In phase III studies have shown that raltegravir in combination achieved significant reductions in viral load during 96 weeks ..

In phase III studies have shown that raltegravir in combination achieved significant reductions in viral load during 96 weeks in previously treated patients whose HIV was resistant to three classes of drugs.

In the phase III studies, BENCHMRK-1 and 2, the integrase inhibitor from Merck Sharp & Dohme (MSD) raltegravir in combination with an optimized base treatment (TBO) produced greater reductions in viral load compared to placebo for 96 more TBO weeks in previously treated patients whose HIV was resistant to three classes of drugs that were not responding to antiretroviral treatment. (Poster 571b).
These results together with data from other studies were presented Monday at the XVI Conference on Retroviruses and Opportunistic Infections (CROI) held in Montreal, Canada.
"As doctors continue using raltegravir in patients treated previously, data from longer term studies BENCHMRK-1 and 2 continues to inspire confidence among physicians when treating patients whose treatment cycle is more advanced," said Dr. Daniel S. Berger, assistant clinical professor, College of Medicine, University of Illinois at Chicago and medical director of Northstar Medical Center.
Raltegravir is indicated in combination with other antiretroviral agents for the treatment of infection with human immunodeficiency virus (HIV-1) in adult patients previously treated and who show signs of HIV-1 replication despite receiving antiretroviral therapy.
This indication is based on data on safety and efficacy trials of two double-blind, placebo-controlled 48 weeks' duration in patients treated previously.

Important safety information about raltegravir.
We need to warn patients that antiretroviral treatment can not cure HIV infection and that has not been shown to prevent HIV transmission to others through blood or sexual contact. Should continue to take appropriate precautions.

In HIV-infected patients with severe immunodeficiency at the time of the introduction of antiretroviral combination therapy (TARC) may be an inflammatory reaction to asymptomatic or residual opportunistic pathogens, which can cause severe clinical disorders or exacerbate symptoms. Usually, such reactions are observed in the first weeks or months after the start of the TARC. Some relevant examples are cytomegalovirus retinitis, mycobacterial infections, and generalized or focal pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). All symptoms should be evaluated inflammatory treatment should be initiated when necessary.

Demonstrated the persistence length and tolerability of raltegravir to week 96 in previously treated patients (BENCHMRK-1 and-2)
The results of the studies BENCHMRK 1 and 2 after 96 weeks showed that in 96 weeks, 57% of patients (262 of 460) treated with raltegravir achieved a more TBO undetectable viral load (less than 50 copies / ml ), compared with 26% of patients (62 of 237) treated with placebo plus TBO, p <0001. In addition, patients treated with the pattern with raltegravir experienced significantly higher increases of CD4 counts (123 células/mm3) than those treated with placebo and TBO (49 células/mm3) at week 96, p <0001.
In BENCHMRK studies, patients received 400 mg of raltegravir orally twice daily in combination with TBO (n = 462) of placebo or 400 mg orally in combination with TBO (n = 237). The data demonstrate that raltegravir plus TBO has an antiretroviral and immunological efficacy powerful and superior to that obtained with placebo over TBO. The reductions in viral load and immunological efficacy was maintained through week 96: 57% of patients treated with raltegravir more TBO had viral load below 50 copies / ml, up to 79% of patients treated with enfuvirtide darunavir and raltegravir with TBO in the viral load remained below 50 copies / ml. There were few withdrawals for adverse events: 4% of patients receiving raltegravir and TBO and 5% of those treated with placebo and TBO. The risk of malignancy was equivalent in the raltegravir groups and control.
Rates adjusted for exposure (per 100) of clinical adverse events related to the medication most common (frequency ≥ 2.0%, of any intensity) observed in patients treated with raltegravir and TBO and in patients treated with placebo and TBO were: headache (2.7 per 100 and 4.5 per 100), nausea (2.3 per 100 and 4.1 per 100), diarrhea (1.8 per 100 and 4.5 per 100) fatigue (1.8 per 100 and 0.7 per 100), abdominal distension (1.5 and 1.2 per 100 for 100), vomiting (0.8 per 100 and 1.9 per 100) and fever (0, 5 per 100 and 2.2 per 100), respectively.
The cancer rate in patients treated with raltegravir and TBO in studies BENCHMRK 1 and 2 was 3.0 per 100 and 2.6 per 100 in those treated with placebo and TBO, which represents a relative risk of 1 , 1 (0.5, 3.1). The rate of new AIDS-defining illnesses or recurring was 2.2 per 100 in the raltegravir group and 4.1 per 100 in the placebo group, representing a relative risk of 0.5 (0.2, 1 , 3).
Raltegravir is indicated in combination with other antiretroviral agents for the treatment of infection with human immunodeficiency virus (HIV 1) in adult patients previously treated and who show signs of HIV-1 replication despite receiving antiretroviral therapy.
This indication is based on data on safety and efficacy trials of two double-blind, placebo-controlled 48 weeks' duration in patients previously treated
The marketing of raltegravir was approved in Spain by the Spanish Ministry of Health in February 2008.

