Clinical trial NCT04880785: Lamivudine/Dolutegravir in Virologically Suppressed Subjects With Expected or Confirmed Resistance to Lamivudine
Official title: Virologic Outcomes of Lamivudine/Dolutegravir in Virologically Suppressed Subjects With Expected or Confirmed Resistance to Lamivudine.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: Fundacion SEIMC-GESIDA
Sponsor class: OTHER
Collaborators: name: ViiV Healthcare
First posted: 2021-05-11
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase IIa, open-label, single arm, multicentric study
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: Week 48
Secondary outcomes:
measure: Estimations of virological control
timeFrame: Week 48 and week 96
measure: Viral resistance in persons experiencing VF.
timeFrame: Throughout all the study, an average of 96 weeks
measure: Time to VF
timeFrame: Throughout all the study, an average of 96 weeks
measure: Proportion of VF in subgroups: Confirmed historical M184V/I vs No resistance mutations
timeFrame: Throughout all the study, an average of 96 weeks
measure: Proportion of VF in subgroups: INSTI exposure vs No prior INSTI exposure
timeFrame: Throughout all the study, an average of 96 weeks
measure: Time virologically suppressed
timeFrame: Throughout all the study, an average of 96 weeks
measure: Proportion of VF in subgroup: Time on 3TC/FTC
timeFrame: Throughout all the study, an average of 96 weeks
measure: Proportion of participants with VF with baseline 3TC or INSTI resistanceassociated mutations detected at baseline by NGS with 1, 5, and 20% threshold.
timeFrame: Throughout all the study, an average of 96 weeks
measure: 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.
timeFrame: Throughout all the study, an average of 96 weeks
measure: Type of resistance mutations (RT and integrase) in proviral DNA measured by NGS.
timeFrame: Throughout all the study, an average of 96 weeks
measure: Frequency of resistance mutations (RT and integrase) in proviral DNA measured by NGS.
timeFrame: Throughout all the study, an average of 96 weeks
measure: Change in CD4+ cell count
timeFrame: Basal, Week 48 and week 96
measure: Change in CD4+/CD8+ cell counts ratio
timeFrame: Basal, Week 48 and week 96
measure: Incidence and severity of AEs and laboratory abnormalities.
timeFrame: Basal, Week 48 and week 96
measure: Proportion of subjects who discontinue treatment due to AEs
timeFrame: Basal, week 48 and week 96
Other outcomes:
Locations:
city: Vigo
country: Spain
facility: H. Álvaro Cunqueiro
state: Pontevedra
city: Alicante
country: Spain
facility: H. de Elche
city: Alicante
country: Spain
facility: H. General de Alicante
city: Barcelona
country: Spain
facility: H. Bellvitge
city: Barcelona
country: Spain
facility: H. Clinic
city: Barcelona
country: Spain
facility: H. del Mar
city: Coruña
country: Spain
facility: CHUAC
city: Donostia
country: Spain
facility: H. de Donosti
city: Madrid
country: Spain
facility: H. Fundación Jimenez Díaz
city: Madrid
country: Spain
facility: H. Infanta Leonor
city: Madrid
country: Spain
facility: H. La Princesa
city: Madrid
country: Spain
facility: H. Príncipe de Asturias
city: Madrid
country: Spain
facility: H. Severo Ochoa
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital General Univ. Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Univ. La Paz
city: Málaga
country: Spain
facility: H. Virgen de la Victoria
Study officials:
References: