Dolutegravir-Lamivudine for naïve HIV-Infected Patients With ≤200 CD4/mm3

Protocol Title: DOLCE: Dolutegravir-Lamivudine for naïve HIV-Infected Patients with ≤200 CD4/mm3

Protocol Number: FH-57

Study Objectives: To assess the antiviral activity at week 48 of DTG+3TC among naïve HIV patients with a CD4 count ≤200 cells /mm3.

Primary endpoint: Proportion of patients with viral load \< 50 copies/mL at week 48 using the ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) population.

Secondary Objectives:

* To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 24
* To evaluate the safety and tolerability of DTG+3TC and DTG+TDF/XTC over time
* To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 48 in patients with baseline viral load \>100,000 c/mL
* To evaluate immunological activity (CD4+ lymphocyte \[CD4 counts\]) at Week 24 and Week 48
* To assess the development of HIV-1 resistance in patients with virologic failure or viral rebound treated with DTG+3TC or DTG+TDF/XTC
* To evaluate the incidence of disease progression (HIV-associated conditions, AIDS and death) of DTG + 3TC and DTG + TDF/XTC over time.

Secondary endpoints:

* Proportion of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL at week 24
* Frequency, type and severity of adverse events and laboratory abnormalities and proportion of patients who discontinue DTG+3TC or DTG+TDF/XTC due to adverse events or death
* Proportion of patients with baseline HIV-1 RNA \>100,000 c/mL that achieve virological suppression at week 48 weeks,
* Changes in CD4 count, CD8 count and CD4/CD8 ratio between baseline and 48 weeks
* Number and type of resistance mutations in case of virologic failure (defined as a confirmed viral above 200 copies/mL after week 24 copies/mL or viral rebound at any timepoint)
* Incidence of IRIS and disease progression (HIV associated conditions, AIDS and death).

Tertiary objectives:

● TDF/XTCTo explore change in health-related quality-of-life for subjects treated with DTG plus 3TC and DTG + TDF/XTC

Tertiary endpoints:

● Change from Baseline in health-related quality of life using EQ-5D-5L and PHQ9 at Weeks 24, and 48

Patient Population:

HIV-1-infected subjects aged \>18 years who are naïve to antiretroviral therapy with ≤200 CD4 cell/mm3

Study Design:

Prospective, Phase IV, randomized, multicenter, parallel group study design

Regimens:

Dolutegravir 50 mg /lamivudine 300 mg QD FDC. Dolutegravir 50 mg QD plus tenofovir 300 mg/emtricitabine 200mg or plus tenofovir 300 mg/ lamivudine 300 mg.

Duration: 48 weeks

Sample size:230 subjects

Eligibility Criteria:
Inclusion Criteria:

1. Subject has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB) / Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject has had the opportunity to ask questions.
2. Documented HIV-1 infection defined as a positive rapid test or ELISA plus a plasma HIV-1 RNA (\>1,000 copies/mL) or a positive western blot. A previous result performed on the last 30 days can be used.
3. ≥18 years of age
4. Naïve to ARV therapies (defined as ≤ 10 days of prior therapy with any antiretroviral therapy following an HIV diagnosis). Previous use of PrEP or PEP is allowed if there is documented HIV seronegativity between the last prophylactic dose and the date of HIV diagnosis.
5. HIV RNA at screening visit \> or = 1,000 copies/mL. A previous result performed on the last 30 days can be used.
6. CD4 at screening \< or = 200 cells/mL A previous result performed on the last 30 days can be used.
7. Subjects can comply with protocol requirements.
8. Subject agrees not to take any medication during the study, including over-the-counter medicines or herbal preparations, without the approval of the trial physician.
9. Subject's general medical condition, in the investigator's opinion, does not interfere with assessments and completion of the study.
10. A female may be eligible to enter and participate in the study if she is not pregnant (as confirmed by serum pregnancy test negative at screening, and a urine negative test at baseline), not lactating and at least one of the following condition applies:

    1. Women with non-reproductive potential, defined as pre-menospausal females with documented tubal ligation or hysterectomy, or bilateral oophorectomy; or as post-menospausal women defined as 12 months of spontaneous amenorrhea, and ≥45 years of age in women without hormonal replacement therapy.
    2. Women with reproductive potential and agrees to follow one of the contraceptive options listed in the Appendix 3 from at least 15 days prior to the first dose of medication and until at least 30 days after the last dose of study medication and completion of the follow-up visit.

Any contraception method must be used consistently, in accordance with the approved product label. All subjects participating in the study should be counselled on safer sexual practices including the use of effective barrier methods and the choice of effective contraceptive method should be documented in the eCRF.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding, or women who plan to become pregnant in the next year
2. Subjects testing positive for Hepatitis B surface antigen (+HBsAg) at screening, or anticipated need for Hepatitis C virus (HCV) therapy with drugs with potential drug-drug interaction during the study
3. Subjects with severe hepatic impairment (Child-Pugh class C), or unstable liver disease (ascites, encephalopathy, coagulopathy, or oesophageal or gastric varices) or cirrhosis.
4. Opportunistic infections that impede to start ART immediately (specifically tuberculosis within the first 2 weeks of anti-tuberculosis treatment, and meningeal tuberculosis or cryptococcosis within the first month of specific treatment. Subjects with other suspected or confirmed active opportunistic infections and subjects with tuberculosis or cryptococcal disease after the initial period can be included if she/he can follow the protocol and if her/his participation could benefit the subject. A clear documentation of these aspects must to be done in the clinical chart of the participant.
5. Subjects who in the investigator's judgment, pose a significant suicidality risk.
6. History or presence of allergy to the study drugs or their components or drugs of their class
7. Treatment with any of the following agents within 28 days of screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses; or treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening; or exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of investigational product
8. Any previous evidence of resistance to dolutegravir (defined as the presence of G118R, Q148 H/K/R or R263K), to lamivudine (presence of the mutation M184V) or resistance to tenofovir (mutation K65R or more than 3 TAMs) with a Sanger sequence method or using next-generation sequencing (NGS) at a frequency \>15%. If the subject does not have a previous resistance test, the investigator can take the samples and randomize the subject while awaiting the results (see section 4.8 for follow up).
9. Any verified Grade 4 abnormality.
10. Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (ULN), or ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with \>35% direct bilirubin)
11. Creatinine clearance of \<50mL/min via Cockroft-Gault method