Reproductive System & Sexual Disorders: Current Research
Open Access

Highly Active Antiretroviral Therapy

 

Highly active antiretroviral therapy (HAART) is a treatment regimen typically comprised of a combination of three or more antiretroviral drugs. HAART may also be called antiretroviral therapy (ART) or combination antiretroviral therapy (cART). A key cornerstone of HAART is the co-administration of different drugs that inhibit viral replication by several mechanisms so that propagation of a virus with resistance to a single agent becomes inhibited by the action of the other two agents. Management of a HAART regimen is a multifaceted process that should be administered by, or in consultation with, a provider with specific training as defined by the Infectious Diseases Society of America. This approach is central to optimizing patient care, as studies have demonstrated provider experience positively correlates with improved patient outcomes.This combination therapy is primarily indicated to treat human immunodeficiency virus type 1 (HIV-1) infected patients. For the treatment of HIV, there are more than 25 different medications in six different classes, for which detailed discussion will follow in further sections. The standard of care for most treatment-naïve patients is a combination of two nucleoside reverse transcriptase inhibitors (typically tenofovir-emtricitabine) plus one non-nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor. Alternative classes or different drugs within each class may be recommended when patients have concurrent conditions or medication interactions, as detailed further below.Reducing the transmission of HIV-1 to others is a primary goal of HAART. With the use of HAART, a reduction of HIV-1 RNA levels has shown to reduce the risk of sexual transmission to partners to nearly zero in some studies, even among couples that engaged in condomless sexual acts. A combination of these drugs is also available for uninfected patients who engage in high-risk behavior and has demonstrated to reduce the risk of acquiring HIV infection by more than 90%. For pregnant patients, the use of HAART is critical in the prevention of mother-to-child transmission. The preferred regimen usually includes a combination of dual nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease or integrase inhibitor; however, dosage adjustments may be necessary to account for pharmacokinetic changes during pregnancy. This treatment is started as soon as possible and continued several months after birth to prevent vertical transmission through breast milk. Intrapartum zidovudine may work to reduce perinatal transmission in patients with a viral load greater than 1000 copies/mL at 38 weeks, and infants may also receive zidovudine as prophylaxis. Patients have the best results when they have started treatment before fertilization, so it is important to screen at-risk patients early.HAART is also utilized in the treatment of HIV-2, though currently there is no specific guideline of recommendations for HIV-2 treatment. Instead, HIV-2 management is under HIV-1 guidelines with some modifications. Genetic differences render HIV-2 intrinsically resistant to certain HAART medication classes (non-nucleoside reverse transcriptase inhibitors) and decrease the efficacy of others (protease inhibitors and fusion inhibitors). Research is ongoing to determine the best initial treatment for patients infected with HIV-2 or dually infected with HIV-1/2.Some NRTIs, lamivudine, and tenofovir, are also indicated in the treatment of hepatitis B (HBV). Monotherapy is unlikely sufficient to treat chronic HBV, therefore a combination of nucleoside/nucleotide analogs and interferon-alpha is generally recommended. However, some recent studies have shown that while combination therapy has shown higher biological suppression, the sustained response with combination therapy is comparable to single therapy regimens.There are six main classes of HAART agents that target different stages in the viral lifecycle. A fundamental cornerstone of HAART is the co-administration of different drugs that inhibit HIV replication by several mechanisms so that propagation of a virus with resistance to a single agent is inhibited by the action of the other two agents. Some agents may be co-formulated to increase ease of patient compliance with these medications.

 

NRTIs require intracellular phosphorylation via host enzymes before they can inhibit viral replication. These agents are nucleoside or nucleotide analogs with an absent hydroxyl at the 3’ end that are incorporated into the growing viral DNA strand. They competitively bind to reverse transcriptase and cause premature DNA chain termination as they inhibit 3’ to 5’ phosphodiester bond formation.

Examples include: abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine.