Johns Hopkins HIV Guide
Raltegravir
INDICATIONS
FDA
- Treatment of HIV-1 infection in combination with other ARV agents in ART-experienced patients with evidence of HIV replication despite ongoing ART.
- Treatment of HIV-1 infection in combination with other ARV agents in ART-naive patients.
NON-FDA APPROVED USES
- HIV-1 nonoccupational postexposure prophylaxis (nPEP): 400 mg tablet twice daily for 28 days in combination with other antiretrovirals. Therapy should be initiated within 72 hours.
- HIV-1 occupational postexposure prophylaxis (oPEP): 400 mg twice daily for 4 weeks with concomitant emtricitabine/tenofovir. Therapy should be initiated as soon as possible after occupational exposure.
- Substitution for other ARV agents due to drug toxicity or intolerance in pts on a suppressive regimen
FORMS
brand name | preparation | manufacturer | route | form | dosage^ | cost* |
Isentress | Raltegravir (RAL) | Merck & Co., Inc. | Oral | tablet | 400 mg | $34.70 per tab |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | chewable tablet | 100 mg, 25 mg | $2.17, $8.68 | |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | suspension | 100 mg per packet | $8.68 | |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | tablet | 600 mg | $34.70 |
*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.
USUAL ADULT DOSING
- Typical dosing: with or without food
- 400 mg film-coated tablet twice daily OR
- 300 mg chewable tablet* PO twice daily OR
- Two 600 mg tablets once daily
- In combination with all PIs, NRTIs, and NNRTIs: use standard dose (400 mg PO twice daily)
*Note: chewable tablets are not interchangeable with film-coated tablets. Avoid chewable tablets in patients with phenylketonuria.
PEDIATRIC DOSING
USUAL PEDIATRIC DOSING
[11]Neonates ≥ 37 weeks GA and weight ≥ 2 kg: empiric treatment dose, dosing using the oral suspension
- Note: if the mother received raltegravir 2 - 24 hours prior to delivery, the neonate’s first dose of raltegravir should be delayed until 24-48 hours after birth. Additional antiretroviral medications should be started as soon as possible.
- Raltegravir cannot be used in preterm neonates or neonates < 2 kg
- Fixed dosing:
- Postnatal age ≤ 7 days:
- 2 to < 3 kg: 4 mg PO once daily
- 3 to < 4 kg: 5 mg PO once daily
- 4 to < 5 kg: 7 mg PO once daily
- Postnatal age 8 - 28 days:
- 2 to < 3 kg: 8 mg PO twice daily
- 3 to < 4 kg: 10 mg PO twice daily
- 4 to < 5 kg: 15 mg PO twice daily
- Postnatal age 29 - 42 days
- 3 to < 4 kg: 25 mg PO twice daily
- 4 to < 6 kg: 30 mg PO twice daily
- 6 to < 8 kg: 40 mg PO twice daily
- Postnatal age ≤ 7 days:
- Weight-based dosing for full-term infants (≥ 37 weeks GA and weight ≥2 kg) (IMPAACT)[2]:
- Postnatal age 0 - 7 days: 1.5 mg/kg/dose PO once daily
- Postnatal age 8 - 28 days: 3 mg/kg/dose PO twice daily
- Postnatal age 29 - 42 days: 6 mg/kg/dose PO twice daily
Infant/Pediatric Dosing (≥4 weeks of age):
- Oral suspension:
- Weight-based dosing: 6 mg/kg/dose PO twice daily; maximum dose 100 mg/dose
- Fixed dosing:
- 3 to < 4 kg: 25 mg PO twice daily
- 4 to < 6 kg: 30 mg PO twice daily
- 6 to < 8 kg: 40 mg PO twice daily
- 8 to < 10 kg: 60 mg PO twice daily
- 10 to < 14 kg: 80 mg PO twice daily
- 14 to < 20 kg: 100 mg PO twice daily (100mg/dose = max dose for PO suspension)
- NOTE: dosing approximates 6 mg/kg/dose PO twice daily
- Chewable tablet dosing (NOTE: CANNOT interchange with PO film-coated tablets)
- 3 to < 6 kg: 25 mg PO twice daily
- 6 to < 10 kg: 50 mg PO twice daily
- 10 to < 14 kg: 75 mg PO twice daily
- 14 to < 20 kg: 100 mg PO twice daily
- 20 to < 28 kg: 150 mg PO twice daily
- 28 to < 40 kg: 200 mg PO twice daily
- >= 40 kg: 300 mg PO twice daily
- NOTE: dosing approximates 6 mg/kg/dose PO twice daily
- Film-coated tablet dosing: (NOTE: CANNOT interchange with PO chew tabs)
- Weight ≥ 25 kg: 400 mg PO twice daily
- Children and adolescents weighing ≥ 40 kg: Two 600 mg tablets once daily (total 1,200 mg)
NOTE: PO suspension, PO chew tabs and PO film-coated tablets are NOT bioequivalent and dosing is not interchangeable.
