Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Isentress (Merck Sharp & Dohme)
400 mg tablets
Approved indication: HIV infection
Australian Medicines Handbook section 5.4
The main classes of antiretroviral drugs inhibit viral enzymes such as reverse transcriptase and protease. Combinations of reverse transcriptase inhibitors and protease inhibitors are effective, but this treatment eventually fails. Drugs acting on other parts of the HIV life cycle are therefore needed to regain control of the patient's viraemia.
The replication of HIV requires viral DNA to be inserted into the genome of the host cells. This process involves HIV integrase, so inhibiting this enzyme should impede viral replication. Raltegravir is the first integrase inhibitor to be approved in Australia.
In a dose-ranging study, 35 patients took raltegravir or a placebo for 10 days. The concentration of viral RNA declined significantly more with the drug than with placebo, paving the way for phase II trials.1
One trial randomised 179 patients to take a placebo or one of three doses of raltegravir twice daily. These patients had been treated for a median of 10 years, but their viral RNA load was greater than 5000 copies/mL. They took an 'optimised background regimen' of 2–7 antiviral drugs in addition to their randomised therapy. After 24 weeks 13% of the placebo group had less than 50 copies/mL. This response was achieved by significantly more of the patients taking raltegravir; 65% with 200 mg, 56% with 400 mg and 67% with 600 mg. There was also a significant increase in CD4 cell counts. With the recommended dose of 400 mg twice daily, there was a mean increase of 113 cells/microlitre compared with an increase of 5 cells/microlitre with placebo.2
The approval of raltegravir is based mainly on the interim results of two phase III trials. These trials had the same design and enrolled previously treated patients infected with HIV resistant to three different classes of antiretroviral drugs. In total, 462 patients added raltegravir to their optimised background regimen and 237 added a placebo. After 16 weeks 436 patients had been treated or discontinued. HIV RNA had fallen below 50 copies/mL in 61–62% of the patients taking raltegravir compared with 33–36% of the placebo group. CD4 cell counts increased by 83–86 cells/mm3 with raltegravir and by 31–40 cells/mm3 with placebo. These differences remained at the 24-week analysis.
Adverse events in patients taking multiple drugs are common. Adding raltegravir did not appear to cause more adverse effects than adding a placebo. Only 2% of patients discontinued treatment because of adverse events. Serious adverse events occurring in the trials included hypersensitivity reactions, hepatitis, anaemia, myocardial infarction and renal failure.
The pharmacokinetics of raltegravir are variable and its bioavailability is unknown. Raltegravir is probably cleared by glucuronidation with most of the dose being eliminated in the faeces. The terminal half-life is approximately nine hours. Atazanavir inhibits glucuronidation so it will increase concentrations of raltegravir, however no dose adjustment has been recommended for patients taking raltegravir with a combination of atazanavir and ritonavir. The combination of tipranavir and ritonavir reduces concentrations of raltegravir, but no dose adjustment is recommended.
Although the final results of the phase III trials are currently unpublished, raltegravir has a significant effect on the markers of HIV infection. Whether this improves the patient's prognosis remains to be seen. Longer-term follow-up is also needed to assess the development of viral resistance and long-term adverse events such as cancer. Although raltegravir has been studied in previously untreated patients3 , this indication is not approved.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Markowitz M, Morales-Ramirez JO, Nguyen B-Y, Kovacs CM, Steigbigel RT, Cooper DA, 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-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006;43:509–15.
- Grinsztejn B, Nguyen B-Y, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multi drug-resistant virus: a phase II randomised controlled trial. Lancet 2007;369:1261-9.
- Markowitz M, Nguyen B-Y, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection. Results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007;46:125-33