RALTEGRAVIR. October Produced by the London New Drugs Group on behalf of the HIV Drugs and Treatment sub-group of the London HIV Consortium

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1 Page 1 Produced by the London New Drugs Group on behalf of the HIV Drugs and Treatment sub-group of the London HIV Consortium RALTEGRAVIR Contents Summary 1 Background 3 Interactions 3 Clinical efficacy 3 BENCHMRK 3 STARTMRK 8 Adverse events 10 Costs 10 References 11 Produced for the London HIV Consortium by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: Med.info@nwlh.nhs.uk Further copies of this document are available from URL: Summary The drug and the review is an integrase strand transfer inhibitor which inhibits HIV-1 replication and viral assembly. The licensed indication for raltegravir was extended in September 2009 to the treatment of HIV-1 in all adult patients, taking into account data from the BENCHMRK studies in treatment-experienced patients and data from the STARTMRK study in treatment-naïve patients. The recommended dose is 400mg twice a day with or without food, in combination with other antiretroviral medicines. The purpose of this review is to evaluate the data to support the use of raltegravir for its licensed indication. In April 2008 the Scottish Medicines Consortium approved the restricted use of raltegravir within NHS Scotland for the treatment of HIV in treatmentexperienced (triple-class resistant) adult patients. Efficacy studies BENCHMRK 1 & 2 These were two identical randomised, double-blind, placebo-controlled studies comparing raltegravir 400mg bd (n=462) with placebo (n=237), both with an optimised background regimen (OBR) in patients with triple-class resistant HIV-1 infection. The primary endpoint was that raltegravir would have superior antiretroviral activity to that of placebo, based on the proportion of patients with HIV-1 RNA <400 copies/ml after 16 weeks. Virologic responses to raltegravir were consistently superior to those seen with placebo, regardless of the baseline HIV-1 RNA level, CD4 count, genotypic or phenotypic sensitivity score, user or non-use of darunavir, enfuvirtide or tipranavir, or demographic characteristics. In the combined analysis (where treatment discontinuation = failure), 73.1% of patients treated with raltegravir vs. 37.4% treated with placebo achieved HIV-1 RNA levels <400 copies/ml, and 62.1% vs. 33.2% achieved levels <50 copies/ ml. STARTMRK This was a double-blind, randomised, non-inferiority study in HIV treatmentnaïve patients. 400mg bd (n=263) or efavirenz 600mg (n=258) was added to tenofovir and emtricitabine (observed-failure method population). The primary endpoint of HIV RNA <50 copies/ml was achieved by 91.6% in the raltegravir group and 89.1% in the efavirenz group at 48 weeks. A more rapid decline in viral load occurred with raltegravir treatment compared with efavirenz. Increases in CD4 counts were greater with raltegravir than with efavirenz treatment (+189 cells/microl vs. +163) at 48 weeks. Virologic efficacy was consistent across baseline demographic factors and noninferiority of raltegravir to efavirenz was shown. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 96-week data has been presented at the 49 th ICAAC (September 2009). In total, 245 (86%) of patients in the raltegravir group and 232 (81.7%) in the efavirenz group completed 96 weeks of treatment and the following results were achieved: HIV RNA<50 copies/ml: raltegravir, 81% vs. efavirenz, 79%, p<0.001, non-inferiority shown. HIV RNA<400 copies/ml: raltegravir, 85% vs. efavirenz, 81%, p<0.001, non-inferiority shown. Mean change in CD4 count: raltegravir, +240 vs. efavirenz, +225; the difference of 15 was not statistically significant. 18 new patients (12 in the raltegravir and 6 in the efavirenz group) met the protocol definition of virologic failure, between weeks 48 and 96. Of these, 7 (4 in the raltegravir group) had HIV RNA >400 copies/ml. No patients in the raltegravir group had detectable resistance to any of the drugs in their regimen whilst 2/3 in the efavirenz group had detectable resistance to any of the drugs in their regimen. A similar number of adverse events occurred between the groups but significantly less drug-related adverse events occurred with raltegravir (132/266, 47%) than with efavirenz (220/275, 78%), p< Suicidal behaviours and depression occurred at a similarly low rate in both treatment arms, and between weeks very few additional CNS adverse events were reported. The changes in lipid levels were significantly greater with efavirenz than with raltegravir (p<0.001 for increases in total, HDL and LDL-cholesterol and p=0.001 for triglycerides). Safety In pooled analysis of the studies in treatment-experienced patients, commonly reported side effects were diarrhoea, nausea, headache and pyrexia. Similar rates of discontinuation were seen in the raltegravir and placebo groups (2.4% and 2.8%). Myopathy and rhabdomyolysis have been reported with raltegravir use; it should be used with caution in patients who have had either of these conditions in the past or who have predisposing factors, such as other medications associated with myopathy/rhabdomyolysis. Cancers that occurred during the trials (such as Kaposi s sarcoma, lymphoma and squamous cell carcinoma) were considered to be expected in a highly immunodeficient population, with low CD4 cell counts and prior AIDS diagnoses. In the STARTMRK study mean changes from baseline in total-, HDL- and LDL-cholesterol and triglycerides were significantly smaller with raltegravir than efavirenz, but the difference between the change in total cholesterol/hdl cholesterol ratio was not significant. Critical evaluation BENCHMRK 1 & 2 In patients who received enfuvirtide and darunavir as part of their OBR (first time use of these therapies), 89% taking raltegravir and 68% taking placebo achieved HIV RNA<50 copies/ml. The high placebo response was due to the first time use of these other agents. Potential benefits over existing technologies is from a new class of antiretrovirals and can be useful in triple-class resistant patients. It should be noted that raltegravir has not been used in combination with other regimens and raltegravir has not been directly compared with regimens that include PIs as initial treatment for treatment-naïve patients. Potential disadvantages over existing technologies The development of resistance to integrase inhibitors is of concern when raltegravir is used with no fully active drugs in the OBR. A quarter of patients (105/462, 23%) had virologic failure by week 48 of the BENCHMRK studies: 64 patients showed genotypic evidence of viral resistance to raltegravir and 48 of these had two or more mutations associated with phenotypic raltegravir resistance. Health Economics No health economy studies were identified. Estimated cost per population No budgetary impact model is available. Guidelines for use To be determined by the HIV Drugs and Treatment Sub-Group.

3 Page 3 Background (Isentress ) was launched in January 2008 for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. 1 In September 2009 the indication was extended to the treatment of HIV-1 in all adult patients, taking into account data from the BENCHMRK studies in treatment experienced patients as well as data from the STARTMRK study in treatment-naïve patients. 2 The recommended dose of raltegravir is 400mg twice a day (bd), with or without food, in combination with other antiretroviral medicines. 3 is an integrase strand transfer inhibitor; integrase inhibitors target an essential enzyme required for HIV-1 viruses to catalyse the insertion of HIV-1 DNA into the genome of the host cell. 4 This process is required for expression and high-level HIV-1 replication. Integrase also affects retrotranscription and viral assembly. Host cells do not have integrase, therefore toxicity at this level is not expected. 4 HIV-1 integrase inhibitors would be expected to maintain activity against HIV-1 resistant to the other classes of antiretroviral drugs and in vitro studies have shown it to be active against multi-drug resistant HIV-1. 5 No dosage adjustment is required for patients with renal impairment or with mild-moderate hepatic impairment. The safety and efficacy of raltegravir in patients with severe hepatic impairment has not been established, and should be used with caution in these patients. 3 Interactions 3 is not a substrate of P450 enzymes and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. 3 It does not induce CYP3A4. It also does not inhibit UGT1A1 or 2B7, or P- glycoprotein-mediated transport. 3 raltegravir dose should be doubled. The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inhibitors, such as efavirenz, nevirapine, rifabutin, glucocorticoids and St John s Wort, may be used with the recommended doses of raltegravir. 3 Potent UGT1A1 inhibitors, such as atazanavir, may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors, such as indinavir and saquinavir, may also increase plasma levels f raltegravir but to a lesser extent. Tenofovir may also increase plasma levels of raltegravir, but the mechanism behind this is unknown. The Summary of Product Characteristics (SmPC) should be consulted for more detailed information on interactions. Overall, the SmPC states that no dosage adjustments are required, with one exception: If co-administration with rifampicin is unavoidable a doubling of the dose of raltegravir can be considered. 3 Clinical efficacy Treatment-experienced patients: BENCHMRK studies The BENCHMRK studies compared the use of raltegravir with placebo, both in combination with an optimised background regimen (OBR), which could include darunavir and tipranavir, which were investigational drugs at the time of study enrolment. 6 The OBR was based on a number of factors, including genotypic and phenotypic resistance. Genotypic sensitivity scores (GSS) indicated the total number of drugs in the optimised background regimen to which the patient s virus showed genotypic sensitivity, whilst phenotypic sensitivity scores (PSS) indicated the total number of drugs in the OBR to which the patient s viral isolate showed phenotypic sensitivity. 5 In these trials lower genotypic sensitivity scores (GSS) were associated with lower responses and patients with GSS or phenotypic sensitivity scores (PSS) of 0 had a higher risk of developing resistance to raltegravir. 5 These scores may underestimate the background activity as even when the virus is resistant there may still be some effects of the drugs on viral load. is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway and therefore caution is required when co-administering it with strong inducers of UGT1A1, such as rifampicin. If the use of rifampicin with raltegravir is unavoidable, the

4 Page 4 Phase III studies: BENCHMRK-1 and -2 The BENCHMRK studies were two identical, randomised, double-blind, placebo-controlled, phase 3 studies of raltegravir 400mg twice daily (n=462) vs. placebo (n=237), both with OBR, in patients with triple-class resistant HIV-1 infection. 6 BENCHMRK-1 was conducted in Europe, Asia, Australia and Peru; BENCHMRK-2 was conducted in North and South America. Inclusion criteria were 16 years of age, HIV-1 RNA 1000 copies/ml whilst on antiretroviral therapy and documented phenotypic or genotypic resistance to at least one drug in each of the three classes of antiretrovirals (NRTI, NNRTI and PI). Patients with stable chronic hepatitis B or C were eligible if their serum aminotransferase levels were <5x upper limit of normal (ULN). Randomisation was stratified according to use or non-use of enfuvirtide in the OBR and the degree of viral resistance to PIs (resistance to 1 vs. >1). At or after week 16 virologic failure was considered to have occurred if the patient did not have a decrease in HIV-1 RNA to <400 copies/ml, or by >1 log 10 copies/ml from baseline, or if they had an increase of >1 log 10 copies/ml or levels >400 copies/ml on two consecutive measurements. Such patients could continue in the blinded portion of the study or enter an open-label phase and receive raltegravir. The pre-specified primary efficacy