Brand Name: Isentress
Generic Name: Raltegravir
Manufacturer: Merck
Drug Class: Antiretroviral Agent, Integrase Strand Transfer Inhibitor (ISTI)1
Uses: Treatment of HIV-1 infection in combination with other antiretroviral agents in
treatment-experienced patients with virus that shows multi-drug resistance and active replication2
Mechanism of Action: Inhibits the catalytic activity of HIV integrase. This is an HIV encoded enzyme needed for viral replication.1 Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome keeping the HIV provirus from being formed. The provirus is needed to direct the production of progeny virus, thus inhibiting integration prevents propagation of the viral infection.1
Pharmacokinetics2,3:
Absorption:
AUC |
increases by 19% with fatty meal |
Protein Binding |
83% |
Vd |
not established |
Cl |
not established |
Half-life |
9 hours |
F |
not established |
Time to peak, plasma |
3 hours |
Metabolism: Primarily hepatic glucuronidation mediated by UGT1A1
Excretion: Feces (51%, as unchanged drug); urine (32%, 9% unchanged Drug)
Efficacy:
Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, et al. Antiretroviral activity, Pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naïve HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006; 43: 509-15.
Study Design: Multicenter, double-blind, randomized, placebo-controlled
Description of study: Thirty-five HIV-infected patients, ART naïve, 18 years of age or older, HIV 1-seropositive and had a plasma HIV-1 RNA level of 5000 copies/mL,CD4 T- cell count of at least 100 cells/mm3, hemoglobin > 9.0 g/dL (female) or >10.0g/dL (male), neutrophil count > 1000 cells/mm3, normal LFT’s, and normal creatinine.4 They were excluded if they were hepatits B or C positive, used immune-based therapy or investigational agents within 1 month of the study, or if they have used adefovir or lamivudine. Other medications were also prohibited from the study.4 Patients were given raltegravir 100mg (7), 200mg (7), 400mg (6), 600mg (8) or placebo (7) twice daily without regard to food. Outcome measures included safety, pharmacokinetic parameters, and antiretroviral effect. A decrease in log10 HIV RNA level of 1.93, 1.98, 1.66 and 2.16 copies/mL were reported in the raltegravir groups respectively, and all were significantly greater than in the placebo group (P< 0.001).4 Also at Day ten, 57%, 57%, 50%, 50% of the treatment groups achieved a HIV RNA level < 400 copies/mL, compared to none in the placebo group. In regards to the pharmacokinetic measurements, the mean plasma concentration at trough (C12) was lowest in the 100 mg dose group and increased as the dose increased, levels exceeding 33nM in all groups.4 Cmax and AUC0-12h also increased up to 400 mg. Half-life could not be estimated during this study. Raltegravir was well tolerated with no serious adverse effects or discontinuation due to adverse effect. Nineteen patients reported clinical adverse experiences that were mild to moderate in severity, with headache and dizziness being the most common.4 Eight patients reported drug-related clinical adverse events, with constipation, flatulence, stomach discomfort, chills, fatigue, anorexia, and dizziness being the most common.4 No dose-related toxicities were reported.
Limitations: The power of the study was not stated, compliance was not addressed, and formal statistical testing was not used to assess safety. Most of the patients were male (94%), this could skew the pharmacokinetic results. This study was very short-term, thus adverse effects could not be properly assessed. The authors also noted that there were no change in cholesterol findings. However, it would take at least six weeks to have an idea of the effect on cholesterol. Conflicts of interest did exist: an employee of Merck played a large role in preparing the manuscript, and Merck is the manufacturer of raltegravir. Merck funded the study.
Conclusion: This study shows that raltegravir has the potential to significantly reduce the viral loads in HIV patients. Its also appears to be a relatively safe drug as far as short-term use is concerned. This study was a preliminary study to determine if a larger, more in depth study needs to be undertaken. The effects shown are positive, but not something that can be extrapolated into the general public at this point.
Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, et al. Rapid and Durable Antiretroviral Effect of the HIV-1 Integrase Inhibitor Raltegravir as part of Combination Therapy in Treatment-Naïve Patients With HIV-1 Infection: Results of a 48-Week Controlled Study. J Acquir Immune Defic Syndr. 2007; 46: 125-133.
Study Design: Multicenter, double-blind, randomized, controlled study.
