A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety, Tolerability of MK-0518 in Treatment-Experienced HIV-1 Infected Adult Patients With Hemophilia

1. Objective

To assess the safety, tolerability and efficacy of MK-0518 compared to placebo when combined with other antiretroviral drugs, in treatment-experienced HIV-infected patients with hemophilia. 2. Background and Significance

Current anti-HIV drugs are mainly reverse transcriptase inhibitors, which include nucleoside reverse transcriptase inhibitors(NRTIs) and non-nucleoside reverse transcriptase inhibitors(NNRTIs), and protease inhibitors(PIs). However, HIV can become rapidly resistant to them due to its high rate of mutation while replicating, which forces people to seek new targets for anti-HIV therapy continually. Integrase is an another enzyme essential for HIV reproduction. To inhibit integrase activity is an effective measure to suppress HIV replication. MK-0518(Raltegravir）was approved by the United States Food and Drug Administration(FDA) on October 12th 2007 due to its potent antiviral activity and became the first-to-market integrase inhibitor.Compared with other antiviral drugs, it has new action mechanism and target site, so there is no cross resistance between it and them, which makes it a good option for patients with multi-drug resistant HIV strains. HIV infection is very common in hemophiliac patients who need continuous infusion of clotting products,and the chance of getting HIV infection for hemophilia patients is very high, especially before 1985 when non-virus-inactivated factor concentrates were widely used. Many hemophilia patients were infected with HIV, and AIDS became their main cause of death.The recommended first-line antiretroviral regimen for HIV/AIDS patients with hemophilia concludes two NRTIs and one NNRTIs, while protease inhibitors are not recommended to use in these patients, because they are likely to worsen bleeding tendency. So, if HIV/AIDS patients with hemophilia are resistant to NRTIs and NNRTIs, there are few remaining options for them to choose as part of second-line drugs. However, MK-0518，a drug with novel anti-HIV mechanism different with NRTIs and NNRTIs, may be used in HIV/AIDS patients with hemophilia as the second-line drug.

3． Study design

1. Patients Enrollment
2. Patients enrolled in the study sign consent form
3. Select an optimized background therapy(OBT) for each subject
4. Randomization: patients are randomly assigned to MK-0518 400 mg twice daily plus OBT group or placebo plus OBT group, each group concludes at least 50 subjects.
5. Data collection: for each patient, detection of HIV viral load and CD4+ T lymphocyte count is done at screening, and at weeks4, 8, 12, 16, and 24. The safety profile of MK-0518 is monitored according to patients' complaints and the results of physical and laboratory examinations.
6. Endpoints of study: The primary endpoint is the the safety and tolerability of MK-0518 400 mg b.i.d. compared to placebo, both in combination with OBT.The secondary endpoint is antiretroviral activity of MK-0518 400 mg b.i.d. compared to placebo, both in combination with OBT.