Management of HIV/AIDS#Treatment as prevention

File:HIV-drug-classes.svg

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".{{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}}

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 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.{{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 }}

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.{{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 }} 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.{{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 }}

Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are nucleoside and nucleotide 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 substrate inhibitors. Examples of NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and of NtRTIs – tenofovir and adefovir.{{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 }}

Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as 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. HIV-2 is intrinsically resistant to NNRTIs.

Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for 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 Mg²⁺ ions at the metal binding site of integrase. As of early 2022, four other clinically approved integrase inhibitors are elvitegravir, dolutegravir, bictegravir, and cabotegravir.{{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 }}

Protease inhibitors 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.{{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 }} 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. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010.{{cite news |url= http://www.AIDSmeds.com/articles/hiv_bevirimat_mpc4326_1667_18528.shtml |title= Myriad Genetics suspends its HIV maturation inhibitor program |work= 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 }} Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.

The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells.{{cite journal | vauthors = Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD | title = HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time | journal = Science | volume = 271 | issue = 5255 | pages = 1582–6 | date = March 1996 | pmid = 8599114 | doi = 10.1126/science.271.5255.1582 | citeseerx = 10.1.1.34.7762 | bibcode = 1996Sci...271.1582P | s2cid = 13638059 }} HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made.{{cite journal | vauthors = Smyth RP, Davenport MP, Mak J | title = The origin of genetic diversity in HIV-1 | journal = Virus Research | volume = 169 | issue = 2 | pages = 415–29 | date = November 2012 | pmid = 22728444 | doi = 10.1016/j.virusres.2012.06.015 }}

When antiretroviral drugs are used improperly, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.{{cite journal | vauthors = Schmit JC, Cogniaux J, Hermans P, Van Vaeck C, Sprecher S, Van Remoortel B, Witvrouw M, Balzarini J, Desmyter J, De Clercq E, Vandamme AM | title = Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain | journal = The Journal of Infectious Diseases | volume = 174 | issue = 5 | pages = 962–8 | date = November 1996 | pmid = 8896496 | doi = 10.1093/infdis/174.5.962 | doi-access = free }}

In contrast, antiretroviral combination therapy defends against resistance by creating multiple obstacles to HIV replication. This keeps the number of viral copies low and reduces the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. Combinations usually consist of three drugs from at least two different classes. This three drug combination is commonly known as a triple cocktail.{{cite news | vauthors = Henkel J |title= Attacking AIDS with a 'cocktail' therapy |url= https://www.fda.gov/FDAC/features/1999/499_AIDS.html |archive-url= https://web.archive.org/web/20090114175433/https://www.fda.gov/FDAC/features/1999/499_AIDS.html |archive-date= 2009-01-14 |magazine= FDA Consumer |date=July–August 1999 |publisher= Food and Drug Administration, US Dept. of Health and Human Services}} Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.{{citation needed|date=April 2021}}

Because of HIV's tendency to mutate, when patients who have started an antiretrovial regimen fail to take it regularly, resistance can develop.{{cite journal|vauthors=Bangsberg DR, Kroetz DL, Deeks SG|date=May 2007|title=Adherence-resistance relationships to combination HIV antiretroviral therapy|journal=Current HIV/AIDS Reports|volume=4|issue=2|pages=65–72|doi=10.1007/s11904-007-0010-0|pmid=17547827|s2cid=45429207}} On the other hand, patients who take their medications regularly can stay on one regimen without developing resistance. This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.{{citation needed|date=April 2021}}

File:Antiretroviral Therapy for HIV Infection (27423001115).png promoting the advancement of single-pill antiretroviral drug combinations]]

In 2000, drug companies have worked together to combine these complex regimens into single-pill fixed-dose combinations.{{Cite web|url = http://www.AIDSmap.com/Fixed-dose-combinations/page/1729748/|title = Fixed-dose combinations|date = March 2011|website = Aidsmap|access-date = 2014-04-09 | archive-url=https://web.archive.org/web/20140413144640/http://www.AIDSmap.com/Fixed-dose-combinations/page/1729748/ | archive-date=April 13, 2014| url-status=dead}} More than 20 antiretroviral fixed-dose combinations have been developed. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence),{{cite journal | vauthors = Bangalore S, Kamalakkannan G, Parkar S, Messerli FH | title = Fixed-dose combinations improve medication compliance: a meta-analysis | journal = The American Journal of Medicine | volume = 120 | issue = 8 | pages = 713–9 | date = August 2007 | pmid = 17679131 | doi = 10.1016/j.amjmed.2006.08.033 }} and thus their effectiveness over the long-term.

Although antiretroviral therapy has helped to improve the quality of life of people living with HIV, there is still a need to explore other ways to further address the disease burden. One such potential strategy that was investigated was to add interleukin 2 as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25 randomized controlled trials that were conducted across six countries.{{cite journal | vauthors = Onwumeh J, Okwundu CI, Kredo T | title = Interleukin-2 as an adjunct to antiretroviral therapy for HIV-positive adults | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 5 | pages = CD009818 | date = May 2017 | pmid = 28542796 | pmc = 5458151 | doi = 10.1002/14651858.CD009818.pub2 }} The researchers found that interleukin 2 increases the CD4 immune cells, but does not make a difference in terms of death and incidence of other infections. Furthermore, there is probably an increase in side-effects with interleukin 2. The findings of this review do not support the use of interleukin 2 as an add-on treatment to antiretroviral therapy for adults with HIV.{{citation needed|date=April 2021}}

Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.{{cite journal | vauthors = Darbyshire J | title = Perspectives in drug therapy of HIV infection | journal = Drugs | volume = 49 Suppl 1 | issue = Supplement 1 | pages = 1–3; discussion 38–40 | year = 1995 | pmid = 7614897 | doi = 10.2165/00003495-199500491-00003 | s2cid = 754662 }}

In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs, illustrating the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.{{cite journal | vauthors = Ho DD | title = Time to hit HIV, early and hard | journal = The New England Journal of Medicine | volume = 333 | issue = 7 | pages = 450–1 | date = August 1995 | pmid = 7616996 | doi = 10.1056/NEJM199508173330710 | author-link = David Ho (scientist) }} Later reviews in the late 90s and early 2000s noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression (CD4 counts less than 350/μL).{{cite journal | vauthors = Harrington M, Carpenter CC | title = Hit HIV-1 hard, but only when necessary | journal = Lancet | volume = 355 | issue = 9221 | pages = 2147–52 | date = June 2000 | pmid = 10902643 | doi = 10.1016/S0140-6736(00)02388-6 | s2cid = 22747572 }} Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.{{cite book | vauthors = Sonenklar C |title= AIDS |series= USA Today Health Reports: Diseases and Disorders |year= 2011 |location= Minneapolis, MN |publisher= Twenty-First Century Books |isbn= 9780822585817 |pages= [https://books.google.com/books?id=1TTu5HQS2l4C&pg=PA90 90–101] |chapter= Chapter 6: Treatment for HIV and AIDS}}

The timing of when to start therapy has continued to be a core controversy within the medical community, though recent{{when|date=April 2020}} studies have led to more clarity. The NA-ACCORD{{cite journal | vauthors = Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, Hogg RS, Deeks SG, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Goedert JJ, Benson CA, Collier AC, Van Rompaey SE, Crane HM, McKaig RG, Lau B, Freeman AM, Moore RD | title = Effect of early versus deferred antiretroviral therapy for HIV on survival | journal = The New England Journal of Medicine | volume = 360 | issue = 18 | pages = 1815–26 | date = April 2009 | pmid = 19339714 | pmc = 2854555 | doi = 10.1056/NEJMoa0807252 }} study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death. In 2015 the START{{cite journal | vauthors = Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD | title = Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection | journal = The New England Journal of Medicine | volume = 373 | issue = 9 | pages = 795–807 | date = August 2015 | pmid = 26192873 | pmc = 4569751 | doi = 10.1056/NEJMoa1506816 }} and TEMPRANO{{cite journal | vauthors = Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, Ouassa T, Ouattara E, Anzian A, Ntakpé JB, Minga A, Kouame GM, Bouhoussou F, Emieme A, Kouamé A, Inwoley A, Toni TD, Ahiboh H, Kabran M, Rabe C, Sidibé B, Nzunetu G, Konan R, Gnokoro J, Gouesse P, Messou E, Dohoun L, Kamagate S, Yao A, Amon S, Kouame AB, Koua A, Kouamé E, Ndri Y, Ba-Gomis O, Daligou M, Ackoundzé S, Hawerlander D, Ani A, Dembélé F, Koné F, Guéhi C, Kanga C, Koule S, Séri J, Oyebi M, Mbakop N, Makaila O, Babatunde C, Babatounde N, Bleoué G, Tchoutedjem M, Kouadio AC, Sena G, Yededji SY, Assi R, Bakayoko A, Mahassadi A, Attia A, Oussou A, Mobio M, Bamba D, Koman M, Horo A, Deschamps N, Chenal H, Sassan-Morokro M, Konate S, Aka K, Aoussi E, Journot V, Nchot C, Karcher S, Chaix ML, Rouzioux C, Sow PS, Perronne C, Girard PM, Menan H, Bissagnene E, Kadio A, Ettiegne-Traore V, Moh-Semdé C, Kouame A, Massumbuko JM, Chêne G, Dosso M, Domoua SK, N'Dri-Yoman T, Salamon R, Eholié SP, Anglaret X | title = A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa | journal = The New England Journal of Medicine | volume = 373 | issue = 9 | pages = 808–22 | date = August 2015 | pmid = 26193126 | doi = 10.1056/NEJMoa1507198 | hdl = 10044/1/41218 | hdl-access = free }} studies both showed that patients lived longer if they started antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 counts to drop to a specified level.

Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems,{{cite journal | vauthors = Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M, Martin JN, Deeks SG | title = Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment | journal = Clinical Infectious Diseases | volume = 48 | issue = 6 | pages = 787–94 | date = March 2009 | pmid = 19193107 | pmc = 2720023 | doi = 10.1086/597093 }} and higher CD4 counts are associated with less cancer.{{cite journal | vauthors = Monforte A, Abrams D, Pradier C, Weber R, Reiss P, Bonnet F, Kirk O, Law M, De Wit S, Friis-Møller N, Phillips AN, Sabin CA, Lundgren JD | title = HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies | journal = AIDS | volume = 22 | issue = 16 | pages = 2143–53 | date = October 2008 | pmid = 18832878 | pmc = 2715844 | doi = 10.1097/QAD.0b013e3283112b77 }}

The European Medicines Agency (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection.{{cite press release | title=First long-acting injectable antiretroviral therapy for HIV recommended approval | website=European Medicines Agency (EMA) | date=16 October 2020 | url=https://www.ema.europa.eu/en/news/first-long-acting-injectable-antiretroviral-therapy-hiv-recommended-approval | access-date=16 October 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The two medicines are the first ARVs that come in a long-acting injectable formulation. This means that instead of daily pills, people receive intramuscular injections monthly or every two months.

The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).

A separate argument for starting antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions.{{cite journal | vauthors = Graham SM, Holte SE, Peshu NM, Richardson BA, Panteleeff DD, Jaoko WG, Ndinya-Achola JO, Mandaliya KN, Overbaugh JM, McClelland RS | title = Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding | journal = AIDS | volume = 21 | issue = 4 | pages = 501–7 | date = February 2007 | pmid = 17301569 | doi = 10.1097/QAD.0b013e32801424bd | s2cid = 21335467 | doi-access = free }}{{cite journal | vauthors = Vernazza PL, Troiani L, Flepp MJ, Cone RW, Schock J, Roth F, Boggian K, Cohen MS, Fiscus SA, Eron JJ | title = Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study | journal = AIDS | volume = 14 | issue = 2 | pages = 117–21 | date = January 2000 | pmid = 10708281 | doi = 10.1097/00002030-200001280-00006 | citeseerx = 10.1.1.567.3563 | s2cid = 3035239 }} This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in nine countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early (after 1.7 years) for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group, consistent with a 96% reduction in risk of transmission while on ART. The single transmission in the experimental group occurred early after starting ART before viral load was likely to be suppressed.{{cite journal | vauthors = Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR | title = Prevention of HIV-1 infection with early antiretroviral therapy | journal = The New England Journal of Medicine | volume = 365 | issue = 6 | pages = 493–505 | date = August 2011 | pmid = 21767103 | pmc = 3200068 | doi = 10.1056/NEJMoa1105243 }} Pre-exposure prophylaxis (PrEP) provides HIV-negative individuals with medication—in conjunction with safer-sex education and regular HIV/STI screenings—in order to reduce the risk of acquiring HIV.{{cite journal | vauthors = Cohen MS, Smith MK, Muessig KE, Hallett TB, Powers KA, Kashuba AD | title = Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here? | journal = Lancet | volume = 382 | issue = 9903 | pages = 1515–24 | date = November 2013 | pmid = 24152938 | pmc = 3880570 | doi = 10.1016/S0140-6736(13)61998-4 }} In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.{{cite journal | vauthors = Cohen J | title = Breakthrough of the year. HIV treatment as prevention | journal = Science | volume = 334 | issue = 6063 | pages = 1628 | date = December 2011 | pmid = 22194547 | doi = 10.1126/science.334.6063.1628 | doi-access = free | bibcode = 2011Sci...334.1628C }}

In July 2016 a consensus document was created by the Prevention Access Campaign which has been endorsed by over 400 organisations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV who has been undetectable for a minimum of six months is negligible to non-existent, with negligible being defined as "so small or unimportant to be not worth considering". The Chair of the British HIV Association (BHIVA), Chloe Orkin, stated in July 2017 that 'there should be no doubt about the clear and simple message that a person with sustained, undetectable levels of HIV virus in their blood cannot transmit HIV to their sexual partners.'

Furthermore, the PARTNER study, which ran from 2010 to 2014, enrolled 1166 serodiscordant couples (where one partner is HIV positive and the other is negative) in a study that found that the estimated rate of transmission through any condomless sex with the HIV-positive partner taking ART with an HIV load less than 200 copies/ml was zero.{{cite journal | vauthors = Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, van Lunzen J, Corbelli GM, Estrada V, Geretti AM, Beloukas A, Asboe D, Viciana P, Gutiérrez F, Clotet B, Pradier C, Gerstoft J, Weber R, Westling K, Wandeler G, Prins JM, Rieger A, Stoeckle M, Kümmerle T, Bini T, Ammassari A, Gilson R, Krznaric I, Ristola M, Zangerle R, Handberg P, Antela A, Allan S, Phillips AN, Lundgren J | title = Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy | journal = JAMA | volume = 316 | issue = 2 | pages = 171–81 | date = July 2016 | pmid = 27404185 | doi = 10.1001/jama.2016.5148 | quote = PARTNER (Partners of People on ART—A New Evaluation of the Risks) | url = http://www.zora.uzh.ch/133349/ | doi-access = free }}

In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more effective and more affordable than ever before."{{Cite book|url =https://www.who.int/hiv/pub/guidelines/arv2013/download/en/ | publisher = WHO |title = Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection< |date = June 30, 2013|isbn = 978-92-4-150572-7 |pages = 38}}

There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect. One trial showed higher rates of opportunistic infections, cancers, heart attacks and death in patients who periodically interrupted their ART.{{cite journal | vauthors = El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fätkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C | title = CD4+ count-guided interruption of antiretroviral treatment | journal = The New England Journal of Medicine | volume = 355 | issue = 22 | pages = 2283–96 | date = November 2006 | pmid = 17135583 | doi = 10.1056/NEJMoa062360 | s2cid = 32501272 | url = http://espace.library.uq.edu.au/view/UQ:632671/UQ632671_OA.pdf }}{{cite journal | vauthors = Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, Hidalgo J, Lourtau L, Neaton JD, Tambussi G, Abrams DI | title = Risk of cancers during interrupted antiretroviral therapy in the SMART study | journal = AIDS | volume = 21 | issue = 14 | pages = 1957–63 | date = September 2007 | pmid = 17721103 | doi = 10.1097/QAD.0b013e3282ed6338 | s2cid = 16090838 | doi-access = free }}

There are several treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the US){{cite journal | vauthors = Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, Burger DM, Cahn P, Gallant JE, Glesby MJ, Reiss P, Saag MS, Thomas DL, Jacobsen DM, Volberding PA | title = Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel | journal = JAMA | volume = 312 | issue = 4 | pages = 410–25 | date = 2014-07-23 | pmid = 25038359 | doi = 10.1001/jama.2014.8722 | doi-access = free }} as well as the US government's Department of Health and Human Services guidelines. In Europe there are the European AIDS Clinical Society guidelines.{{Cite web |title=EACS Guidelines 12.0 |url=https://www.eacsociety.org/guidelines/eacs-guidelines/ |access-date=2023-10-20 |website=www.eacsociety.org}}

For resource limited countries, most national guidelines closely follow the World Health Organization (WHO) guidelines.

The guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and his or her doctor.{{citation needed|date=April 2021}}

The US DHHS guidelines (published April 8, 2015) state:{{citation needed|date=September 2022}}

• Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
• ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
• Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

The newest WHO guidelines (dated September 30, 2015) now agree and state:

• Antiretroviral therapy (ART) should be initiated in everyone living with HIV at any CD4 cell count

Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. In countries with a high rate of baseline resistance, resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing.{{Cite book|title = Antiretroviral Resistance in Clinical Practice |publisher = Mediscript|year = 2006|isbn = 978-0-955-16690-7| veditors = Geretti|chapter = 9}} In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.{{cite journal | vauthors = Cane P, Chrystie I, Dunn D, Evans B, Geretti AM, Green H, Phillips A, Pillay D, Porter K, Pozniak A, Sabin C, Smit E, Weber J, Zuckerman M | title = Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study | journal = BMJ | volume = 331 | issue = 7529 | pages = 1368 | date = December 2005 | pmid = 16299012 | pmc = 1309643 | doi = 10.1136/bmj.38665.534595.55 }} In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005.{{cite journal | vauthors = Novak RM, Chen L, MacArthur RD, Baxter JD, Huppler Hullsiek K, Peng G, Xiang Y, Henely C, Schmetter B, Uy J, van den Berg-Wolf M, Kozal M | title = Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy | journal = Clinical Infectious Diseases | volume = 40 | issue = 3 | pages = 468–74 | date = February 2005 | pmid = 15668873 | doi = 10.1086/427212 | doi-access = free }} Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues.{{cite journal | vauthors = Descamps D, Assoumou L, Chaix ML, Chaillon A, Pakianather S, de Rougemont A, Storto A, Dos Santos G, Krivine A, Delaugerre C, Montes B, Izopet J, Charpentier C, Wirden M, Maillard A, Morand-Joubert L, Pallier C, Plantier JC, Guinard J, Tamalet C, Cottalorda J, Marcelin AG, Desbois D, Henquell C, Calvez V, Brun-Vézinet F, Masquelier B, Costagliola D | title = National sentinel surveillance of transmitted drug resistance in antiretroviral-naive chronically HIV-infected patients in France over a decade: 2001-2011 | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 11 | pages = 2626–31 | date = November 2013 | pmid = 23798669 | doi = 10.1093/jac/dkt238 | doi-access = free }}{{cite journal | vauthors = Sungkanuparph S, Pasomsub E, Chantratita W | title = Surveillance of transmitted HIV drug resistance in antiretroviral-naive patients aged less than 25 years, in Bangkok, Thailand | journal = Journal of the International Association of Providers of AIDS Care | volume = 13 | issue = 1 | pages = 12–4 | date = Jan–Feb 2014 | pmid = 23708678 | doi = 10.1177/2325957413488200 | doi-access = free }}{{cite journal | vauthors = Gagliardo C, Brozovich A, Birnbaum J, Radix A, Foca M, Nelson J, Saiman L, Yin M, Carras-Terzian E, West E, Neu N | title = A multicenter study of initiation of antiretroviral therapy and transmitted drug resistance in antiretroviral-naive adolescents and young adults with HIV in New York City | journal = Clinical Infectious Diseases | volume = 58 | issue = 6 | pages = 865–72 | date = March 2014 | pmid = 24429431 | pmc = 3988426 | doi = 10.1093/cid/ciu003 }}{{cite journal | vauthors = Pérez L, Kourí V, Alemán Y, Abrahantes Y, Correa C, Aragonés C, Martínez O, Pérez J, Fonseca C, Campos J, Álvarez D, Schrooten Y, Dekeersmaeker N, Imbrechts S, Beheydt G, Vinken L, Soto Y, Álvarez A, Vandamme AM, Van Laethem K | title = Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba | journal = Infection, Genetics and Evolution | volume = 16 | pages = 144–50 | date = June 2013 | pmid = 23416260 | doi = 10.1016/j.meegid.2013.02.002 | bibcode = 2013InfGE..16..144P }} With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient.{{citation needed|date=April 2021}}

Most HAART regimens consist of three drugs: Two NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.

