HIV/AIDS: Antiretroviral Drugs


The last three decades have seen amazing progress in the treatment and prevention of HIV infection, with over 25 approved antiretrovirals and several experimental drugs in advanced development. Research in the basic science of HIV replication has enabled targeted drug discovery efforts, and these are, in turn, contributing to an improved understanding of the molecular biology of HIV infection. Refinement of therapeutic strategies continues, in pursuit of high virological efficacy, excellent safety and tolerability, convenience of administration and effective use of available resources. These aspirations now extend to the subset of patients who have experienced multiple antiretrovirals, for whom it is increasingly possible to construct optimised regimens that overcome drug resistance or poor tolerability. The next decade will test two‐drug combinations, most likely as a way of simplifying therapy once virological suppression is achieved with three‐drug regimens, whereas long‐acting injectable formulations will establish their role as a therapeutic and prophylactic option.

Key Concepts

  • Antiretroviral drugs target multiple steps of the HIV replication cycle, from the initial attachment to the target CD4 cell to the final step of maturation of a new virus particle.
  • Treatment regimens usually consist of three drugs with two different mechanisms of action, which are often coformulated into a single tablet.
  • Antiretroviral therapy is highly efficacious; most patients can expect to achieve long‐term HIV control, provided they maintain consistently good adherence. Antiretroviral therapy is not curative and must be taken for life to prevent viral rebound.
  • Current antiretroviral drugs are generally safe and well tolerated. They have distinct profiles, however, and some pose safety and tolerability problems for some patients, whereas others are well tolerated but less efficacious. Many have unfavourable interactions with concomitant medications.
  • Patients starting ART have a choice of treatment options. Most commonly, the initial regimen consists of two NRTIs that form the backbone and a third agent with a different mechanism of action, which may be an INSTI, an NNRTI or a PI/b. Whilst INSTIs are preferred, treatment selection is optimised based on HIV‐related clinical parameters, concurrent infectious and noninfectious comorbidities and concomitant medications, and considerations related to preference and life‐style, as well as cost. Treatment options and opportunities for tailoring the regimen are fewer in resource‐limited settings.
  • Plasma viral load – that is, the quantity of circulating HIV RNA – provides the measure of the efficacy of antiretroviral therapy: the goal is to achieve a fully suppressed (undetectable) viral load.
  • Studies have tested the hypothesis that once viral load suppression is achieved with triple ART, it may be possible to simplify treatment using fewer drugs. Results of maintenance monotherapy with PI/b or dolutegravir have been disappointing. More promising data have been obtained with two‐drug combinations where one of the two drugs is a PI/b, dolutegravir or cabotegravir.
  • Patients who experience viraemia while on treatment require prompt management to avoid the emergence of drug resistance; the subsequent regimen is optimised according to the specific circumstances and may include three or more drugs chosen among those most likely to retain activity while continuing to meet the requirement for good safety and tolerability. Resource‐limited countries have few drugs for second‐line treatment and even fewer options for subsequent lines of therapy.
  • Experimental agents in advanced development include drugs with new mechanisms of action such as novel entry inhibitors, NRTTIs, and capsid and maturation inhibitors, as well as new drugs within existing classes such as the recently approved bictegravir and doravirine. Some of the new agents hold promise that they may either prevent or overcome drug resistance.
  • There is considerable interest in long‐acting injectables that allow infrequent dosing (e.g. monthly) and are intended for either treatment or prevention.

Keywords: ART; NRTI; NNRTI; PI; INSTI; booster; long‐acting

Figure 1. Simplified representation of the replicative cycle of HIV with the targets of antiretroviral drugs.
Figure 2. Schematic representation of the HIV particle.
Figure 3. The integrase enzyme.
Figure 4. Cleavage steps of the Gag polyprotein. Arrows indicate each cleavage steps. MA, matrix; CA, capsid; SP1, spacer peptide 1; NC, nucleocapsid; SP2, spacer peptide 2.
Figure 5. Model of HIV‐1 reverse transcriptase, with NNRTI (yellow), DNA primer (light grey) and template (dark grey) and incoming dNTP (green). The fingers (blue), palm (purple), thumb (green), connection (yellow) and RNaseH (red) subdomains of the p66 subunit and the p51 subunit (white) are shown. The region circled includes the polymerase active site and NNRTI‐binding pocket. Pata et al. . Reproduced with permission of National Academy of Sciences, U.S.A.


