Comparative Efficacy and Safety Study of Dolutegravir and Lopinavir/Ritonavir in Second-line Treatment

Phase 3

Completed

Conditions: HIV Infections

Interventions: Drug: DTG
Drug: LPV/RTV
Drug: Two NRTIs

Registration Number: NCT02227238

Lead Sponsor: ViiV Healthcare

Brief Summary: For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment and subjects originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 627

Inclusion Criteria

HIV-1 infected subjects >=18 years of age.
A female subject may be eligible to enter and participate in the study if she:

is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy throughout the study and for at least 2 weeks after discontinuation of all study medication.

HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening.
Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of >=400 c/mL.
Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study.
Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI.
Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening.

Exclusion Criteria

Women who are breastfeeding.
Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels <200 cells per cubic millimeter
Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study.
History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject.
Subjects who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, systemically administered immunomodulators.
Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B [e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) / Emtricitabine (FTC)] after discussion and agreement between the investigator and the medical monitor.
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 IP.
Any evidence of primary viral resistance to PIs or INIs based on the presence of any major resistance-associated mutation.
The subject's virus does not yield results using genotype at Screening (assay data is essential for eligibility determination).
Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result.
Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound.
Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DTG arm	DTG	Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
DTG arm	Two NRTIs	Subjects will receive one oral tablet of 50 mg DTG once daily plus two NRTIs selected by the investigator
LPV/RTV arm	LPV/RTV	Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator
LPV/RTV arm	Two NRTIs	Subjects will receive four oral tablets of200/50 mg LPV/RTV once daily or two oral tablets of 200/50 mg LPV/RTV twice daily plus two NRTIs selected by the investigator

