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Effect of High Dose Vitamin D Supplementation on HIV Latency (VIVA)

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ClinicalTrials.gov Identifier: NCT03426592
Recruitment Status : Active, not recruiting
First Posted : February 8, 2018
Last Update Posted : August 13, 2018
Sponsor:
Collaborators:
Melbourne Health
The Alfred
Melbourne Sexual Health Centre
University of Illinois at Chicago
Information provided by (Responsible Party):
Sharon Lewin, University of Melbourne

February 1, 2018
February 8, 2018
August 13, 2018
January 29, 2018
January 2019   (Final data collection date for primary outcome measure)
Change in total HIV DNA level [ Time Frame: weeks 0 and 24 ]
The difference between the vitamin D and placebo arms in the mean change in frequency of total HIV DNA within CD4+ T cells from week 0 to week 24
Same as current
Complete list of historical versions of study NCT03426592 on ClinicalTrials.gov Archive Site
  • Change in other DNA markers of HIV persistence [ Time Frame: Weeks 0, 12, 24, 36 ]
    Total HIV DNA, integrated HIV DNA and 2-LTR circles in peripheral blood CD4+ T cells using PCR
  • Change in cell-associated HIV RNA [ Time Frame: Weeks 0, 12, 24, 36 ]
    Cell-associated unspliced and multiply spliced HIV RNA in peripheral blood CD4+ T cells using RT-PCR and Tat/rev Induced Limiting Dilution Assay (TILDA)
  • Change in proportion of immune cells [ Time Frame: Weeks 0, 12, 24, 36 ]
    T helper and T cytotoxic subsets, monocytes, dendritic cells and natural killer cells using flow cytometry
  • Change in T cell subset phenotype [ Time Frame: Weeks 0, 12, 24, 36 ]
    T cell subset activation and exhaustion marker and chemokine receptor expression using flow cytometry
  • Change in HIV-specific immunity [ Time Frame: Weeks 0, 12, 24, 36 ]
    HIV-specific CD4+ and CD8+ T cell frequency and polyfunctionality using HIV peptides and flow cytometry
  • Change in CD4+ T cell transcriptional profile [ Time Frame: Weeks 0, 12, 24, 36 ]
    CD4+ T cell transcriptional profile using RNA Seq
  • Change in high sensitivity C-reactive protein (hsCRP) [ Time Frame: Weeks 0, 12, 24, 36 ]
    hsCRP levels
  • Change in gut barrier permeability [ Time Frame: Weeks 0, 12, 24, 36 ]
    Gut barrier permeability using plasma lipopolysaccharide (LPS), soluble CD14 and intestinal fatty acid binding protein (I-FABP)
  • Change in gut microbiome diversity [ Time Frame: Weeks 0, 24, 36 ]
    Gut microbiome diversity using 16S rRNA sequencing and metagenomics
  • 25-hydroxyvitamin D levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Serum 25-hydroxyvitamin D levels and correlation between level achieved and each of the other endpoints (efficacy analysis)
  • Serum calcium levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Serum calcium corrected for albumin
  • Urinary calcium levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Urinary calcium:creatinine ratios and, where these are abnormal, 24 hour urinary calcium levels
  • Adverse events [ Time Frame: Weeks 0, 12, 24, 36 ]
    Incidence and severity of adverse events
  • Study protocol adherence [ Time Frame: Weeks 0 to 24 ]
    Adherence to study drug and 1g daily dietary calcium intake as measured by pill count and participant report
  • Change in other DNA markers of HIV persistence [ Time Frame: Weeks 0, 12, 24, 36 ]
    Total HIV DNA, integrated HIV DNA and 2-LTR circles in peripheral blood CD4+ T cells using PCR
  • Change in cell-associated HIV RNA [ Time Frame: Weeks 0, 12, 24, 36 ]
    Cell-associated unspliced and multiply spliced HIV RNA in peripheral blood CD4+ T cells using RT-PCR and Tat/rev Induced Limiting Dilution Assay (TILDA)
  • Change in proportion of immune cells [ Time Frame: Weeks 0, 12, 24, 36 ]
    T helper and T cytotoxic subsets, monocytes, dendritic cells and natural killer cells using flow cytometry
  • Change in T cell subset phenotype [ Time Frame: Weeks 0, 12, 24, 36 ]
    T cell subset activation and exhaustion marker and chemokine receptor expression using flow cytometry
  • Change in HIV-specific immunity [ Time Frame: Weeks 0, 12, 24, 36 ]
    HIV-specific CD4+ and CD8+ T cell frequency and polyfunctionality using HIV peptides and flow cytometry
  • Change in CD4+ T cell transcriptional profile [ Time Frame: Weeks 0, 12, 24, 36 ]
    CD4+ T cell transcriptional profile using RNA Seq
  • Change in high sensitivity C-reactive protein (hsCRP) [ Time Frame: Weeks 0, 12, 24, 36 ]
    hcCRP levels
  • Change in gut barrier permeability [ Time Frame: Weeks 0, 12, 24, 36 ]
    Gut barrier permeability using plasma lipopolysaccharide (LPS), soluble CD14 and intestinal fatty acid binding protein (I-FABP)
  • Change in gut microbiome diversity [ Time Frame: Weeks 0, 24, 36 ]
    Gut microbiome diversity using 16S rRNA sequencing and metagenomics
  • 25-hydroxyvitamin D levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Serum 25-hydroxyvitamin D levels and correlation between level achieved and each of the other endpoints (efficacy analysis)
  • Serum calcium levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Serum calcium corrected for albumin
  • Urinary calcium levels [ Time Frame: Weeks 0, 12, 24, 36 ]
    Urinary calcium:creatinine ratios and, where these are abnormal, 24 hour urinary calcium levels
  • Adverse events [ Time Frame: Weeks 0, 12, 24, 36 ]
    Incidence and severity of adverse events
  • Study protocol adherence [ Time Frame: Weeks 0 to 24 ]
    Adherence to study drug and 1g daily dietary calcium intake as measured by pill count and participant report
Not Provided
Not Provided
 
