HIV Integrase Inhibitors Show Potent Activity in Clinical Trials

Special Report

By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine

Dr. Winslow is a consultant for Bayer Diagnostics, and on the speaker's bureau for GlaxoSmithKline and Pfizer.

Since 1995, the outlook for patients with hiv infection has improved significantly with the advent of triple-drug-potent antiretroviral (ARV) therapy regimens. The current, preferred regimen includes 2 nucleoside analog reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). These triple-drug regimens have allowed thousands of patients who were virtually on death's door with AIDS-defining opportunistic infections to live and, in many cases, recover their health to the extent they can return to full-time employment. In addition, the introduction of well-tolerated and potent ritonavir-boosted PIs (which in many cases can be dosed once daily) have been additional incremental advances. Only one attachment/entry inhibitor is currently approved by the FDA — enfuvirtide (FuzeonTM). While this drug plays a role in improving the likelihood of successful salvage therapy in patients infected with multiple-class ARV resistance, its need for twice-daily subcutaneous injections and frequent severe injection-site reactions makes it a tough drug to take for a chronic illness. The CCR5 co-receptor inhibitors currently in late-stage clinical development have been somewhat disappointing when studied in patients with advanced disease and resistant virus. This is probably related to the fact that many patients with late-stage HIV disease have CXCR4 or dual-tropic virus.

It is clear that developing antiretroviral agents that are active against viral targets other than RT and protease is desirable. During the late 1980s and early 1990s, there was brief enthusiasm for targeting processes such as glycosylation and myristoylation, which, while necessary for post-translational modification of cellular proteins, are also ubiquitous cellular processes and inhibitors targeting these processes proved to be extremely toxic in vivo.

Integrase (IN) is the third gene product of the HIV polymerase gene (the others being protease and RT). It performs two basic molecular functions: a) causes 3' processing of the double-stranded cDNA product of reverse transcription, then b) catalyzes strand transfer to incorporate the cDNA into the host cell genome. Merck and Company began a drug discovery program targeting HIV integrase back in the late 1980s and early 1990s. While identifying a number of lead compounds which displayed good in vitro activity against HIV, many of their compounds did not make it into clinical development due to either poor bioavailability or toxicity in animals. The company's persistence and patience seems to have finally been rewarded with MK-0518. Both MK-0518 and a second integrase inhibitor in development by Gilead, GS 9137, act on this latter step by inhibiting strand transfer.

MK-0518 is administered orally every 12 hours, does not require ritonavir boosting, is metabolized by glucuronidation, and is neither a substrate nor an inducer of the cytochrome P450 system. The drug appears to be safe and well tolerated with adverse events comparable to placebo.1 There is no significant food effect2 and no known drug interactions.3

In a 16-week Phase II monotherapy dose-ranging study in 30 treatment-naïve patients, MK-0518 produced > 50 × viral load reductions in all patients with HIV RNA levels < 400 copies/mL in 50–57% and < 50 copies/mL in 13–29% of patients. During the second phase of the study, the original 30 patients plus an additional 168 patients received tenofovir (TDF) and lamivudine (3TC) plus either MK-0518 or efavirenz. After 24 weeks of therapy 85–95% of MK-0518 patients and 92% of efavirenz patients achieved HIV RNA levels of < 50 copies/mL.1

A second Phase II, randomized, double-blind, placebo-controlled trial compared 200, 400, and 600mg BID regimens vs placebo. All patients received optimized background therapy (OBT). Inclusion criteria included the requirement that all patients were failing ARVs and had resistance to at least one drug across the three conventional ARV classes. In this tough patient population at the 16 week interim analysis point, dose levels of MK-0518 produced HIV viral loads of < 400 copies/mL in 64–84% vs only 22% for placebo.3

Earlier this year Merck began two Phase III, randomized, double-blind, placebo-controlled trials in patients failing HAART on OBT and will evaluate MK-0518 vs placebo. In addition, sites are being selected in the United States to evaluate MK-0518 as part of an expanded access program.

In addition to the Merck entry in this field, Gilead Sciences recently in-licensed from Japan a quinolone-based strand transfer inhibitor, now identified as GS 9137. This compound also appears to display favorable pharmacokinetics and may be dosed BID or once daily when boosted with low-dose ritonavir.4 Its absorption is enhanced in the presence of food.5 In a small Phase I/II dose ranging study in treatment naïve patients GS 9137 showed significant antiretroviral activity compared with placebo.4

Integrase inhibitors show excellent in vitro activity against HIVs resistant to all 3 of the traditional antiretroviral drug classes. So far, their in vivo activity appears excellent as well, even in patients with advanced disease and those infected with broad ARV-resistant virus. The ultimate role of integrase inhibitors in our therapeutic arsenal will be determined by longer term clinical trials. While resistance to integrase inhibitors has been demonstrated in vitro,6 additional experience is needed to assess the potential for resistance development in vivo.

Expanded Access Research Program

EARMRK, the expanded access research program from Merck, is intended to provide early access to MK-0518, the company's investigational HIV medication, for patients who are resistant to existing classes of antiretroviral medications and who require an HIV treatment regimen containing a medication to which they may not be resistant. EARMRK is a global program that will provide free MK-0518 to qualified patients for the duration of the program through a research study.

To qualify for the EARMRK program, patients must have documented resistance or intolerance to at least on drug in each of the 3 major classes of anti-HIV medications — nucleoside analogues (RTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs).

Patients who qualify must not be adequately suppressing viral load on their current regimen and be at risk of clinical or immunologic progression. Their physician must determine that they need such an investigational medication to construct a potentially viable regimen. To be eligible, patients must be at least 16 years old.

The safety and efficacy of MK-0518 has not been established. To increase the likelihood that patients will respond to treatment, patients are encouraged to optimize their current regimen when beginning therapy with MK-0518. To do this, it is recommended that patients failing their current regimen receive at least 2 new antiretroviral medications to which their virus is still sensitive.

Eligible patients will be able to use MK-0518 with any available antiretroviral medications, including other medications available through expanded access research programs sponsored by other manufacturers after review and approval by the sponsor.

Patients are ineligible if they are currently or were previously participating in a clinical trial with MK-0518. They also are ineligible if they are taking any medications prohibited by the study protocol, including phenobarbital, phenytoin, and rifampin. Patients with acute hepatitis and patients who are pregnant or breast-feeding are also ineligible. Other exclusions apply.

Physicians interested in participating in the EARMRK expanded access research program should access


  1. Merck and Company — Research and Development News: An Investigational Oral HIV Integrase Inhibitor, MK-0518, in Combination Therapy Achieved Comparable HIV RNA Reduction to Efavirenz in Combination Therapy. August 12, 2006. Available at:
  2. — Conference Reports: 10th European AIDS Conference. MK-0518, the First Integrase Inhibitor for HIV. Available at:
  3. Merck and Company — Research and Development News: Merck Announces Interim Results from Phase II Study of MK-0518, an Investigational Oral HIV Integrase Inhibitor (press release), February 9, 2006. Available at:
  4. 13th Conference on Retroviruses and Opportunistic Infections, Abstract 160LB, February 2006.
  5. 13th Conference on Retroviruses and Opportunistic Infections, Poster 580, February 2006.
  6. Lataillade M, et al. Natural Polymorphisms of the HIV-1 Integrase Gene and Mutations Associated with Integrase Inhibitor Resistance. Antiviral Therapy 2006;11:S28.