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Current Status and Prospects of HIV Treatment

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Current Status and Prospects of HIV Treatment Available online at www.sciencedirect.com ScienceDirect Current status and prospects of HIV treatment 1 2 Tomas Cihlar and Marshall Fordyce Current antiviral treatments can reduce HIV-associated at suppressing plasma viremia, and significant progress morbidity, prolong survival, and prevent HIV transmission. has been made toward regimen simplification through the Combination antiretroviral therapy (cART) containing preferably combination of three active drugs into single-tablet regi- three active drugs from two or more classes is required for mens (STRs) (Figure 1) and optimization of drug profiles durable virologic suppression. Regimen selection is based on that maximize long-term tolerability and safety. Lifelong, virologic efficacy, potential for adverse effects, pill burden and chronic therapy without treatment interruption is the dosing frequency, drug–drug interaction potential, resistance standard of care, and the availability of multiple effective test results, comorbid conditions, social status, and cost. With drugs in several classes with differing resistance, safety, prolonged virologic suppression, improved clinical outcomes, and tolerability profiles provides choices after failure of and longer survival, patients will be exposed to antiretroviral first-line treatment. agents for decades. Therefore, maximizing the safety and tolerability of cART is a high priority. Emergence of resistance Herein, we review the current status of antiretroviral and/or lack of tolerability in individual patients require therapy and guidelines for HIV-infected adults, as well availability of a range of treatment options. Development of new as prospects for further innovation in HIV treatment to drugs is focused on improving safety (e.g. tenofovir benefit patients and optimize their long-term health. alafenamide) and/or resistance profile (e.g. doravirine) within the existing drug classes, combination therapies with improved Goals of antiretroviral therapy adherence (e.g. single-tablet regimens), novel mechanisms of Eradication of HIV cannot be achieved with current action (e.g. attachment inhibitors, maturation inhibitors, cART due to the pool of latently infected CD4 T cells broadly neutralizing antibodies), and treatment simplification established early during acute infection. However, cART with infrequent dosing (e.g. long-acting injectables). In parallel can reduce HIV-associated morbidity, prolong survival, with cART innovations, research and development efforts and prevent HIV transmission [1–4]. Maximal and dura- focused on agents that target persistent HIV reservoirs may ble suppression of plasma viremia restores and preserves lead to prolonged drug-free remission and HIV cure. immunologic function, delays or prevents the develop- Addresses ment of drug-resistant mutations, and may also decrease 1 Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA the immune activation and inflammation thought to con- 2 HIV Clinical Development, Gilead Sciences, Inc., Foster City, CA, USA tribute to end-organ damage [5–7]. Suppressing plasma viremia below detection limits is possible within weeks of Corresponding author: Cihlar, Tomas ([email protected]) therapy and depends on adherence to an efficacious regimen. Current Opinion in Virology 2016, 18:50–56 This review comes from a themed issue on Antiviral strategies Morbidity and mortality in HIV-infected subjects is in- Edited by Raymond Schinazi and Erik De Clercq creasingly driven by non-AIDS associated comorbidities such as kidney, liver, and heart disease [8,9] (Linley L et al., Abstract B08-1, 2007 National HIV Prevention Conference, Atlanta, GA, December 2007). Even with http://dx.doi.org/10.1016/j.coviro.2016.03.004 cART, aging patient populations with HIV-1 infection 1879-6257/# 2016 The Authors. Published by Elsevier B.V. This is an experience more age-related comorbidities, such as dia- open access article under the CC BY-NC-ND license (http:// betes, and cardiovascular, renal, and bone disease, which creativecommons.org/licenses/by-nc-nd/4.0/). manifest earlier than in HIV-uninfected peers [10 ]. With prolonged virologic suppression, improved clinical out- comes, and longer survival, patients may be exposed to Introduction antiretroviral