC/FTC(Throughout all the study, an average of 96 weeks)
- Proportion of participants with transient viral rebounds with baseline 3TC or INSTI resistance- associated mutations detected at baseline by NGS with 1, 5, and 20% threshold.(Throughout all the study, an average of 96 weeks)
- Change in CD4+ cell count(Basal, Week 48 and week 96)
- Proportion of subjects who discontinue treatment due to AEs(Basal, week 48 and week 96)
- Incidence and severity of AEs and laboratory abnormalities.(Basal, Week 48 and week 96)
- Time to VF(Throughout all the study, an average of 96 weeks)
- Estimations of Virological Control(Week 48 and week 96)
- Viral Resistance in Persons Experiencing VF.(Throughout all the study, an average of 96 weeks)
- Proportion of VF in Subgroups: Confirmed Historical M184V/I vs No Resistance Mutations(Throughout all the study, an average of 96 weeks)
- Proportion of VF in Subgroups: INSTI Exposure vs No Prior INSTI Exposure(Throughout all the study, an average of 96 weeks)
- Time Virologically Suppressed(Throughout all the study, an average of 96 weeks)
- Proportion of VF in Subgroup: Time on 3TC/FTC(Throughout all the study, an average of 96 weeks)
- Percentage of Participants With VF With Baseline 3TC or INSTI Resistanceassociated Mutations Detected at Baseline by NGS With 1, 5, and 20% Threshold.(Throughout all the study, an average of 96 weeks)
- Proportion of Participants With Transient Viral Rebounds With Baseline 3TC or INSTI Resistance- Associated Mutations Detected at Baseline by NGS With 1, 5, and 20% Threshold.(Throughout all the study, an average of 96 weeks)
- Number of Participants With M184V/I Presence by Successful Plasma RNA NGS in Participants With Virological Dropout(Throughout all the study, an average of 96 weeks)
- Frequency of Resistance Mutations (RT and Integrase) in Proviral DNA Measured by NGS.(Throughout all the study, an average of 96 weeks)
- Change in CD4+ Cell Count(Basal, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72 and week 96)
- Change in CD4+/CD8+ Cell Counts Ratio(Basal, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72 and week 96)
- Percentage and Severity of AEs and Laboratory Abnormalities.(Basal, Week 48 and week 96)
- Proportion of Subjects Who Discontinue Treatment Due to AEs(Basal, week 48 and week 96)