RaltegravirEdit

Raltegravir is an antiretroviral medication used to treat HIV-1 infection in adults and certain pediatric patients as part of combination therapy. Marketed under the brand name Isentress and, in some formulations, Isentress HD, it is the first approved agent in the class of integrase strand transfer inhibitors (Integrase strand transfer inhibitors). Since its initial approval by the U.S. Food and Drug Administration in 2007 for treatment-experienced adults, raltegravir has become a standard component of many modern antiretroviral regimens, with use expanding to treatment-naive patients and to selected pediatric populations. The drug is produced by Merck and is listed in major treatment guidelines for HIV-1 management as a recommended option in various therapeutic scenarios.

Raltegravir is distinguished by its mechanism of action: it inhibits the HIV integrase enzyme, which is responsible for inserting viral DNA into the host genome. By blocking this step, raltegravir interferes with the replication cycle of HIV-1 and helps reduce the amount of virus circulating in the body when used in combination with other antiretrovirals (antiretroviral therapy). This mechanistic approach targets a different stage of the viral life cycle than drugs that inhibit reverse transcription or proteolysis, contributing to combination strategies that aim to prevent resistance and maintain virologic suppression.

Mechanism of action

Raltegravir is an integrase inhibitor that specifically inhibits the strand transfer step of HIV DNA integration into the host genome. This prevents the establishment of a permanent proviral reservoir and disrupts ongoing viral replication.
As an agent within a combination regimen, raltegravir relies on other antiretrovirals to provide complementary antiviral activity and to reduce the likelihood of resistance development.

Pharmacokinetics and dosing

Raltegravir is taken orally and is generally administered twice daily in most regimens, though dosing may vary in specific therapeutic contexts.
It is primarily metabolized by UGT1A1-mediated glucuronidation rather than by major hepatic cytochrome P450 enzymes, which influences its interaction profile.
Absorption is sufficient to achieve therapeutic plasma concentrations, and the drug is eliminated through fecal and renal routes.
Certain concomitant medications can affect raltegravir levels. For example, rifampin lowers raltegravir exposure, and clinicians may adjust dosing or choose alternative regimens when coadministration is necessary. Cations present in antacids or mineral supplements can chelate raltegravir, so patients are advised to time dosing away from these products.
Raltegravir has been studied in adults and in selected pediatric populations, with dosing and safety data guiding use in younger patients within approved age ranges.

Clinical use and guidelines

Raltegravir is used as part of combination ART for treatment-naive and treatment-experienced adults, as well as certain pediatric patients, in a variety of regimens that aim to maximize virologic suppression while preserving tolerability.
It is commonly included in regimens that pair an INSTI with two nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs), though exact regimens are tailored to the individual patient’s history and comorbidities.
In guideline documents from major health authorities, raltegravir is recommended as a first-line or alternative agent in certain contexts, reflecting its favorable safety profile, convenient administration, and robust antiviral activity in many patients. See for example discussions in comprehensive HIV treatment guidelines published by national health programs and international societies NIH Guidelines and EACS Guidelines.

Safety, adverse effects, and safety monitoring

Common adverse effects reported with raltegravir include headaches, gastrointestinal symptoms (nausea, diarrhea), fatigue, and sleep disturbances. These side effects are typically mild to moderate and manageable in many patients.
Serious but less common adverse events can occur. A hypersensitivity reaction or severe immune reconstitution inflammatory syndrome (IRIS) may require discontinuation. Raltegravir has also been associated with muscle-related symptoms, including myopathy and rhabdomyolysis in rare cases, especially when used with certain other medications or in patients with risk factors.
There is a potential for drug interactions, particularly with agents that affect glucuronidation pathways (e.g., strong inducers or inhibitors of UGT1A1) and with medications that can alter the absorption of raltegravir through chelation with polyvalent cations. Clinicians consult drug interaction resources when patients are on complex regimens.

Resistance and durability of response

As with other antiretrovirals, adherence is critical to maintaining virologic suppression and preventing resistance. Resistance to raltegravir can emerge, particularly in the setting of suboptimal adherence or when used as monotherapy. Mutations in the HIV integrase gene may reduce susceptibility to raltegravir and can, in some cases, influence cross-resistance patterns with other integrase inhibitors.
In clinical practice, raltegravir is typically used as part of combination regimens to minimize the likelihood of resistance and to preserve future treatment options.

History and development

Raltegravir was the first approved agent in the integrase inhibitor class, representing a significant advance in the diversification of antiretroviral mechanisms. Its development and approval reflected a broader strategy in HIV therapy to target multiple steps in the viral life cycle, supporting long-term viral suppression and improved treatment durability.
Over time, raltegravir has been joined by second- and third-generation integrase inhibitors that offer differing dosing regimens and resistance profiles, but raltegravir remains an important component of many regimens and a reference point in INSTI-based therapy. See Isentress for brand-context information and historical development details.