PEDIATRIC RENAL DOSING
- No renal dosage adjustment is necessary. Dose post-HD on days of dialysis.
OTHER PEDIATRIC INFORMATION
PO suspension, PO chew tabs and PO film-coated tablets are NOT bioequivalent and dosing is not interchangeable.
RENAL DOSING
DOSING IN HEMODIALYSIS
No data. Dose post-HD on days of dialysis.
DOSING IN PERITONEAL DIALYSIS
No data.
DOSING IN RENAL REPLACEMENT THERAPY
No data.
ADVERSE DRUG REACTIONS
GENERAL
- Generally well tolerated with comparable ADR rates to placebo. Rates of discontinuation of therapy due to AEs were 4% with RAL+ optimized background therapy (OBT) and 5% with placebo + OBT.
OCCASIONAL
- GI: nausea, diarrhea, flatulence
- Headache
- Dizziness
- Fever (unclear association)
- Pruritis
- Creatine kinase elevation
- Transaminase elevation (discontinue RAL with LFT elevation and drug rash)
- CNS: e.g., depression, paranoia, and suicidal ideation and behaviors
- Rash
RARE
- Myopathy and rhabdomyolysis: CPK elevation (grade 3/4) is more common in pts treated with RAL compared to EFV.
- Malignancies (3.5% in RAL recipients at 48 weeks vs. 2.6% in placebo recipients; difference did not persist, but post FDA-approval surveillance for malignancies in progress)
- Cerebellar ataxia
- Thrombocytopenia
- Severe rash (including SJS, TEN, and DRESS--drug rash with eosinophilia and systemic symptoms)
DRUG INTERACTIONS
Drug | Effect of Interaction | Recommendations/Comments |
Antacid (e.g., Maalox) | RAL AUC and Cmin decreased by 24% and 67%, respectively. | Avoid co-administration. Administer RAL 2-4 hours before antacid administration. |
With ATV/r, RAL AUC and Cmin increased 41% and 77%, respectively. With unboosted ATV 300 mg twice-daily + RAL 400 mg twice-daily resulted in ATV AUC and Cmin reduction of 17% and 29%, respectively. Mean QTc was not increased, but QRS interval increased 11 ms (range 2-25 ms). | Recommended dose ATV/r 300/100 mg once-daily plus RAL 400 mg twice daily. The clinical significance of QRS interval increase and lower ATV concentrations observed with ATV 300 mg twice-daily + RAL 400 mg twice-daily remains to be determined. With RAL co-administration, use boosted ATV/r 300/100 mg once daily. | |
RAL AUC decreased by 36%, but Cmin was not significantly affected. | Use standard dose RAL. | |
RAL PK is unchanged. ETR AUC increased 10%. | Use standard dose | |
RAL and APV AUC decreased 37% and 36%, respectively (with unboosted FPV). RAL AUC decreased 55% (with FPV/r 700/100 mg bid). | Clinical significance is unknown. Avoid unboosted FPV with RAL co-administration. Use FPV/r with close monitoring or consider alternative boosted PI with RAL co-administration. | |
RAL Cmin decreased 30%. | Use standard dose | |
RAL PK unchanged | Use standard dose | |
Methadone | No change in RAL and methadone PK. | Use standard dose. |
May decrease RAL serum concentrations. | Use standard dose RAL with close monitoring of virologic efficacy. | |
Omeprazole | RAL AUC and Cmin increased by 3-fold and 1.5-fold, respectively. | Unclear clinical significance. Use standard dose. |
Phenobarbital | Phenobarbital may significantly decrease RAL serum concentrations. | Avoid co-administration. Consider valproic acid or levetiracetam |
