Impact of Raltegravir on HIV-1 cDNA Slope Following Antiretroviral Therapy (ART) Initiation

NCT01168167 | Completed

• 1 other identifier: JWG-HIVCENTER-Hopp1
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Recent clinical trials of combination antiretroviral therapy (cART) containing the first approved integrase inhibitor (i.e. raltegravir) have demonstrated a more rapid decay of HIV-1 RNA in plasma, compared to conventional potent antiretroviral combinations. This was observed especially during the early phase (up to week 12) following initiation of cART. To explain this, two mechanistic hypotheses have been developed:

1. 1.\- Macrophage reservoir death hypothesis. A major source of virus production during the second phase decay are believed to be long-lived infected cells with continuous virus production - e.g. macrophages. An accumulation of unintegrated, episomal HIV-1 cDNAs can promote apoptosis (Li et al. Embo J. 2001;20: 3272). In case of HIV superinfection of such a productively infected cell, an INI-based cART may induce apoptosis and thus contribute to a decrease in HIV RNA load during second phase decay. However, no study has thus far addressed the consequences of INI treatment on HIV-1 cDNA species on any cell population in vivo.
2. 2.\- Resting CD4 T-cell reservoir integration block hypothesis. Resting CD4 T-cells may represent a substantial reservoir for HIV replication during the second phase decay as well. A special characteristic of these cells is that HIV-1 cDNA is typically localized to the nucleus in a not-integrated form (Chun et al., PNAS 1997;94:13193). These resting cells likely integrate HIV-DNA upon activation and then contribute to HIV viremia and viral spread. Conceptually, integration could be prevented by RGV, but not by RTI or PI. An accumulation of circular episomal HIV-1 cDNA species may also be a consequence of RGV treatment in this cell type.

Conditions

HIV-1

Keywords

Antiretroviral Therapy, Highly Active; MK 0518; HIV-1 DNA species; viral slope; Ribonucleic Acid; DNA, Complementary

Outcome Measures

Primary Outcomes (1)

• Dynamical measurement of HIV-1 DNA-species extracted from whole blood-PBMCs

  one year

Secondary Outcomes (2)

• CD4 cell counts

  one year

• plasma-HIV-1 RNA

  one year

Study Arms (2)

raltegravir-based cART

Patients who begin cART in regular clinical routine with 2N(t)RTI plus raltegravir (n=10 patients) will be offered to participate in this observation arm, but only if no other antiretroviral drugs and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of \>5,000 copies/mL and CD4-cell count of \>200/µL within 12 weeks before cART initiation.

standard of care-cART

Patients who begin cART in regular clinical routine with 2N(t)RTI plus either a boosted protease inhibitor or efavirenz (n=10 patients) at standard doses will be offered to participate in this observation arm. They will be offered to participate in this trial only if no other antiretroviral drugs and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of \>5,000 copies/mL and CD4-cell count of \>200/µL within 12 weeks before cART initiation.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients who begin cART in regular clinical routine with 2N(t)RTI plus either (n=10 patients) raltegravir or (n=10 patients) a boosted protease inhibitor/ alternatively an NNRTI as third substance will be offered to participate in this non-interventional study. Observation time is a period of 4 months after cART initiation.

You may qualify if:

• Initiation of antiretroviral therapy, consisting of 2 nucleoside/ nucleotide reverse transcriptase inhibitors at physician's disposition plus a third substance, i.e. either raltegravir (n=10 patients) or a standard third substance (efavirenz or boosted protease inhibitor)
• Men or women with a documented HIV-1 infection, treated at the study center
• age at least 18 years old
• physical examination and vital signs, according to the treating physician do not give any hint for a active AIDS-defining illness or other serious disease
• patients are naive to cART or in therapy interruption for at least 3 months
• last available HIV-1 RNA was \>5,000 copies/mL within 3 months prior to cART initiation
• last available CD4-cell count showed at least 200 cells/µL within 3 months prior to cART initiation
• according to German-Austrian antiretroviral treatment recommendations, there is a given therapy indication

You may not qualify if:

• cART with other than the above mentioned drugs
• administration of concomitant drugs with relevant impact on antiretroviral's pharmacokinetics
• documented problems with patient visit- or medication-adherence
• any condition or disease requiring a medication that may interact relevantly with cART

Sponsors & Collaborators

• Christoph Stephan: lead
• University Hospital Heidelberg: collaborator

Study Sites (1)

Johann Wolfgang Goethe-University Hospital

Frankfurt am Main, Hesse, 65520, Germany

Location

Related Publications (1)

• Stephan C, Baldauf HM, Barry J, Giordano FA, Bartholomae CC, Haberl A, Bickel M, Schmidt M, Laufs S, Kaderali L, Keppler OT. Impact of raltegravir on HIV-1 RNA and DNA forms following initiation of antiretroviral therapy in treatment-naive patients. J Antimicrob Chemother. 2014 Oct;69(10):2809-18. doi: 10.1093/jac/dku213. Epub 2014 Jun 23.

  PMID: 24962031 RESULT

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 21, 2010
• First Posted: July 23, 2010
• Study Start: June 1, 2010
• Primary Completion: March 1, 2011
• Study Completion: May 1, 2012
• Last Updated: March 23, 2016

Record last verified: 2016-03

Locations

DE (1)