pyrimethamine for HIV-1 infection

Inclusion criteria

• {"criterion_text":"- Documented HIV-1 infection by 4th generation ELISA, Western Blot or PCR.\n- ≥ 18 years old.\n- World Health Organization (WHO) performance status 0 or 1.\n- Current plasma HIV RNA <50 copies/ml measured on the last 2 occasions, with measurements being at least 3 months apart.\n- Uninterrupted prescribed ART for a minimum of two consecutive years.\n- Considered >95% adherent to ART by treating physician.\n- Current blood CD4+T-cell count of ≥200 cells/mm3\n- No clinical signs of cellular immunodeficiency or AIDS.\n- Pre-ART plasma HIV RNA ≥1000 copies/mL.\n- Confirmed HIV subtype B. People with a high likelihood of subtype B can participate if they live in a HIV subtype B endemic region with HIV acquired there and in whom no HIV sequencing is available or can be done on stored samples.\n- People should be considered capable mentally and somatically by their treating physician to understand the informed consent procedure and undergo the study treatment."}

Exclusion criteria

• {"criterion_text":"- A potential subject who meets any of the following criteria will be excluded from participation in this study:\n- Previous exposure to any of the studied LRAs in the last year\n- Acute or chronic co-infection with hepatitis B and/or C by the presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA in blood.\n- Co-medication with clinically significant interactions with LRA (see chapter 15.h for list)\n- Comorbidities affected by LRA compounds, such as but not limited to: known Glucose-6-phospate-dehydrogenase (G6PD) deficiency with anaemia, untreated haemolysis of any cause or hereditary thrombophilia not currently treated by anticoagulation.\n- Prolonged Qtc time >480ms at screening, as measured by electrocardiogram (ECG).\n- Patients of childbearing potential unless double contraceptive measures are taken. Non-childbearing is defined by one of the following criteria: amenorrhoea for ≥ 1 year, premature ovarian failure, assigned male at birth, or having undergone previous bilateral salpingo-oophorectomy, or hysterectomy\n- Sexual active patients unwilling to abstain from sex unless willing to use condom protection during and until 1 week after administration of study medication.\n- Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi’s sarcoma treated with ARTalone or other indolent malignancies.\n- Registered allergies for any of the investigational medical products\n- Any lab abnormalities at screening as listed below:\n- Moderate kidney impairment, def ined as eGFR <50 mL/min. In PLWH on dolutegravir- or bictegravir-based ART regimens, cystatin C-based eGFR can be used, as creatinine-based eGFR is underestimat ed due to drug interf erence with tubular creatinine excretion which leads to eGFR underestimation.\n- Moderate hepatic impairment, defined as bilirubin > 3 x upper limit of normal (ULN) or ALT > 3x ULN\n- Inadequate blood counts, defined as: Haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds, serum sodium <130 mmol/L, serum potassium <3.0 mmol/L, serum phosphate <0.5 mmol/L, serum calcium <1.9 mmol/L, serum magnesium <0.5 mmol/L."}

Primary endpoints

• {"endpoint_text":"- The fold change in cell-associated HIV-RNA at time points 6 and 24 hours as compared to baseline (time point 0 hour)","definition_or_measurement_approach":"Measured as fold change in cell-associated HIV-RNA at 6 and 24 hours compared to baseline (time point 0 hour). (Time points specified; specific assay not detailed in provided record.)"}
• {"endpoint_text":"- The number and severity of clinical and biochemical adverse events considered by the investigator to be related to any of the investigational drugs.","definition_or_measurement_approach":"Count and grade the number and severity of clinical and biochemical adverse events as judged by the investigator to be related to the investigational drugs (grading scale not specified in provided record)."}

Secondary endpoints

• {"endpoint_text":"- 1.\tThe fold change in cell-associated HIV-RNA on LRA monotherapy components compared to combination LRA treatments.","definition_or_measurement_approach":"Comparison of fold change in cell-associated HIV-RNA between LRA monotherapy components and combination LRA treatments (fold-change measurement; specific assays not detailed)."}
• {"endpoint_text":"- 2.\tThe change in the HIV reservoir size and genetic composition from baseline to the end of the study.","definition_or_measurement_approach":"Assessment of HIV reservoir size and genetic composition at baseline and at end of study (methods not specified in provided record)."}
• {"endpoint_text":"- 3.\tThe level of immune activation, and phenotype and functionality of the cellular immunity as compared from baseline to end of treatment.","definition_or_measurement_approach":"Measurement of immune activation markers, cellular immune phenotype and function at baseline and end of treatment (assays not specified)."}
• {"endpoint_text":"- 4.\tThe plasma concentrations of the investigational drugs during treatment.","definition_or_measurement_approach":"Pharmacokinetic measurement of plasma concentrations of investigational drugs during treatment (timing and assays not specified)."}
• {"endpoint_text":"- 5.\tCorrelations of ex vivo and in-vivo cell associated HIV-RNA responses to the investigational drugs.","definition_or_measurement_approach":"Correlation analyses between ex vivo and in vivo cell-associated HIV-RNA responses to investigational drugs (methods not detailed)."}
• {"endpoint_text":"- 6.\tThe association between clinical variables and the primary endpoints.","definition_or_measurement_approach":"Statistical assessment of associations between clinical variables and the primary endpoints (specific variables and methods not specified)."}
• {"endpoint_text":"- 7.\tThe number and frequency of measurable (above limit of detection or above limit of quantitation) plasma HIV-RNA during treatment.","definition_or_measurement_approach":"Counting and frequency analysis of measurable plasma HIV-RNA above detection/quantitation limits during treatment (assay limits not specified)."}
• {"endpoint_text":"- 8.\tNumber of upward and downward counterfactuals","definition_or_measurement_approach":"Counting upward and downward counterfactuals (definition of 'counterfactuals' not provided in the record)."}

Netherlands

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

07-03-2025

Processing Time Days

324

Number Of Sites

3

Number Of Participants

49

Primary sponsor

Full Name

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands