Clinical trial NCT05323396: HIV And Parasitic Infection (HAPI) Study
Official title: Impact of Parasitic Infections on Intestinal Epithelial Barrier and Immune Activation Among Persons Living With HIV in Lilongwe, Malawi
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Coinfection
Keywords: parasitic infection
chronic immune activation
HIV coinfection
Malawi
sCD14
sCD163
I-FABP
intestinal damage
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Fogarty International Center of the National Institute of Health
First posted: 2022-04-12
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This trial is closest to a parallel trial, but different from most clinical trials in that the participants will not be randomized by the study team. The two groups will be determined based on the results of the initial sample collection. Those with a result positive for intestinal parasitic infection (by either stool microscopy, stool PCR, or Strongyloides IgG) will be in the "parasite-positive" group for the remainder of the study. Those negative for all of these will be in the "parasite-negative" group. The markers sCD14, sCD163, and I-FABP will be compared between the two groups. Additionally a comparison will be made between the pre-treatment and post-treatment levels of the "parasite-positive" participants.
Primary purpose: TREATMENT

Brief summary: The overall goal of this study is to determine if periodic de-worming of persons living with HIV in intestinal parasite-endemic regions will lead to decreased morbidity and mortality associated with HIV by reducing immune activation and intestinal damage associated with these diseases. The hypothesis for this project is that intestinal parasitic infections contribute to a modifiable pro-inflammatory state in persons living with HIV (PLWH).

Aim 1: Determine the prevalence of intestinal parasitic infections in PLWH receiving care at an HIV-treatment center in Lilongwe, Malawi using a highly sensitive multi-parallel stool PCR test. Hypothesis: highly sensitive stool PCR testing will demonstrate that disease burden of parasitic infection in PLWH in Malawi is higher than historically reported based on stool microscopy.

Aim 2: Determine the impact of parasitic infection on intestinal damage and immune activation by measuring sCD14, sCD163, and intestinal fatty acid binding protein (I-FABP) in PLWH. Hypothesis: plasma biomarkers reflecting intestinal damage and immune activation are elevated in those with HIV and parasitic co-infection compared with parasite-negative participants with HIV.

Aim 3: Determine the impact of eradication of parasitic infection on intestinal damage and immune activation by measuring sCD14, sCD163, and intestinal fatty acid binding protein (I-FABP) in PLWH before and after treatment of parasitic co-infection. Hypothesis: plasma biomarkers reflecting intestinal damage and immune activation are elevated in those with HIV and parasitic co-infection, and these biomarkers decrease with anti-parasitic treatment.

Detailed description: This is a prospective study in which participants will be enrolled in outpatient HIV clinics associated with Kamuzu Central Hospital in Lilongwe, Malawi, where there are over 25,000 patients in care with over 90% virally suppressed on ART.

Any subject meeting inclusion criteria and lacking exclusion criteria who is currently receiving care at the clinics affiliated with Kamuzu Central Hospital or Bwaila Hospital will be eligible to participate in this study. After informed consent is signed, a total of 10ml of blood, 20g stool sample, and 20mL urine sample will be collected. Each participant will be asked a series of questions. Clinical variables including age, sex, CD4+ T-cell count, and CD4% will be collected from the participant's medical chart.

Stool samples will be processed by stool microscopy in the local UNC Project Malawi laboratory, and the remaining sample will be stored at -80 degrees Celsius (C) until transported to the Laboratory of Parasitology National School of Tropical Medicine Baylor College of Medicine in Houston, Texas for detection of 9 different parasites and quantification of parasite burden by stool qPCR. Blood samples will be collected in EDTA-blood collection tubes and centrifuged. Plasma will be frozen at -80 degrees C at UNC Project Malawi until transport to the National School of Tropical Medicine Baylor College of Medicine for determination of levels of immune activation and gut mucosal impairment (sCD14, sCD163, and I-FABP) and Strongyloides stercoralis IgG. Urine samples will be evaluated by microscopy to look for Schistosoma haematobium at UNC Project Malawi laboratory.

Multi-parallel real-time quantitative PCR (qPCR) performed on stool will evaluate for 9 different parasites including Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Schistosoma mansonii, Strongyloides stercoralis, Taenia solium, Trichuris trichiura, Entamoeba histolytica, and Giardia lamblia.