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48	Week 48	Percentage of participants with plasma HIV 1 RNA \<50 c/mL at Week 48 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to demonstrate the non-inferior activity of DTG plus 2 NRTI's compared to LPV/RTV plus 2 NRTI's. Analysis was performed on Intent-to-treat exposed (ITT-E) Population, which comprised of all randomized participants who received at least one dose of study medication. Percentage values are rounded off.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24	Week 24	Percentage of participants with plasma HIV 1 RNA \<50 c/mL at Week 24 using the FDA snapshot algorithm was assessed to demonstrate the non-inferior activity of DTG plus 2 NRTI's compared to LPV/RTV plus 2 NRTI's. Percentage values are rounded off.
Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48	Week 24 and Week 48	Percentage of participants with plasma HIV 1 RNA \<400 c/mL at Week 24 and 48 using the FDA snapshot algorithm were evaluated. Percentage values are rounded off.
Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48	Week 24 and Week 48	Virologic or tolerability failure was defined as treatment-related discontinuation (meeting confirmed virologic withdrawal criteria, treatment-related adverse event, safety stopping criteria, and lack of efficacy). Percentage of participants without virologic failure by Week 24 and Week 48 have been presented. Participants who did not met the protocol defined confirmed virologic withdrawal criteria and are ongoing in the study, or who had discontinued for non-treatment related reasons were censored.
Time to Viral Suppression at Week 48	Week 48	Viral suppression was defined as HIV-1 RNA \<50 c/mL. Time to viral suppression was analyzed and median and interquartile range has been presented.
Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48	Baseline (Day 1, Pre-dose), Week 24 and Week 48	Blood was collected and CD4+ cell count assessment was carried out at indicated time points to evaluate the immunological activity of DTG compared to LPV/RTV. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Number of Participants With Disease Progression-Randomized + Continuation Phase	Up to Week 348	Disease progression included HIV-associated conditions, acquired immune deficiency syndrome (AIDS) and death. Number of participants with disease progression to Centers for Disease Control and Prevention (CDC) class C or death have been presented.
Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase	Up to Week 52	Number of participants, who met confirmed virologic withdrawal (CVW) criteria with paired Baseline and time of CVW resistance data with treatment emergent genotypic resistance to Integrase strand transfer inhibitor (INSTI), NRTI, Protease inhibitor (PI) were summarized. Viral Genotypic Population comprised of all participants in the ITT-E population with available On-treatment genotypic resistance data at the time confirmed virologic withdrawal criterion was met during Randomized Phase.
Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase	Up to Week 295	Number of participants, who met confirmed virologic withdrawal criteria with paired Baseline and time of CVW resistance data, with treatment emergent genotypic resistance to Integrase strand transfer inhibitor (INSTI), NRTI, Protease inhibitor (PI) were summarized. Analysis was performed on Viral Genotypic Continuation Population which comprised all participants in the ITT-E- Continuation Population with available on-treatment genotypic resistance data in the Continuation Phase.
Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase	Baseline (Day 1, Pre-dose) and up to Week 52	Number of participants with fold change in treatment-emergent phenotypic resistance from Baseline to DTG, LPV/RTV was counted to assess the development of viral resistance. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value. Change in grade 0 to \>2 from Baseline is presented. Analysis was performed on viral phenotypic Population, which comprised of all participants in the ITT-E Population with available On-treatment phenotypic resistance data at the time confirmed virologic withdrawal criterion is met during Randomized Phase.
Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase	Baseline (Day 1, Pre-dose) and up to Week 295	Number of participants with fold change in treatment-emergent phenotypic resistance from Baseline to DTG was counted to assess the development of viral resistance. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-dose visit value minus Baseline value. Change in grade 0 to \>2 from Baseline is presented. Analysis was performed on Viral Phenotypic Continuation Population which comprises all participants in the ITT-E- Continuation Population with available on-treatment phenotypic resistance data in the Continuation Phase.
Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase	Up to Week 52	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Safety Population was used which comprised of all participants who received at least one dose of study treatment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase	Up to Week 295	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Adverse events which were not Serious were considered as non-serious AEs.
Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase	Up to Week 348	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, other situations as per medical or scientific judgment and is associated with liver injury or impaired liver function. Adverse events which were not Serious were considered as non-serious AEs.
Number of Participants With Hematology Toxicities -Randomized Phase	Up to Week 52	Number of participants with hematology toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Data has been reported for hematology parameters including Hemoglobin, Leukocytes, Neutrophils and Platelets.
Change From Baseline in Glucose, Chloride, Carbon-di-oxide (CO2), Potassium, Phosphate, Sodium, Urea, Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol and Triglycerides	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical chemistry parameters including glucose, chloride, carbon-di-oxide (CO2), potassium, phosphate, sodium, urea, cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. Lipid parameters were evaluated in fasting condition. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical chemistry parameters including ALP, ALT, AST and creatine kinase. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Albumin Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical chemistry parameter including albumin. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Creatinine and Bilirubin Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical chemistry parameters including creatinine and bilirubin. Change from Baseline in clinical chemistry parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Lipase Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical chemistry parameter including lipase. Change from Baseline in lipase at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Number of Participants With Clinical Chemistry Toxicities -Randomized Phase	Up to Week 52	Number of participants with clinical chemistry toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Lipids and glucose parameters were summarized on fasting data. Data has been reported for clinical chemistry parameters including serum glucose, ALT, Albumin, ALP, AST, Bilirubin, CO2, Creatine kinase, LDL cholesterol calculation, LDL cholesterol direct, Lipase, Phosphate, Potassium, Sodium, Cholesterol, Creatinine and Serum Triglycerides.
