HIV Infections
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGDolutegravir 50 MG / Lamivudine 300 MG Oral Tablet [Dovato]
change of current antiretroviral treatment to DTG 50 mg/3TC 300 mg QD
Sponsors
Fundacion SEIMC-GESIDA
ViiV Healthcare
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase IIa, open-label, single arm, multicentric study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults (\>=18 years old) with HIV-1 infection able to understand and give informed written consent. 2. 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. 3. 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. 4. CD4 count \> 200 cel/μL at screening. 5. 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.
Exclusion criteria
1. Participants with M184V/I or K65R in screening visit proviral DNA Sanger genotype. 2. 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 3. INSTI resistance mutations in historical RNA genotype. 4. 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. 5. 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. 6. Patients with active opportunistic infections or cancer requiring intravenous treatment and/or chemotherapy at screening. 7. Any comorbidities or treatment with experimental drugs that according to the investigator could bias study results or entail additional risks for the participant. 8. Participants receiving other medications that according to study drug label are contraindicated. 9. Severe hepatic impairment (Class C) as determined by Child-Pugh classification. 10. Alanine aminotransferase (ALT) over 5 times the upper limit of normal (ULN) or ALT over 3xULN and bilirubin over 1.5xULN. 11. 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); 12. Creatinine clearance of \<30 mL/min/1.73m2 via CKD-EPI method. 13. Any verified Grade 4 laboratory abnormality that to the investigators criteria would affect the safety of the participant if included in the study. 14. History or presence of allergy to dolutegravir or lamivudine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Participants who discontinue treatment due to AEs (al week 96) |
| Estimations of Virological Control | Week 48 and week 96 | Proportion of VF (≥50 copies/mL) ITT-e, per protocol population (PP), Proportion of VF (≥200 copies/mL), ITT-e and PP population, FDA snapshot. Proportion of Confirmed Virologic Withdrawal (\[CVW\]: A VL≥ 50 copies/mL followed by a VL≥ 200 copies/mL in retest), ITT-e and PP population, FDA snapshot. Proportion of Precautionary Virologic Withdrawal (\[PVW\]: three consecutive VL between 50- 200 copies/mL), ITT-e and PP population, FDA snapshot. Proportion of participants with VL\<50 copies/mL, ITT-e and per protocol population, FDA snapshot. |
| Viral Resistance in Persons Experiencing VF. | Throughout all the study, an average of 96 weeks | Percentage of VF with drug resistance associated mutations. \- Describe number and type of resistanceassociated mutations in VF |
| Time to VF | Throughout all the study, an average of 96 weeks | Due to the low number of events, the analysis of factors associated with VF (i.e., time to VF) was not performed. Additionally, because of the limited number of events, analyses of NGS-related outcomes were conducted only at the 5% level. The pre-specified subgroup analyses were modified and replaced with analyses based on baseline 3TC or FTC use, confirmed prior resistance to 3TC, and prior exposure to INSTIs. |
| 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 | All participants with M184V/I detected at baseline in proviral DNA NGS had a VL \<50 copies/mL at week 48 or last study visit. |
| Time Virologically Suppressed | Throughout all the study, an average of 96 weeks | Participants were virologically suppressed for 9 years before the study |
| 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 | Percentage of VF with drug resistance associated mutations and proportion of participants with VF with baseline 3TC or INSTI resistance- associated mutations detected at baseline by NGS with 5% threshold. |
| 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 | Proportion of participants with transient viral rebounds with baseline 3TC or INSTI resistance- associated mutations detected at baseline by NGS with 5% threshold. |
| 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 | Next-generation sequencing (NGS) of plasma RNA was successful in one of the two virological withdrawal cases. |
| Change in CD4+ Cell Count | Basal, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72 and week 96 | CD4+ count values were observed throughout the 96 weeks. |
| Frequency of Resistance Mutations (RT and Integrase) in Proviral DNA Measured by NGS. | Throughout all the study, an average of 96 weeks | — |
Countries
Spain
Participant flow
Recruitment details
Sixteen participants discontinued by the following reasons: two virological withdrawals (1 Confirmed Virologic Withdrawal \[CVW\], 1 Precautionary Virologic Withdrawal \[PVW\]), four adverse-event withdrawals, two investigator decisions, two protocol violations, two consent withdrawals, three lost to follow-up and one unrelated death from Chronic Obstructive Pulmonary Disease (COPD) at week 96.
Pre-assignment details
Between 28 July 2021 and 11 April 2022, 167 individuals were enrolled (signed the informed consent): 46 were screening failures and 121 were included (all received ≥1 dose of Dolutegravir/lamivudine \[DTG/3TC\] and constitute the ITT-e population). Twelve participants discontinued before week 48 and a further four between weeks 48 and 96, leaving 105 (86.8 %) on study at week 96.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56.3 years |
| ART duration | 8 years |
| Baseline CD4+ count | 706 cells/mm3 |
| Nadir CD4 | 180 cells/mm^3 |
| Number of Participants with 3TC or FTC at baseline | 66 Participants |
| Number of Participants with Baseline antiretroviral regimen 2 NRTI + 1bPI | 27 Participants |
| Number of Participants with Baseline antiretroviral regimen 2NRTI + 1 INS | 30 Participants |
| Number of Participants with Baseline antiretroviral regimen 2 NRTI + 1 NNRTI | 3 Participants |
| Number of Participants with Baseline antiretroviral regimen bPI monotherapy | 20 Participants |
| Number of Participants with Baseline antiretroviral regimen Other | 5 Participants |
| Number of Participants with Baseline antiretroviral regimen Two-drug regimens | 36 Participants |
| Number of Participants with Baseline M184V/I in NGS > 20% threshold | 17 Participants |
| Number of Participants with Baseline M184V/I in NGS > 5% threshold | 24 Participants |
| Number of Participants with Confirmed prior 3TC resistance | 114 Participants |
| Number of Participants with Historical K65R mutation | 6 Participants |
| Number of Participants with Historical M184I/undefined | 6 Participants |
| Number of Participants with Historical M184V mutation | 107 Participants |
| Number of Participants with Prior exposure to dolutegravir | 40 Participants |
| Number of Participants with Prior exposure to INSTIs | 68 Participants |
| Number of Participants with Suspected prior 3TC resistance | 7 Participants |
| Race/Ethnicity, Customized Afroamerican | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 102 Participants |
| Race/Ethnicity, Customized Latin | 18 Participants |
| Route of transmission Blood transfusion | 1 Participants |
| Route of transmission Heterosexual sex | 36 Participants |
| Route of transmission Intravenous drug use | 35 Participants |
| Route of transmission Men who have sex with men | 43 Participants |
| Route of transmission Other/Unknown | 6 Participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 86 Participants |
| Supressed plasma HIV RNA | 9.2 years |
| Time since genotype with 3TC resistance | 15.2 years |
| Years since HIV diagnosis | 26.2 years |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 167 |
| other Total, other adverse events | 65 / 167 |
| serious Total, serious adverse events | 17 / 167 |
Outcome results
None listed