Effect of High Dose Vitamin D Supplementation on HIV Latency
Effect of High Dose Vitamin D Supplementation on HIV Latency: A Pilot Randomized Controlled Trial
HIV persists despite antiretroviral therapy (ART) and is associated with chronic inflammation. This inflammation is thought to prevent an effective immune response against the virus and is mediated at least in part by gut epithelial permeability and microbial translocation. HIV accumulates preferentially within Th17 cells with time on ART; these memory CD4+ T cells are highly susceptible to HIV infection and are concentrated within the gut. Vitamin D promotes gut epithelial integrity in animal models and exerts anti-inflammatory effects on the human immune system including down-modulation of Th17 cell frequency. This study will evaluate whether high dose vitamin D is able to reduce immune activation and Th17 cell frequency, to improve gut barrier integrity and the gut microbiome and reduce HIV persistence in participants on long-term suppressive ART.

The major barrier to a cure for HIV infection is the persistence of latently infected CD4+ T cells on antiretroviral therapy (ART). HIV is concentrated in vivo in Th17 cells in blood and the gastrointestinal tract. Th17 cells are critical mediators of mucosal immunity against bacteria and fungi and are rapidly depleted in the gut following HIV acquisition with subsequent gut epithelial permeability, microbial translocation and ensuing chronic inflammation which is not completely reversed on ART. Such inflammation may contribute to HIV persistence by potentiating T cell proliferation and thereby clonal expansion of infected cells, by exacerbating CD8+ T cell exhaustion and potentially by promoting viral replication despite ART.

Vitamin D has pleiotropic effects on the immune system including directing naïve CD4+ T cells away from the Th17 phenotype toward an anti-inflammatory regulatory T cell phenotype. It may also have beneficial effects on dendritic cell and CD8+ T cell immunity. Furthermore, vitamin D has been shown in animal models to strengthen gut epithelial integrity and in healthy volunteers to promote a more diverse gut microbiome.

The investigators plan to perform a pilot randomized double-blind placebo-controlled trial of high dose vitamin D supplementation in HIV-infected participants on suppressive ART and to determine its effect on immune activation, Th17 cell frequency, gut barrier integrity, the gut microbiome and HIV persistence.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Human Immunodeficiency Virus
  • Drug: Vitamin D3, 10000 Intl Units Oral Capsule

    Vitamin D capsule. Over-encapsulated to mimic placebo oral capsule.

    Eligible study participants will be randomized 1:1 to vitamin D or placebo one capsule daily from week 0 to week 24. All participants will be advised to achieve 1 gram daily dietary calcium intake whilst on study drug.

    Blood and urine will be taken at 0, 12, 24 and 36 weeks to evaluate the primary and secondary endpoints.

    Rectal swabs will be taken at 0, 24 and 36 weeks.

    All participants will continue antiretroviral therapy throughout the study.

    Other Name: Treatment Group
  • Drug: Placebo oral capsule

    Capsule containing oleic acid. Over-encapsulated to mimic vitamin D3 capsule.