Number of Participants With Clinical Chemistry Toxicities-Continuation Phase	Up to Week 295	Number of participants with clinical chemistry toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Lipids and glucose parameters were summarized on fasting data. Data has been reported for clinical chemistry parameters including serum glucose, ALT, Albumin, ALP, AST, Bilirubin, CO2, Creatine kinase, LDL cholesterol calculation, LDL cholesterol direct, Lipase, Phosphate, Potassium, Sodium, Cholesterol, Creatinine and Serum Triglycerides.
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Change from Baseline in clinical hematology parameters at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Hematocrit Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52	Blood samples were collected from participants to evaluate clinical hematology parameter including hematocrit. Change from Baseline in hematocrit values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Hemoglobin Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 52	Blood samples were collected from participants to evaluate clinical hematology parameter including hemoglobin. Change from Baseline in hemoglobin values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Number of Participants With Hematology Toxicities-Continuation Phase	Up to Week 295	Number of participants with hematology toxicities has been presented. Toxicities were based on the Division of AIDS (DAIDS) grading system. Grade 1=Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Potentially life-threatening. Higher the grade, more severe the symptoms. Data has been reported for hematology parameters including Hemoglobin, Leukocytes, Neutrophils and Platelets.
Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase	Up to Week 52	Number of participants who discontinued study treatment due to AEs or SAEs were summarized.
Change From Baseline in Mean Corpuscular Volume (MCV)	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and and Week 52	Blood samples were collected from participants to evaluate clinical hematology parameter including MCV. Change from Baseline in MCV values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Change From Baseline in Erythrocyte Values	Baseline (Day 1, Pre-dose), Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and up to Week 52	Blood samples were collected from participants to evaluate clinical hematology parameter including erythrocyte. Change from Baseline in erythrocyte values at Weeks 4, 8, 16, 24, 36, 48, 52 are presented. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value.
Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase	Up to Week 295	Number of participants who discontinued study treatment due to AEs were summarized.
Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48	Baseline (Day 1, Pre-dose), Week 24 and Week 48	Blood samples were collected from participants in fasting state to evaluate LDL cholesterol. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Analysis was performed using multiple imputation with missing at random assumption. Only participants available at the time of evaluation were analyzed.
Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio	Baseline (Day 1, Pre-dose), Week 24 and Week 48	Blood samples were collected from participants in fasting state to evaluate total cholesterol/HDL cholesterol ratio. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Only participants available at the time of evaluation were analyzed. Analysis was performed using multiple imputation with missing at random assumption.
Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol	Up to Week 48	Blood samples were collected from participants in fasting state at indicated time-points to evaluate LDL cholesterol. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Number of participants who experienced maximum grade 2 or greater toxicity post-Baseline in fasting LDL cholesterol was summarized. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. Higher the grade, more severe the symptoms.
Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea	Week 24 and Week 48	Number of participants who experienced maximum grade 2 or greater toxicity post-Baseline in drug-related diarrhea was summarized. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. Higher the grade, more severe the symptoms.
Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score	Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48	The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea and Constipation. The scale ranges from 1= no discomfort to 7= very severe discomfort for each symptom cluster. Higher scores show greater severity of symptoms. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. The analysis was performed using Last Observation Carried Forward (LOCF) dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.
Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score	Baseline (Day 1, Pre-dose), Week 4, Week 24, Week 48	The HIVTSQ is a self-reported scales that measure overall satisfaction with treatment. The score ranges from 0-10. The higher the score, the greater the improvement in treatment satisfaction as compared to the past few weeks. A smaller score represents a decline in treatment satisfaction compared to the past few weeks. Baseline was defined as the latest pre-dose assessment value. Change from Baseline was calculated as post-Baseline visit values minus Baseline value. The analysis was performed using LOCF dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.
Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8)	Baseline (Day 1, Pre-dose), Week 4, Week 24 and Week 48	Treatment compliance was evaluated through MMAS-8. It is an eight-item self-reported measure of medication-taking behavior. The score ranges from 0-8 where scores of 8 indicate high or near perfect adherence, and scores of less than 6 indicate poor or inadequate adherence on the MMAS-8 scale. Number of participants showing low, medium and high adherence to treatment are presented. Low adherence is a score 0-5.75, medium adherence is a score of 6-7.75 and high adherence is a score of 8. The analysis was performed using LOCF dataset. In the LOCF dataset, missing values were carried forward from the previous, non-missing available on-treatment assessment.