Participants that test positive for parasitic infection will be contacted and appropriate treatment administered according to the local standard of care. Albendazole single 400mg dose will be given for infection with Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Trichuris trichiura. Albendazole 400mg daily for 5 days will be given for Strongyloides stercoralis. Praziquantel single dose 40mg/kg will be given for infection with Schistosoma mansoni and Schistosoma haematobium. Praziquantel single dose 10mg/kg will be given to treat intestinal infection with Taenia solium. Metronidazole 500mg two times a day x5 days for Giardia lamblia and 500mg three times a day x7 days for Entamoeba histolytica.

Follow up appointments will be performed 8-12 weeks after treatment and will include repeated blood and stool sample collection.

The study team anticipates enrollment of 100 patients in a period of 8-12 weeks. With an estimated intestinal parasite prevalence of 30%, the study team predicts 30 cases and 70 controls will be enrolled. Participants found to be positive at both the initial and follow up visit will be considered reinfected rather than treatment failure. These will be included in the analysis of prevalence, but the change in markers of immune activation will not be measured in this group since parasite clearance not established. Using Student's unpaired t-test to compare mean values of biomarkers between study groups, there will be 80% power to detect a difference of 0.434 x106 pg/ml, 0.56 mg/l, and 598 pg/ml between groups for biomarkers sCD14, sCD163, and I-FABP, respectively with effect sizes within the range of prior studies. Using paired t-tests to compare pre- and post-treatment biomarker levels, there will be 80% power to detect post-treatment changes of 0.317 x106/ml, 0.41 mg/l, and 435 pg/ml in sCD14, CD163, and I-FABP respectively.

Clinical variables including age, sex, and most recent CD4 count will be recorded. Clinical predictors of parasitic infection (eg CD4%) will be determined using multivariable logistical regression. Univariable linear regression will be used to determine associations between markers of immune activation (continuous outcome variable) and predictors including the clinical variables above as well as presence of multiple parasitic infections.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* currently living in Malawi
* HIV-1 infection
* on ART ≥ 1 year with undetectable HIV RNA level at the last evaluation
* willingness to be treated with anti-parasitic therapy if infection with intestinal parasite is identified.

Exclusion Criteria:

* Use of antibiotics other than prophylaxis with trimethoprim-sulfamethoxazole within 60 days of screening
* Use of antiparasitic medication (ex- albendazole, praziquantel, metronidazole) in the last year
* Inflammatory bowel disease
* Gastrointestinal tract malignancy
* Major intestinal surgery during prior 2 years
* Coinfection with Mycobacterium tuberculosis
* Pregnancy, breastfeeding mother, or planning pregnancy.

Primary outcomes:
measure: Prevalence of Participants With Intestinal Parasitic Infection
timeFrame: Baseline
measure: Mean Soluble CD14 (sCD14) Levels
timeFrame: Baseline
measure: Mean Soluble CD163 (sCD163) Levels
timeFrame: Baseline
measure: Mean Intestinal Fatty-acid Binding Protein (I-FABP) Levels
timeFrame: Baseline
measure: Change in sCD14 Levels Pre- and Post-treatment
timeFrame: Baseline, 6 months after baseline visit
measure: Change in sCD163 Levels Pre- and Post-treatment
timeFrame: Baseline, 6 months after baseline visit
measure: Change in I-FABP Levels Pre- and Post-treatment
timeFrame: Baseline, 6 months after baseline visit
Secondary outcomes:
Other outcomes:
Locations:
city: Lilongwe
country: Malawi
facility: Lighthouse Clinic
Study officials:
affiliation: University of North Carolina
name: Melissa Reimer-McAtee, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC; INSIGHT SMART Study Group. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011 Mar 15;203(6):780-90. doi: 10.1093/infdis/jiq118. Epub 2011 Jan 20.
citation: Knudsen TB, Ertner G, Petersen J, Moller HJ, Moestrup SK, Eugen-Olsen J, Kronborg G, Benfield T. Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals. J Infect Dis. 2016 Oct 15;214(8):1198-204. doi: 10.1093/infdis/jiw263. Epub 2016 Jun 28.
citation: Cheru LT, Park EA, Saylor CF, Burdo TH, Fitch KV, Looby S, Weiner J, Robinson JA, Hubbard J, Torriani M, Lo J. I-FABP Is Higher in People With Chronic HIV Than Elite Controllers, Related to Sugar and Fatty Acid Intake and Inversely Related to Body Fat in People With HIV. Open Forum Infect Dis. 2018 Nov 5;5(11):ofy288. doi: 10.1093/ofid/ofy288. eCollection 2018 Nov.