Placebo 7.5 mg once-daily First 8 weeks of ART Only Control arm

Tuberculosis

Meloxicam 7.5mg daily for 8 weeks

Stellenbosch University Tygerberg Hospital

TB-IRIS NSAID Cox-2 Inhibitor Prevention Trial

A Double-Blind Randomized Placebo Controlled Trial for Prevention of Tuberculosis-Immune Reconstitution Inflammatory Syndrome With Non-Steroid Anti-Inflammatory Drugs (NSAIDs) in HIV-Infected Adults

Prof Jean Nachega

Professor Extraordinary

University of Stellenbosch

University of Pittsburgh

Oral Valgancyclovir 900 mg twice in a day during 4 weeks prior to initiation of cART (combined antirretroviral therapy) until suppression of HHV-8.

Standard treatment with cART according to current HIV Therapy Mexican guidelines.

Kaposi Sarcoma

Human Immunodeficiency Virus

Immune Reconstitution Syndrome

The experimental group will receive Valganciclovir 900 mg twice in a day before the initiation of cART until viral load of HHV-8 is undetectable.

Valganciclovir

Patients will receive standard antiretroviral treatment as recommended

Antiretroviral Combinations

Instituto Nacional de Cancerologia

Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for Disseminated Kaposi Sarcoma

Valganciclovir for Suppression of HHV-8 Four Weeks Prior to Initiation of cART in Patients With Disseminated Kaposi Sarcoma Compare With Standard Therapy, Its Impact on the Development of IRIS and Attributable Mortality

Measure mortality attributable to IRIS-KS in all the groups

Volkow Fernandez Patricia Amalia

Infectious disease consultant, Clinical Professor

National Institute of Cancerología

Instituto Nacional de Enfermedades Respiratorias

Pomalidomide and liposomal doxorubicin given at escalating doses to patients with KS requiring systemic therapy

Pomalidomide and liposomal doxorubicin, given at the highest tolerated dose to patients with KS requiring systemic therapy

Pomalidomide with liposomal doxorubicin given at escalating doses in to patients with advanced KS or KS and concurrent KSHV-associated MCD or KICS requiring systemic therapy

Pomalidomide and liposomal doxorubicin, given at the highest tolerated dose to patients with KS or KS with concurrent KSHVassociated MCD or KICS requiring systemic therapy

liposomal doxorubicin IV day 1 of a 28-day cycle

liposomal doxorubicin

pomalidomide once a day, days 1- 21 of a 28-day cycle, at the dose levels described in dose escalation plan

pomalidomide

National Institutes of Health Clinical Center, 9000 Rockville Pike

Pomalidomide in Combination With Liposomal Doxorubicin in People With Advanced or Refractory Kaposi Sarcoma

A Phase 1 Trial of Pomalidomide in Combination With Liposomal Doxorubicin in Patients With Advanced or Refractory Kaposi Sarcoma

Incidence of dose limiting toxicity and emerging adverse events

assess changes in quality of life in subjects receiving pomalidomide in combination with liposomal doxorubicin

To assess the effect of the combination on pulmonary function, as measured by pulmonary function tests (PFTs) in patients with pulmonary KS

evaluate the characteristics of 18fluoro-thymidine (FLT) positron emission tomography (PET) in patients with KS and concurrent KSHV-associated MCD or KICS

National Cancer Institute (NCI)

Blood for DNA isolation (no sequencing, only SNP array) Stool for microbiome analysis Saliva for microbiome analysis Plasma and serum for metabolomics Urine for creatinine analysis

HIV Infections

Onze Lieve Vrouwe Gasthuis

Radboudumc

Erasmus MC

Elisabeth Twee-Steden ziekenhuis

2000 HIV Human Functional Genomics Partnership Program

Change in liver fibrosis measurement by FibroScan (method by Echosens)

Change in liver steatosis measurement by FibroScan (method by Echosens) and liver ultrasound (method developed by Radboudumc)

Recoring of cadiovascular diseases from patient file:
Stroke/ TIA
Angina pectoris
Myocardial infarction
Claudicatio intermittens
Venous thrombo-embolism
Other …