The US DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are:

• tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
• tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
• abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
• tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
• tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)

Both efavirenz and nevirapine showed similar benefits when combined with NRTI respectively.{{cite journal | vauthors = Mbuagbaw L, Mursleen S, Irlam JH, Spaulding AB, Rutherford GW, Siegfried N | title = Efavirenz or nevirapine in three-drug combination therapy with two nucleoside or nucleotide-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD004246 | date = December 2016 | issue = 12 | pmid = 27943261 | pmc = 5450880 | doi = 10.1002/14651858.CD004246.pub4 | collaboration = Cochrane Infectious Diseases Group }}

In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450 enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day.{{Cite book|title = Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases | edition = 7th |publisher = Churchill Livingstone|year = 2009|isbn = 978-0-443-06839-3|chapter = Antiretroviral Therapy for Human Immunodeficiency Virus Infection|chapter-url = http://www.mdconsult.com/books/linkTo?type=bookPage&isbn=978-0-443-06839-3&eid=4-u1.0-B978-0-443-06839-3..00128-4--s0080}} Cobicistat is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself.{{cite journal | vauthors = Lepist EI, Phan TK, Roy A, Tong L, Maclennan K, Murray B, Ray AS | title = Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 10 | pages = 5409–13 | date = October 2012 | pmid = 22850510 | pmc = 3457391 | doi = 10.1128/AAC.01089-12 }}

The WHO preferred initial regimen for adults and adolescents as of June 30, 2013, is:

• tenofovir + lamivudine (or emtricitabine) + efavirenz

In the first six months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on viral reservoirs). The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.{{cite journal | vauthors = Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, Rees H, Fisher M, Schechter M, Kaleebu P, Tambussi G, Kinloch S, Miro JM, Kelleher A, McClure M, Kaye S, Gabriel M, Phillips R, Weber J, Babiker A | title = Short-course antiretroviral therapy in primary HIV infection | journal = The New England Journal of Medicine | volume = 368 | issue = 3 | pages = 207–17 | date = January 2013 | pmid = 23323897 | pmc = 4131004 | doi = 10.1056/NEJMoa1110039 }}

Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission.{{cite journal | vauthors = Hollingsworth TD, Anderson RM, Fraser C | title = HIV-1 transmission, by stage of infection | journal = The Journal of Infectious Diseases | volume = 198 | issue = 5 | pages = 687–93 | date = September 2008 | pmid = 18662132 | doi = 10.1086/590501 | doi-access = free | hdl = 10044/1/4267 | hdl-access = free }} By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on treatment as prevention). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS.

HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2.{{cite journal | vauthors = Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F | title = Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis | journal = Lancet | volume = 364 | issue = 9441 | pages = 1236–43 | date = October 8, 2004 | pmid = 15464184 | doi = 10.1016/S0140-6736(04)17140-7 | s2cid = 24511465 }} By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml. DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms.{{Cite web |url = http://AIDSinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf |title = Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection|date = February 12, 2014|access-date = April 11, 2014|publisher = US Department of Health and Human Services|pages = 50–61}}

As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of nevirapine (an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance.{{cite journal | vauthors = Musiime V, Ssali F, Kayiwa J, Namala W, Kizito H, Kityo C, Mugyenyi P | title = Response to nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-infected children with perinatal exposure to single-dose nevirapine | journal = AIDS Research and Human Retroviruses | volume = 25 | issue = 10 | pages = 989–96 | date = October 2009 | pmid = 19778270 | doi = 10.1089/aid.2009.0054 }} Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past.{{cite journal | vauthors = Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P | title = Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children | journal = The New England Journal of Medicine | volume = 366 | issue = 25 | pages = 2380–9 | date = June 2012 | pmid = 22716976 | pmc = 3443859 | doi = 10.1056/NEJMoa1113249 }} Thus the WHO recommends PI based regimens for children less than 3.

The WHO recommends for children less than 3 years:

• abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir

and for children 3 years to less than 10 years and adolescents <35 kilograms:

• abacavir + lamivudine + efavirenz

US DHHS guidelines are similar but include PI based options for children > 3 years old.

A systematic review assessed the effects and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years of age when compared to regimens with other NRTIs.{{cite journal | vauthors = Adetokunboh OO, Schoonees A, Balogun TA, Wiysonge CS | title = Efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV infected children and adolescents: a systematic review and meta-analysis | journal = BMC Infectious Diseases | volume = 15 | issue = 1 | pages = 469 | date = October 2015 | pmid = 26502899 | pmc = 4623925 | doi = 10.1186/s12879-015-1183-6 | doi-access = free }} This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and adverse events. The authors found that there is no meaningful difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence is of low to moderate quality and therefore it is likely that future research may change these findings.{{citation needed|date=April 2021}}

{{Main|HIV and pregnancy|Breastfeeding by HIV infected mothers}}

The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%.{{cite journal | vauthors = Garcia PM, Kalish LA, Pitt J, Minkoff H, Quinn TC, Burchett SK, Kornegay J, Jackson B, Moye J, Hanson C, Zorrilla C, Lew JF | title = Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group | journal = The New England Journal of Medicine | volume = 341 | issue = 6 | pages = 394–402 | date = August 1999 | pmid = 10432324 | doi = 10.1056/NEJM199908053410602 | doi-access = free }} The risk when viral loads are < 1000 copies/ml are less than 1%.{{cite journal | title = Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy | journal = Clinical Infectious Diseases | volume = 40 | issue = 3 | pages = 458–65 | date = February 2005 | pmid = 15668871 | doi = 10.1086/427287 | author1 = European Collaborative Study | doi-access = free | hdl = 11577/2435265 | hdl-access = free }} ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission.{{Cite web|url = http://AIDSinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf|title = Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States|date = March 28, 2014|access-date = 2014-04-11|publisher = US DHHS}} The mode of delivery is also important, with a planned Caesarian section having a lower risk than vaginal delivery or emergency Caesarian section.

HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding.{{cite journal | vauthors = Rousseau CM, Nduati RW, Richardson BA, Steele MS, John-Stewart GC, Mbori-Ngacha DA, Kreiss JK, Overbaugh J | title = Longitudinal analysis of human immunodeficiency virus type 1 RNA in breast milk and of its relationship to infant infection and maternal disease | journal = The Journal of Infectious Diseases | volume = 187 | issue = 5 | pages = 741–7 | date = March 2003 | pmid = 12599047 | pmc = 3384731 | doi = 10.1086/374273 }} The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, pneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART. In the US, the DHHS recommends against women with HIV breastfeeding.

With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy.{{cite journal | vauthors = May MT, Gompels M, Delpech V, Porter K, Orkin C, Kegg S, Hay P, Johnson M, Palfreeman A, Gilson R, Chadwick D, Martin F, Hill T, Walsh J, Post F, Fisher M, Ainsworth J, Jose S, Leen C, Nelson M, Anderson J, Sabin C | title = Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy | journal = AIDS | volume = 28 | issue = 8 | pages = 1193–202 | date = May 2014 | pmid = 24556869 | pmc = 4004637 | doi = 10.1097/QAD.0000000000000243 }}{{cite journal | vauthors = Nakagawa F, May M, Phillips A | title = Life expectancy living with HIV: recent estimates and future implications | journal = Current Opinion in Infectious Diseases | volume = 26 | issue = 1 | pages = 17–25 | date = February 2013 | pmid = 23221765 | doi = 10.1097/QCO.0b013e32835ba6b1 | s2cid = 7554571 | doi-access = free }} This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels.{{cite journal | vauthors = Silverberg MJ, Leyden W, Horberg MA, DeLorenze GN, Klein D, Quesenberry CP | title = Older age and the response to and tolerability of antiretroviral therapy | journal = Archives of Internal Medicine | volume = 167 | issue = 7 | pages = 684–91 | date = April 2007 | pmid = 17420427 | doi = 10.1001/archinte.167.7.684 | doi-access = free }} However, not all studies have seen a difference in response to therapy.{{cite journal | vauthors = Althoff KN, Justice AC, Gange SJ, Deeks SG, Saag MS, Silverberg MJ, Gill MJ, Lau B, Napravnik S, Tedaldi E, Klein MB, Gebo KA | title = Virologic and immunologic response to HAART, by age and regimen class | journal = AIDS | volume = 24 | issue = 16 | pages = 2469–79 | date = October 2010 | pmid = 20829678 | pmc = 3136814 | doi = 10.1097/QAD.0b013e32833e6d14 }} The guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications.{{cite journal | vauthors = Greene M, Justice AC, Lampiris HW, Valcour V | title = Management of human immunodeficiency virus infection in advanced age | journal = JAMA | volume = 309 | issue = 13 | pages = 1397–405 | date = April 2013 | pmid = 23549585 | pmc = 3684249 | doi = 10.1001/jama.2013.2963 }} There are also increased rates of HIV associated non-AIDS conditions (HANA) such as heart disease, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like hepatitis B, hepatitis C, and human papilloma virus (HPV) as well as HIV treatment.

Many factors may contribute to depression in adults living with HIV, such as the effects of the virus on the brain, other infections or tumours, antiretroviral drugs and other medical treatment.{{cite journal | vauthors = Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA | title = Antidepressants for depression in adults with HIV infection | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD008525 | date = January 2018 | pmid = 29355886 | pmc = 6491182 | doi = 10.1002/14651858.CD008525.pub3 }} Rates of major depression are higher in people living with HIV compared to the general population, and this may negatively influence antiretroviral treatment. In a systematic review, Cochrane researchers assessed whether giving antidepressants to adults living with both HIV and depression may improve depression. Ten trials, of which eight were done in high-income countries, with 709 participants were included. Results indicated that antidepressants may be better in improving depression compared to placebo, but the quality of the evidence is low and future research is likely to impact on the findings.{{citation needed|date=April 2021}}

There are several concerns about antiretroviral regimens that should be addressed before initiating:

• Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly.
• Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance.{{cite journal | vauthors = Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR | title = Antiretroviral medication adherence and the development of class-specific antiretroviral resistance | journal = AIDS | volume = 23 | issue = 9 | pages = 1035–46 | date = June 2009 | pmid = 19381075 | pmc = 2704206 | doi = 10.1097/QAD.0b013e32832ba8ec }}
• Cost: The WHO maintains a database of world ART costs{{Cite web|url =https://www.who.int/hiv/amds/gprm/en/|archive-url =https://web.archive.org/web/20060520235424/http://www.who.int/hiv/amds/gprm/en/|url-status =dead|archive-date =May 20, 2006|title = Global Price Reporting Mechanism for HIV, tuberculosis and malaria|access-date = 2014-04-11|publisher = World Health Organization}} which have dropped dramatically in recent{{when|date=April 2020}} years as more first line drugs have gone off-patent.{{Cite web|url = http://www.avert.org/antiretroviral-drug-prices.htm|title = Antiretroviral Drug Prices|access-date = 2014-04-12|publisher = Avert}} A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month.{{Cite web|url = http://www.rawstory.com/rs/2013/04/08/new-one-pill-10-per-month-anti-retroviral-AIDS-treatment-debuts-in-south-africa/|title = New one-pill, $10-per-month anti-retroviral AIDS treatment debuts in South Africa|date = 2013|website = The Raw Story|publisher = Agence France-Presse|access-date = 2019-06-02|archive-date = 2014-04-16|archive-url = https://web.archive.org/web/20140416182904/http://www.rawstory.com/rs/2013/04/08/new-one-pill-10-per-month-anti-retroviral-aids-treatment-debuts-in-south-africa/|url-status = dead}} One 2013 study estimated an overall cost savings to ART therapy in South Africa given reduced transmission.{{cite journal | vauthors = Walensky RP, Ross EL, Kumarasamy N, Wood R, Noubary F, Paltiel AD, Nakamura YM, Godbole SV, Panchia R, Sanne I, Weinstein MC, Losina E, Mayer KH, Chen YQ, Wang L, McCauley M, Gamble T, Seage GR, Cohen MS, Freedberg KA | title = Cost-effectiveness of HIV treatment as prevention in serodiscordant couples | journal = The New England Journal of Medicine | volume = 369 | issue = 18 | pages = 1715–25 | date = October 2013 | pmid = 24171517 | pmc = 3913536 | doi = 10.1056/NEJMsa1214720 }} In the United States, new on-patent regimens can cost up to $28,500 per patient, per year.{{Cite web|url = http://www.aidsmeds.com/articles/hiv_stribild_cost_1667_22878.shtml|title = Activists Protest Stribild's $28,500 Price Tag|date = August 28, 2012|access-date = 2014-04-11|vauthors = Horn T|website = AIDSMeds|archive-date = 2014-04-14|archive-url = https://web.archive.org/web/20140414205159/http://www.aidsmeds.com/articles/hiv_stribild_cost_1667_22878.shtml|url-status = dead}}{{Cite web|url = http://www.goodrx.com/stribild|title = Stribild|access-date = 2014-04-11|website = GoodRx}}
• Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others.{{cite journal | vauthors = Beardsley T | title = Coping with HIV's ethical dilemmas | journal = Scientific American | volume = 279 | issue = 1 | pages = 106–7 | date = July 1998 | pmid = 9648307 | doi = 10.1038/scientificamerican0798-106 | bibcode = 1998SciAm.279a.106B }}

Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART. This should happen by 24 weeks after starting combination therapy.{{cite journal | vauthors = Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, Eron JJ, Günthard HF, Hammer SM, Reiss P, Richman DD, Rizzardini G, Thomas DL, Jacobsen DM, Volberding PA | title = Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel | journal = JAMA | volume = 308 | issue = 4 | pages = 387–402 | date = July 2012 | pmid = 22820792 | doi = 10.1001/jama.2012.7961 | s2cid = 205038135 }} Viral load monitoring is the most important predictor of response to treatment with ART.{{cite journal | vauthors = Murray JS, Elashoff MR, Iacono-Connors LC, Cvetkovich TA, Struble KA | title = The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs | journal = AIDS | volume = 13 | issue = 7 | pages = 797–804 | date = May 1999 | pmid = 10357378 | doi = 10.1097/00002030-199905070-00008 | doi-access = free }} Lack of viral load suppression on ART is termed virologic failure. Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance.

Research has shown that people with an undetectable viral load are unable to transmit the virus through condomless sex with a partner of either gender. The 'Swiss Statement' of 2008 described the chance of transmission as 'very low' or 'negligible,'{{cite web |publisher=HIV i-Base |title=The Swiss statement |url=http://i-base.info/qa/factsheets/the-swiss-statement |date=15 October 2016 |author=Swiss National AIDS Commission |access-date=2 April 2019}} but multiple studies have since shown that this mode of sexual transmission is impossible where the HIV-positive person has a consistently undetectable viral load. This discovery has led to the formation of the Prevention Access Campaign are their 'U=U' or 'Undetectable=Untransmittable' public information strategy,{{cite journal | title = U=U taking off in 2017 | journal = The Lancet. HIV | volume = 4 | issue = 11 | pages = e475 | date = November 2017 | pmid = 29096785 | doi = 10.1016/S2352-3018(17)30183-2 | department = Editorial | doi-access = free |last1 = The Lancet Hiv}}{{cite web |publisher=Terrence Higgins Trust |year=2019 |title=Can't Pass It On |url=https://www.tht.org.uk/our-work/our-campaigns/cant-pass-it-on |access-date=2 April 2019 |archive-url=https://web.archive.org/web/20190407233322/https://www.tht.org.uk/our-work/our-campaigns/cant-pass-it-on |archive-date=7 April 2019 |url-status=live}} an approach that has gained widespread support amongst HIV/AIDS-related medical, charitable, and research organisations. The studies demonstrating that U=U is an effective strategy for preventing HIV transmission in serodiscordant couples so long as "the partner living with HIV [has] a durably suppressed viral load" include: Opposites Attract,{{cite journal | vauthors = Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, Jin F, Fairley CK, Moore R, Roth N, Bloch M, Pell C, McNulty AM, Baker D, Hoy J, Tee BK, Templeton DJ, Cooper DA, Emery S, Kelleher A, Grulich AE | title = Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study | journal = The Lancet. HIV | volume = 5 | issue = 8 | pages = e438–e447 | date = August 2018 | pmid = 30025681 | doi = 10.1016/S2352-3018(18)30132-2 | s2cid = 51702998 }} PARTNER 1, PARTNER 2,{{cite conference |author=Rodger, A. (for the PARTNER study group) |title=Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: The PARTNER2 Study extended results in gay men |conference=AIDS2018: 22nd International AIDS Conference |location=Amsterdam, the Netherlands |date=July 2018 |url=https://programme.aids2018.org/Abstract/Abstract/13470 |access-date=2 April 2019 |archive-date=27 November 2021 |archive-url=https://web.archive.org/web/20211127110959/https://programme.aids2018.org/Abstract/Abstract/13470 |url-status=dead }} (for male–male couples) and HPTN052{{cite journal | vauthors = Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Cottle L, Zhang XC, Makhema J, Mills LA, Panchia R, Faesen S, Eron J, Gallant J, Havlir D, Swindells S, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano DD, Essex M, Hudelson SE, Redd AD, Fleming TR | title = Antiretroviral Therapy for the Prevention of HIV-1 Transmission | journal = The New England Journal of Medicine | volume = 375 | issue = 9 | pages = 830–9 | date = September 2016 | pmid = 27424812 | pmc = 5049503 | doi = 10.1056/NEJMoa1600693 | author-link1 = Myron S. Cohen | doi-access = free }} (for heterosexual couples). In these studies, couples where one partner was HIV-positive and one partner was HIV-negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported, there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load.{{cite conference |date=17 November 2017 |title=U=U: Talking to patients about transmission risk |url=https://www.bhiva.org/file/iGHaSOpwVeAQY/MatthewHodson.pdf |conference=British HIV Association Autumn Conference 2017 |access-date=3 May 2019 |vauthors=Hodson M}} ([https://www.bhiva.org/171117MatthewHodson abstract] for presentation on behalf of NAM / AIDSmap) Following this the U=U consensus statement advocating the use of 'zero risk' was signed by hundreds of individuals and organisations including the US CDC, British HIV Association and The Lancet medical journal.{{cite web |publisher=Prevention Access Campaign |title=Consensus statement: Risk of Sexual Transmission of HIV from a Person Living with HIV who has an Undetectable Viral Load |url=https://www.preventionaccess.org/consensus |date=21 July 2016 |access-date=2 April 2019}} Note: When the statement and list of endorsements was retrieved, it had last been updated on 23 August 2018 and included "over 850 organizations from nearly 100 countries." The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust as "impossible to overstate", while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable ... can help end the HIV pandemic by preventing HIV transmission."{{cite news|title = End to AIDS in sight as huge study finds drugs stop HIV transmission|first1 = Sarah|last1 = Boseley|first2 = Hannah|last2 = Devlin |author-link2 = Hannah Devlin|date = 3 May 2019|newspaper = The Guardian|access-date = 3 May 2019|url = https://www.theguardian.com/society/2019/may/02/end-to-AIDS-in-sight-as-huge-study-finds-drugs-stop-hiv-transmission}} The authors summarised their findings in The Lancet as follows:{{cite journal | vauthors = Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, Corbelli GM, Estrada V, Geretti AM, Beloukas A, Raben D, Coll P, Antinori A, Nwokolo N, Rieger A, Prins JM, Blaxhult A, Weber R, Van Eeden A, Brockmeyer NH, Clarke A, Del Romero Guerrero J, Raffi F, Bogner JR, Wandeler G, Gerstoft J, Gutiérrez F, Brinkman K, Kitchen M, Ostergaard L, Leon A, Ristola M, Jessen H, Stellbrink HJ, Phillips AN, Lundgren J | title = Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study | journal = Lancet | volume = 393| issue = 10189| pages = 2428–2438 | date = May 2019 | pmid = 31056293 | pmc = 6584382 | doi = 10.1016/S0140-6736(19)30418-0 | doi-access = free }}

{{blockquote|text = Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.}}

This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, that U=U is an effective HIV prevention method when an undetectable viral load is maintained.{{cite journal | vauthors = Eisinger RW, Dieffenbach CW, Fauci AS | title = HIV Viral Load and Transmissibility of HIV Infection: Undetectable Equals Untransmittable | journal = JAMA | volume = 321 | issue = 5 | pages = 451–452 | date = February 2019 | pmid = 30629090 | doi = 10.1001/jama.2018.21167 | s2cid = 58599661 | author-link3 = Anthony S. Fauci }}{{cite press release|title = The science is clear: with HIV, undetectable equals untransmittable|date = 10 January 2019|first = Hillary|last = Hoffman |agency = National Institute of Allergy and Infectious Diseases|publisher = National Institutes of Health|url = https://www.nih.gov/news-events/news-releases/science-clear-hiv-undetectable-equals-untransmittable|access-date = 3 May 2019|quote = NIAID Director Anthony S. Fauci, M.D., and colleagues summarize results from large clinical trials and cohort studies validating U=U. The landmark NIH-funded HPTN 052 clinical trial showed that no linked HIV transmissions occurred among HIV serodifferent heterosexual couples when the partner living with HIV had a durably suppressed viral load. Subsequently, the PARTNER and Opposites Attract studies confirmed these findings and extended them to male–male couples. ... The success of U=U as an HIV prevention method depends on achieving and maintaining an undetectable viral load by taking ART daily as prescribed.}}

CD4 cell counts are another key measure of immune status and ART effectiveness. CD4 counts should rise 50 to 100 cells per ml in the first year of therapy. There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concomitant infections.{{cite journal | vauthors = Hughes MD, Stein DS, Gundacker HM, Valentine FT, Phair JP, Volberding PA | title = Within-subject variation in CD4 lymphocyte count in asymptomatic human immunodeficiency virus infection: implications for patient monitoring | journal = The Journal of Infectious Diseases | volume = 169 | issue = 1 | pages = 28–36 | date = January 1994 | pmid = 7903975 | doi = 10.1093/infdis/169.1.28 }} In one long-term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts.{{cite journal | vauthors = Lok JJ, Bosch RJ, Benson CA, Collier AC, Robbins GK, Shafer RW, Hughes MD | title = Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection | journal = AIDS | volume = 24 | issue = 12 | pages = 1867–76 | date = July 2010 | pmid = 20467286 | pmc = 3018341 | doi = 10.1097/QAD.0b013e32833adbcf }} When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen.{{cite journal | vauthors = Gazzola L, Tincati C, Bellistrì GM, Monforte A, Marchetti G | title = The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: clinical risk, immunological gaps, and therapeutic options | journal = Clinical Infectious Diseases | volume = 48 | issue = 3 | pages = 328–37 | date = February 2009 | pmid = 19123868 | doi = 10.1086/695852 }}