Description of study: 205 patients were selected from 29 sites in the UnitedStates, Canada, Latin America, Thailand, and Australia.5 The study lasted for 48 weeks. Patients received either raltegravir (RAL) 100 mg, 200 mg, 400 mg, or 600 mg twice daily or efavirenz 600 mg/d (EFV).5 All patients received tenofovir 300 mg/day and lamivudine 300 mg/day. The raltegravir and its placebo were taken twice daily without regard to food.5 Efavirenz and its placebo were taken once daily at bedtime on an empty stomach. The primary outcome was the proportion of patients achieving a plasma HIV-1 RNA level < 400 copies/mL on the MPLICOR HIV-1 Monitor Standard assay.5 The secondary outcome was the proportion of patients achieving a plasma HIV-1 RNA level <50 copies/mL on the UltraSensitive assay, and the change from baseline in CD4+ T-cell count.5 These outcomes were measured at weeks 24 and 48. A total of 185 (93.4%) patients completed the study, 39/41, 34/40, 40/41, 37/40, and 35/39 from the 100 mg, 200 mg, 400 mg, 600 mg, and EFV groups respectively.5 For patients with HIV-1 RNA < 400 copies/mL at week 24 the results were as follows: 37/39 (95%) for 100 mg RAL (95% CI, 83 to 99), 34/40 (85%) for 200 mg RAL (95% CI, 70-94), 40/41 (98%) for 400 mg RAL (95% CI, 87 to 100), 38/40 (95%) for 600 mg RAL (95% CI, 83 to 99), and 35/37 (95%) for EFV (95% CI, 82 to 99).5 At week 48, three groups had changed: 38/39 (97%) for 100 mg RAL (95% CI, 87 to 100), 36/40 (90%) of 600 mg RAL (95% CI, 76 to 97), and 33/38 (87%) of EFV (95% CI, 72 to 96).5 Secondary outcomes were reported as well and showed promising results for all RAL groups, as well as good, but not as favorable results for the EFV group. There was no association between occurrence of adverse events and the dose of raltegravir. There was an incidence rate of 6% for serious adverse events for the raltegravir group and 5% for the efavirenz group.5 However, none of these adverse events were attributed to the dosing regimen. Drug-related adverse events were reported by fewer raltegravir patients versus efavirenz patients (P= 0.04 for 100, 400, 600 mg; P= 0.07 for 200 mg).5 Overall, raltegravir was shown to be safe.
Limitations: This study was an estimation study and was not properly powered to make a formal efficacy comparison.5 The study was funded by Merck and Co., Inc., the manufacturers of raltegravir. This presents a direct conflict of interest. Data was also collected by each site’s clinical site investigators. This does not provide uniformity with results. The results of the study showed that there were declines in copies/mL. However, over time, the initial decrease begins to increase. Thus, this study would be more useful and accurate if it followed the patients for five or ten years, as opposed to two years.
Conclusion: Overall, raltegravir does show a promising reduction in HIV-1 RNA levels. The 400 mg RAL group in particular seems to show consistent promising results. However, until this drug has been on the market for several years, the true benefits will not be known. This study is a start to showing its benefits, but a longer follow-up period is necessary to assess its true efficacy and safety.
Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomized controlled trial. Lancet. 2007; 369: 1261-9.
Study Design: Triple-blinded, randomized, placebo-controlled study
Description of study: Patients were assigned to receive 200 mg, 400 mg, or 600 mg, of
raltegravir or placebo twice daily.6 There were 44, 45, 45, and 45 patients in each group
respectively. The primary endpoints were change in viral load at baseline, week 24, and week 48, and safety.6 The mean viral load at baseline was 4.7 log10 copies per mL.6 A total of 45 patients discontinued the study, 4 from adverse effects (1 from the placebo group) and 44 due to lack of efficacy (27 from the placebo group). At week 24, the average change in viral load for the 200 mg group was –1.80 (95% CI –2.10 to –1.50) log10 copies per mL, in the 400 mg group it was –1.87 (-2.16 to –1.58) log10 copies per mL, -1.84 (-2.10 to –1.58) log10 copies per mL in the 600 mg group, and –0.35 (-0.61 to -.09) log10 copies per mL for the placebo group.6 The safety profile for raltegravir was similar to placebo with no dose related toxicities.
