Good News for People in Salvage Therapy: Merck to start its expanded access program for its integrase inhibitor MRK 518

I am very excited about this expanded access of Merck’s integrase inhibitor, MRK 518.

I have been taking it for 3 months now with the new protease (Prezista) and have been able to reach undetectable viral load for the first time in 23 years. My CD4 cells have more than doubled from 180 to 440 cells/ml

The response to MRK 518 seems to be faster than most drugs in the past. In a naive study presented this week in Toronto that compared MRK 518 plus Truvada with Sustiva+Truvada, it was seen that MRK 518 can drive viral load down faster than Sustiva, although the Sustiva arm eventually matched the MRK 518 arm at week 24.

So far, no significant side effects have been observed besides an increased in flatulence in some patients.

MRK 518 is taken in one pill twice a day without Norvir ( no need for Norvir boosting is welcomed by many of us!). It seems that it does not have problematic interactions with most drugs since it is not metabolized in the P450 cytochrome in the liver.

I think MRK 518 will be an excellent drug in combination with Prezista and/or Fuzeon for those of us who have run out of options. It may present the first chance for many of us to have undetectable viral load.

NATAP http://natap.org/
_______________________________________________

Expanded Access Program for MK-0518, an Investigational HIV Integrase Inhibitor, Established for Patients with Limited Available Treatment Options

Worldwide Access Program Will Be Conducted Along With Phase III Studies

TORONTO, Aug. 17, 2006 — A worldwide expanded access program for HIV/AIDS patients with limited or no treatment options was announced today by Merck & Co., Inc., Whitehouse Station, N.J., U.S.A., with respect to its investigational HIV integrase inhibitor, MK-0518, now in Phase III development. Program enrollment will begin in the next few months, pending regulatory review and approvals.

“Making MK-0518 available to those who would like access to this investigational drug but who are unable to participate in the clinical studies underscores our commitment to patients,” said Dr. Peter S. Kim, president, Merck Research Laboratories (MRL).

MK-0518 belongs to a new class of investigational antiretroviral therapy (ART) agents called integrase inhibitors that inhibit the insertion of the HIV viral DNA into human DNA. Integrase is one of three HIV enzymes – reverse transcriptase, protease and integrase – required by the virus to reproduce. Drugs are available that inhibit the functions of the protease and reverse transcriptase enzymes but, to date, there are no approved drugs that target the integration stage of the HIV-1 lifecycle.

Expanded access

“The MK-0518 program is another example of Merck’s dedication to people living with HIV/AIDS around the world,” commented Dr. Randi Leavitt, senior director, Infectious Diseases – Clinical Research, MRL and lead coordinator of the expanded access program. “This makes the third expanded access program that Merck has initiated. In mid and late 1990, the Company implemented expanded access programs for two other investigational drugs for treatment of HIV,” Dr. Leavitt explained.

Expanded access is a mechanism supported by regulatory agencies for getting investigational treatment to patients who have a life threatening disease and who cannot be satisfactorily treated with an alternative therapy or available drug. Expanded access programs are not required by regulatory agencies. These
programs are initiated and supported by drug manufacturers in recognition of the promise an unapproved drug may hold for patients facing a life-threatening disease.

MK-0518 expanded access study design

The expanded access program with MK-0518 is a non-comparative, multi-center, open-label, voluntary treatment use study. Investigators will follow patients according to standard of care. The study will continue until approximately three months after MK-0518 has been launched in the local market.

To be eligible to participate, patients must have documented HIV-1 infection, be at least 16 years old, have limited or no treatment options available to them due to resistance or intolerance to multiple anti-retroviral regimens, are not achieving adequate virologic suppression on current regimen and be at risk of clinical or immunologic progression, and be clinically stable. Patients are excluded from the study if they have received MK-0518 in a clinical trial, require any medications prohibited by the protocol, have acute hepatitis due to any cause or clinically significant chronic liver disease, have a condition which the investigator deems will interfere with adherence and safety, or are pregnant.

Patients will receive open-label MK-0518 400 mg twice daily, in addition to optimized background therapy (OBT). Investigators will select the OBT based on the patient’s prior treatment history and anti-retroviral resistance testing. OBT will not be provided by Merck. Safety and tolerability of MK-0518 will be monitored.

The program will be managed by a clinical research organization (CRO). The CRO will collect all case report information including serious adverse events and drug-related adverse events that result in Grade 3 or above laboratory toxicity, leading to treatment interruption or discontinuation. No efficacy data will be collected.

About Merck’s HIV/AIDS research program

Merck’s HIV clinical research program began in 1985. Merck scientists were among the first to discover and develop medicines for the treatment of HIV/AIDS. In 1996, Merck introduced a protease inhibitor, which was followed by the introduction in 1999 of a non-nucleoside reverse transcriptase inhibitor (NNRTI).

In addition to MK-0518, Merck is focused on developing new treatments for millions of individuals who are already infected with HIV, as well as on preventing HIV transmission through the development of a vaccine. Merck also licensed a compound to the International Partnership for Microbicides (IPM) for development as a possible means of preventing HIV infection in women.

Polycythemia, Anabolic Steroids and HIV Wasting

Some HIV positive people need to gain lean body mass and weight but develop polycythemia when using nandrolone or other anabolics, so their doctors refuse to prescribe these important medicines. Polycythemia is an increase in red blood cells and hematocrit that can cause increased blood viscosity, making it more difficult for the heart to pump blood. This can cause heart attackes or strokes, so it is important to know how to manage this problem. Lyckily, only a very small number of people using anabolics have this problem. We still do not know what makes one person more suceptible than other.

