Impact of Recombinant Human Growth Hormone on HIV Persistence
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|ClinicalTrials.gov Identifier: NCT03091374|
Recruitment Status : Unknown
Verified September 2019 by Jean-Pierre Routy, McGill University Health Centre/Research Institute of the McGill University Health Centre.
Recruitment status was: Recruiting
First Posted : March 27, 2017
Last Update Posted : September 18, 2019
|First Submitted Date ICMJE||March 21, 2017|
|First Posted Date ICMJE||March 27, 2017|
|Last Update Posted Date||September 18, 2019|
|Study Start Date ICMJE||December 2016|
|Estimated Primary Completion Date||February 2020 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Change in the frequency of CD4+ T cells harbouring replication competent HIV (per 106 CD4+ T cells) between baseline (average of 2 assessments at study week -2 and 0) and 48 weeks recombinant human growth hormone administration (study week 48). [ Time Frame: Baseline and 48 weeks ]|
|Original Primary Outcome Measures ICMJE
||Change in the frequency of CD4+ T cells harbouring replication competent HIV (per 106 CD4+ T cells) between baseline (average of 2 assessments at study week -2 and 0) and 48 weeks recombinant human growth hormone administration (study week 48). [ Time Frame: 48 weeks ]|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Impact of Recombinant Human Growth Hormone on HIV Persistence|
|Official Title ICMJE||A Proof-of-concept Study to Assess the Effect of Recombinant Human Growth Hormone on the Size of the Replication-competent Viral Reservoir in HIV-infected Individuals on Suppressive Antiretroviral Therapy|
Antiretroviral therapy (ART) has improved the health of more than 18 million people infected with HIV by controlling viral replication, AIDS and non-AIDS events, and by reducing the risk of transmission. However, the existence of latent viral reservoirs in long-lived memory CD4 T cells remains a hurdle to curing HIV infection; consequently patients must remain on ART for the rest of their lives. Recently, a more realistic approach under limelight is to identify strategies leading to a functional cure, which is defined as the natural control of viral reservoir by the host. Use of recombinant human growth hormone has been shown to improve immune function by several mechanisms. This study hypothesizes that treatment with recombinant human growth hormone will decrease the size of the replication competent HIV reservoir in HIV-infected immune-reconstituted individuals.
The specific study objectives include:
For this purpose, the investigators will add recombinant human growth hormone treatment for the patients receiving stable ART. Approximately 22 participants will be enrolled in this study at the Chronic Viral Illness Service of the McGill University Health Centre (Montreal, Canada), which will last about 52 weeks. Participants will be treated with recombinant human growth hormone for a total of 48 weeks. The initial recombinant human growth hormone dose will be 3 mg/day (30-40 µg/kg/d) for 24 weeks administered by subcutaneous injection on an outpatient basis, followed by dose reduction to 1.5 mg/day for the final 24 weeks of the treatment period, also conducted on an outpatient basis. The study inclusion criteria include male and female participants, ≥18 and <40 years of age, with an undetectable viral load (the quantity of the HIV virus in the blood must be less than 50 copies/ml) during last 24 months and with a CD4 T-cell count ≥350 cells/mm3 obtained within 30 days prior to study entry. The findings from this study will contribute to the development of novel strategies to eradicate HIV.
Antiretroviral therapy (ART) has dramatically reduced the death rate from AIDS and improved the quality of life of many HIV-infected individuals. However, ART does not eradicate HIV as demonstrated by the rapid return of viremia whenever treatment is interrupted. The possible long-term toxicity associated with ART, viral resistance, stigma and cost all contribute to the necessity of finding a cure. A sterilizing cure, in which the virus is completely eradicated, would require the elimination of all replication-competent viruses throughout the body. An alternative approach, probably more realistic, would be to aim for a kind of "cancer model" of cure, where an individual would enjoy long-term health in the absence of ART, or a disease "remission", which might be achieved after reducing the amount of residual HIV during ART (the "reservoir") to levels which the immune system can effectively control. This is commonly referred to as a functional cure in which the viral reservoir is naturally controlled by the host. Both forms of cure (sterilizing and functional) would require eliminating, or at least reducing, the reservoirs of HIV infection.
