The Role of Probiotics in HIV Patients With Immunological Non-Responder

Study Overview
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Brief Summary
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This study will address HIV patients who are on antiretroviral treatment (ART) and experiencing immunological failure. The cause of immunological failure in HIV patients could be due to several factors such as age, gender, Cluster of Differentiation (CD4)+ count before started treatment and some inflammation in the gut. The C-C Chemokine Receptor 5 (CCR5) receptor on T lymphocyte CD4+ are abundantly found in the gut and attacked by HIV virus during acute infection causing irreversible damage. The disruption of gut integrity and chronic inflammation further causing translocation of bacteria in gut lumen to the blood. Thus resulting persistent low CD4+ or immunological failure. This evaluation plan is designed to establish the role of investigation product (probiotics) to improve gut inflammation in HIV patients.

Detailed Description
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HIV patients could develop immunological failure despite being treated with antiretroviral therapy (ART). Thus resulting the increase of morbidity and mortality among HIV patients, especially in Indonesia. The immunological failure is associated with decreased gut integrity and immunity, increased gut inflammation, and gut bacterial translocation to the blood. Memory CD4+ T cell damage in gut associated lymphoid tissue (GALT) by HIV-1 virus leads to decreased production of Th17 in gut mucosal layer. Furthermore, low level of Th17 facilitates bacterial translocation in HIV patients. Probiotic supplementation (Lactobacillus) could decrease the gut inflammation in some diseases including HIV infection; thus helps increasing the gut integrity and immunity by repairing the gut mucosal tight junction, increasing mucin production, and regulating gut Th17. As a result, the gut inflammation and bacterial translocation decreases. Nevertheless, the benefit in HIV patients with immunological non responder status has not been established. The investigators plan to perform double blind randomized clinical trial of probiotics (containing Lactobacillus plantarum, Streptococcus thermophiles, Bifidobacterium bifidum) in HIV patients with immunological non responder status. The Subject who fulfill inclusion criteria, willing to participate and sign informed consent will be randomized into two groups: the group receiving probiotics (n=40) and the group of placebo (n=40). Intervention will be held for 12 weeks. This study will evaluate the gut mucosal integrity and immunity by Th17 measurement; bacterial translocation by 16S ribosomal RNA (16S RNA) measurement; and gut inflammation by fecal calprotectin measurement before and after the intervention. Moreover, the investigators will measure the CD4+ level to assess immune status recovery before and after the intervention. Side effects, HIV symptom index, Food Frequency Questionnaire will also be assessed every 4 weeks. Statistical analysis will uses: paired and independent t test (if normally distributed) or using Wilcoxon and Mann Whitney test (if not normally distributed). HIV symptom index and Food frequency will be reported descriptively.

Official Title
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The Role of Probiotics L. Plantarum, S. Thermophiles, B. Bifidum on Gut Inflammation, Bacterial Translocation, and CD4+ Cell Count in HIV Patients With Immunological Non-Responder

Conditions
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HIV Infections, Immunological Abnormality

Intervention / Treatment
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* Drug: Rillus®
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV patient with immunological non-responder status which defined as: first line antiretroviral therapy (ART) treated for minimal 6 months CD4+ level between 200-410 cell/μL HIV viral load <34 copies/mL giving consent to participate the study Exclusion Criteria: being pregnant lactating known Lactobacillus allergy BMI <16 kg/m2 under Tuberculosis treatment or other acute illness acute diarrhea routinely taking selenium containing vitamin in last 1 month routinely consuming probiotics containing product in last 1 month

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double blind placebo control study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics Rillus®<br>Rillus®, Chewing tablet containing viable cell 1.0 x 10^9 colony forming unit (Lactobacillus plantarum 8.55 mg, Streptococcus thermophilus 8.55 mg, Bifidobacterium bifidum 2.55 mg, fructooligosaccharide 480 mg), isomalt, xylitol, milk flavour, vanilla flavour Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks | Drug: Rillus®<br>* Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks.<br>* Other names: Rillus® Treatment group;|
| Placebo Comparator: Placebo<br>Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks | Other: Placebo<br>* Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks.<br>* Other names: Control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4+ level | Change in CD4+ level in blood to assess immune status recovery, measured in cell/μL | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Th17 level | Change in Th17 level in blood to assess improvement of gut mucosal integrity and immunity, measured in cell/μL | 12 weeks | 
| 16S ribosomal RNA (rRNA) level | Change in 16SrRNA of translocated gut bacteria in blood, measured in copies/mL | 12 weeks | 
| Fecal calprotectin level | Change in calprotectin level in feces to assess gut inflammation, measured in μg/g. | 12 weeks | 
| Change in HIV Symptoms Index score | A questionnaire containing 20 questions to assess HIV related symptoms in patients. Self administered. Each item is scored 0-4 (0= not experiencing the symptom; 4 = severely disturbing). The result will be presented descriptively | 0, 4, 8, and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, immunological non responder, gut inflammation