Abdullahi A, Fopoussi OM, Torimiro J, et al. (2018) Hepatitis B virus (HBV) infection and re‐activation during nucleos (t) ide reverse transcriptase inhibitor‐sparing antiretroviral therapy in a high‐HBV endemicity setting. Open Forum Infectious Diseases 5: ofy251.

Achhra AC, Mwasakifwa G, Amin J and Boyd MA (2016) Efficacy and safety of contemporary dual‐drug antiretroviral regimens as first‐line treatment or as a simplification strategy: a systematic review and meta‐analysis. Lancet HIV 3: e351–e360.

Beccari MV, Mogle BT, Sidman EF, et al. (2019) Ibalizumab, a novel monoclonal antibody for the management of multidrug‐resistant HIV‐1 infection. Antimicrobial Agents and Chemotherapy 63.

Bedimo R, Rosenblatt L and Myers J (2016) Systematic review of renal and bone safety of the antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection. HIV Clinical Trials 17: 246–266.

Blair HA (2018) Dolutegravir/rilpivirine: a review in HIV‐1 infection. Drugs 78: 1741–1750.

Blanco JL, Varghese V, Rhee SY, Gatell JM and Shafer RW (2011) HIV‐1 integrase inhibitor resistance and its clinical implications. Journal of Infectious Diseases 203: 1204.

Blanco JL, Marcelin AG, Katlama C and Martinez E (2018) Dolutegravir resistance mutations: lessons from monotherapy studies. Current Opinion in Infectious Diseases 31: 237–245.

Cahn P, Fink V and Patterson P (2018) Fostemsavir: a new CD4 attachment inhibitor. Current Opinion in HIV and AIDS 13: 341–345.

Carey D, Puls R, Amin J, et al. (2015) Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96‐week data from the randomised, double‐blind, placebo‐controlled, non‐inferiority ENCORE1 study. Lancet Infectious Diseases 15: 793–802.

Carnes SK, Sheehan JH and Aiken C (2018) Inhibitors of the HIV‐1 capsid, a target of opportunity. Current Opinion in HIV and AIDS 13: 359–365.

Chen B (2019 Jun) Molecular mechanism of HIV‐1 entry. Trends in Microbiology 28.

Clutter DS, Jordan MR, Bertagnolio S and Shafer RW (2016) HIV‐1 drug resistance and resistance testing. Infection, Genetics and Evolution 46: 292–307.

Cohen CJ, Molina JM, Cassetti I, et al. (2013) Week 96 efficacy and safety of rilpivirine in treatment‐naive, HIV‐1 patients in two phase III randomized trials. AIDS 27: 939.

Colombier MA and Molina JM (2018) Doravirine: a review. Current Opinion in HIV and AIDS 13: 308–314.

d'Arminio Monforte A, Reiss P, Ryom L, et al. (2013) Atazanavir is not associated with an increased risk of cardio‐ or cerebrovascular disease events. AIDS 27: 407.

Department of Health & Human Services (DHHS) (2018) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. (accessed August 2019).

Domingo P, Mateo MG, Gutierrez MDM and Vidal F (2018) Tolerability of current antiretroviral single‐tablet regimens. AIDS Reviews 20: 141–149.

Doyle T, Dunn DT, Ceccherini‐Silberstein F, et al. (2015) Integrase inhibitor (INI) genotypic resistance in treatment‐naive and raltegravir – experienced patients infected with diverse HIV‐1 clades. Journal of Antimicrobial Chemotherapy 70: 3080–3086.

Echecopar‐Sabogal J, D'Angelo‐Piaggio L, Chanamé‐Baca DM and Ugarte‐Gil C (2018) Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV‐infected patients: a systematic review and meta‐analysis. International Journal of STD & AIDS 29: 443–452.

Engelman AN and Singh PK (2018) Cellular and molecular mechanisms of HIV‐1 integration targeting. Cellular and Molecular Life Sciences 75: 2491–2507.

Eron JJ, Clotet B, Durant J, et al. (2013) Safety and efficacy of dolutegravir in treatment‐experienced subjects with raltegravir‐resistant HIV type 1 infection: 24‐week results of the VIKING study. Journal of Infectious Diseases 207: 740.

European AIDS Clinical Society (EACS) (2018) Guidelines. Version 9.1.‐9.1‐english.pdf (accessed August 2019).

Ferretti F and Boffito M (2018) Rilpivirine long‐acting for the prevention and treatment of HIV infection. Current Opinion in HIV and AIDS: 13300–13307.

Gendelman HE, McMillan J, Bade AN, Edagwa B and Kevadiya BD (2019) The promise of long‐acting antiretroviral therapies: from need to manufacture. Trends in Microbiology 27: 593–606.

Geretti AM (2008) Shifting paradigms: the resistance profile of etravirine. Journal of Antimicrobial Chemotherapy 62: 643–647.

Geretti AM, Fox Z, Johnson JA, et al. (2013) Sensitive assessment of the virologic outcomes of stopping and restarting non‐nucleoside reverse transcriptase inhibitor‐based antiretroviral therapy. PLoS One 8: e69266.

Geretti AM, White E, Orkin C, et al. (2019) Virological outcomes of boosted protease inhibitor‐based first‐line ART in subjects harbouring thymidine analogue‐associated mutations as the sole form of transmitted drug resistance. Journal of Antimicrobial Chemotherapy 74: 746–753.

Hazuda DJ, Felock P, Witmer M, et al. (2000) Inhibitors of strand transfer that prevent integration and inhibit HIV‐1 replication in cells. Science 287: 646.

Hill AM, Mitchell N, Hughes S and Pozniak AL (2018) Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta‐analysis of randomized trials. Current Opinion in HIV and AIDS 13: 102–111.

Lewis W, Day BJ and Copeland WC (2003) Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nature Reviews. Drug Discovery 2: 812–822.

Lewis M, Mori J, Toma J, et al. (2018) Clonal analysis of HIV‐1 genotype and function associated with virologic failure in treatment‐experienced persons receiving maraviroc: results from the MOTIVATE phase 3 randomized, placebo‐controlled trials. PLoS One 13: e0204099.

Llibre JM, Hung CC, Brinson C, et al. (2018) Efficacy, safety, and tolerability of dolutegravir‐rilpivirine for the maintenance of virological suppression in adults with HIV‐1: phase 3, randomised, noninferiority SWORD‐1 and SWORD‐2 studies. Lancet 391: 839–839.

Markham A (2018) Bictegravir: first global approval. Drugs 78: 601–606.

McComsey GA, Kitch D, Daar ES, et al. (2011) Bone mineral density and fractures in antiretroviral‐naive persons randomized to receive abacavir‐lamivudine or tenofovir disoproxil fumarate‐emtricitabine along with efavirenz or atazanavir‐ritonavir. Journal of Infectious Diseases 203: 1791–1801.

de Miguel Buckley R, Montejano R, Stella‐Ascariz N and Arribas JR (2018) New strategies of ARV: the road to simplification. Current HIV/AIDS Reports 15: 11–19.

Mollan KR, Tierney C, Hellwege JN, et al. (2017) Race/ethnicity and the pharmacogenetics of reported suicidality with efavirenz among clinical trials participants. Journal of Infectious Diseases 216: 554.

Oliveira M, Ibanescu RI, Anstett K, et al. (2018) Selective resistance profiles emerging in patient‐derived clinical isolates with cabotegravir, bictegravir, dolutegravir and elvitegravir. Retrovirology 15: 56.

Osterholzer DA and Goldman M (2014) Dolutegravir: a next‐generation integrase inhibitor for treatment of HIV infection. Clinical Infectious Diseases 59: 265–271.

Pata JD, Stirtan WG, Goldstein SW and Steitz TA (2004) Structure of HIV‐1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. Proceedings of the National Academy of Sciences of the United States of America 101: 10548–10553.

Pornillos O and Ganser‐Pornillos BK (2019) Maturation of retroviruses. Current Opinion in Virology 36: 47–55.

Radford M, Parks DC, Ferrante S and Punekar Y (2019) Dolutegravir and lamivudine vs other antiviral regimens in HIV‐1 treatment‐naïve patients: a systematic review and network meta‐analysis. AIDS 33: 1739–1749.

Rai MA, Pannek S and Fichtenbaum CJ (2018) Emerging reverse transcriptase inhibitors for HIV‐1 infection. Expert Opinion on Emerging Drugs 23: 149–157.

Rhee SY, Grant PM, Tzou PL, et al. (2019) A systematic review of the genetic mechanisms of dolutegravir resistance. Journal of Antimicrobial Chemotherapy 74: 3135–3149.

Ryom L, Lundgren JD, El‐Sadr W, et al. (2018) Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV 5: e291–e300.

Sax PE, Tierney C, Collier AC, et al. (2011) Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. Journal of Infectious Diseases 204: 1191–1201.

Sax PE, Wohl D, Yin MT, et al. (2015) Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV‐1 infection: two randomised, double‐blind, phase 3, non‐inferiority trials. Lancet 385: 2606–2615.

Smith SJ, Zhao XZ, Burke TR Jr and Hughes SH (2018) Efficacies of cabotegravir and bictegravir against drug‐resistant HIV‐1 integrase mutants. Retrovirology 15: 37.

Spagnuolo V, Castagna A and Lazzarin A (2018) Darunavir for the treatment of HIV infection. Expert Opinion on Pharmacotherapy 19: 1149–1163.

Stellbrink HJ and Hoffmann C (2018) Cabotegravir: its potential for antiretroviral therapy and preexposure prophylaxis. Current Opinion in HIV and AIDS 13: 334–340.

Stockdale AJ, Saunders MJ, Boyd MA, et al. (2018) Effectiveness of protease inhibitor/nucleos(t)ide reverse transcriptase inhibitor‐based second‐line antiretroviral therapy for the treatment of human immunodeficiency virus type 1 infection in sub‐Saharan Africa: a systematic review and meta‐analysis. Clinical Infectious Diseases 66: 1846–1857.

Thompson MA (2018) The return of PRO 140, a CCR5‐directed mAb. Current Opinion in HIV and AIDS 13: 346–353.

Urano E, Timilsina U, Kaplan JA, et al. (2019) Resistance to second‐generation HIV‐1 maturation inhibitors. Journal of Virology 93: e02017–e02018.

Vandekerckhove LP, Wensing AM, Kaiser R, et al. (2011) European guidelines on the clinical management of HIV‐1 tropism testing. Lancet Infectious Diseases 11: 394–407.

Venter WDF, Moorhouse M, Sokhela S, et al. (2019) Dolutegravir plus two different prodrugs of tenofovir to treat HIV. New England Journal of Medicine 381: 803–815.

Walmsley SL, Antela A, Clumeck N, et al. (2013) Dolutegravir plus abacavir‐lamivudine for the treatment of HIV‐1 infection. New England Journal of Medicine 369: 1807–1818.

World Health Organisation (WHO) (2018) Updated recommendations on first‐line and second‐line antiretroviral regimens and post‐exposure prophylaxis and recommendations on early infant diagnosis of HIV. Interim guidance. (accessed August 2019).

Zash R, Makhema J and Shapiro RL (2018) Neural‐tube defects with dolutegravir treatment from the time of conception. New England Journal of Medicine 379: 979.

Further Reading

Llano M, Saenz DT, Meehan A, et al. (2006) An essential role for LEDGF/p75 in HIV integration. Science 314: 461–464.

Mamede JI, Cianci GC, Anderson MR, et al. (2017) Early cytoplasmic uncoating is associated with infectivity of HIV‐1. Proceedings of the National Academy of Sciences of the United States of America 114: E7169–E7178.

Martin‐Blondel G, Brassat D, Bauer J, Lassmann H and Liblau RS (2016) CCR5 blockade for neuroinflammatory diseases‐beyond control of HIV. Nature Reviews. Neurology 12: 95–105.

Miri L, Bouvier G, Kettani A, et al. (2014) Stabilization of the integrase‐DNA complex by Mg2+ ions and prediction of key residues for binding HIV‐1 integrase inhibitors. Proteins 82: 466–478.

Milián L, Peris JE, Gandía P, et al. (2017) Tenofovir‐induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria. AIDS 31: 1679–1684.

Mollan KR, Smurzynski M, Eron JJ, et al. (2014) Association between efavirenz as initial therapy for HIV‐1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Annals of Internal Medicine 161 (1): 1–10.

Tarasova O, Poroikov V and Veselovsky A (2018) Molecular docking studies of HIV‐1 resistance to reverse transcriptase inhibitors: mini‐review. Molecules 23: pii: E1233.

Wang T, Ueda Y, Zhang Z, et al. (2018) Discovery of the HIV‐1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir. Journal of Medicinal Chemistry 61: 6308–6327.

Zhu P, Liu J, Bess J Jr, et al. (2006) Distribution and three‐dimensional structure of AIDS virus envelope spikes. Nature 441: 847–852.

Zimmermann AE, Pizzoferrato T, Bedford J, et al. (2006) Tenofovir‐associated acute and chronic kidney disease: a case of multiple drug interactions. Clinical Infectious Diseases 42: 283.

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Geretti, Anna M(Jan 2020) HIV/AIDS: Antiretroviral Drugs. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028523]