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The HIV epidemic represents one of the greatest health challenges worldwide, with important social and economic implications for public health. Although combination antiretroviral therapy (TAR) is effective in controlling infection and delaying disease onset, as well as improving the quality of life of infected persons, the relevant medical needs caused by HIV-1 infection are not yet fully met by TAR. The main obstacle to curing HIV is the establishment and maintenance of the viral reservoir. Therefore, we believe that this clinical trial will provide knowledge, for the first time, of the increase of antiretroviral drug levels in lymphatic tissue achieved by simultaneous administration of antiretroviral drugs at higher than usual doses, and their effect on persistent viral replication in intestinal lymphatic tissue and, as a consequence, on the latent cellular reservoir of HIV.
Data on the penetration of antiretrovirals into the tissues of long-term treated HIV patients are very limited. Previous pharmacokinetic studies indicate that tissue concentrations of the drug are much lower than those observed in plasma of HIV-infected patients or healthy volunteers. In addition, another study has reported that intracellular levels of antiretrovirals are much lower in lymphoid tissues than in peripheral blood after 6 months of TAR initiation, and these levels correlated inversely with ongoing viral replication.
In the line of research that we are raising, a previous study has reported a decrease in intracellular HIV RNA in lymphoid tissue when dolutegravir was administered at higher than usual doses. This is an important advance and new studies should be implemented with a design that allows to potentiate this strategy and significantly decrease the size of the viral reservoir in tissues.
If the hypothesis of the project, which consists mainly in the reduction or elimination of the HIV reservoir, is demonstrated, there would be very important consequences in the area of functional cure of HIV and/or reduction of chronic persistent inflammation, which could generate changes in conventional treatment schemes with great scalability. In addition, it is possible that by decreasing levels of persistent viral replication, an improvement in levels of immune activation and inflammation may also be observed, which would contribute positively to the overall health of the patient. Oral antiretroviral medication is proposed in order to compound a three-drug antiretroviral regimen. The three antiretroviral drugs have been chosen because they are the only ones that allow administration at higher doses without causing increased toxicity: dolutegravir 50 mg/12 h, maraviroc 300 mg/12 h and lamivudine 300 mg/12 h.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | Active Comparator | Triple therapy antiretroviral drugs on their usual regimen containing an integrase inhibitor |
|
| Intervention | Experimental | High doses of triple therapy antiretroviral drugs: dolutegravir 50 mg/12 h, maraviroc 300 mg/12 h and lamivudine 300 mg/12 h. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standardised triple antiretroviral therapy | Drug | patients have to use Triple therapy antiretroviral drugs on their usual regimen containing an integrase inhibitor. There are many types of drugs within this group, so they are not specified. |
| Measure | Description | Time Frame |
|---|---|---|
| To evaluate the variation in the size of the latent cellular reservoir of HIV-1 in lymphoid tissue and peripheral blood after administration of high doses of antiretroviral drugs. | Latent cell reservoir size by measuring total and intact proviral DNA (IPDA). | 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| To evaluate the variation of intracellular HIV RNA in total CD4+ T cells and memory phenotypes from baseline to weeks 24 and 48 in both blood and lymphoid tissue. | HIV replication by measuring cell-associated HIV RNA (ca-HIV-RNA) and HIV RNA levels in blood and lymphoid tissue. | 48 weeks |
| To compare changes in distribution and activation markers ( CD25, HLA-DR among others) in T-cell subpopulations (naïve and memory phenotypes). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Santiago Moreno Guillen, PhD | Contact | 91 336 87 10 | smguillen@salud.madrid.org | |
| Erick de la Torre | Contact | erick.delatorretarazona@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Santiago Moreno Guillen | IRYCIS. Hospital Universitario Ramón y Cajal. Madrid, Spain. | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitario Ramón y Cajal | Not yet recruiting | Madrid | Madrid | 28034 | Spain | |
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| High doses Triple therapy antiretroviral drugs | Drug | dolutegravir 50 mg/12 h, maraviroc 300 mg/12 h and lamivudine 300 mg/12 h |
|
Activation/inflammation markers (HLA-DR, CD25, among others) in blood and intestinal T-cell subpopulations. |
| 48 weeks |
| To evaluate the effects of the intervention on markers of inflammation and bacterial translocation. | Levels of plasma biomarkers of activation/inflammation and bacterial translocation (IL-6, CRP, TNF, sCD14, among others). | 48 weeks |
| To determine antiretroviral drug concentrations in blood and gastrointestinal tract tissue. | Antiretroviral drug concentrations in lymphoid tissue and peripheral blood. | 48 weeks |
| To correlate markers of viral persistence (intact HIV DNA and ca-HIV RNA) with drug concentrations, as well as with activation and inflammation parameters of cell subpopulations and plasma. | Colonoscopy examination and collection of intestinal tissue samples (biopsy) for determination of viral reservoir variables (proviral DNA and intracellular HIV RNA) and antiretroviral drug levels. | 48 weeks |
| Incidence of Adverse Events with experimental treatment regimen (Safety and Tolerability) | Incidence and types of adverse reactions. | 48 weeks |
| Hospital Universitario 12 de Octubre |
| Recruiting |
| Madrid |
| Spain |
|