raltegravir
Regulatory sources consulted
Approved indications
- Combination treatment of HIV-1 in pediatric patients weighing at least 11 kg using the chewable formulation and weight-appropriate regimen.
Contraindications
Absolute
- Hypersensitivity to raltegravir.
Clinical warnings
- It may cause severe skin reactions or DRESS with liver involvement; stop for signs of severe hypersensitivity. — CIMA/AEMPS, ficha técnica 107436004
- Major warning · Myopathy and rhabdomyolysis have been reported; assess muscle pain or weakness and creatine kinase as clinically indicated. — CIMA/AEMPS, ficha técnica 107436004
Drug interactions
- HighAluminum- or magnesium-containing antacids
Mechanism: Cations reduce raltegravir absorption.
Recommendation: Concomitant administration is not recommended.
CIMA/AEMPS, ficha técnica 107436004
- HighRifampicin
Mechanism: It induces UGT1A1 and reduces raltegravir.
Recommendation: Adjust only with the formulation and regimen allowed by the label; do not double chewable-tablet doses.
CIMA/AEMPS, ficha técnica 107436004
Adverse events
Common (≥1%)
Nausea, headache, diarrhea, fatigue, insomnia, and increased transaminases
Rare but serious
DRESS, Stevens-Johnson syndrome, rhabdomyolysis, and hepatitis
Pregnancy and lactation
Pregnancy data are insufficient; use raltegravir only if expected benefit justifies the possible risk. Do not breastfeed during HIV treatment.
Recent literature (PubMed)
Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of viral resistance and have a high rate of cross-resistance. To counteract these resistant mutants, second-generation INSTI drugs have been developed: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC). However, HIV is also able to develop resistance mechanisms against the second-generation of INSTIs. This review describes the mode of action of INSTIs and then summarizes and evaluates some typical resistance mutations, such as substitution and insertion mutations. The role of unintegrated viral DNA is also discussed as a new pathway involved in conferring resistance to INSTIs. This allows us to have a more detailed understanding of HIV resistance to these inhibitors, which may contribute to the development of new INSTIs in the future.
Advances in antiretroviral drug development have led to safer drugs with improved tolerability, enhanced activity against drug-resistant HIV, higher genetic barrier to resistance, and fewer drug-drug interactions. Genetic polymorphisms in drug-metabolizing enzymes, transporters, and immune pathways contribute to interindividual variability in antiretroviral pharmacokinetics and toxicity. HLA-B *57:01 screening prior to abacavir initiation is an example of clinically implemented pharmacogenetics in high-income settings. Conversely, despite robust evidence linking UGT1A1 variants to atazanavir-associated hyperbilirubinaemia, routine UGT1A1 testing has not been widely adopted. We conducted a narrative review of genetic polymorphisms associated with the toxicity and pharmacokinetics of current antiretroviral therapy. We searched Pharmacogenomics Knowledgebase (PharmGKB®) for abacavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, emtricitabine, dolutegravir, elvitegravir, raltegravir, bictegravir, cabotegravir, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, lenacapavir, rilpivirine and doravirine. We supplemented our review with targeted searches in PubMed®. We found that most pharmacogenetic associations for current antiretroviral drugs come from single studies and lack replication. Although UGT1A1 loss-of-function alleles increase dolutegravir and cabotegravir exposure, no association with toxicity has been shown. No relevant studies were identified for doravirine, lenacapavir or bictegravir. Actionable pharmacogenetic associations with antiretroviral drugs remain limited to abacavir. Future research should prioritize replicating pharmacogenetic associations across diverse populations and establishing clinical relevance.