Results from the REALMRK clinical study have shown that after 48 weeks of treatment in an open-label, single-arm, observational study, the integrase inhibitor Raltegravir ( Isentress ) tablets in combination therapy demonstrated efficacy and tolerability, regardless of gender or race, in a diverse population of adult patients with HIV-1 infection similar to results from other phase III studies.

The REALMRK study enrolled 74.6% black patients ( 156 out of 209 ) and 46.9% female patients ( 98 out of 209 ).

Raltegravir is indicated in combination with other antiretroviral ( ARV ) agents for the treatment of HIV-1 infection in adult patients. The label for Raltegravir is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled phase III clinical studies of Raltegravir. Two of these studies were conducted in clinically advanced, three-class ARV [ non-nucleoside reverse transcriptase inhibitor ( NNRTI ), nucleoside reverse transcriptase inhibitor ( NRTI ), protease inhibitor ( PI ) ] treatment-experienced adults and one was conducted in treatment-naive adults. The use of other active agents with Raltegravir is associated with a greater likelihood of treatment response. The safety and efficacy of Raltegravir have not been established in pediatric patients.

The phase III, multicenter, open-label, single-arm observational study enrolled a diverse cohort of 209 HIV-1-infected adult patients, including treatment-naive HIV-1-infected adult patients ( n=22 ), as well as treatment-experienced HIV-1-infected adult patients who were failing previous treatment ( n=98 ) or were intolerant to current therapy ( n=89 ). The treatment group included 97 female and 153 black HIV-1-infected adult patients, all of whom received Raltegravir 400 mg twice daily in combination therapy for up to 48 weeks. The antiretroviral treatments used as part of combination therapy were selected at baseline and limited to approved and licensed agents. Of the 209 patients who entered the study, three were randomized but not treated. Patients were enrolled at trial sites in North America, South America, the Caribbean and Southern Africa.

The primary endpoint of the study was the proportion of patients with viral load levels less than 50 copies/mL at week 48. Secondary endpoints, at week 48, included the proportion of patients with viral load levels less than 400 copies/mL, mean change from baseline in CD4 cell count, change from baseline for viral load and time to loss of virologic response.

Based on the Treatment-Related Discontinuation equals failure approach, 11 randomized and treated patients were excluded from the primary analysis due to discontinuation prior to week 48 for non-treatment related reasons.

After 48 weeks, treatment with Raltegravir in combination therapy suppressed HIV-1 viral load levels to below 50 copies/mL in 70.3% of the patients ( 137 out of 195 ) overall in this diverse cohort of HIV-1-infected adults.

Results showed that 67.8% ( 61 out of 90 ) of HIV-1-infected female patients and 72.4% ( 76 out of 105 ) of male patients achieved viral load levels of less than 50 copies/mL. Additionally, 67.6% ( 98 out of 145 ) of black HIV-1-infected patients and 78.0% ( 39 out of 50 ) of non-black patients achieved viral load levels of less than 50 copies/mL.

In the REALMRK study, the overall increase from baseline in mean CD4 cell count was 111 cells/mm(3) after 48 weeks of treatment with Raltegravir in combination therapy. Patients who discontinued due to lack of efficacy prior to week 48 had their baseline values carried forward according to the observed failure approach of handling missing data; otherwise, patients were excluded who discontinued prior to week 48 or had missing data at week 48.

After 48 weeks, patients treated with Raltegravir in combination therapy had an overall discontinuation rate of 14.8%. The overall discontinuation rate was 17.3% in women and 12.6% in men.

The study found that 69.1% of female patients and 75.2% of male patients experienced clinical adverse events. Drug-related clinical adverse events were noted in 26.8% of female patients and 14.7% of male patients, with 3.1% of female and 0.9% of male patients discontinuing treatment due to clinical adverse events.
Results showed that 69.9% of black patients and 79.2% of non-black patients experienced clinical adverse events. Drug-related clinical adverse events occurred in 21.6% of black and 17.0% of non-black patients, with 2.6% of black and zero percent of non-black patients discontinuing treatment due to clinical adverse events.

The most commonly reported drug-related clinical adverse events ( present in greater than or equal to 2% of any group ) from the study included abdominal discomfort, diarrhea, nausea, vomiting, myalgia and headache.

Raltegravir is integrase inhibitor for the treatment of HIV-1 infection in treatment-naive and treatment-experienced adult patients as part of combination therapy. Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process ( protease and reverse transcriptase ) but Raltegravir is the only approved drug that inhibits the integrase enzyme.

The most common adverse reactions of moderate to severe intensity greater than or equal to two percent that occurred at a higher rate than the comparator were insomnia in treatment-naive patients and headache in treatment-experienced patients. Intensities were defined as follows: moderate ( discomfort enough to cause interference with usual activity ); or severe ( incapacitating with inability to work or do usual activity ).

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with Raltegravir. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing Raltegravir and Darunavir / Ritonavir compared to patients receiving Raltegravir without Darunavir / Ritonavir or Darunavir / Ritonavir without Raltegravir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Raltegravir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

For the treatment of adult patients with HIV-1 infection, the dosage of Raltegravir is 400 mg administered orally, twice daily with or without food, in combination therapy. During coadministration with Rifampin, the recommended dosage of Raltegravir is 800 mg twice daily with or without food.

Coadministration of Raltegravir with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase ( UGT ) 1A1 may result in reduced plasma concentrations of Raltegravir. Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of Raltegravir. Therefore, the dose of Raltegravir should be increased during coadministration with Rifampin. The impact of other inducers of drug metabolizing enzymes, such as Phenytoin and Phenobarbital, on UGT1A1 is unknown.

In drug interaction studies, Raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, Methadone, Lamivudine, Tenofovir, Etravirine and Darunavir / Ritonavir. Coadministration of Raltegravir with drugs that inhibit UGT1A1 may increase plasma levels of Raltegravir.

Source: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy ( ICAAC ), 2011

XagenaMedicine2011


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