HIV/AIDS: An Update ________________________________________________________________________
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) NRTIs, used singularly or in combination, can increase CD4 count, decrease viral load, and prolong survival. Sequential monotherapy is followed eventually by clinical failure based on the emergence of drug resistance in HIV. Combinations of two NRTIs result in better viral suppression, more sustained CD4 counts and decreased emergence of resistance. Available NRTI agents include: abacavir (Ziagen, ABC); zidovudine (Retrovir, ZDV, AZT); lamivudine (Epivir, 3TC); and emtric- itabine (Emtriva, FTC) [43]. Tenofovir (Viread, TDF) is often categorized as an NRTI but is actually a nucleotide reverse transcriptase inhibitor [43].
resistant to multiple agents [43]. Because both fusion inhibitors and CCR5 antagonists block HIV from entering CD4 cells, they are sometimes grouped together under the category of entry inhibitors. Integrase Strand Transfer Inhibitors (INSTIs) Integrase strand transfer inhibitors act by preventing the viral DNA from inserting into the host DNA, effectively limiting infection of additional cells and decreasing viral load. INSTIs are approved for use in combination with other antiretrovirals in treatment-experienced and treatment-naïve patients with evi- dence of HIV replication. Available agents include raltegravir (Isentress, RAL, Isentress HD), dolutegravir (Tivicay, DTG, Tivicay PD), and cabotegravir (Vocabria, CAB) [43]. gp120 Attachment Inhibitors In 2020, the FDA approved the first gp120 attachment inhibi- tor, fostemsavir (Rukobia, FTR), for the treatment of HIV in patients whose infection cannot be successfully treated with other therapies because of resistance, intolerance, or safety considerations. Fostemsavir acts by binding to the gp120 protein on the outer surface of the HIV virus, preventing it from entering CD4 cells [58]. Capsid Inhibitors In 2022, the FDA approved lenacapavir (Sunlenca, GS-6207, GS-HIV, GS-CA2, GS-CA1), the first capsid inhibitor, for the treatment of HIV-1 infection in adults for whom other available treatments have failed or are inappropriate due to resistance, intolerance, or safety considerations. These agents directly target virus’ protein shell (the capsid), interfering with multiple essential steps of the viral lifecycle [43]. Post-Attachment Inhibitors Post-attachment inhibitors block CD4 receptors on the surface of certain immune cells that HIV needs to enter the cells. In 2018, the FDA approved ibalizumab (Trogarzo, IBA), the first of its class [43]. Pharmacokinetic Enhancers In an effort to improve the efficacy of other antiretroviral medications in an ART regimen, a pharmacokinetic enhancer may also be included. The agents most commonly used for this purpose are cobicistat and ritonavir (a PI). Both of these agents inhibit cytochrome P450 (CYP) 3A enzymes, prolonging the effects of other medications [43; 47]. However, they are not interchangeable; cobicistat is a more potent inhibitor of CYP [47]. The use of pharmacokinetic enhancers increases systemic exposure of effective antiretroviral medications, allowing for less frequent dosing and a lower pill burden. Multi-Class Combination Products Patient compliance may be improved with therapies that com- bine more than one drug into a single pill, making it easier for patients to comply with their medication regimen. Available oral combination medications include [43]:
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTIs have a high affinity for the active site of HIV-RT. When used as a single agent, this class is associated with rapid emergence of resistance in as little as six weeks. Thus, these drugs should not be used as single agents but are best employed in combination regimens for patients who have not received prior antiretroviral therapy. Available agents include: efavirenz (Sustiva, EFV); doravirine (Pifeltro, DOR); nevirapine (Viramune, NVP; viramune XR); etravirine (Intelence, ETR); and rilpivirine (Edurant, RPV, Endurant PED) [43]. Protease Inhibitors (PIs) Development of mature infectious virus depends upon enzymatic cleavage of HIV transcribed polyprotein by HIV protease. In binding to the active site of the HIV protease, PIs interrupt the formation of mature infectious particles and reduce viral replication by as much as 99%. Resistance to PIs develops rapidly when these agents are used alone. However, in combination with nucleoside analogs the effect can last for years, often resulting in a reduction of viral load to undetectable levels. Available agents include: atazanavir (Reyataz, ATZ); tipranavir (Aptivus, TPV); darunavir (Prezista; DRV); fosamprenavir (Lexiva, FPV); and ritonavir (Norvir, RTV) [43]. Although ritonavir is a PI, it is generally used as a pharmacokinetic enhancer [42; 43]. Fusion Inhibitors (FIs) Enfuvirtide (Fuzeon, T-20), a fusion inhibitor, works by blocking the ability of HIV to infect healthy CD4 cells [43]. When used in combination with other anti-HIV medications, enfuvirtide can reduce the amount of HIV in the blood and increase the number of CD4 cells, slowing the progression of HIV in patients who have developed resistance to currently available medications. CCR5 Antagonists Maraviroc (Selzentry, MVC) is a CCR5 antagonist; it blocks replication of the virus by preventing it from entering nonin- fected CD4 cells via the predominant route of entry, the CCR5 co-receptor. This medication is intended for use in combina- tion with other antiretroviral agents in treatment-experienced patients with evidence of viral replication and HIV-1 strains
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MDCT2026
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