Phenytoin | Phenytoin may significantly decrease RAL serum concentrations. | Avoid co-administration. Consider valproic acid or levetiracetam |
Rifabutin reduces RAL trough by 20%, but RAL AUC is not affected. | Use RAL 400 mg twice daily plus rifabutin 300 mg once daily | |
Rifampin | Rifampin decreases RAL AUC and Cmin by 40% and 61%, respectively. | Increasing RAL to 800 mg twice daily resulted in adequate AUC, but Cmin was decreased by 53%. Limited clinical data. Avoid co-administration if possible. Consider rifabutin with RAL co-administration. |
RAL PK unchanged | Use standard dose | |
Sirolimus | Drug interaction unlikely | Case report of safe co-administration of RAL and sirolimus. Use standard dose. |
St John’s wort | May decrease RAL serum concentrations. | Avoid co-administration until PK data become available. |
Tacrolimus | No significant interaction. | Case series of favorable outcomes in pts treated with RAL-based regimen s/p solid organ transplant on tacrolimus. Use standard dose. |
RAL AUC increased 49% | Standard dose. | |
RAL Cmin decreased by 55%, but AUC decreased by 24% (NS). | Use with close monitoring of virologic efficacy. Clinical significance unclear; comparable efficacy observed in a subgroup of pts who received TPV/r plus RAL relative to pts not receiving TPV/r. Hepatic necrolysis was reported in 3 patients on TPV/r + RAL: monitor transaminases. |
- Not a substrate, inhibitor, or inducer of CYP3A4; therefore, significant drug interactions with CYP3A4 substrates, inhibitors, and inducers are unlikely. RAL is primarily metabolized by glucuronidation via the enzyme UDP-glucuronosyltransferase (UGT) 1A1.
RESISTANCE
- Two pathways to resistance with mutations in integrase gene: (1) N155H + (E92Q,V151I, T97A, G163R, L74M); and (2) Q148K/R/H + (G140S/A, E138K).
- Other pathways may exist, e.g. Y143R/C/H + (L74A/I, E92Q, T97A, I203M, S230R).
- Evidence of cross-resistance with elvitegravir. Q148 pathway leads to cross-resistance to dolutegravir.
PHARMACOLOGY
MECHANISM
RAL inhibits integrase, an essential enzyme responsible for catalyzing the insertion of HIV DNA into the host genome.
PHARMACOKINETIC PARAMETERS
Absorption
Absolute bioavailability not established. Compared to the 400 mg formulation, the 600 mg tablet formulation has higher relative bioavailability. Steady-state is generally reached in 2 days for both the 400 mg and 600 mg formulations.
AUC decreased by ~6% with high-fat meal (not clinically significant)
Metabolism and Excretion
Eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. RAL-glucuronide and RAL are eliminated excreted in feces (51%) and urine (32%).
Protein Binding
83%
Cmax, Cmin, and AUC
Geometric mean AUC 0-12h and Cmin were 14.3 microM per hr and 142 nM, respectively. Efficacy is not associated with Cmin, but In vitro, an antiviral response is associated with AUC/EC50.
T1/2
9 hrs. RAL exhibited a long residence time on the integrase/DNA complexes. Clinical trials evaluating once-daily RAL are underway.
Distribution
CNS to plasma ratio of 7.3%. RAL CSF concentrations exceeded IC50 of wild-type HIV.
DOSING FOR DECREASED HEPATIC FUNCTION
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of RAL has not been studied.
PREGNANCY RISK
- Raltegravir has high transfer across the human placenta. No increased risk of overall teratogenic effects has been observed following first-trimester exposure.
- There is variability in the pharmacokinetics of raltegravir so once-daily dosing (i.e., raltegravir 600 mg tablet formulation) is not recommended. However, no dose adjustments are required for patients who are pregnant.
BREAST FEEDING COMPATIBILITY
No human data, but based on animal studies, RAL concentrated in breast milk.
COMMENTS
- Pro:
- Highly effective when used in combination with OBT in heavily treatment-experienced pts with extensive resistance to currently approved ARVs.
- Good short-term safety and few drug interactions.
- More rapid VL reduction at 4 and 8 wks and better tolerability vs. EFV in treatment-naive pts with comparable 96-wk results. Clinical significance is of more rapid VL reduction unknown.
- Con:
- Cross-resistance to elvitegravir and lower barrier to resistance compared to newer generation INSTIs and recommendation for use has been downgraded in the DHHS guidelines
- Pill burden - either once-daily dosing with two tablets or one tablet twice-daily dosing
Basis for recommendation
- Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv. Accessed 2/8/22.
Comment: DHHS recommendations for dosing of raltegravir in pediatric patients.
References
- Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir (RAL) in Neonates: Dosing, Pharmacokinetics (PK), and Safety in HIV-1-Exposed Neonates at Risk of Infection (IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. [PMID:31913995]
Comment: Phase 1 dose-finding study of raltegravir in infants exposed to HIV infection. PK data from the first cohort of patients was included in population modeling and simulations to guide dosing for infants in a second cohort. The basis for weight-based dosing recommendations of raltegravir for full-term neonates.
- Lommerse J, Clarke D, Kerbusch T, et al. Maternal-Neonatal Raltegravir Population Pharmacokinetics Modeling: Implications for Initial Neonatal Dosing. CPT Pharmacometrics Syst Pharmacol. 2019;8(9):643-653. [PMID:31215170]
Comment: The basis for recommendation to delay the first dose of raltegravir to a neonate until 1-2 days of age in neonates born to mothers who received raltegravir during pregnancy up until the point of delivery.
- Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396-407. [PMID:20074791]
Comment: SWITCHMRK 1 and 2 evaluated switch to RAL in ART-experienced pts who were virologically controlled on stable LPVr-based regimen. Pts had a median of 5 previous ARVs. Patients randomized to switch LPV/r to RAL (n=350) or continue on LPV/r (n=352) while remaining on the same background ART, which included at least 2 NRTI. Switch to RAL resulted in lower cholesterol and triglycerides; however, at week 24, RAL did not demonstrate non-inferiority compared to LPV/r. 293 of 347 (84.4%) vs 319 of 352 (90.6%) pts had HIV RNA < 50 in RAL and LPVr groups, respectively; treatment difference -6.2 % (95%CI -11.2 to -1.3 ; NC = F). Demonstrates the importance of evaluating ART history and resistance before switching to the regimen with a lower barrier to resistance.
- Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr. 2009;52(3):350-6. [PMID:19648823]
Comment: Randomized, double-blind, study of RAL vs EFV, both combined with TDF/FTC, in 198 ART-naive pts. At wk 96, 83% of RAL and 84% of EFV-treated pts achieved undetectable VL (< 50). As expected, lower CNS adverse events were observed in RAL-treated pts.
- Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339-54. [PMID:18650512]
Comment: Randomized, double-blind studies of RAL vs. placebo, each with OBT, in 699 treatment-experienced - pts failing ARTs with HIV resistant to PIs, NNRTIs, and NRTIs. In a combined analysis, At 48 wks, 62.1 % taking RAL+ OBT vs 32.9 % taking placebo + OBT achieved VL <50 (p<0.001). CD4 increased by 84 in RAL group vs 37 in placebo group (p<0.001). In a sub-analysis, first use of ENF, DRV, or both in the OBT + RAL resulted in VL <50 in 82%, 68%, 80% of treated pts, respectively. In RAL treated pts with genotypic sensitivity score (GSS) of >/-0 , VL <50 achieved in 44% and 71%, respectively. No difference in virologic suppression between GSS score of 1 and 2 or greater in RAL treated pts, but may have been due to partial activity of the OBT.