Innate lymphoid cells (ILC) are another class of immune cell that is depleted during HIV infection. However, if ART is initiated before this depletion at around 7 days post infection, ILC levels can be maintained. While CD4 cell counts typically replenish after effective ART, ILCs depletion is irreversible with ART initiated after the depletion despite suppression of viremia.{{cite journal | vauthors = Kløverpris HN, Kazer SW, Mjösberg J, Mabuka JM, Wellmann A, Ndhlovu Z, Yadon MC, Nhamoyebonde S, Muenchhoff M, Simoni Y, Andersson F, Kuhn W, Garrett N, Burgers WA, Kamya P, Pretorius K, Dong K, Moodley A, Newell EW, Kasprowicz V, Abdool Karim SS, Goulder P, Shalek AK, Walker BD, Ndung'u T, Leslie A | title = Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression | journal = Immunity | volume = 44 | issue = 2 | pages = 391–405 | date = February 2016 | pmid = 26850658 | pmc = 6836297 | doi = 10.1016/j.immuni.2016.01.006 }} Since one of the roles of ILCs is to regulate the immune response to commensal bacteria and to maintain an effective gut barrier,{{cite journal | vauthors = Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D | title = Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria | journal = Science | volume = 336 | issue = 6086 | pages = 1321–5 | date = June 2012 | pmid = 22674331 | pmc = 3659421 | doi = 10.1126/science.1222551 | bibcode = 2012Sci...336.1321S }} it has been hypothesized that the irreversible depletion of ILCs plays a role in the weakened gut barrier of HIV patients, even after successful ART.{{cite journal | vauthors = Chung CY, Alden SL, Funderburg NT, Fu P, Levine AD | title = Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals | journal = PLOS Pathogens | volume = 10 | issue = 6 | pages = e1004198 | date = June 2014 | pmid = 24968145 | pmc = 4072797 | doi = 10.1371/journal.ppat.1004198 | doi-access = free }}

In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a genotype is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy.{{Cite web|url = http://hivdb.stanford.edu/|title = Stanford University HIV Drug Resistance Database|access-date = 2014-04-13}} Resistance testing may improve virological outcomes in those who have treatment failures. However, there is lack of evidence of effectiveness of such testing in those who have not done any treatment before.{{cite journal | vauthors = Aves T, Tambe J, Siemieniuk RA, Mbuagbaw L | title = Antiretroviral resistance testing in HIV-positive people | journal = The Cochrane Database of Systematic Reviews | volume = 11 | pages = CD006495 | date = November 2018 | issue = 11 | pmid = 30411789 | doi = 10.1002/14651858.CD006495.pub5 | collaboration = Cochrane Infectious Diseases Group | pmc = 6517236 }}

If there is extensive resistance a phenotypic test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred. Using information from a genotype or phenotype, a regimen of three drugs from at least two classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed salvage therapy, and when six or more drugs are needed it is termed mega-HAART.{{cite journal | vauthors = Miller V, Cozzi-Lepri A, Hertogs K, Gute P, Larder B, Bloor S, Klauke S, Rabenau H, Phillips A, Staszewski S | title = HIV drug susceptibility and treatment response to mega-HAART regimen in patients from the Frankfurt HIV cohort | journal = Antiviral Therapy | volume = 5 | issue = 1 | pages = 49–55 | date = March 2000 | doi = 10.1177/135965350000500113 | pmid = 10846593 | s2cid = 33402816 | doi-access = free }}

Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays.{{cite journal | vauthors = Simon V, Ho DD, Abdool Karim Q | title = HIV/AIDS epidemiology, pathogenesis, prevention, and treatment | journal = Lancet | volume = 368 | issue = 9534 | pages = 489–504 | date = August 2006 | pmid = 16890836 | pmc = 2913538 | doi = 10.1016/S0140-6736(06)69157-5 }} With the exception of post-exposure prophylaxis (PEP), treatment guidelines do not call for the interruption of drug therapy once it has been initiated.

Each class and individual antiretroviral carries unique risks of adverse side effects.

The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy. First-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.{{cite journal | vauthors = Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, Johnson KA | title = Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 44 | pages = 40847–57 | date = November 2001 | pmid = 11526116 | doi = 10.1074/jbc.M106743200 | doi-access = free }}{{cite journal | vauthors = Birkus G, Hitchcock MJ, Cihlar T | title = Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 3 | pages = 716–23 | date = March 2002 | pmid = 11850253 | pmc = 127499 | doi = 10.1128/aac.46.3.716-723.2002 }}

Mitochondrial Haplogroups(mtDNA), non pathologic mutations inherited from the maternal line, have been linked to the efficacy of CD4+ count following ART.{{cite journal | vauthors = Hulgan T, Robbins GK, Kalams SA, Samuels DC, Grady B, Shafer R, Murdock DG, Selph D, Haas DW, Pollard RB | title = T cell activation markers and African mitochondrial DNA haplogroups among non-Hispanic black participants in AIDS clinical trials group study 384 | journal = PLOS ONE | volume = 7 | issue = 8 | pages = e43803 | date = 27 August 2012 | pmid = 22970105 | pmc = 3433792 | doi = 10.1371/journal.pone.0043803 | doi-access = free | bibcode = 2012PLoSO...743803H }}{{cite journal | vauthors = Guzmán-Fulgencio M, Berenguer J, Micheloud D, Fernández-Rodríguez A, García-Álvarez M, Jiménez-Sousa MA, Bellón JM, Campos Y, Cosín J, Aldámiz-Echevarría T, Catalán P, López JC, Resino S | title = European mitochondrial haplogroups are associated with CD4+ T cell recovery in HIV-infected patients on combination antiretroviral therapy | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 10 | pages = 2349–2357 | date = October 2013 | pmid = 23749950 | doi = 10.1093/jac/dkt206 | doi-access = free | hdl = 20.500.12105/10623 | hdl-access = free }}{{cite journal | vauthors = Hart AB, Samuels DC, Hulgan T | title = The other genome: a systematic review of studies of mitochondrial DNA haplogroups and outcomes of HIV infection and antiretroviral therapy | journal = AIDS Reviews | volume = 15 | issue = 4 | pages = 213–220 | date = October 2013 | pmid = 24322381 | pmc = 4001077 }}Mitochondrial haplogroup H is related to CD4+ T cell recovery in HIV infected patients starting combination antiretroviral therapy Idiosyncratic toxicity with mtDNA haplogroup is also well studied (Boeisteril et al., 2007).{{cite journal | vauthors = Boelsterli UA, Lim PL | title = Mitochondrial abnormalities--a link to idiosyncratic drug hepatotoxicity? | journal = Toxicology and Applied Pharmacology | volume = 220 | issue = 1 | pages = 92–107 | date = April 2007 | pmid = 17275868 | doi = 10.1016/j.taap.2006.12.013 | bibcode = 2007ToxAP.220...92B }}

NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts.{{cite journal | vauthors = Usach I, Melis V, Peris JE | title = Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability | journal = Journal of the International AIDS Society | volume = 16 | issue = 1 | pages = 18567 | date = September 2013 | pmid = 24008177 | pmc = 3764307 | doi = 10.7448/ias.16.1.18567 }}

Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.{{cite journal | vauthors = Walmsley S | title = Protease inhibitor-based regimens for HIV therapy: safety and efficacy | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 45 Suppl 1 | issue = Supplement 1 | pages = S5–13; quiz S28–31 | date = June 2007 | pmid = 17525691 | doi = 10.1097/QAI.0b013e3180600709 | s2cid = 3113311 | doi-access = free }}

Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy.{{cite journal | vauthors = Lee FJ, Carr A | title = Tolerability of HIV integrase inhibitors | journal = Current Opinion in HIV and AIDS | volume = 7 | issue = 5 | pages = 422–8 | date = September 2012 | pmid = 22886031 | doi = 10.1097/COH.0b013e328356682a | s2cid = 29497910 }}

{{Further|Post-exposure prophylaxis#HIV}}

When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with mucous membranes or contact with damaged skin, they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3%{{cite journal | vauthors = Bell DM | title = Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview | journal = The American Journal of Medicine | volume = 102 | issue = 5B | pages = 9–15 | date = May 1997 | pmid = 9845490 | doi = 10.1016/s0002-9343(97)89441-7 }} and mucous membrane exposures 0.63%.{{cite journal | vauthors = Ippolito G, Puro V, De Carli G | title = The risk of occupational human immunodeficiency virus infection in health care workers. Italian Multicenter Study. The Italian Study Group on Occupational Risk of HIV infection | journal = Archives of Internal Medicine | volume = 153 | issue = 12 | pages = 1451–8 | date = June 1993 | pmid = 8512436 | doi = 10.1001/archinte.1993.00410120035005 }} United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody."{{cite journal | vauthors = Kuhar DT, Henderson DK, Struble KA, Heneine W, Thomas V, Cheever LW, Gomaa A, Panlilio AL | title = Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis | journal = Infection Control and Hospital Epidemiology | volume = 34 | issue = 9 | pages = 875–92 | date = September 2013 | pmid = 23917901 | doi = 10.1086/672271 | author9 = US Public Health Service Working Group | jstor = 672271 | s2cid = 17032413 | url = https://zenodo.org/record/1235708 }} Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission.{{cite journal | vauthors = Cardo DM, Culver DH, Ciesielski CA, Srivastava PU, Marcus R, Abiteboul D, Heptonstall J, Ippolito G, Lot F, McKibben PS, Bell DM | title = A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group | journal = The New England Journal of Medicine | volume = 337 | issue = 21 | pages = 1485–90 | date = November 1997 | pmid = 9366579 | doi = 10.1056/NEJM199711203372101 | doi-access = free }} It is unknown if three medications are better than two. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to a week after exposure. They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions." People who are exposed to HIV should have follow up HIV testing at 6, 12, and 24 weeks.{{citation needed|date=April 2021}}

{{Further|HIV and pregnancy}}

Women with HIV have been shown to have decreased fertility which can affect available reproductive options.{{cite journal | vauthors = Glynn JR, Buvé A, Caraël M, Kahindo M, Macauley IB, Musonda RM, Jungmann E, Tembo F, Zekeng L | title = Decreased fertility among HIV-1-infected women attending antenatal clinics in three African cities | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 25 | issue = 4 | pages = 345–52 | date = December 2000 | pmid = 11114835 | doi = 10.1097/00126334-200012010-00008 | s2cid = 22980353 | doi-access = free }} In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man has achieved an undetectable plasma viral load.{{cite journal | vauthors = Savasi V, Mandia L, Laoreti A, Cetin I | title = Reproductive assistance in HIV serodiscordant couples | journal = Human Reproduction Update | volume = 19 | issue = 2 | pages = 136–50 | year = 2012 | pmid = 23146867 | doi = 10.1093/humupd/dms046 | doi-access = free }} In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination,{{cite journal | title = HIV-1 infection and artificial insemination with processed semen | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 39 | issue = 15 | pages = 249, 255–6 | date = April 1990 | pmid = 2109169 | author1 = Centers for Disease Control (CDC) }} but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission.{{cite journal | vauthors = Savasi V, Ferrazzi E, Lanzani C, Oneta M, Parrilla B, Persico T | title = Safety of sperm washing and ART outcome in 741 HIV-1-serodiscordant couples | journal = Human Reproduction | volume = 22 | issue = 3 | pages = 772–7 | date = March 2007 | pmid = 17107974 | doi = 10.1093/humrep/del422 | doi-access = free }}

For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination. With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%.{{cite journal | vauthors = Coutsoudis A, Kwaan L, Thomson M | title = Prevention of vertical transmission of HIV-1 in resource-limited settings | journal = Expert Review of Anti-Infective Therapy | volume = 8 | issue = 10 | pages = 1163–75 | date = October 2010 | pmid = 20954881 | doi = 10.1586/eri.10.94 | s2cid = 46624541 }}

Several buyers clubs sprang up since 1986 to combat HIV. The drug zidovudine (AZT), a nucleoside reverse-transcriptase inhibitor (NRTI), was not effective on its own. It was approved by the US FDA in 1987.{{Cite web|url = https://www.nytimes.com/1987/03/21/us/us-approves-drug-to-prolong-lives-of-aids-patients.html|title = U.S Approves Drug to Prolong Lives of AIDS Patients|date = 1987-03-21|work = New York Times}} The FDA bypassed stages of its review for safety and effectiveness in order to distribute this drug earlier.{{Cite book | url=https://www.nap.edu/read/771/chapter/2#19 | doi=10.17226/771| pmid=25032454| title=Confronting AIDS| year=1988| isbn=978-0-309-03879-9| author1=Institute of Medicine (US) Committee for the Oversight of AIDS Activities}} Subsequently, several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died.{{cite journal | vauthors = Moore RD, Chaisson RE | title = Natural history of opportunistic disease in an HIV-infected urban clinical cohort | journal = Annals of Internal Medicine | volume = 124 | issue = 7 | pages = 633–42 | date = April 1996 | pmid = 8607591 | doi = 10.7326/0003-4819-124-7-199604010-00003 | s2cid = 20023137 }} To distinguish from this early antiretroviral therapy (ART), the term highly active antiretroviral therapy (HAART) was introduced. In 1996 two sequential publications in The New England Journal of Medicine by Hammer and colleagues{{cite journal | vauthors = Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ, Feinberg JE, Balfour HH, Deyton LR, Chodakewitz JA, Fischl MA | title = A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team | journal = The New England Journal of Medicine | volume = 337 | issue = 11 | pages = 725–33 | date = September 1997 | pmid = 9287227 | doi = 10.1056/NEJM199709113371101 | s2cid = 24043435 | url = https://cdr.lib.unc.edu/downloads/db78th536 | doi-access = free }} and Gulick and colleagues{{cite journal | vauthors = Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA | title = Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy | journal = The New England Journal of Medicine | volume = 337 | issue = 11 | pages = 734–9 | date = September 1997 | pmid = 9287228 | doi = 10.1056/NEJM199709113371102 | doi-access = free }} illustrated the substantial benefit of combining two NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir. This concept of three-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization.{{cite journal | vauthors = Moore RD, Chaisson RE | title = Natural history of HIV infection in the era of combination antiretroviral therapy | journal = AIDS | volume = 13 | issue = 14 | pages = 1933–42 | date = October 1999 | pmid = 10513653 | doi = 10.1097/00002030-199910010-00017 | doi-access = free }} It would also create a new period of optimism at the 11th International AIDS Conference that was held in Vancouver that year.

As HAART became widespread, fixed dose combinations were made available to ease the administration. Later, the term combination antiretroviral therapy (cART) gained favor with some physicians as a more accurate name, not conveying to patients any misguided idea of the nature of the therapy.{{Citation |last1=Sifris |first1=Dennis |last2=Myhre |first2=James |year=2017 |title=When Did HAART Become ART? Change Is About More Than Just Semantics [reviewed by a board-certified physician] |url=https://www.verywell.com/cart-hiv-combination-antiretroviral-therapy-48921 |postscript=.}} Today multidrug, highly effective regimens are long since the default in ART, which is why they are increasingly called simply ART instead of HAART or cART. This retronymic process is linguistically comparable to the way that the words electronic computer and digital computer at first were needed to make useful distinctions in computing technology, but with the later irrelevance of the distinction, computer alone now covers their meaning. Thus as "all computers are digital now", so "all ART is combination ART now." However, the names HAART and cART, reinforced by thousands of earlier mentions in medical literature still being regularly cited, also remain in use.{{citation needed|date=April 2021}} In 1997, the new number of new HIV/AIDS cases in the United States would see its first significant decline at 47%, with credit going to the effectiveness of HAART.{{cite news|url=https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline|title=A Timeline of HIV and AIDS|publisher=hiv.gov|access-date=September 16, 2024}}

People living with HIV can expect to live a nearly normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still have higher rates of cardiovascular, kidney, liver and neurologic disease.{{cite journal | vauthors = Passaes CP, Sáez-Cirión A | title = HIV cure research: advances and prospects | journal = Virology | volume = 454–455 | pages = 340–52 | date = April 2014 | pmid = 24636252 | doi = 10.1016/j.virol.2014.02.021 | s2cid = 205649442 | url = https://hal-pasteur.archives-ouvertes.fr/pasteur-01420527/file/Passaes%20and%20Saez-Cirion-2%20with%20highlights.pdf }} This has prompted further research towards a cure for HIV.

The so-called "Berlin patient" has been potentially cured of HIV infection and has been off of treatment since 2006 with no detectable virus.{{Cite web|url = http://nymag.com/health/features/AIDS-cure-2011-6/|title = The Man Who Had HIV and Now Does Not|date = May 29, 2011|access-date = 2014-04-12|last = Rosenberg|first = Tina |website = New York Magazine}} This was achieved through two bone marrow transplants that replaced his immune system with a donor's that did not have the CCR5 cell surface receptor, which is needed for some variants of HIV to enter a cell.{{cite journal | vauthors = Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E | title = Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation | journal = The New England Journal of Medicine | volume = 360 | issue = 7 | pages = 692–8 | date = February 2009 | pmid = 19213682 | doi = 10.1056/NEJMoa0802905 | s2cid = 14905671 | doi-access = free }} Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option. It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure zinc-finger nuclease-based gene knockout has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment.{{cite journal | vauthors = Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH | title = Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 901–10 | date = March 2014 | pmid = 24597865 | pmc = 4084652 | doi = 10.1056/NEJMoa1300662 }} Attempt to reproduce this failed in 2016. Analysis of the failure showed that gene therapy only successfully treats 11–28% of cells, leaving the majority of CD4+ cells capable of being infected. The analysis found that only patients where less than 40% of cells were infected had reduced viral load. The gene therapy was not effective if the native CD4+ cells remained. This is the main limitation which must be overcome for this treatment to become effective.HIV-1 CCR5 gene therapy will fail unless it is combined with a suicide gene

Aridaman Pandit & Rob J. de Boer. Scientific Reports volume 5, Article number: 18088 (2016)

After the "Berlin patient", two additional patients with both HIV infection and cancer were reported to have no traceable HIV virus after successful stem cell transplants. Virologist Annemarie Wensing of the University Medical Center Utrecht announced this development during her presentation at the 2016 "Towards an HIV Cure" symposium.{{cite news

| last = Senthilingam | first = Meera

| date = 18 July 2016

| title = HIV cure study provides insight into 2008 case

| url = https://edition.cnn.com/2016/07/17/health/hiv-cure-study/

| newspaper = CNN

| access-date = 21 July 2016

}}{{cite web

| url = http://www.utrechtcentral.com/news/international/no-trace-hiv-virus-stem-cell-transplantation-44453/

| title = No trace of HIV virus after successful stem cell transplantation

| last = Darmanin | first = Michael

| date = 21 July 2016

| website = UtrechtCentral.com

| access-date = 21 July 2016

}}{{cite web | url = http://www.iasociety.org/Web/WebContent/File/HIV_Cure_2016_Symposium_Programme_July.pdf | title = 2016 Towards an HIV Cure Symposium Programme. 16 & 17 July 2016 | location = Durban International Convention Centre (ICC), Durban, South Africa | date = 21 June 2016 | publisher = AIDS Society (IAS) | access-date = 21 July 2016 | archive-date = 21 September 2016 | archive-url = https://web.archive.org/web/20160921034256/http://www.iasociety.org/Web/WebContent/File/HIV_Cure_2016_Symposium_Programme_July.pdf | url-status = dead }} However, these two patients are still on antiretroviral therapy, which is not the case for the Berlin patient. Therefore, it is not known whether or not the two patients are cured of HIV infection. The cure might be confirmed if the therapy were to be stopped and no viral rebound occurred.{{cite web

| url = http://www.natap.org/2016/IAC/IAC_05.htm

| title = Allogeneic Stem Cell Transplantation in HIV-1 infected individuals; the EpiStem Consortium [Conference Reports for NATAP] [IAS Durban HIV cure Symposium July 16–17 2016]

| last = Levin

| first = Jules

| date = 19 July 2016

| website = National AIDS Treatment Advocacy Project (NATAP)

| access-date = 23 July 2016}}

In March 2019, a second patient, referred to as the "London Patient", was confirmed to be in complete remission of HIV. Like the Berlin Patient, the London Patient received a bone marrow transplant from a donor who has the same CCR5 mutation. He has been off antiviral drugs since September 2017, indicating the Berlin Patient was not a "one-off".{{cite news |last=Johnson |first=Carolyn |title=A decade after the first person was cured of HIV, a second patient is in long-term remission

|url=https://www.washingtonpost.com/health/2019/03/05/decade-after-first-person-was-cured-hiv-second-patient-is-long-term-remission/ |date=5 March 2019 |newspaper=The Washington Post |access-date=5 March 2019 }}{{cite news |last=May |first=Ashley |title=HIV patient seemingly cured in second remarkable case, London doctors report

|url=https://www.usatoday.com/story/news/health/2019/03/05/hiv-cure-london-patient-AIDS-treatment/3063749002/ |date=5 March 2019 |work=USA Today |access-date=5 March 2019 }}

Alternative approaches aiming to mimic one's biological immunity to HIV through the absence or mutation of the CCR5 gene is being conducted in current research efforts. The efforts of which are done through the introduction of induced pluripotent stem cells that have been CCR5 disrupted through the CRISPR/Cas9 gene editing system.{{cite journal | vauthors = Kang H, Minder P, Park MA, Mesquitta WT, Torbett BE, Slukvin II | title = CCR5 Disruption in Induced Pluripotent Stem Cells Using CRISPR/Cas9 Provides Selective Resistance of Immune Cells to CCR5-tropic HIV-1 Virus | journal = Molecular Therapy. Nucleic Acids | volume = 4 | pages = e268 | date = December 2015 | pmid = 26670276 | doi = 10.1038/mtna.2015.42 | doi-access = free }}{{cite journal | vauthors = Charpentier E | title = CRISPR-Cas9: how research on a bacterial RNA-guided mechanism opened new perspectives in biotechnology and biomedicine | journal = EMBO Molecular Medicine | volume = 7 | issue = 4 | pages = 363–365 | date = April 2015 | pmid = 25796552 | doi = 10.15252/emmm.201504847 | pmc = 4403038 }}