More important safety information about raltegravir.
Raltegravir should be used with caution when given concurrently with potent inducers of uridine diphosphate glucuronosiltransferasa (UGT) 1A1 (eg., Rifampin). Rifampicin reduces plasma concentrations of raltegravir; unknown impact on the efficacy of raltegravir. However, if coadministration with rifampin is inevitable, we can consider doubling the dose of raltegravir.
The safety assessment of raltegravir in patients previously treated is based on the pooled safety data from three randomized clinical trials. These studies used the recommended dose of 400 mg twice daily in combination with an optimized base treatment (TBO) in 507 patients, compared with those obtained in 282 patients who received placebo in combination with TBO. During the double blind treatment, the total period of follow-up was 504.1 patient-years in the group of raltegravir 400 mg twice a day and 202.5 patient-years in the placebo group.
In group 400 mg of raltegravir twice daily + TBO and the comparison group of TBO + placebo, adverse reactions reported most frequently (> 10% of patients in each group) of any degree of intensity and independently of causality were: diarrhea in 17.6% and 20.6%, nausea in 11.2% and 15.2% and headache in 10.1% and 12.4%, pyrexia in 6.3% and 11.0% of patients, respectively. In this pooled analysis, the rates of discontinuation for adverse events were 2.4% in patients receiving raltegravir TBO + and 2.8% in patients receiving placebo + TBO.
There have been reports of myopathy and rhabdomyolysis, but it ignores the relationship of raltegravir to these events. Use with caution in patients who have had in the past myopathy or rhabdomyolysis, or having any factor, including other pharmaceutical products associated with these diseases.

Other posters on raltegravir presented at the CROI
In addition to studies BENCHMRK 1 and 2 previously treated patients, were presented at CROI two other posters in that also evaluates the safety and efficacy of raltegravir. They are:
• A review of cancer incidence in clinical trials of raltegravir in patients previously treated and untreated, which until now have not observed differences in risk among HIV-infected patients treated with raltegravir and treaties with other antiretroviral (Poster 859) and
• A review of preliminary data from a prospective, open, non-randomized and dose determination currently on raltegravir TBO more in children and adolescents aged 6 to 18 years previously treated (IMPAACT P1066). These results will be presented by the National Institutes of Health.

Review of cancer incidence in clinical trials of raltegravir.
We reviewed the incidence of cancer, a well known complication of HIV infection, in five randomized clinical trials and double blind study of raltegravir in patients previously treated and untreated, and in an expanded access program in the open. In an analysis of pooled data from two Phase II studies (protocols 004 and 005) and three phase III studies (BENCHMRK-1, BENCHMRK-2 and STARTMRK) to monitor at least 48 weeks and 120 at most ( exposure to raltegravir than 1700) showed that during double-blind cancer rates were slightly lower in patients treated with raltegravir (rate 1.7 per 100, is a broad definition of cancer, including recurrences, cancers other than melanoma and carcinoma in situ) without reaching statistical significance compared to patients receiving antiretroviral comparison (rate 2.2 per 100, definition of cancer). This was a relative risk of 0.75 with a confidence interval of 0.40 to 1.46.
With an additional exposure to raltegravir approximately 600 double-blind phases, cancer rates remained similar (rate 2.1 per 100) to those observed in the double blind phase. In a context of expanded access, after a median follow up of 24 weeks in more than 5,400 patients (raltegravir exposure to more than 2,200), cancer rates were similar to those observed in clinical trials with raltegravir.
In protocol 004, raltegravir was administered at doses of 100 to 600 mg twice daily for 48 weeks and a maximum of 400 mg thereafter. In protocol 005, raltegravir was administered at doses of 200 to 600 mg twice daily for 24 weeks at least in part double-blind study, all patients received a dose of 400 mg in the open part of the test. In the analysis of the combination of studies in phases II and III involved 1039 patients who received raltegravir, was assigned a treatment compared to 605 patients, 173 of whom went on to receive raltegravir at the open stage. In all cases, raltegravir is used in combination with other antiretrovirals. Made public the details of at least 48 weeks in the phase III trial STARTMRK of 96 weeks in trials BENCHMRK 1 and BENCHMRK 2 and at least 120 weeks in Phase II (protocols 004 and 005). We included double-blind and open data.

About raltegravir
Raltegravir is the first drug approved for a new class of antiretrovirals called integrase inhibitors,. Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. By preventing the integrase to perform its function, limiting the ability of the virus to multiply and infect other cells. It is currently used drugs that inhibit two other enzymes critical to the replication process of HIV protease and reverse transcriptase, but raltegravir is the only drug approved that inhibits integrase.
Raltegravir is in a single tablet of 400 mg administered twice daily, regardless of meals. Raltegravir does not require reinforcement with ritonavir.

Global approval of raltegravir
Since 2007, raltegravir was approved in over 50 countries worldwide for use in combination with other antiretroviral agents for the treatment of adult patients infected by HIV-1 and previously treated who show signs of HIV-1 replication despite receiving antiretroviral treatment. MSD continues to submit applications for approval in other countries.

Merck's research on HIV
MSD is committed to developing innovative treatments that involve advances in the treatment of infectious diseases, including HIV infection. MSD's efforts to develop experimental treatments for HIV and AIDS reach over 20 years and continues today.
Merck began its research on the integrase inhibitor for HIV in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.
Raltegravir is part of MSD in the history of research on HIV, including the development of indinavir sulfate, a protease inhibitor and efavirenz, a reverse transcriptase inhibitor non-nucleoside, and ongoing research into other options treatment.

Worldwide prevalence of HIV infection and AIDS
It is estimated that in the world 33 million people infected with HIV and AIDS, 1 and that in 2007 there were approximately 2.7 million cases of AIDS contagio.1 is a major cause of mortality from infectious diseases All mundo1 in 2007 and was responsible for approximately two million deaths.

About MSD
Merck & Co. Inc., Whitehouse Station, NJ, USA, which operates in many countries as MSD (Merck Sharp & Dohme) is an international pharmaceutical company based on research whose primary concern are the patients. Founded in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to meet unmet medical needs. The company also devotes great efforts to improve access to medicines through far-reaching programs that not only donate Merck medicines but help to distribute them to people who need them. Furthermore, MSD publishes objective information on health nonprofit. For more information, visit www.merck.com. / Www.msd.es


Bibliography:
1. UNAIDS. 2008 Report on the global AIDS epidemic. Available at: http://www.unaids.org/en/KnowledgeCentre/HIVData/ GlobalReport/2008/2008_Global_report.asp. Accessed on January 30, 2009.