Genome-wide genotype data including >8 million SNPs per individual

Colonizing microbiome profile will be generated from stool and saliva samples

RNA-sequencing will be performed in PBMCs

Metabolomics analysis by multiplex immunoassays will be performed in plasma or serum

Ex vivo cytokine responses of isolated PBMCs to a range of stimuli (TLR ligands, killed pathogens and viral antigen stimuli)

Extensive phenotyping of circulating immune cells by flow cytometry analysis

Note changes in ECG performed at baseline and two years

Ultrasound measurement of intima-media thickness in the carotid artery as a measure for atherosclerosis and cardiovasculr disease risk.

Radboud University

ViiV Healthcare

Elisabeth-TweeSteden Ziekenhuis

Erasmus Medical Center

standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks

standard anti-tuberculosis drugs plus placebo for 6-8 weeks

Tuberculous Meningitis

Drug-Induced Liver Injury

IRIS

Active treatment with dexamethasone from randomisation (IV followed by oral according to disease severity at the start of treatment): dexamethasone for intravenous injection and dexamethasone for oral ingestion

Dexamethasone

Treatment with matched placebo:
Standard saline for intravenous injection and placebo oral tablets containing cellulose

Placebo

Cipto Mangunkusumo Hospital

Eijkman-Oxford Clinical Research Unit

RSUP Persahabatan Hospital

Hospital for Tropical Diseases

Oxford University Clinical Research Unit

Pham Ngoc Thach Hospital

Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial)

A Randomized Double Blind Placebo Controlled Trial of Adjunctive Dexamethasone for the Treatment of HIV-infected Adults With Tuberculous Meningitis

The primary endpoint is overall survival, i.e. the time from randomization to death, during a follow-up period of 12 months. Survivors known to be alive at 12 months will be censored at that time-point and subjects who withdrew or were lost to follow-up before 12 months will be censored at the date they were last known to be alive.

Neurological disability will be assessed by the modified Rankin score (see below) on months 3, 6, 9, 12, 18 and 24 from randomisation. The main endpoint is the 12 month assessment and subjects who died before 12 months will be treated as having a score of 6 ('Dead').
The Modified Rankin Scale Score Description 0 No symptoms
Minor symptoms not interfering with lifestyle
Symptoms that lead to some restriction in lifestyle, but do not interfere with the patients ability to look after themselves
Symptoms that restrict lifestyle and prevent totally independent living
Symptoms that clearly prevent independent living, although the patient does not need constant care and attention.
Totally dependent, requiring constant help day and night.
Death

A neurological event is defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the onset of any of the following clinical adverse events: cerebellar symptoms, focal neurological signs, or onset of seizures.

The rate is defined as the number of IRIS events divided by the observed person-time of follow-up in each treatment group.

AIDS-defining illnesses will be defined as per the WHO classification.

Comparison of the frequency of serious adverse events between treatment groups will form an important part of the study analysis.

The three major HIV-associated malignancies are Kaposi sarcoma, high grade B-cell non-Hodgkin lymphoma and invasive cervical cancer.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and overall survival will be reported once 24 month follow-up has been completed for all participants.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and neurological disability will be reported once 24 month follow-up has been completed for all participants.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and this outcome will be reported once 24 month follow-up has been completed for all participants.

The Oxford University Clinical Research Unit recognizes the ethical obligation to ensure that optimal use is made of the data and specimens that the investigators collect for our research and the value of sharing individual level data. The investigators aim to ensure that data generated from all our research are collected, curated, managed and shared in a way that maximizes their benefit. When sharing data the investigators have an obligation to ensure that the interests of research participants, researchers and other stakeholders are appropriately protected. The Oxford University Clinical Research Unit data sharing policy and the data request form outline the default procedures for data sharing.

iris/sarcoma

TB-IRIS NSAID Cox-2 Inhibitor Prevention Trial

Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for Disseminated Kaposi Sarcoma

Pomalidomide in Combination With Liposomal Doxorubicin in People With Advanced or Refractory Kaposi Sarcoma

2000 HIV Human Functional Genomics Partnership Program

Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial)

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