    Eligible study participants will be randomized 1:1 to vitamin D or placebo one capsule daily from week 0 to week 24. All participants will be advised to achieve 1 gram daily dietary calcium intake whilst on study drug.

    Blood and urine will be taken at 0, 12, 24 and 36 weeks to evaluate the primary and secondary endpoints.

    Rectal swabs will be taken at 0, 24 and 36 weeks.

    All participants will continue antiretroviral therapy throughout the study.

    Other Name: Control Group
  • Active Comparator: Vitamin D3, 10000 Intl Units Oral Capsule
    Vitamin D3, 10000 Intl Units Oral Capsule, daily for 6 months
    Intervention: Drug: Vitamin D3, 10000 Intl Units Oral Capsule
  • Placebo Comparator: Placebo oral capsule
    Oleic acid capsule by mouth, daily for 6 months
    Intervention: Drug: Placebo oral capsule
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
30
Same as current
July 2019
January 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Written informed consent obtained
  • At least 18 years of age
  • Documented HIV-1 infection
  • Receiving combination antiretroviral therapy continuously for at least 3 years
  • Viral load suppressed below 40 copies/mL, or below assay limit of quantification where limit of quantification is above 40 copies/mL, for at least 3 years (excluding single episodes of HIV viral load 40-500 copies/mL where subsequent viral load was below 40 copies/mL or below assay limit of quantification where limit of quantification is above 40 copies/mL)
  • Viral load < 40 copies/ml at screening
  • Screening 25-hydroxyvitamin D level within 12 months prior to recruitment between 50nM and 125nM
  • Agreement not to take any vitamin D containing compounds other than study drug between screening and conclusion of the study
  • Agreement not to have vitamin D level checked by a treating doctor during the study unless medically required

Exclusion Criteria:

  • Any planned change to ART regimen within next 12 months (other than switching tenofovir disoproxil fumarate to tenofovir alafenamide)
  • Known current acute or chronic hepatitis B, known current acute or chronic hepatitis C or positive HBsAg or HCV PCR in blood at screening
  • Completion of curative treatment for HCV within 6 months prior to screening
  • HIV-2 infection
  • Any vitamin D supplementation from 6 months prior to the screening 25(OH) vitamin D test until study commencement (including multivitamins containing vitamin D and cod liver oil)
  • Any medical indication for vitamin D supplementation, eg osteoporosis, renal impairment (estimated glomerular filtration rate < 60ml/minute), liver cirrhosis
  • Chronic diarrhoea or fat malabsorption
  • Body mass index (BMI >= 35)
  • Current hypercalcaemia (corrected calcium greater than 2.60mM), current primary hyperparathyroidism or any history of nephrolithiasis
  • Current hyperthyroidism
  • History of sarcoidosis or active tuberculosis
  • Grade 3 or 4 abnormalities in screening pathology laboratory tests not already excluded by the above criteria at the discretion of the Principal Investigator
  • Hypersensitivity to vitamin D preparations
  • Concurrent medication with adverse interactions with vitamin D (eg oral glucocorticoids, phenytoin, carbamazepine, barbiturates, rifampicin, rifabutin, St John's wort, thiazide diuretics, digoxin, ketoconazole, itraconazole, nefazodone, isoniazid, cholestyramine, aluminium hydroxide, aripiprazole, danazol, orlistat, perhexiline or sucralfate use) or possible such use within next 12 months
  • Current interferon, immune checkpoint blocker, histone deacetylase inhibitor, oral vitamin A or other oral vitamin A analogue (eg acitretin, isotretinoin or tretinoin, also known as all-trans retinoic acid or ATRA) usage or possible use within next 12 months
  • Current participation in another interventional HIV cure study
  • Pregnancy or breast-feeding
  • Participants of child-bearing potential unwilling to use at least one form of effective contraception (with failure rate <1%, eg hormonal contraception, intrauterine device, abstinence, tubal ligation or partner with vasectomy) from at least 2 weeks prior to study commencement until at least 4 weeks after discontinuation of all study medication
  • Inability to consent
  • Inability to speak English
  • Medicare ineligibility
  • Major medical or psychiatric illness or substance misuse that could in the opinion of the investigator impair adherence to the study protocol
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia
 
 
NCT03426592
2016.362
No
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Sharon Lewin, University of Melbourne
University of Melbourne
  • Melbourne Health
  • The Alfred
  • Melbourne Sexual Health Centre
  • University of Illinois at Chicago
Principal Investigator: Sharon Lewin, FRACP PhD The Peter Doherty Institute for Infection and Immunity, University of Melbourne
University of Melbourne
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP