Pilot Study of the Impact of Adding Raltegravir (MK-0518) to Antiretroviral Therapy in Patients With Undetectable Plasma Virus

HIV Infections Clinical Trial

Official title:

Investigating the Source of HIV-1 Viremia in Patients on Antiretroviral Therapy Through Intensification With MK-0518

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00618371
• Other study ID #: 27XS050
• Status: Recruiting
• Phase: N/A
• First received: September 29, 2007
• Last updated: October 13, 2008
• Start date: October 2007
• Est. completion date: March 2009

Study information

• Verified date: October 2008
• Source: University of Pittsburgh
• Contact: Deborah McMahon, MD
• Phone: 412-647-6710
• Email: mcmahon[@]dom.pitt.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The medicines used to treat HIV can suppress but cannot kill all the virus in the body. A small amount of virus remains at low levels in the part of the blood called the plasma. It is of crucial importance to identify the source of the residual virus in patients receiving antiretroviral therapy. The purpose of this study is to investigate whether the source of low level plasma virus is from latent (old) infection or ongoing (new) infection. MK-0518 is a investigational drug, which means that is not yet FDA approved, that works in a different way to other anti-HIV medicines to help kill the virus. We hypothesize that addition of MK-0518 to a stable anti-HIV regimen will reduce the viral load further in patients with undetectable plasma virus.

Description:

This is a non-randomized, non-comparative, single center trial of antiretroviral therapy intensification using the investigational integrase inhibitor MK-0518 and an investigational viral load assay to measure response to additional antiviral therapy. Eighteen patients will receive open-label MK-0518 400 mg P.O. every 12 hours for 28 days in addition to their prescribed antiretroviral therapy. Patients will take their doses of MK-0518 without regard to food. The study will enroll patients on antiretroviral therapy regimens with CD4 counts greater than 200 cells/ul, HIV-1 RNA levels <50 copies RNA/ml plasma using a commercial assay(conventional Amplicor) and with detectable plasma virus (viral loads ≥ 1 copies RNA/ml plasma, SCA assay). Acceptable antiretroviral regimens will include those on NRTIs + PI, NRTIs + NNRTI + PI, or NRTIs + NNRTI-containing regimens. Patients cannot have prior evidence of resistance to antiretroviral drugs. Patients will be screened for intensification by history, physical exam, and laboratory evaluations (see below). Patients who are eligible and who agree to participate will intensify their antiretroviral therapy for 28 days with MK-0518 400 mg by mouth twice a day. During the 28- day drug addition, patients will have samples drawn for SCA assay at entry and on days 7, 14, 21, and 28 (+/- 1 d), with the last day of intensification as day 28. Patients will have additional phlebotomy after intensification on days 29, 30, 35, 42, 49 and 58 (+/- 1 day). The intensification period is followed by a post- intensification period to determine whether removal of the drug resulted in viral RNA changes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: March 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV-1 infection documented by positive HIV-1 ELISA and positive

• Male or female at least 18 years of age, and able to provide written, informed consent

• Current antiretroviral therapy with DHHS-recommended regimen: NRTIs + PI, NRTIs + NNRTI + PI, or NRTIs + NNRTI

• Screening CD4 > 200 cells/ µl and CD4%> 14%; does not require prophylaxis for opportunistic infections

• Receiving a stable antiretroviral regimen for 4 months prior to screening

• HIV-1 RNA level below the limit of detection by commercial HIV-1 RNA determination assays for at least 12 months prior to screening.

• HIV RNA = 0.6 copy RNA/ml plasma by SCA(single copy assay)

• Hgb = 9.0 mg/dl, absolute neutrophil count > 1000/mm3, platelet count > 100,000/mm3

• Alkaline phosphatase, AST and ALT < 2.0 x upper limit of normal

• Willing to take MK-0518 for 28 days in addition to ongoing antiretroviral therapy

• Be considered clinically stable, in the opinion of the investigator, at the time of entry into the study; i.e., clinical status and all chronic medications should be unchanged for at least two weeks prior to entry.

Exclusion Criteria:

• Prior participation in an MK-0518 or other integrase inhibitor trial

• Requires prohibited medications noted in the protocol

• Requires cytotoxic agents including hydroxyurea or vaccinations during the study period

• Received immunosuppressive therapy including steroids within one month prior to treatment in this study

• Used any investigational agents within a month prior to treatment in this study

• Documented resistance to any drug in each of the 4 classes of licensed antiretroviral agents by genotype or phenotype

• Any febrile illness (T>38oC) in the 3 weeks prior to enrollment

• Any vaccination in the 6 weeks prior to enrollment

• Diagnosis of acute hepatitis due to any cause

• Positive Hepatitis B surface antigen

• Severe renal insufficiency defined as a calculated creatinine clearance at time of screening as < 30 ml/min, based on the Cockcroft-Gault equation.

• Condition (including but not limited to alcohol or other substance use) which in the opinion of the investigator would interfere with patient compliance or safety

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Raltegravir (MK-0518)
Raltegravir 400mg PO every 12 hours for 28 days in addition to the prescribed antiretroviral therapy

Locations

Country	Name	City	State
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (6)

Dornadula G, Zhang H, VanUitert B, Stern J, Livornese L Jr, Ingerman MJ, Witek J, Kedanis RJ, Natkin J, DeSimone J, Pomerantz RJ. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA. 1999 Nov 3;282(17):1627-32. — View Citation

Hazuda DJ, Wolfe AL, Hastings JC, Robbins HL, Graham PL, LaFemina RL, Emini EA. Viral long terminal repeat substrate binding characteristics of the human immunodeficiency virus type 1 integrase. J Biol Chem. 1994 Feb 11;269(6):3999-4004. — View Citation

Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007 Apr;3(4):e46. — View Citation

Natarajan V, Bosche M, Metcalf JA, Ward DJ, Lane HC, Kovacs JA. HIV-1 replication in patients with undetectable plasma virus receiving HAART. Highly active antiretroviral therapy. Lancet. 1999 Jan 9;353(9147):119-20. — View Citation

Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, Dewar RL, Planta A, Liu S, Metcalf JA, Mellors JW, Coffin JM. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003 Oct;41(10):4531-6. — View Citation

Zhang L, Ramratnam B, Tenner-Racz K, He Y, Vesanen M, Lewin S, Talal A, Racz P, Perelson AS, Korber BT, Markowitz M, Ho DD. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med. 1999 May 27;340(21):1605-13. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HIV-1 RNA response: = 1 log decrease in viral load		4 weeks	No
Secondary	Proviral DNA response, HIV-1 sequence variation		4 weeks	No