Highly active antiretroviral therapy | Antimicrobials | Pharmacology

HAART or Highly active antiretroviral therapy: It is a combination of three or more types of antiretroviral drugs given in the treatment of HIV infection. Cornerstone of HAART is prevention of antiviral resistant strains and to increase efficacy.

Drugs used in HAART

Drug and class	Mechanism of action	Adverse effects
Nucleoside or nucleotide reverse transcriptase inhibitors or NRTIs: Abacavir, didanosine, lamivudine, stavudine, zidovudine and tenofovir	Nucleoside or nucleotide analogues that inhibit viral reverse transcriptase enzyme and viral replication. Need to be activated by phosphorylation by cellular kinases; Zidovudine is an analogue of thymidine, emtricitabine and lamivudine are analogues of cytidine, abacavir of deoxyguanosine, tenofovir (prodrug) of adenosine	Peripheral neuropathy, lactic acidosis, myelosuppression, anemia, lipodystrophy, renal failure; Tenofovir may decrease bone mineral density; Abacavir may cause hypersensitivity reactions; Didanosine may cause pancreatitis and hepatomegaly
Non-nucleoside reverse transcriptase inhibitors or NNRTIs: Nevirapine, efavirenz, delavirdine, rilpivirine	They bind to viral reverse transcriptase at a site different from nucleoside binding site, and cause an allosteric inhibition of reverse transcriptase	Skin rash, SJS, hepatitis, hepatic failure, prolongation of QTc, cyt P450 interactions; Efavirenz cause delusions, psychosis, vivid dreams, mania
Protease inhibitors or PIs: indinavir, darunavir, atazanavir, nelfinavir, lopinavir etc.	Inhibit HIV protease that is essential for viral maturation and cleavage of gag/pol	Metabolic syndrome, insulin resistance, lipodystrophy, dyslipidemia, CAD, stroke. Atazanavir has fewer adverse effects of carbohydrate metabolism; Indinavir and saquinavir may cause nephrolithiasis
Integrase inhibitors: dolutegravir, elvitegravir and raltegravir	Prevent the formation of covalent bonds between viral and host DNA, thereby inhibits integration of viral DNA with the host DNA	Dizziness, depression, sleep disorders, myopathy, rhabdomyolysis; Dolutegravir causes renal failure, may cause neural tube defects
Fusion inhibitors: enfuvirtide	Bind to viral gp41 and block fusion of viral particle with the host cell, hence preventing the entry of virus into the cell	Peripheral neuropathy, injection site reactions
Chemokine receptor antagonists or CCR5 antagonists: maraviroc	Bind to CCR5 chemokine co-receptor, blocking the interaction of viral gp120 with host cell CCR5, thereby preventing entry of HIV into the cell	Dizziness, skin rashes, hepatotoxicity, caution with cyt P450 affecting drugs

HAART regimens typically include a combination of two NRTIs with one NNRTI or integrase inhibitor or PI. In pregnant patients HAART regimens are composed of two NRTIs plus a PI or integrase inhibitor, to prevent vertical and breast milk transmission. Intrapartum zidovudine is given in the presence of high viral loads >1000 copies/ml at 38 weeks, and is also administered to the newborn as prophylaxis. Lipid profile and blood glucose should be monitored before and after initiation of HAART. Therapy should begin as soon as HIV positivity is detected. Maintaining a plasma HIV RNA viral load of <200 copies/mL, including any measurable value below this threshold value with ART prevents sexual transmission of HIV to sexual partners. Delavirdine, didanosine, indinavir, nelfinavir and stavudine are no longer used due to availability of better drugs, lower potency and increased incidence of adverse effects.