I had this problem for 5 months back when I was on Crixivan. For reasons that I do not understand yet, it went away once I stopped Crixivan. I also think using AZT may have a controlling effect on red blood cells.

This first article explains why anabolics increase red blood cells

Anabolic Steroids and Red Blood Cellshttp://www.mesomorphosis.com/articles/llewellyn/steroids-and-red-blood-cells.htm

Dr Scally has been able to write a very good article to teach doctors how to manage the problem

How to Manage Polycythemia Induced by Anabolic Steroids
By Michael C. Scally M.D.

For better formatting , see
http://health.groups.yahoo.com/group/PozHealth/message/16494

Dr. Michael C. Scally a Harvard and MIT trained physician and researcher in private practice in Houston who has written extensively on hormonal issues and HIV.

During the past few years, his focus have been on managing induced hypogonadism (low testosterone production by the body) after anabolic steroid therapy by restoring HPGA (Hypothalamic Pituitary Gonadal Axis) and managing polycythemia (increased red blood count that increases blood viscosity and cardiovascular disease risks.) This takes on particular importance as hormonal therapies become standard of care in HIV. His development of a new therapeutic approach is detailed in this report, and we are very excited to make it available to our readers.

Anabolic Steroid Use in HIV: Managing Androgen Induced Polycythemia and Hypogonadism

Wasting is one of the most common symptoms of human immunodeficiency virus (HIV). Wasting syndrome is widely considered the involuntary loss of 10% of initial body weight, many times in combination with diarrhea, weakness, and fever (Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morb. Mortal Wkly. Rep. 1987; 36 Supp.l 1). This condition may be attributed from malnutrition, diarrhea, altered metabolism, malabsorption, or hypogonadism associated with HIV infection. Since there is an increased mortality rate of HIV patients suffering with substantial body weight loss, aggressive therapies aimed at retaining lean body mass have been pursued.

One particular modality that has shown to be effective in preserving lean body weight is anabolic androgenic steroid (AAS) or androgen therapy. Multiple studies have evaluated the effects of androgens on combating wasting in HIV+ males. These reports have shown significant improvements in lean body mass up to 5.6 kg over short-term usage. While other HIV associated wasting and retroviral therapies may improve total body weight, androgen therapy has demonstrated an increase in fat free weight without a concurrent increase in fat mass. Unfortunately, therapies utilizing protease inhibitors or dietary counseling for wasting syndrome have found larger increases in fat tissue than improvements in muscle mass, thus granting minimal improvements in immune function and metabolism.

Along with the documentation and dissemination of the benefits of androgen therapy in treating wasting syndrome has come an associated acceptability within the medical community in prescribing these medicines. Research articles discussing the use of androgens in HIV+ patients are becoming more prevalent in the medical literature. A drawback of the increased utilization of androgens, however, are those scenarios where patients are administered these medicines for lengthy durations. Extended, uninterrupted use of androgens has been shown to induce polycythemia. Defined as a chronic myeloproliferative disorder characterized by an increase in hemoglobin concentration and red blood cell (RBC) mass (erythrocytosis), polycythemia increases the risk of thrombosis, post polycythemia myeloid metaplasia, and acute leukemia. Androgens, by increasing the endogenous production of erythropoietin, enhance the body’s rate of erythropoiesis and subsequently hemoglobin and RBC mass. With increased viscosity of the blood and platelets, an increased risk of blood clotting, heart attack, and stroke becomes a primary concern with patients afflicted with polycythemia. In terms of androgens, uninterrupted treatment may potentially do greater harm than good when faced with the possibility of problematic polycythemia secondary to androgen therapy.

The following is a report of problematic polycythemia as a result of long-term androgen therapy in an HIV+ male.

Case

A 46-year old HIV+ male presented with complaints of shortness-of breath, fatigue, excessive sweating and facial erythema. Medical history revealed a record of uninterrupted testosterone administration for the two years prior to presentation. The patient was administered testosterone cypionate, 200 mg IM per week, for two years to help sustain lean muscle mass in the prevention of HIV associated wasting syndrome. Laboratory studies revealed polycythemia but were otherwise unremarkable. An attempt at discontinuation of androgen therapy precipitated problematic hypogonadism exhibited by lethargy, diminished libido, decreased energy, sleep disturbance and depression. Testosterone treatment was restarted and the patient referred for consultation.

On presentation vital signs and weight, 75kg, were within normal limits. Original baseline laboratory studies prior to testosterone administration revealed normal CBC and hormone profile, Table 1.

Table 1.

Test
Hgb (gm/dL)
Hct (%)
RBC (M/uL)
LH(mIU/mL)
T (ng/dL)

Value
15.8
48.2
5.48
3.4
470

Reference

Range
13.2-17.1
38.5-50.0
4.2-5.8
1.5-9.3
241-827

Hgb “ Hemoglobin

Hct “ Hematocrit

LH “ Luteinizing Hormone

T- Total Testosterone

Laboratory values on the consultation presentation are shown in Table 2.

Table 2.

Test
Hgb (gm/dL)
Hct (%)
RBC (M/uL)
LH (mIU/mL)
T (ng/dL)

Value
18.0
60.0
6.09