The main obstacle to complete elimination of HIV infection by conventional antiretroviral therapy is that HIV is able to integrate itself into the DNA of host cells and rest in a latent state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lies dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional memory CD4+ T cells.{{cite journal | vauthors = Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sékaly RP | title = HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation | journal = Nature Medicine | volume = 15 | issue = 8 | pages = 893–900 | date = August 2009 | pmid = 19543283 | pmc = 2859814 | doi = 10.1038/nm.1972 }} In 2014 there were reports of the cure of HIV in two infants,{{Cite web|url = https://www.nytimes.com/2014/03/06/health/second-success-raises-hope-for-a-way-to-rid-babies-of-hiv.html|title = Early Treatment Is Found to Clear H.I.V. in a 2nd Baby|date = 2014|work = The New York Times|last = McNeil|first = Donald}} presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir.{{cite journal | vauthors = Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Chun TW, Strain M, Richman D, Luzuriaga K | title = Absence of detectable HIV-1 viremia after treatment cessation in an infant | journal = The New England Journal of Medicine | volume = 369 | issue = 19 | pages = 1828–35 | date = November 2013 | pmid = 24152233 | pmc = 3954754 | doi = 10.1056/NEJMoa1302976 }} There is work being done{{when|date=January 2021}} to try to activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include histone deacetylase (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat have been used in human trials with only preliminary results so far.{{cite journal | vauthors = Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM | title = Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9390 | date = February 2010 | pmid = 20186346 | pmc = 2826423 | doi = 10.1371/journal.pone.0009390 | bibcode = 2010PLoSO...5.9390A | doi-access = free }}{{cite journal | vauthors = Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM | title = Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy | journal = Nature | volume = 487 | issue = 7408 | pages = 482–5 | date = July 2012 | pmid = 22837004 | pmc = 3704185 | doi = 10.1038/nature11286 | bibcode = 2012Natur.487..482A }}

Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells. Strategies include using cytokines to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses.{{cite journal | vauthors = Carcelain G, Autran B | title = Immune interventions in HIV infection | journal = Immunological Reviews | volume = 254 | issue = 1 | pages = 355–71 | date = July 2013 | pmid = 23772631 | doi = 10.1111/imr.12083 | s2cid = 34104811 }} One such candidate vaccine is Tat Oyi, developed by Biosantech.{{Cite web|title=Programs TAT – Vaccin VIH {{!}} BIOSANTECH SA ®|url=http://www.biosantech.org/En/nos-programmes/|archive-url=https://web.archive.org/web/20160601120505/http://www.biosantech.org/En/nos-programmes/|archive-date=2016-06-01|access-date=2015-10-27|website=www.biosantech.org}} This vaccine is based on the HIV protein tat. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia.{{cite journal | vauthors = Watkins JD, Lancelot S, Campbell GR, Esquieu D, de Mareuil J, Opi S, Annappa S, Salles JP, Loret EP | title = Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine | journal = Retrovirology | volume = 3 | pages = 8 | date = January 2006 | pmid = 16441880 | pmc = 1434768 | doi = 10.1186/1742-4690-3-8 | doi-access = free }}

HIV vaccine development is an active area of research and an important tool for managing the global AIDS epidemic. Research into a vaccine for HIV has been ongoing for decades with no lasting success for preventing infection.{{cite journal | vauthors = Haynes BF, Burton DR | title = Developing an HIV vaccine | journal = Science | volume = 355 | issue = 6330 | pages = 1129–1130 | date = March 2017 | pmid = 28302812 | pmc = 5569908 | doi = 10.1126/science.aan0662 | bibcode = 2017Sci...355.1129H }} The rapid development, though, of mRNA vaccines to deal with the COVID-19 pandemic may provide a new path forward.{{citation needed|date=November 2022}}

Like SARS-CoV-2, the virus that causes COVID-19, HIV has a spike protein. In retroviruses like HIV, the spike protein is formed by two proteins expressed by the Env gene. This viral envelope binds to the host cell's receptor and is what gains the virus entry into the cell.{{cite journal | vauthors = Checkley MA, Luttge BG, Freed EO | title = HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation | journal = Journal of Molecular Biology | volume = 410 | issue = 4 | pages = 582–608 | date = July 2011 | pmid = 21762802 | pmc = 3139147 | doi = 10.1016/j.jmb.2011.04.042 }} With mRNA vaccines, mRNA or messenger RNA, contains the instructions for how to make the spike protein. The mRNA is put into lipid-based nanoparticles for drug delivery. This was a key breakthrough in optimizing the efficiency and efficacy of in vivo delivery.{{cite journal | vauthors = Pardi N, Hogan MJ, Porter FW, Weissman D | title = mRNA vaccines - a new era in vaccinology | journal = Nature Reviews. Drug Discovery | volume = 17 | issue = 4 | pages = 261–279 | date = April 2018 | pmid = 29326426 | pmc = 5906799 | doi = 10.1038/nrd.2017.243 }}{{cite journal | vauthors = Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, Julander JG, Tang WW, Shresta S, Pierson TC, Ciaramella G, Diamond MS | title = Modified mRNA Vaccines Protect against Zika Virus Infection | journal = Cell | volume = 168 | issue = 6 | pages = 1114–1125.e10 | date = March 2017 | pmid = 28222903 | pmc = 5388441 | doi = 10.1016/j.cell.2017.02.017 }} When the vaccine is injected, the mRNA enters cells and joins up with a ribosome. The ribosome then translates the mRNA instructions into the spike protein. The immune system detects the presence of the spike protein and B cells, a type of white blood cell, begin to develop antibodies. Should the actual virus later enter the system, the external spike protein will be recognized by memory B cells, whose function is to memorize the characteristics of the original antigen. Memory B cells then produce the antibodies, hopefully destroying the virus before it can bind to another cell and repeat the HIV life cycle.{{Cite web|title=The HIV Life Cycle {{!}} NIH|url=https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-life-cycle|access-date=2021-11-30|website=hivinfo.nih.gov|language=en}} 

SARS-CoV-2 and HIV-1 have similarities—notably both are RNA viruses—but there are important differences. As a retrovirus, HIV-1 can insert a copy of its RNA genome into the host's DNA, making total eradication more difficult.{{cite journal | vauthors = Fischer W, Giorgi EE, Chakraborty S, Nguyen K, Bhattacharya T, Theiler J, Goloboff PA, Yoon H, Abfalterer W, Foley BT, Tegally H, San JE, de Oliveira T, Gnanakaran S, Korber B | title = HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens | journal = Cell Host & Microbe | volume = 29 | issue = 7 | pages = 1093–1110 | date = July 2021 | pmid = 34242582 | pmc = 8173590 | doi = 10.1016/j.chom.2021.05.012 }} The virus is also highly mutable making it a challenge for the adaptive immune system to develop a response. As a chronic infection, HIV-1 and the adaptive immune system undergo reciprocal selective pressures leading to the evolutionary arms race of coevolution.{{cite journal | vauthors = Liao HX, Lynch R, Zhou T, Gao F, Alam SM, Boyd SD, Fire AZ, Roskin KM, Schramm CA, Zhang Z, Zhu J, Shapiro L, Mullikin JC, Gnanakaran S, Hraber P, Wiehe K, Kelsoe G, Yang G, Xia SM, Montefiori DC, Parks R, Lloyd KE, Scearce RM, Soderberg KA, Cohen M, Kamanga G, Louder MK, Tran LM, Chen Y, Cai F, Chen S, Moquin S, Du X, Joyce MG, Srivatsan S, Zhang B, Zheng A, Shaw GM, Hahn BH, Kepler TB, Korber BT, Kwong PD, Mascola JR, Haynes BF | title = Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus | journal = Nature | volume = 496 | issue = 7446 | pages = 469–476 | date = April 2013 | pmid = 23552890 | pmc = 3637846 | doi = 10.1038/nature12053 | bibcode = 2013Natur.496..469. }}

Broadly neutralizing HIV-1 antibodies, or bnAbs, have been shown to attach to the Env spike protein envelope regardless of the specific HIV mutations.{{cite journal | vauthors = Pejchal R, Doores KJ, Walker LM, Khayat R, Huang PS, Wang SK, Stanfield RL, Julien JP, Ramos A, Crispin M, Depetris R, Katpally U, Marozsan A, Cupo A, Maloveste S, Liu Y, McBride R, Ito Y, Sanders RW, Ogohara C, Paulson JC, Feizi T, Scanlan CN, Wong CH, Moore JP, Olson WC, Ward AB, Poignard P, Schief WR, Burton DR, Wilson IA | title = A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield | journal = Science | volume = 334 | issue = 6059 | pages = 1097–1103 | date = November 2011 | pmid = 21998254 | pmc = 3280215 | doi = 10.1126/science.1213256 | bibcode = 2011Sci...334.1097P }}{{cite journal | vauthors = Burton DR, Hangartner L | title = Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design | journal = Annual Review of Immunology | volume = 34 | issue = 1 | pages = 635–659 | date = May 2016 | pmid = 27168247 | pmc = 6034635 | doi = 10.1146/annurev-immunol-041015-055515 }}{{cite journal | vauthors = McCoy LE | title = The expanding array of HIV broadly neutralizing antibodies | journal = Retrovirology | volume = 15 | issue = 1 | pages = 70 | date = October 2018 | pmid = 30326938 | pmc = 6192334 | doi = 10.1186/s12977-018-0453-y | doi-access = free }} This bodes well for vaccine development. Complicating matters, though, naive B cells—mature B cells not yet exposed to any antigen and are the progenitors of bnAbs—are rare. Further, the mutation events needed to turn these B cells into bnAbs are also rare.{{cite journal | vauthors = Mu Z, Haynes BF, Cain DW | title = HIV mRNA Vaccines-Progress and Future Paths | journal = Vaccines | volume = 9 | issue = 2 | pages = 134 | date = February 2021 | pmid = 33562203 | pmc = 7915550 | doi = 10.3390/vaccines9020134 | doi-access = free }}{{Cite web|title=First-in-human clinical trial confirms novel HIV vaccine approach developed by IAVI and Scripps Research|url=https://www.scripps.edu/news-and-events/press-room/2021/20210203-hiv-vaccine.html|access-date=2021-11-30|website=www.scripps.edu|language=en}} Because of this, there is a growing consensus that an effective HIV vaccine will need to create not only humoral (antibody-mediated) immunity, but a T-cell-mediated immunity.{{cite journal | vauthors = Jones LD, Moody MA, Thompson AB | title = Innovations in HIV-1 Vaccine Design | journal = Clinical Therapeutics | volume = 42 | issue = 3 | pages = 499–514 | date = March 2020 | pmid = 32035643 | pmc = 7102617 | doi = 10.1016/j.clinthera.2020.01.009 }}

mRNA vaccines have advantages over traditional vaccines which may help deal with some of the challenges presented by the HIV virus. The mRNA in the vaccine only codes for the protein spike, not the whole virus, so the possibility of reverse transcription, where the virus copies its genetic material into the host's genome, is not present. Another advantage when compared to traditional vaccines is the speed of development. mRNA vaccines take months not years, which means a multipart sequential vaccine regime is possible.{{citation needed|date=November 2022}}

Attempts to elicit an immune response that triggers broadly neutralizing antibodies (bnAbs) with a single vaccine dose have been unsuccessful. A multipart sequential mRNA vaccine regime, however, might guide the immune response in the right direction. The first shot triggers an immune response for the correct naive B cells. Later vaccinations encourage the development of these cells further, eventually turning them into memory b cells, and later into plasma cells, which can secrete the broadly neutralizing antibodies:

In essence, the sequential immunization approach represents an attempt to mimic Env evolution that would occur with natural infection.... In contrast to traditional prime/boost strategies, in which the same immunogen is used repeatedly for vaccination, the sequential immunization approach relies on a series of different immunogens with the goal of eventually inducing bnAb(s).