hypothesis for each study was that, when used in combination with the OBR, raltegravir would have superior antiretroviral activity to that of placebo, based on the proportion of patients with HIV-1 RNA <400 copies/ml after 16 weeks. All treated patients were included in the efficacy and safety analyses. Virologic response rates were adjusted for covariates that might have affected the likelihood of achieving HIV-1 RNA suppression, such as baseline HIV-1 RNA, presence or absence of an active PI in the OBR and first use of darunavir or enfuvirtide in the OBR. Baseline characteristics were well balanced between the two treatment groups. Overall 12% of the participants were female, and ~32% were non-white. Before enrolment 46.2% and 7.3% of patients had received enfuvirtide and darunavir respectively. 16.2% of patients had hepatitis B or C coinfection and 20% had a history of cancer/ premalignant condition. Few patients discontinued either BENCHMRK study early and treatment-related discontinuations were counted as treatment failures. - On the basis of the primary, prespecified analysis counting treatment-related discontinuation as failure results were as follows (table 1a). Table 1a: Primary analysis, treatment discontinuation = treatment failure 6 HIV-1 RNA levels <400 copies/ml, week 16 Placebo BENCHMRK 1 178/277 (78.4%) p< /117 (41.0%) BENCHMRK 2 177/226 (78.3%) p< /118 (43.2%) Combined 1 and 2 332/454 (73.1%) p< /237 (37.4%) HIV-1 RNA levels <50 copies/ml, week 48 Placebo BENCHMRK 1 141/227 (62.1%), p< /117 (33.3%) BENCHMRK 2 142/226 (62.8%) p< /118 (36.4%) Combined 1 and 2 285/454 (62.1%) p< /235 (33.2%)

5 Page 5 When any non-completion was counted as a treatment failure (more stringent analysis) results were (table 1b): Table 1b: Non-completion = treatment failure 6 BENCHMRK 1 and 2: week 16 Placebo HIV-1 RNA levels <400 copies/ml 355/458 (77.5%) p< /236 (41.9%) HIV RNA <50copies/mL 61.8% p< % BENCHMRK 1 and 2: week 48 Placebo HIV-1 RNA levels <400 copies/ml 332/459 (72.3%) p< /237 (37/1%) HIV RNA <50copies/mL 285/459 (62.1%) p< /237 (32.9%) On the basis of the approach considering observed lack of efficacy as treatment failure, results were (table 1c): Table 1c: Lack of efficacy = treatment failure 6 BENCHMRK 1 and 2: week 48 Placebo HIV-1 RNA levels <400 copies/ml 332/454 (73.1%) p< /228 (38.6%) HIV RNA <50copies/mL 285/443 (64.3%) p< /228 (34.2%) Overall mean change in log 10 HIV-1 RNA copies/ml Mean change in CD4 cell counts from baseline -1.7 (95% CI -1.8 to -1.6) p< /mm 3 (95% CI 98 to 121) p< (95% CI -0.9 to -0.6) 45/mm 3 (95% CI 32 to 57)

6 Page 6 The BENCHMRK studies were not actually powered to show significant effects within a sub-group but virologic responses to raltegravir were consistently superior to those to placebo, regardless of the baseline values of HIV-RNA level, CD4 count, genotypic or phenotypic sensitivity score, use or non-use of darunavir, enfuvirtide or tipranavir or demographic characteristics. 7 Only in the small number of patients who had genotypic or phenotypic sensitivity scores of 3 was the treatment advantage of raltegravir not significantly greater. Table 2 shows 48-week data from sub-group analyses, according to baseline prognostic factors. The subgroup analyses were based on non-completion = treatment failure. In general, patients with lower HIV-1 RNA levels or higher CD4 counts had higher response rates than patients with higher HIV-1 RNA levels/lower CD4 counts. The potential emergence of resistance to raltegravir was investigated inpatients with virologic failure by genotyping the integrase coding sequence. 7 A total of 105/462 patients (23%) had virologic failure by week Integrase genotyping had been carried out in 94 of these patients (90%): 64 patients (68%) had genotypic evidence of viral resistance to raltegravir when tested at the time of viral rebound. Of these 64 patients, 48 (75%) had two or more mutations associated with phenotypic raltegravir resistance. Confirmed AIDS-defining clinical events occurred in 17/462 (3.7%) patients in the raltegravir group and 11/237 (4.6%) patients in the placebo group. 