Limitations: This study was funded by Merck; the manufacturer of raltegravir. The power of the study was not stated and the sample size was too small, thus increasing the likelihood of type II error. Substudy analysis was performed, and again, the power was not addressed. No P values were given throughout the entire article, thus, statistical significance could not be determined.
Conclusion: Based on the results of the study, raltegravir does exhibit antiviral activity in patients experienced to treatment. However, none of the data reported in this article seem to be statistically significant. Thus, one cannot determine if the treatment is clinically relevant. Repeating this trial, or a similar trial, with a larger number of participants that allows for appropriate statistical analysis would explore the true usefulness of this drug.
Contraindications: None listed in manufacturer’s labeling3
Precautions:
Immune reconstitution syndrome (characterized by the worsening of symptoms of a
healing infection, and increased CD4 counts. This occurs when a HIV/AIDS patient’s
immune system is rebuilding itself and triggers an inflammatory response to an infection)- Patients may develop this due to an inflammatory response to an indolent or
residual opportunistic infection2
Mypopathy- Grade 2-4 creatine kinase increases have been observed, and myopathy or
rabdomyolysis have occurred, use with caution in patients with risk factors for CK elevations and/or skeletal muscle abnormalities2
Pediatrics- safety and efficacy is not established in children < 16 years of age2
Adverse Effects1,2:
Central Nervous System: Headache (2%), fatigue, dizziness
Dermatological: Pruritus (4%)
Endocrine and metabolic: glucose increased (> 250 mg/dL, 9%), lipodystrophy
GI: vomiting (4%), nausea (10%), diarrhea (16%), amylase increased (grade 3, 4%),
lipase increased (3%), abdominal pain
Hepatic: hyperbilirubinemia (9%; 2.6-5 times ULN: 3%), AST increased (2.6-5 times
ULN: 9%), ALT increased (5.1-10 times ULN: 3%), alkaline phosphatase
increased (2%)
Neuromuscular and skeletal: creatine kinase increased (2%), weakness
Other: anemia, neutropenia, MI, gastritis, hepatitis, nephropathy, renal failure, renal
tubular necrosis
Drug Interactions1,2,3:
UGT1A1 inducers: May decrease serum level/effect of raltegravir.
Examples include: tipranavir, efavirenz, nevirapine, rifabutin, rifampin (strong),
and St. John’s wort
UGT1A1 inhibitors: may increase serum levels/effects of raltegravir.
Examples include: atazanavir (strong), no adjustment needed in clinical
trials
Other: fibric acid derivatives, statins (both have a severity of high)
Ethanol/Nutrition/Herb Interactions:2
Food: High-fat meal increased AUC by 19%
Herb/Nutraceutical: St. John’s wort may decrease the levels/effects
Dosing/Administration:
Usual: 400 mg twice daily with or without food3
Geriatric dose: Dosing should be cautious, accounting for increased hepatic, renal
and cardiac dysfunction, concomitant disease, or other drug therapy.3 There
were not enough subjects over 65 y.o.a. to determine the exact guidelines for the
elderly.3
Pediatric dose: Has not been established for children under 16 years of age3
Renal impairment dose: No dose adjustment needed3
Hepatic impairment dose: No dose adjustment is needed for mild to moderate
hepatic dysfunction. Not enough information is given to assess in severe hepatic
dysfuction.3
Use in special circumstances:
Pregnancy – Pregnancy Risk Factor C2
Lactation – excretion into breast milk is unknown2
*CDC does not recommend that HIV positive mothers breastfeed to prevent
the transmission of the virus*1
Monitoring Parameters: plasma HIV RNA, CD4 count1,2
Storage: 15oC to 30oC (59oF to 86oF)2
Conclusion: Raltegravir is an integrase inhibitor, the first of this class to be approved by the FDA. Its unique mechanism of action prevents the unintegrated linear HIV DNA from being introduced to the host cell genome.1 Therefore, raltegravir may be promising in HIV patients that are resistant to other classes of drugs. All of these studies have shown that raltegravir has a good safety profile thus far. There were no dose related toxicities reported.6 Raltegravir used in combination with tenofovir and lamivudine or alone as monotherapy, has shown decreases in the viral loads of HIV patients.4,5,6 However, all of these studies had a relatively small amount of patients. Thus, to truly comprehend the efficacy of raltegravir, larger studies will need to be performed.
Recommended References:
Prepared by: Lindsey Gorrell, Doctor of Pharmacy Candidate