Dolutegravir/Lamivudine in Treatment-Naïve Pregnant Women

Evaluating the Efficacy and Safety of Dolutegravir/Lamivudine (DTG/3TC) in ART-Naïve Pregnant Women

Protocol Number: FH-94

Study Objetives:

Primary:

• To evaluate the virological response to Dolutegravir/Lamivudine in naive pregnant women with HIV who are starting antiretroviral therapy and vertical transmission in exposed neonates.

Secondary:

• To evaluate the incidence of maternal adverse events.
• To evaluate perinatal outcomes at delivery.
• To evaluate maximum virological suppression at delivery.
• To evaluate the incidence of changes in body weight exceeding what is expected for gestation.
• To evaluate the immune response based on changes in CD4, CD8, and CD4/CD8 ratio values during pregnancy.
• Assess baseline resistance and the development of resistance to virological failure to integrase inhibitors and INTRs during treatment with DTG+3TC or DTG+TDF/XTC or DTG+TAF/FTC.
• To evaluate the incidence of HIV infection in children that breastfeed.
• To evaluate safety outcomes and virological response of DTG+3TC compared to DTG+TDF/XTC or DTG+TAF/FTC.

Exploratory:

• To explore the non-inferiority of DTG+3TC therapy compared to DTG+TDF/XTC or DTG+TAF/FTC treatment.
• To evaluate the frequency of antiretroviral therapy withdrawal or modification before delivery.

Primary endpoints:

• Proportion of pregnant women who achieve an HIV-1 plasma viral load <200 copies/mL at delivery after starting DTG+3TC (Intention-to-Treat Exposed analysis).
• Proportion of children born without HIV infection at 6 weeks & 6 months of age, defined by the negative result of negative virological tests (PCR) performed at birth (delivery visit and up to 72 hours after delivery), at 6 weeks, and at 6 months

Secondary endpoints:

• Frequency of grade 2 or higher maternal adverse events, by type and severity, from baseline to 6 months postpartum.
• Frequency of spontaneous abortion, preterm delivery, congenital malformations at birth or identified and reported during the first 6 month of life, or intrauterine fetal death.
• Proportion of pregnant women with plasma viral load below 50 copies/mL at delivery.
• Average total weight gain and BMI during pregnancy, compared with recommendations based on pre-pregnancy BMI.
• Changes in CD4 lymphocyte count and CD4/CD8 ratio between baseline and delivery visit values.
• Frequency and type of mutations according to the International AIDS Society (IAS-USA drug resistance mutations, 2025) mutation guidelines panel at the baseline visit and in case of virological failure at any time during the study.
• Proportion of HIV infection among breastfed children.
• Frequency of grade 2 or higher maternal adverse events, by type and severity, between the two arms. Frequency of pregnant women with plasma viral load <200 copies/mL in the two arms at delivery visit.

Exploratory endpoints:

• Difference in the proportion of pregnant women who achieve an HIV-1 plasma viral load of less than 50 copies/mL at delivery between the DTG+3TC and DTG+TDF/XTC or DTG+TAF/FTC groups, to explore the non-inferiority of the dual regimen.
• Proportion of participants requiring a change in antiretroviral regimen (due to lack of efficacy, adverse events, medical decision, or other reasons) before delivery.

Patient Population: HIV-1-infected Pregnant Women aged >16 years (>15 years for Brazil's sites) who are naïve to antiretroviral therapy Study design: Phase IV. Randomized, non-comparative, open-label, multicenter study.

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 or tenofovir alafenamide 25 mg/emtricitabine 200 mg.

Duration: 14 months approximately months (depending on gestational age at entry).

Sample size: 210 subjects

Inclusion Criteria:

All persons who are eligible must meet all of the following:

1. Confirmed HIV-1 infection: All tests must use blood, serum, or plasma samples. Documentation may be obtained from medical records. HIV-1 positive is defined as having HIV-1 RNA in plasma ≥ 1000 copies/mL, plus one antibody test or two positive HIV antibody tests (two different rapid tests or one rapid test and one positive ELISA/EIE test). If any of these diagnostic test results are not available, they will be performed at the SCR visit. In all cases, an HIV viral load test will be performed.
2. Not exposed to prior antiretroviral therapy (ART): No prior antiretroviral therapy, including exposure to PrEP and/or PEP in the last 6 months.
3. Ability to sign the informed consent form.
4. Plasma HIV-1 RNA ≥1000 copies/mL. Viral load from the last 30 days may be valid. . Age ≥ 16 years or older in Argentina, ≥ 15 years or older in Brazil. The participant must be of the age required in their country of residence to give legal informed consent. Otherwise, informed consent must be signed by a parent or legal guardian, according to country guidelines, in addition to the participant.

6. Pregnant at any gestational age up to 32 weeks at the time of the screening visit: Viable pregnancy with a gestational age ≤32 weeks, defined according to menstrual history and/or ultrasound. Note: If the menstrual history is unknown or if there is a discrepancy between the menstrual history and the ultrasound, the gestational age will be determined based on the best technology available at each center.

7. The participant intends to continue with the pregnancy.

Exclusion Criteria:

All eligible individuals must NOT meet any of the following criteria:

1. Documented resistance to 3TC (presence of the M184V/I mutation) or DTG (defined as the presence of G118R, Q148 H/K/R, or R263K).
2. Active hepatitis C infection. 3. Active hepatitis B (HBsAg positive or detectable HBV viral load in cases with isolated positive HBV anti-core).
3. Hemoglobin <8 g/dL.
4. Fetal abnormalities detected on ultrasound
5. Concomitant medications required with possible drug interactions specified in section 5.10.
6. ALT >=5 times the ULN, or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin). Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification
7. Presence of severe preeclampsia or other pregnancy-related events, in current or previous pregnancies, such as renal or hepatic abnormalities (grade 2 or higher proteinuria, elevated serum creatinine, CrCl <50 mL/min, total bilirubin, ALT, or AST).
8. Active opportunistic infection at screening: active severe opportunistic infections and/or severe bacterial infection, including active tuberculosis or severe disease or unstable clinical condition within 14 days prior to study entry.
9. Any patient or disease-related condition that, in the investigator's opinion, would prevent the patient from adhering to study medication or complying with study visits or procedures.
10. Problematic drug and/or alcohol use, which in the opinion of the site investigator could interfere with therapeutic compliance with study requirements.
11. Known allergy or sensitivity to any of the study medications or their formulations.
12. Vomiting or any other reason generating inability to swallow medications due to a pre-existing active disorder that prevents proper swallowing and absorption of study medications.
13. Creatinine Clearance of <30 mL/min . If a creatinine value was obtained within 30 days prior to the screening visit, it may be used to calculate the CrCl.