6 Adverse events considered to be related to the study drug occurred in 54.8% of patients taking raltegravir and 55.3% taking placebo. The most common drug-related laboratory adverse events were increased serum cholesterol and ALT levels in the raltegravir groups, and increased cholesterol and creatinine levels, and decreased neutrophil counts in the placebo groups. At the cut-off date for the analysis, 16 patients taking raltegravir (3.5%) and 4 taking placebo (1.7%) had been diagnosed with a new, recurrent or progressive cancer, not related to the study drug except for one case of lymphoma which was considered possibly drug-related. When data from three studies of heavily pre-treated patients were combined with the data from a study of previously untreated patients, the relative risk of cancer associated with raltegravir, as compared with placebo, was 1.2, with a composite rate of 2.2 cancers per 100 patient-years in the raltegravir group vs. 1.8 in the placebo groups. The types and frequencies were similar to those reported in patients with advance HIV. No evidence of carcinogenicity was apparent from the preclinical data with raltegravir. In treatment-experienced patients raltegravir 400mg bd, given with optimised background therapy, had a rapid and potent antiretroviral effect superior to that of the optimised background therapy alone, at week These results were consistent across both BENCHMRK studies. The inferior virologic responses in the placebo group were consistent with the findings of other studies in with similar patient populations: the majority of patients had AIDS at entry and had failure of multiple previous anti-retroviral regimens, with the emergence of highly resistant virus. The development of resistance to integrase inhibitors is of concern when raltegravir is used with no fully active drugs in the OBR. In patients who received enfuvirtide and darunavir as part of their OBR (first time use of these therapies), 89% on raltegravir achieved HIV RNA <50 copies/ml, compared with 68% on placebo. 7 The placebo/obr response rate was high because darunavir, tipranavir and T20 were used for the first time in triple-class resistant patients in their OBR. T20 and darunavir are usually used at an earlier disease stage in patients with a lower viral load and higher CD4 counts, which are both linked to a better prognosis. Virologic failure was generally associated with mutations at one of two primary residues, Q148 or N155, in combination with at least one other mutation.

7 Page 7 Table 2: 48 week response rates from the BENCHMRK-1 and -2 studies according to baseline characteristic 7 Baseline HIV-RNA Placebo 50 copies/ml 74%, 156/210 47%, 56/118 >50,000 copies/ml 55%, 129/233 20%, 22/ ,000 copies/ml 73%, 210/287 43%, 66/152 > 100,000 copies/ml 48%, 75/156 16%, 12/76 Baseline CD4-count 50 cells/mm 3 50%, 69/139 20%, 15/75 > 50 and 200 cells/mm 3 67%, 112/167 39%, 32/82 > 200 cells/mm 3 76%, 103/136 44%, 2171 No. of active PIs in OBT 0 54%, 88/163 14%, 12/ %, 188/264 49%, 64/130 Use of enfuvirtide or darunavir Enfuvirtide + darunavir 89%, 39/44 68%, 15/22 Enfuvirtide 80%, 36/45 57%, 13/23 Darunavir 69%, 52/75 47%, 22/47 Neither 60%, 115/191 20%, 18/90 Use of tipranavir No 66%, 230/346 36%, 67/188 Yes (resistant, phenotypic test) 49%, 20/41 22%, 4/18 Yes (sensitive, phenotypic test) 62%, 32/52 32%, 7/22 Yes (resistant, genotypic test) 36%, 16/44 15%, 3/20 Yes (sensitive, genotypic test) 73%, 38/52 40%, 8/20 Phenotypic sensitivity scores 0 51%, 33/65 2, 1/ %, 88/137 29%, 20/ %, 99/139 39%, 24/ %, 58/82 61%, 28/46 Genotypic sensitivity scores 0 45%, 50/112 3%, 2/ %, 111/166 37%, 34/ %, 84/109 62%, 29/ %, 58/82 61%, 28/46 Response rate = HIV RNA <50 copies/ml ART: antiretroviral therapy Genotypic sensitivity scores (GSS): total number of drugs in OBR to which the patient s virus showed genotypic sensitivity. Phenotypic sensitivity scores (PSS): total number of drugs in the OBR to which the patient s viral isolate showed phenotypic sensitivity.

