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The Dawn of a New Treatment

A Look at Experimental HIV Integrase Inhibitors

May/June 2006

Daniel S. Berger, M.D.


Combating HIV with antivirals has been restricted to attacking the virus through only one or two viral enzymes. The virus uses its enzymes, proteins that facilitate biochemical reactions, to synthesize its viral components, enabling it to replicate. As targets, our current antivirals are inhibitors of HIV's reverse transcriptase and protease enzymes. An additional treatment employs a drug that blocks HIV from fusing to the T-cell (Fuzeon), but its use has been limited because of the requirement of patient self-injection twice daily. However, a new and promising enzyme target is coming to a local clinic near you -- integrase inhibitors.

It is estimated that up to 78% of patients who fail antiretroviral drugs have developed resistance to more than one therapeutic class of antiviral medicines and increased drug resistance is now increasingly observed, even in drug-naive individuals (patients who've never been treated for HIV). Thus, development of a new class of antiretroviral drugs couldn't come at a better time.

Why Integrase?

HIV integrase has become the third enzyme protein being investigated as an anti-HIV therapy. However, unlike the reverse transcriptase and protease inhibitors, HIV uses the integrase enzyme to integrate itself, or incorporate its genes, into the human cell's gene (DNA), which is a unique and new viral site target.

Inhibiting integrase has been a difficult challenge for drug development; there is no complete structure of the enzyme found in the human body (in vivo). Pertaining to HIV, the integration stage occurs after the step where the reverse transcriptase enzyme has allowed the viral RNA to be transcribed into viral DNA (viral genes). HIV eventually forms a pre-integration complex which employs integrase to splice itself and insert its DNA into the host human cell.

In other words, integrase is absolutely necessary for the virus to trick the host cell as it becomes incorporated into it for replication; thus it is an attractive strategy and adds another target to our ammunition to protect healthy (human) cells from infection.

Discovering and developing an integrase inhibitor has proved difficult, and advancement towards human clinical trials has been slow. So finally seeing the first integrase inhibitor candidates in the clinic seems almost miraculous. Additionally, no homologue (similar structure) for integrase exists in human cells. Thus integrase inhibitors should be very specific to blocking the virus and may limit side effects to human cells because of its specificity for the virus.

However, integrase inhibitors will need to be combined with antivirals as in all antiviral treatment cocktails consistent with HAART (highly active antiretroviral therapy). Integrase is a strategy that blocks infection and integration in cells, but for the cells that are already infected, the other antiviral components of HAART add greater effect towards halting HIV replication.

Integrase inhibitors are active against virus that is resistant to nukes, non-nukes, and protease inhibitors. For treatment-experienced patients needing new active drugs due to resistance, this class of antivirals will be very useful, assisting in the control of HIV replication. However, just as resistance is observed to existing antivirals, there is no reason to expect anything less with integrase inhibitors. But it is hoped that integrase resistant mutations may contribute to decreased replicative capacity of the virus, or a poorly viable (weakened) HIV.

Disintegrating HIV Integration: The Clinical Studies

Currently there are two integrase inhibitors in clinical development. Both Merck (MK-0518) and Gilead Sciences (GS 9137) presented results of their candidate oral integrase inhibitors in a late breaker session at the 13th Retrovirus Conference in Denver in February. Both compounds showed tremendous 2 log reduction in viral load and little or no toxicities. For the first time, there are two drugs in a completely new class that have shown preliminary data of a dramatic and profound effect on HIV.


Interim Phase 2 results were presented of Merck's compound, MK-0518, which was studied in 167 patients with advanced HIV. The patients were individuals failing antiretroviral therapy, having viruses resistant to at least one drug in each of the three available classes of HIV treatment. In combination with optimized background therapy (OBT) -- chosen by the physician based on resistance testing -- the experimental integrase inhibitor at all three doses studied (200 mg, 400 mg, and 600 mg orally, twice daily) combined with background treatment had greater antiretroviral activity than placebo.

To summarize the results, at week 16 of study, the percentage of patients achieving viral loads (HIV RNA) below 400 copies/mL ranged from 64-84% for MK-0518 plus OBT versus 22% (6 of 27 patients) for placebo plus OBT. And the percentage of patients achieving viral loads less than 50 copies/mL ranged from 56-72% for MK-0518 plus OBT across all doses studied (200 mg, 400 mg, and 600 mg, twice daily).

MK-0518 was generally well tolerated, and the most common side effects reported for at least five percent of patients in each dose arm was diarrhea, nausea, fatigue, headache, and itching.

GS 9137

Gilead Sciences' integrase inhibitor is unique in that it is metabolized by the liver enzyme system (it is a CYP3A4 inducer) and thus can be boosted by ritonavir, similar to most protease inhibitors. As such, GS 9137 can be dosed once daily, as opposed to MK-0518.

An early Phase I study was presented as a late-breaker presentation in Denver. Forty patients were randomized and received one of five doses of GS 9137 or placebo with food for 10 days. The study evaluated GS 9137 at 200 mg twice daily (BID), 400 mg BID, 800 mg BID, 800 mg once daily (QD), and 50 mg boosted with 100 mg ritonavir QD. At study entry, all patients were not receiving antivirals and had viral loads between 10,000 and 300,000 copies/mL and CD4 T-cells equal to or greater than 200 cells/µL. The patient population included both individuals naive to treatment as well as treatment-experienced patients.

During this Phase 1 study, after 10 days of treatment, viral loads decreased by 2 logs in both the ritonavir-boosted once daily arm and the unboosted 400 mg BID dose (similar to Merck's findings). No patients discontinued or dropped out of the study.

As an author and investigator of this study presented in Denver, I can state very confidently that the drug was very well tolerated. In fact, most of our patients at NorthStar Healthcare thought they were receiving placebo, when in fact they were not. Most side effects were mild and included diarrhea, headache and nausea.

At this time NorthStar Healthcare has already started Phase 2 study of three different doses of boosted GS 9137, once daily, for treatment-experienced patients. For any inquiries, contact Curtis Hainds, PA-C of NorthStar, at (773) 296-2400.

Daniel S. Berger, MD, is Medical Director & full-time practitioner at Chicago's largest private HIV treatment and research center, NorthStar Healthcare, and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He serves as medical consultant and columnist for Positively Aware, serves on the HIV Medical Issues Committee for the Illinois AIDS Drug Assistance Program, the Board of Directors for the AIDS Foundation of Chicago and the Editorial Board of Contagion: Reports, Cases, and Commentaries in HIV and Infectious Disease Research. Dr. Berger can be reached at or (773) 296-2400;

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This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.