A Phase 1 clinical trial by Scripps Research and the International AIDS Vaccine Initiative of an mRNA vaccine showed that 97 percent of participants had the desired initial “priming” immune response of naive b cells. This is a positive result for developing the first shot in a vaccine sequence. Moderna is partnering with Scripps and the International AIDS Vaccine Initiative for a follow-up phase 1 clinical trial of an HIV mRNA vaccine (mRNA-1644) starting later in 2021.{{Cite web |last=International AIDS Vaccine Initiative|date=2021-09-29|others=ModernaTX, Inc., The University of Texas at San Antonio, George Washington University, Fred Hutchinson Cancer Research Center, Emory University|title=A Phase 1, Randomized, First-in-human, Open-label Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) in HIV-1 Uninfected Adults in Good General Health|url=https://clinicaltrials.gov/ct2/show/NCT05001373}}

Direct-to-consumer and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous models rather than typical people with HIV/AIDS. Usually, these people will present with debilitating conditions or illnesses as a result of HIV/AIDS. In contrast, by featuring people in unrealistically strenuous activities, such as mountain climbing;{{cite journal | vauthors = Kallen A, Woloshin S, Shu J, Juhl E, Schwartz L | title = Direct-to-consumer advertisements for HIV antiretroviral medications: a progress report | journal = Health Affairs | volume = 26 | issue = 5 | pages = 1392–1398 | date = 2007-10-01 | pmid = 17848450 | doi = 10.1377/hlthaff.26.5.1392 | s2cid = 12536749 }} this proved to be offensive and insensitive to the suffering of people who are HIV positive. The US FDA reprimanded multiple pharmaceutical manufacturers for publishing such adverts in 2001, as the misleading advertisements harmed consumers by implying unproven benefits and failing to disclose important information about the drugs.{{cite journal | vauthors = Josefson D | title = FDA warning to manufacturers of AIDS drugs | journal = BMJ | volume = 322 | issue = 7295 | pages = 1143 | date = May 2001 | pmid = 11348904 | pmc = 1120280 | doi = 10.1136/bmj.322.7295.1143 }} Overall, some drug companies chose not to present their drugs in a realistic way, which consequently harmed the general public's ideas{{Citation needed|date=October 2020}}, suggesting that HIV would not affect you as much as suggested. This led to people not wanting to get tested{{Citation needed|date=October 2020}}, for fear of being HIV positive, because at the time (in the 1980s and 1990s particularly), having contracted HIV was seen as a death sentence, as there was no known cure. An example of such a case is Freddie Mercury{{Citation needed|reason=This section suggests Freddie Mercury did not want to get tested for HIV. Please cite a reliable source for this.|date=October 2020}}, who died in 1991, aged 45, of AIDS-related pneumonia.

The preamble to the World Health Organization's Constitution defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity."{{Cite web|url=https://www.who.int/about/who-we-are/constitution|archive-url=https://web.archive.org/web/20190317234054/https://www.who.int/about/who-we-are/constitution|url-status=dead|archive-date=March 17, 2019|title=Constitution|website=www.who.int|language=en|access-date=2019-03-07}} Those living with HIV today are met with other challenges that go beyond the singular goal of lowering their viral load. A 2009 meta-analysis studying the correlates of HIV-stigma found that individuals living with higher stigma burden were more likely to have poorer physical and mental health. Insufficient social support and delayed diagnosis due to decreased frequency of HIV testing and knowledge of risk reduction were cited as some of the reasons.{{cite journal | vauthors = Miners A, Phillips A, Kreif N, Rodger A, Speakman A, Fisher M, Anderson J, Collins S, Hart G, Sherr L, Lampe FC | title = Health-related quality-of-life of people with HIV in the era of combination antiretroviral treatment: a cross-sectional comparison with the general population | language = en | journal = The Lancet. HIV | volume = 1 | issue = 1 | pages = e32-40 | date = October 2014 | pmid = 26423814 | doi = 10.1016/S2352-3018(14)70018-9 | doi-access = free }}{{cite journal | vauthors = Gakhar H, Kamali A, Holodniy M | title = Health-related quality of life assessment after antiretroviral therapy: a review of the literature | journal = Drugs | volume = 73 | issue = 7 | pages = 651–72 | date = May 2013 | pmid = 23591907 | pmc = 4448913| doi = 10.1007/s40265-013-0040-4 }}{{cite journal | vauthors = Mak WW, Poon CY, Pun LY, Cheung SF | title = Meta-analysis of stigma and mental health | journal = Social Science & Medicine | volume = 65 | issue = 2 | pages = 245–61 | date = July 2007 | pmid = 17462800 | doi = 10.1016/j.socscimed.2007.03.015 }} People living with HIV (PLHIV) have lower health related quality of life (HRQoL) scores than do the general population. The stigma of having HIV is often compounded with the stigma of identifying with the LGBTQ community or the stigma of being an injecting drug user (IDU) even though heterosexual sexual transmission accounts for 85% of all HIV-1 infections worldwide.{{cite journal | vauthors = Wolfe D, Carrieri MP, Shepard D | title = Treatment and care for injecting drug users with HIV infection: a review of barriers and ways forward | journal = Lancet | volume = 376 | issue = 9738 | pages = 355–66 | date = July 2010 | pmid = 20650513 | doi = 10.1016/S0140-6736(10)60832-X | s2cid = 13205040 }} AIDS has been cited as the most heavily stigmatized medical condition among infectious diseases. Part of the consequence of this stigma toward PLHIV is the belief that they are seen as responsible for their status and less deserving of treatment.

A 2016 study sharing the WHO's definition of health critiques its 90-90-90 target goal, which is part of a larger strategy that aims to eliminate the AIDS epidemic as a public health threat by 2030, by arguing that it does not go far enough in ensuring the holistic health of PLHIV. The study suggests that maintenance of HIV and AIDS should go beyond the suppression of viral load and the prevention of opportunistic infection. It proposes adding a 'fourth 90' addressing a new 'quality of life' target that would focus specifically on increasing the quality of life for those that are able to suppress their viral load to undetectable levels along with new metrics to track the progress toward that target. This study serves as an example of the shifting paradigm in the dynamics of the health care system from being heavily 'disease-oriented' to more 'human-centered'. Though questions remain of what exactly a more 'human-centered' method of treatment looks like in practice, it generally aims to ask what kind of support, other than medical support, PLHIV need to cope with and eliminate HIV-related stigmas. Campaigns and marketing aimed at educating the general public in order to reduce any misplaced fears of HIV contraction is one example. Also encouraged is the capacity-building and guided development of PLHIV into more leadership roles with the goal of having a greater representation of this population in decision making positions. Structural legal intervention has also been proposed, specifically referring to legal interventions to put in place protections against discrimination and improve access to employment opportunities. On the side of the practitioner, greater competence for the experience of people living with HIV is encouraged alongside the promotion of an environment of nonjudgment and confidentiality.

Psychosocial group interventions such as psychotherapy, relaxation, group support, and education may have some beneficial effects on depression in HIV positive people.{{cite journal | vauthors = van der Heijden I, Abrahams N, Sinclair D | title = Psychosocial group interventions to improve psychological well-being in adults living with HIV | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD010806 | date = March 2017 | issue = 3 | pmid = 28291302 | pmc = 5461871 | doi = 10.1002/14651858.CD010806.pub2 | collaboration = Cochrane Infectious Diseases Group }}

The successful treatment and management of HIV/AIDS is affected by a plethora of factors which ranges from successfully taking prescribed medications, preventing opportunistic infection, and food access etc. Food insecurity is a condition in which households lack access to adequate food because of limited money or other resources. Food insecurity is a global issue that has affected billions of people yearly, including those living in developed countries.{{citation needed|date=September 2022}}

Food insecurity is a major public health disparity in the United States of America, which significantly affects minority groups, people living at or below the poverty line, and those who are living with one or more morbidity. As of December 31, 2017, there were approximately 126,742 people living with HIV/AIDS (PLWHA) in NYC, of whom 87.6% can be described as living with some level of poverty and food insecurity as reported by the NYC Department of Health on March 31, 2019.{{Cite web|url=https://www1.nyc.gov/assets/doh/downloads/pdf/ah/surveillance2017-table-all.pdf|title=HIV/AIDS in NYC}} Having access to a consistent food supply that is safe and healthy is an important part in the treatment and management of HIV/AIDS. PLWHA are also greatly affected by food inequities and food deserts which causes them to be food insecure. Food insecurity, which can cause malnutrition, can also negatively impact HIV treatment and recovery from opportunistic infections. Similarly, PLWHA require additional calories and nutritionally support that require foods free from contamination to prevent further immunocompromising. Food insecurity can further exacerbate the progression of HIV/AIDS and can prevent PLWHA from consistently following their prescribed regimen, which will lead to poor outcomes.{{citation needed|date=September 2022}}

It is imperative that these food insecurity among PLWHA are addressed and rectified to reduce this health inequity.{{Citation needed|date=January 2023}} It is important to recognized that socioeconomic status, access to medical care, geographic location, public policy, race and ethnicity all play a pivotal role in the treatment and management of HIV/AIDS. The lack of sufficient and constant income does limit the options for food, treatment, and medications. The same can be inferred for those who are among the oppressed groups in society who are marginalized and may be less inclined or encouraged to seek care and assistance. Endeavors to address food insecurity should be included in HIV treatment programs and may help improve health outcomes if it also focuses on health equity among the diagnosed as much as it focuses on medications. Access to consistently safe and nutritious foods is one of the most important facets in ensuring PLWHA are being provided the best possible care. By altering the narratives for HIV treatment so that more support can be garnered to reduce food insecurity and other health disparities mortality rates will decrease for people living with HIV/AIDS.{{citation needed|date=September 2022}}

• AV-HALT
• Discovery and development of HIV-protease inhibitors
• Discovery and development of non-nucleoside reverse-transcriptase inhibitors
• Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
• HIV capsid inhibition

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• {{cite journal | vauthors = Strayer DS, Akkina R, Bunnell BA, Dropulic B, Planelles V, Pomerantz RJ, Rossi JJ, Zaia JA | title = Current status of gene therapy strategies to treat HIV/AIDS | journal = Molecular Therapy | volume = 11 | issue = 6 | pages = 823–42 | date = June 2005 | pmid = 15922953 | doi = 10.1016/j.ymthe.2005.01.020 | doi-access = free }}

• [https://hivinfo.nih.gov/home-page HIVinfo] at US Department of Health and Human Services

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Category:Hepatotoxins

Category:Prevention of HIV/AIDS