8 Page 8 Treatment-naive patients: STARTMRK study Transmission of resistant HIV-1 to treatmentnaïve patients places them at risk of suboptimum responses to first-line treatments, such as NNRTIs. The British HIV Association (BHIVA) guidelines 8 recommend that therapy should be initiated in all patients with a CD4 count <350cells/mm 3. The goal of treatment is to achieve a viral load <50 copies/ml within 4-6 months of starting treatment. Highly active antiretroviral regimens (HAART) must be individualised for each patient. BHIVA recommendations are that efavirenz (NNRTI) is considered first line in all patients. Truvada (tenofovir and emtricitabine) or Kivexa (abacavir and lamivudine) should be the first choice nucleoside backbone used with efavirenz. The STARTMRK study was a double-blind, randomised (1:1), non-inferiority phase III study. 9 In the study HIV treatment-naïve patients at least 18 years of age (n=563) and with a viral load >5000 copies/ml, with no resistance to efavirenz, tenofovir (TDF) or emtricitabine (FTC) were randomised to treatment with either raltegravir (400mg bd) or efavirenz (600mg daily), each with TDF/FTC. Treatment was given for 96 weeks. Stratification was by baseline HIV RNA ( /> 50,000 copies/ml) and hepatitis status. Patients were excluded if they had acute or decompensated chronic hepatitis. The endpoints were assessed at week 48. The primary endpoint was the percentage of patients achieving RNA <50 copies/ml. Secondary endpoints were the achievement of a viral load < 400 copies/ml and the change from baseline in CD4 cell count. The primary analysis was on the per-protocol population and the non-completer = failure approach was used. The observed-failure method was used to analyse subgroups: only patients who discontinued the study because of lack of efficacy were considered to have treatment failure at subsequent time points whilst those who discontinued due to intolerability or other reasons unrelated to treatment were not considered. Patients were intended to continue with blinded treatment until week 96. Noninferiority would be assumed if the lower bound of the 95% confidence interval for the difference between the two treatments was higher than -12%. The study was carried out worldwide, with 65% of patients from the Americas, 23% from EU/ Australia and 11% from Asia. A fifth of patients (19%) were female, the mean age was 37 years and 42% were white. The mean CD4 count was 218 (±129) cells/mm 3, with 52% of patients have >200 cells/mm 3. Most patients (71%) had HIV RNA levels >50,000 copies/ml. Table 3 shows the proportion of patients with viral RNA<50 copies/ml at week 48, by selected baseline factors. Both raltegravir and efavirenz had virologic efficacy that was generally consistent across baseline demographic factors. was non-inferior to efavirenz for the primary endpoint in both the non-completer = failure and observed-failure analyses. The observed-failure analysis showed that noninferiority was not solely due to higher numbers of discontinuations in the efavirenz group (17 patients) compared with the raltegravir group (9 patients). More patients treated with raltegravir achieved viral suppression to <50 copies/ml at earlier time points (weeks 2-16) than with efavirenz; the clinical significance of a more rapid viral load decline has not been established. Greater CD4 count increases were achieved with raltegravir treatment that was consistent across demographic factors. 10 was well tolerated compared with efavirenz. More than one clinical adverse event occurred in 90% of patients in the raltegravir group vs. 96.5% in the efavirenz group (difference -6.4%, p=0.002). Drug related clinical adverse events occurred in 44.1% and 77.0% respectively (difference -32.8%, p<0.0001). There was no difference in the number of patients having serious clinical adverse events (raltegravir 10%, efavirenz 9.6%) or serious drug-related clinical adverse events (1.4% vs. 1.8%). More patients treated with efavirenz had laboratory-associated adverse events (14.5% vs. 9.6%) but this was not statistically significant (p=0.092). There were no statistical differences in the proportions of patients discontinuing the study due to clinical adverse events: 9 patients in the raltegravir group, 3.2% vs. 17 in efavirenz group, 6.0%, p= Increases in total-, HDL- and LDL- cholesterol were greater with efavirenz that with raltegravir treatment, but the difference in the total cholesterol/hdl ratio was not statistically significant. Triglycerides were raised in the efavirenz group and lowered with raltegravir (p<0.0001).