Different types of cells carry persistent HIV in virally suppressed individuals. Although myeloid cells may also contribute to HIV persistence, it is well established that the majority of replication competent viral genomes persist in memory CD4 T cells during ART. In contrast, naïve CD4 T cells are rarely infected in virally suppressed individuals. As a result of their low infection rate, the frequency of naïve cells negatively correlates with the size of the viral reservoir. Therefore, increasing the frequency of naïve cells may actively reduce the size of the latent HIV reservoir.
The thymic activity gradually decreases with age. The production of recent thymic emigrants (RTEs) is drastically reduced in the elderly, resulting in a decrease in the proportion of new naïve cells in the CD4 compartment, which is compensated by the proliferation of naïve cells in the periphery. Thus, the stability of the naïve cell pool is ensured by different mechanisms in young and elderly, with a major contribution of the thymus in young people. The study investigators preliminary data indicate that the size of the reservoir as measured by integrated DNA strongly correlates with the age of virally suppressed individuals, with younger individuals displaying a smaller reservoir). Although the mechanism underlying this remarkable association is unknown and likely to be multi-factorial, continued generation of naïve CD4 T cells during ART could lead over time to replenishment of infected memory cells with new uninfected memory cells.
Recombinant human growth hormone (rhGH) administered to ART-treated HIV infected individuals has been found to reverse thymic involution, increase total and naïve CD4 T cell counts and reduce the expression of activation and apoptosis markers. Reconstitution of the thymus in immunosuppressed adults through rhGH hormone treatment restores both HIV-specific cellular and antibody responses. Altogether, these observations suggest that the administration of rhGH may reduce the size of the latent HIV reservoir by 1) increasing the frequency of naïve cells 2) reducing the levels of immune activation and 3) restoring HIV specific immune responses, three parameters that are associated with the size of the latent HIV reservoir.
In clinical trials conducted to date using pharmacologic doses of GH, the most common adverse effects have been arthralgia and edema, both occurring in approximately 35% of patients; and myalgia, which was observed in about 30% of patients on GH. Other less common effects that are believed to be related to GH treatment include increased blood pressure, headaches, hyperglycemia and diabetes, enlargement of male breast tissue, carpal tunnel syndrome, and pancreatitis. Other, extremely rare, potential side effects that may be related to GH are allergic reactions to GH, idiopathic intracranial hypertension, hypothyroidism, and leukemia. There is conflicting evidence about whether GH increases the occurrence of lymphoma or other cancers in patients infected with HIV.
While participant enrolled in this trial might not benefit directly from the strategy, it is expected that the trial will provide useful information that relates directly to the status of the study participants (HIV infection HIV reservoirs, immunotherapeutic approaches etc.). In addition, study participants enrolled in the trial will receive compensation, clinical monitoring, laboratory monitoring and continued adherence counseling.
The investigators' primary hypothesis is that treatment with recombinant human growth hormone will result in a decrease in the size of the replication competent HIV reservoir in HIV-infected immune-reconstituted individuals. A reduction in the size of the HIV reservoir is unlikely to have any direct clinical benefits for the participants. However, this may contribute, in association with other therapies, to the development of novel strategies to eradicate HIV in the future.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Somatotropin (Human)|
|Study Arms ICMJE||Experimental: Growth Hormone
Intervention: Drug: Somatotropin (Human)
|Publications *||Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sekaly RP. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009 Aug;15(8):893-900. doi: 10.1038/nm.1972. Epub 2009 Jun 21.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||December 2020|
|Estimated Primary Completion Date||February 2020 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 40 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT03091374|
|Other Study ID Numbers ICMJE||MS700149_0002|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Current Responsible Party||Jean-Pierre Routy, McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||EMD Serono|
|Investigators ICMJE||Not Provided|
|PRS Account||McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Verification Date||September 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP