Integrase InhibitorEdit
Integrase inhibitors are a cornerstone of modern HIV treatment, offering a potent option for suppressing the virus when used as part of a well-chosen combination regimen. By blocking the HIV integrase enzyme, these drugs interrupt a critical step in the viral life cycle—integration of viral DNA into the host genome. The result is lower viral replication and better preservation of the immune system for many patients. The most widely used members of this class today include Dolutegravir, Bictegravir, Elvitegravir, and Raltegravir. They are commonly prescribed alongside other antiretrovirals, particularly nucleoside reverse transcriptase inhibitors such as Tenofovir disoproxil fumarate and Emtricitabine or Lamivudine, forming regimens that emphasize simplicity and adherence.
In practice, integrase inhibitors have helped shift the HIV treatment landscape toward highly effective, once-daily or twice-daily regimens with favorable tolerability profiles. They are frequently used in first-line therapy and are compatible with various fixed-dose combinations that reduce pill burden and improve real-world adherence. In addition to treatment, a related use of this drug class is in pre-exposure prophylaxis (PrEP) regimens, including long-acting formulations like cabotegravir for people seeking to prevent infection. For context, see Human immunodeficiency virus and antiretroviral therapy.
Mechanism of action
Integrase inhibitors target the viral integrase enzyme, which the virus uses to insert its genetic material into the host’s DNA. The enzyme carries out a two-step process: 3' processing of viral DNA ends and the strand transfer step that integrates the viral DNA into the host genome. INSTIs (integrase strand transfer inhibitors) bind to the active site of integrase in the presence of divalent metal ions, blocking the strand transfer reaction. This halts the integration step, preventing productive infection of new cells and allowing the immune system to recover under suppressive therapy.
Because integration is a bottleneck in the viral life cycle, these drugs tend to work well with other agents that inhibit different stages of replication. They are often paired with nucleoside reverse transcriptase inhibitors (NRTIs) in regimens that minimize additional complexity for patients. See Integrase inhibitors for more background on the class.
Clinical uses and regimens
Integrase inhibitors are used in a variety of regimens, with preferences evolving as new data emerge. In many guidelines, dolutegravir-based regimens are recommended as first-line therapy in diverse populations due to their strong efficacy, high barrier to resistance, and favorable tolerability. For example, combinations that include Dolutegravir with NRTIs such as Tenofovir disoproxil fumarate and Emtricitabine—or with the newer backbones like Tenofovir alafenamide—are widely adopted in clinical practice. See HIV treatment guidelines for country-specific recommendations and updates.
Pregnancy poses careful considerations. Early concerns about rare neural tube defects associated with some dolutegravir exposure led to cautious use in certain circumstances; subsequent evidence has helped refine recommendations, balancing potential risks against the benefits of effective maternal viral suppression. Clinicians weigh timing of ART initiation and regimen choice on a case-by-case basis, with many settings allowing continued use of certain INSTI-based regimens when benefits are judged to outweigh risks. See Pregnancy and HIV for discussion of evolving data and recommendations.
Beyond treatment, integrase inhibitors play a role in PrEP strategies through long-acting formulations like cabotegravir, which offer alternatives to daily oral regimens for individuals at ongoing risk of HIV exposure. See cabotegravir, Pre-exposure prophylaxis, and HIV prevention for broader context.
Drug interactions are a practical consideration. Integrase inhibitors generally have fewer drug interactions than some other antiretroviral classes, but absorption with polyvalent cations (for example, calcium or magnesium tablets) can be affected; dosing schedules are typically arranged to avoid coadministration with such minerals. See drug interactions for a fuller discussion.
Resistance and monitoring
Viral resistance can arise when viral replication persists on suboptimal therapy. Raltegravir and elvitegravir were among the first INSTIs to show resistance with specific integrase mutations, and cross-resistance patterns can occur within the class. Dolutegravir and bictegravir have higher barriers to resistance in many clinical scenarios, making them particularly robust choices in several first-line regimens, though resistance can still emerge under certain circumstances. Monitoring includes routine measurement of plasma HIV RNA, assessment of adherence, and resistance testing when virologic rebound occurs. See antiretroviral resistance and genotypic resistance testing for more detail.
Safety and adverse effects
Integrase inhibitors are generally well tolerated, but they are not without side effects. Common complaints include headaches, nausea, and occasional sleep disturbances. Some patients report weight gain or metabolic changes over time, particularly with certain regimens, though the clinical significance varies. Less common but important considerations include neuropsychiatric symptoms with dolutegravir in some individuals and rare hypersensitivity reactions. As with all medicines, risks must be weighed against benefits in the context of an individual patient’s health status and comorbidities. See adverse effects of antiretroviral therapy for a broader view.
Long-acting injectable options where applicable also raise practical considerations, such as adherence to injection schedules, site reactions, and the logistics of ongoing care. See cabotegravir for details on the injectable approach to INSTI-based prevention and treatment.
History and development
Raltegravir became the first approved integrase inhibitor in 2007, marking a turning point in HIV therapy by offering a distinct mechanism with a favorable tolerability profile. Elvitegravir followed, with fixed-dose combinations that simplified regimens. Dolutegravir entered clinical use in the mid-2010s and rapidly rose to prominence due to combination efficacy and a robust resistance barrier. Bictegravir, approved thereafter, added another option with a similar performance profile. Together, these agents have propelled a shift toward simpler, highly effective regimens that patients can reasonably adhere to in everyday life. See antiretroviral therapy history and drug development for broader context.