9 Page 9 Virological failure occurred in 66 patients (10% on raltegravir vs. 14% on efavirenz). Of these, 16 had a viral load >400 copies/ml, allowing genotypic susceptibility tests to be done. The virus was shown to be resistant to raltegravir in 4/8 patients and resistant to efavirenz in 3/7 patients. The findings of the STARTMRK study show that raltegravir is effective and well tolerated in treatment-naïve patients. It should be noted that raltegravir has not been used in combination with other regimens and raltegravir has not been directly compared with regimens that include PIs as initial treatment for treatment-naïve patients. In September 2009, 96-week data from the STARTMRK study was presented at the 49 th ICAAC conference. 10 In total, 245 (86%) of patients in the raltegravir group and 232 (81.7%) in the efavirenz group completed 96 weeks of treatment. Results are as follows: HIV RNA<50 copies/ml: raltegravir, 81% vs. efavirenz, 79%, p<0.001, noninferiority shown. HIV RNA<400 copies/ml: raltegravir, 85% vs. efavirenz, 81%, p<0.001, noninferiority shown. Mean change in CD4 count: raltegravir, +240 vs. efavirenz, +225; the difference of 15 was not statistically significant. 18 new patients (12 in the raltegravir and 6 in the efavirenz group) met the protocol definition of virologic failure, between weeks 48 and 96. Of these, 7 (4 in the Table 3: 48 week results of the STARTMRK study 9 HIV RNA <50 copies/ml at week 48 Overall; noncompleters = failures Overall; observedfailure method % (95% CI) Efavirenz 241/ / / (87.6, 94.7) 230/258 % (95% CI) 89.1 (84.7, 92.7) Difference in response rates 4.2% (-1.9, 10.3), p< for noninferiority 2.5 (-2.6, 7.7) HIV RNA <50 copies/ml at week 48 according to baseline plasma HIV RNA (observed-failure method) 100,000 copies/ ml >100,000 copies/ ml 111/ / (86.2, 96.5) 90.0 (85.0, 95.1) 114/ / (82.3, 93.9) 89.2 (82.6, 94.0) 3.4 (-4.1, 11.0) 1.7 (-5.6, 9.2) HIV RNA <50 copies/ml at week 48 according to baseline CD4 cell counts (observed-failure method) 50 cells/mm 3 21/25 > cells/ mm 3 85/95 >200 cells/mm 3 135/ (63.9, 95.5) 89.5 (81.5, 94.8) 94.4 (89.3, 97.6) 24/28 83/97 Missing - - 1/1 Mean change in CD4 count +189 cells/ mm / cells/ mm 3 HIV RNA <50 copies/ml at week 48 according to viral subtype 85.7 (67.3, 96.0) 85.6 (77.0, 91.9) 92.4 (86.5, 96.3) 100 (2.5, 100) (-23.0, 18.7) 3.9 (-5.7, 13.7) 2.0 (-4.1, 8.5) - Difference 26 cells, (4-47), p= Clade B 186/ (85.4, 94.0) 185/ (83.4, 92.5) 1.8 (-4.3, 7.9) Non-Clade B 52/ (87.3, 99.5) 40/ (78.3, 97.5) 5.4 (-4.9, 18.0) missing 3/3 100 (29.2, 100) 5/5 100 (47.8, 100) 0.0 (-59.4, 46.8)

10 Page 10 raltegravir group) had HIV RNA >400 copies/ml. No patients in the raltegravir group had detectable resistance to any of the drugs in their regimen whilst 2/3 in the efavirenz group had detectable resistance to any of the drugs in their regimen. At week 96, statistically significant predictors of increase in CD4 count were baseline CD4 count and log drop in week 8 HIV RNA level. At week 48, this had also included treatment group. A similar number of adverse events occurred between the groups but significantly less drug-related adverse events occurred with raltegravir (132/266, 47%) than with efavirenz (220/275, 78%), p< Three patients died (all in the raltegravir group) but no death was considered drug-related. Of the 14 malignancies that occurred, 3 were in the raltegravir group. Suicidal behaviours and depression occurred at a similarly low rate in both treatment arms, and between weeks very few additional CNS adverse events were reported. The changes in lipid levels were significantly greater with efavirenz than with raltegravir (p<0.001 for increases in total, HDL and LDL-cholesterol and p=0.001 for triglycerides). Adverse events In pooled analysis of the studies in treatment-experienced patients, the most commonly reported adverse events in the raltegravir and placebo groups were diarrhoea (17.6% vs. 20.6%), nausea (11.1% vs. 15.2%), headache (10.1% vs. 12.4%) and pyrexia (6.3% vs. 11.0%). 