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

Phase 2

Completed

Conditions: Immunological Abnormality
HIV Infections

Interventions: Other: Placebo
Drug: Rillus®

Registration Number: NCT03568812

Lead Sponsor: Indonesia University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	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
Probiotics Rillus®	Rillus®	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

Primary Outcome Measures

Name	Time	Method
CD4+ Level	12 weeks	CD4 level in blood (cell/μL) indicate immune status of patient receiving probiotics or placebo, measure between baseline and at 12 weeks of intervention. Analysis will include CD4 T cell levels after intervention, adjusted with duration of ARV therapy and baseline CD4 levels, as well as unadjusted.

Secondary Outcome Measures

Name	Time	Method
16S Ribosomal RNA (rRNA) Total	12 weeks	Total of 16SrRNA of translocated gut bacteria in blood, measured in copies/mL, presented as median and interquartile range.
Th17 Level Change	12 weeks	Change in Th17 level in blood to assess improvement of gut mucosal integrity and immunity between baseline and at 12 weeks, measured in cell/μL The results was divided in to unadjusted and adjusted Th17 level change.
Fecal Calprotectin Level Change	12 weeks	Change in calprotectin level in feces to assess gut inflammation between baseline and at 12 weeks, measured in μg/g. The results was divided in to unadjusted and adjusted fecal calprotectin level change
Amount of Participants With HIV Related Symptoms	0,4,8,12 weeks	A questionnaire called HIV Symptoms Index (Have been validated in Indonesian language) containing self administered 20 questions consisted of 15 somatic and 5 psychological symptoms to assess Human Immunodeficiency Virus (HIV) related symptoms in patients. The total score is calculated by summing the numbers of each symptom (0 = no symptoms, 1 = no disturbing symptoms, 2 = there are symptoms that are a little annoying, 3 = there are disturbing symptoms, 4 = there are very disturbing symptoms), with a minimum score of 0 and maximum 80. Somatic symptoms range from 0-60 and psychological symptoms range from 0-20. An increase in score indicates a worsening condition. Change in HIV Symptoms Index score to assess improvement of somatic and psychological symptoms between baseline and at 12 weeks. The results was divided into somatic and psychological symptoms. Both of them were divided again into unadjusted and adjusted HIV Symptoms Index score Change.