Editing Management of HIV/AIDS (section)

== Classes of medication ==
[[File:HIV-drug-classes.svg|thumb|upright=1.75|Schematic description of the mechanism of the four classes of available antiretroviral drugs against HIV]]

There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the [[retrovirus]] life-cycle that the drug inhibits. Typical combinations include two nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with one non-nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base".<ref name=":0">{{Cite web |title = Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents|date = 2015-04-08|url = https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/what-start-initial-combination-regimens?view=full|ref = DHHS_guidelines|publisher = Clinicalinfo}}</ref>

===Entry inhibitors===
[[Entry inhibitors]] (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. [[Maraviroc]], [[enfuvirtide]] and [[Ibalizumab]] are available agents in this class. Maraviroc works by targeting [[CCR5]], a co-receptor located on human helper T-cells. Caution should be used when administering this drug, however, due to a possible shift in [[HIV tropism|tropism]] which allows HIV to target an alternative co-receptor such as [[CXCR4]].{{citation needed|date=April 2021}} Ibalizumab is effective against both CCR5 and CXCR4 tropic HIV viruses.<ref>{{cite journal | vauthors = Beccari MV, Mogle BT, Sidman EF, Mastro KA, Asiago-Reddy E, Kufel WD | title = Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection | journal = Antimicrobial Agents and Chemotherapy | volume = 63 | issue = 6 | pages = 110=19 | date = June 2019 | pmid = 30885900 | doi = 10.1128/AAC.00110-19 | pmc = 6535568 }}</ref>

In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant.<ref>{{cite journal | vauthors = Lieberman-Blum SS, Fung HB, Bandres JC | title = Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1228–50 | date = July 2008 | pmid = 18691983 | doi = 10.1016/S0149-2918(08)80048-3 }}</ref> To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.<ref>{{cite journal | vauthors = Bai Y, Xue H, Wang K, Cai L, Qiu J, Bi S, Lai L, Cheng M, Liu S, Liu K | title = Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket | journal = Amino Acids | volume = 44 | issue = 2 | pages = 701–13 | date = February 2013 | pmid = 22961335 | doi = 10.1007/s00726-012-1394-8 | s2cid = 18521851 }}</ref>

===Nucleoside/nucleotide reverse-transcriptase inhibitors===
[[Reverse-transcriptase inhibitor|Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI)]] are [[nucleoside]] and [[nucleotide]] [[Structural analog|analogues]] which inhibit reverse transcription. HIV is an RNA virus, so it can not be integrated into the DNA in the nucleus of the human cell unless it is first "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not naturally done in the mammalian cell, it is performed by a viral protein, [[reverse transcriptase]], which makes it a selective target for inhibition. NRTIs are chain terminators. Once NRTIs are incorporated into the DNA chain, their lack of a 3' OH group prevents the subsequent incorporation of other nucleosides. Both NRTIs and NtRTIs act as [[competitive inhibitor|competitive substrate inhibitors]]. Examples of NRTIs include [[zidovudine]], [[abacavir]], [[lamivudine]], [[emtricitabine]], and of NtRTIs – [[tenofovir]] and [[adefovir]].<ref name="Kalyan Das 2013 111-118">{{cite journal | vauthors = Das K, Arnold E | title = HIV-1 reverse transcriptase and antiviral drug resistance. Part 1 | journal = Current Opinion in Virology | volume = 3 | issue = 2 | pages = 111–8 | date = April 2013 | pmid = 23602471 | pmc = 4097814 | doi = 10.1016/j.coviro.2013.03.012 }}</ref>

===Non-nucleoside reverse-transcriptase inhibitors===
[[Reverse-transcriptase inhibitor|Non-nucleoside reverse-transcriptase inhibitors (NNRTI)]] inhibit reverse transcriptase by binding to an [[Allosteric regulation|allosteric site]] of the enzyme; NNRTIs act as [[Non-competitive inhibition|non-competitive inhibitors]] of [[reverse transcriptase]]. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include [[nevirapine]] and [[efavirenz]]. 2nd generation NNRTIs are [[etravirine]] and [[rilpivirine]].<ref name="Kalyan Das 2013 111-118"/> [[Subtypes of HIV#HIV-2|HIV-2]] is intrinsically resistant to NNRTIs.<ref name=":13" />

===Integrase inhibitors===
[[Integrase inhibitor]]s (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme [[integrase]], which is responsible for [[retroviral integration|integration]] of viral DNA into the DNA of the infected cell. There are several integrase inhibitors under clinical trial,{{when|date=January 2021}} and [[raltegravir]] became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg<sup>2+</sup> ions at the metal binding site of integrase. As of early 2022, four other clinically approved integrase inhibitors are [[elvitegravir]], [[dolutegravir]], [[bictegravir]], and [[cabotegravir]].<ref>{{cite book | vauthors = Métifiot M, Marchand C, Pommier Y | chapter = HIV integrase inhibitors: 20-year landmark and challenges  | volume = 67 | pages = 75–105 | year = 2013 | pmid = 23885999 | doi = 10.1016/B978-0-12-405880-4.00003-2 | isbn = 9780124058804 | series = Advances in Pharmacology | title = Antiviral Agents | pmc = 7569752 | chapter-url = https://zenodo.org/record/1258666 }}</ref>

===Protease inhibitors===
[[Protease inhibitor (pharmacology)|Protease inhibitor]]s block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins.<ref name="Wensing AM 2010 59-74">{{cite journal | vauthors = Wensing AM, van Maarseveen NM, Nijhuis M | title = Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance | journal = Antiviral Research | volume = 85 | issue = 1 | pages = 59–74 | date = January 2010 | pmid = 19853627 | doi = 10.1016/j.antiviral.2009.10.003 }}</ref> Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are [[lopinavir]], [[indinavir]], [[nelfinavir]], [[amprenavir]] and [[ritonavir]]. [[Darunavir]] and [[atazanavir]] are recommended as first line therapy choices.<ref name=":0" /> [[Maturation inhibitor]]s have a similar effect by binding to gag, but development of two experimental drugs in this class, [[bevirimat]] and [[vivecon]], was halted in 2010.<ref>{{cite news |url= http://www.AIDSmeds.com/articles/hiv_bevirimat_mpc4326_1667_18528.shtml |title= Myriad Genetics suspends its HIV maturation inhibitor program |work= [[Peter Staley#AIDSmeds.com|AIDSmeds]] |date= 8 June 2012 |access-date= 27 June 2012 |archive-url= https://web.archive.org/web/20150908132831/http://www.aidsmeds.com/articles/hiv_bevirimat_mpc4326_1667_18528.shtml |archive-date= 8 September 2015 |url-status= dead }}</ref> Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.<ref name="Wensing AM 2010 59-74"/>