- Markowitz M, Nguyen BY, Gotuzzo E, 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(2):125-33. [PMID:17721395]
Comment: Randomized trial of ART-naive pts (n=198) comparing RAL (100, 200, 400, and 600 twice daily) to EFV, both in combination with TDF/FTC. Baseline VL 4.6-4.8 log and CD4 271-314. VL < 50 achieved in 85% to 88% of pts across all arms at 48 wks. At 96 wks, RAL continued to be effective with virologic suppression (< 50 c/mL) observed in 83% vs 84% of RAL and EFV-treated pts, respectively. The efficacy was comparable between EFV and RAL arms across all dosages. However, a more rapid reduction in VL to < 50 was observed in the RAL compared to EFV arm at wks 4 and 8. CNS AEs were more common in the EFV arm than their RAL counterparts.
Rating: Important - 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(9569):1261-1269. [PMID:17434401]
Comment: Randomized, double-blind, multi-dose (200, 400, 600 mg twice daily) placebo-controlled trial of RAL in pts with multiple-drug resistant HIV. All pts were genotypically or phenotypically resistant to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs). Baseline characteristics are comparable between the 2 groups. Of the 133 pts randomized to RAL + OBR, VL= 4.7 log, CD4= 240, and 9.9 yrs of prior ARTs. OBR contained a median of 4 ARVs with 45 (36%) receiving ENF. At 24-wks, VL< 50 VL was achieved in 65-67% and 13% of RAL and control pts, respectively. Due to the virologic benefit seen in the RAL arm, all pts (including those in the placebo arm) were switched to RAL 400 mg twice daily after 24 wks. Overall, those who had achieved virologic suppression on RAL at 24 wks had largely maintained it to 48 vs 54% taking any dose of RAL had VL < 50.
- Cahn P, Sax PE, Squires K. ONCEMRK Study Group. Raltegravir 1200 mg Once Daily vs 400 mg Twice Daily, With Emtricitabine and Tenofovir Disoproxil Fumarate, for Previously Untreated HIV-1 Infection: Week 96 Results From ONCEMRK, a Randomized, Double-Blind, Noninferiority Trial. J Acquir Immune Defic Syndr. 2018 Aug 15;78(5):589-598. doi: 10.1097/QAI.0000000000001723. PMID: 29771789; PMCID: PMC6075877.
Comment: Phase 3, double-blind, noninferiority trial comparing raltegravir 1200 mg once daily with raltegravir 400 mg BID plus emtricitabine and tenofovir disoproxil fumarate in 797 treatment-naive patients living with HIV for 96 weeks. Discontinuations occurred in 1.1% of participants due to lack of efficacy in both groups and adverse events in 1.3% compared to 2.3% in once daily and twice daily respectively. There was a nonsignificant treatment difference of 1.4% in participants who achieved HIV-1 RNA < 40 copies/milliliter by week 96. Adverse events were found to be similar for the two groups.
- Eron J, et al. CROI 2011. Abstract 150LB QDMRK, A Phase III Study of the Safety and Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV-Infected Patients (Pts)
Comment: Randomized study of RAL 800 mg once-daily vs. RAL 400 mg twice daily, each with TDF/FTC, in 770 ART-naive pts. At 48 wks, 83.2 % taking RAL once daily vs 88.9% RAL twice daily achieved VL < 50. Treatment difference of -5.7% (CI -10.7%, -0.83%) did not meet criteria for non-inferiority. The difference was largely driven by pts with high VL. Among those with VL >1000,000, 74.3% of the once-daily group vs. 84.2% of the twice-daily group had undetectable VL.
- Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Transmission in the United States. Available at: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Peri.... Accessed 2/8/22.
Comment: DHHS guidelines for HIV in pregnancy and perinatal transmission prevention.