3 The rates of discontinuation of therapy due to adverse events were 2.4% in the raltegravir group and 2.8% in the placebo group. Commonly reported side effects in addition to those listed above 3 were insomnia, dizziness, abdominal pain and distension, constipation, flatulence, vomiting, hyperhidrosis, night sweats, itching, rash, arthralgia, fatigue and changes in laboratory values such as ALT, AST and lipids. (Commonly occurring: 1/100 to <1/10). Serious adverse reactions that occurred with raltegravir (alone or in combination with OBR) were genital herpes, drug hypersensitivity, gastritis, hepatitis and renal failure. Myopathy and rhabdomyolysis have been reported with raltegravir use. 3 It should be used with caution in patients who have had either of these conditions in the past or who have any predisposing factors, such as other medications associated with myopathy/ rhabdomyolysis. Osteonecrosis has been reported in some patients, usually those with acknowledged risk factors, advanced HIV or long-term exposure to combination antiretroviral therapy. 3 The cancers that occurred during the trials were considered to be expected in a highly immunodeficient population, many of whom had CD4 counts <50 cells/mm 3 and most had prior AIDS diagnoses. 3 The cancers included Kaposi s sarcoma, lymphoma, squamous cell carcinoma and hepatocellular carcinoma. Patients also had other risk factors, such as tobacco use and papillomavirus infection. Cost The Basic NHS Price is x 60 11, excluding VAT, and not including any potential discount. The cost of raltegravir is more than that of Kaletra, and, therefore, could have a significant financial impact for providers if use extends beyond highly-treatment resistant patients. In April 2008 the Scottish Medicines Consortium approved the restricted use of raltegravir within NHS Scotland for the treatment of HIV in treatment-experienced (triple-class resistant) adult patients. 12

11 Page 11 Reference List (1) MSD launches raltegravir (Isentress) vr.aspx?id= Accessed: (2) NeLM News. EU approves licence extension of raltegravir (Isentress) in treatment-naive adults with HIV-1. NeLM Accessed via on 16/09/09. (3) Summary of Product Characteristics. Isentress 400mg film-coated tablets. Date of revision of the text: 14 July Merck Sharp & Dohme Limited. Accessed via: on 25/08/09. (4) Cahn P, Sued O. : a new antiretroviral class for salvage therapy. Lancet 2007; 369: (5) Grinsztejn B, Nguyen BY, Katlama C 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 randomised controlled trial. Lancet 2007; 369: (6) Steigbigel RT, Cooper DA, Kumar PN et al. with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359(4): content/full/359/4/339 (7) Cooper DA, Steigbigel RT, Gatell JM et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359(4): content/full/359/4/355 (8) British HIV Association guidelines for the treatment of HIV-1 infected adults with antiretroviral therapy BG Gazzard on behalf of the BHIVA Treatment Guidelines Writing Group. Accessed via: on 22/09/09. (9) Lennox JL, DeJesus E, Lazzarin A et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374(9692): (10) Lennox JL, DeJesus E, Lazzarin A et al. demonstrates durable efficacy through 96 weeks: results from STARTMRK, a phase III study of raltegravir-based vs. efavirenz-based therapy in treatment-naive HIV+ patients. Poster #H924b. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, California. September 2009.: 2009 (11) British National Formulary, 57th edition. March Ed. Martin J. British Medical Association and Royal Pharmaceutical Society of Great Britain. Accessed via (12), 400mg film-coated tablet (Isentress). No. (461/08). Scottish Medicines Consortium Accessed via: on 10/09/09. Written by the London New Drugs Group on behalf of the HIV Drugs and Treatment Subgroup of the HIV Consortium. Merck Sharp & Dohme have commented on this review.