agents for decades [11 ]. Thus, maximizing Since the approval of zidovudine (AZT) in 1987, over the safety and tolerability of cART regimens while main- 25 antiretroviral agents in six mechanistic classes have taining strong clinical efficacy is a high priority. been approved to treat HIV infection (Figure 1). Combi- nation antiretroviral therapy (cART) is the treatment Guidelines and preferred regimens for first- paradigm established in the late 1990s responsible for line therapy the dramatic decline in AIDS deaths and is composed of Therapy used to be initiated based on decreasing CD4 two nucleoside/nucleotide reverse transcriptase inhibitors cell count or clinical evidence of AIDS. More recently, (NRTIs) plus a third active drug from a different therapy is being initiated regardless of the CD4 cell class. Contemporary HIV treatment is highly effective count, often immediately after a patient’s diagnosis, a Current Opinion in Virology 2016, 18:50–56 www.sciencedirect.com Treatment of HIV infection Cihlar and Fordyce 51 Figure 1 SQV ddC 3TC saquinavir zalcitabine lamivudine AZT ddI d4T hard gel zidovudine didanosine stavudine 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 NVP SQV* saquinavir FTC nevirapine soft gel emtricitabine IDV DEL ABC indinavir delavirdine ATV abacavir atazanavir RTV NFV EFV APV ddIEC T-20 FPV TPV ritonavir nelfinavir efavirenz amprenavir didanosineEC enfuviritide fosamprenavir tipranavir 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 3TC/AZT LPV/RTV ABC/3TC/AZT ABC/3TC TDF/FTC Combivir Kaletra Trizivir Epzicom Truvada MVC ETR maraviroc RAL etravirine EVG elvitegravir DRV raltegravir NPVXR RPV DTG COBI** darunavir nevirapine rilpivirine dolutegravir cobicistat 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 TDF/FTC/RPV TDF/FTC/EFV Complera(STR) ATV/COBI DRV/COBI Atripla(STR) TDF/FTC/ Evotaz Prezcobix EVG/COBI Stribild(STR) TAF/FTC/ NRTI PI ABC/3TC/DTG EVG/COBI Triumeq(STR) Genvoya(STR) NNRTI Entry inhibitor INSTI Pharmacokinetic booster Current Opinion in Virology FDA-approved individual antiretroviral drugs and drug combinations. *Saquinavir soft gel (Fortovase) is no longer marketed. **COBI has no antiretroviral activity; COBI is a pharmacokinetic enhancer that is used to increase (boost) the systemic exposure of EVG and protease inhibitors; COBI is co-formulated in fixed dose combinations with ATV or DRV. ER, enteric-coated; XR, extended release; STR, single-tablet regimen. clinical decision in part facilitated by the improved agent such as an integrase strand transfer inhibitor tolerability and safety of contemporary cART drugs. (INSTI), a non-nucleoside reverse transcriptase inhibitor Antiretroviral regimens that contain at least two and (NNRTI), or a pharmacologically boosted protease inhib- preferably three active drugs from two or more classes itor (PI). Global and regional guidelines have generally are recommended for virologic suppression. Initial thera- consistent recommendations for first-line therapy py generally consists of two NRTIs combined with a third (Table 1); US and European guidelines have begun to www.sciencedirect.com Current Opinion in Virology 2016, 18:50–56 52 Antiviral strategies Table 1 a Recommended antiretroviral regimens for treatment-naı¨ve patients based on US DHHS guidelines Regimen Components STR available Comment NRTI NRTI Third agent INSTI-based ABC 3TC DTG Yes (Triumeq) Only for patients who are HLA-B*5701 negative TDF FTC DTG No TDF FTC EVG/COBI Yes (Stribild) Only for patients with pre-antiretroviral therapy CrCl >70 mL/min TAF FTC EVG/COBI Yes (Genvoya) Only for patients with pre-antiretroviral therapy CrCl 30 mL/min TDF FTC RAL No PI-based TDF FTC DRV/RTV No 3TC: lamivudine; ABC: abacavir; COBI: cobicistat; CrCl: creatinine clearance; DHHS: Department of Health and Human Services; DRV: darunavir; DTG: dolutegravir; EVG: elvitegravir; FTC: emtricitabine; INSTI: integrase strand transfer inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; PI: protease inhibitor; RAL: raltegravir; RTV: ritonavir; STR: single-tablet regimen; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate. a Based on guidelines developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents (https://aidsinfo.nih.gov/guidelines). emphasize INSTIs because of their high virologic efficacy on individuals at risk of acquiring HIV, recent evidence and excellent safety and tolerability profiles (e.g. Federally has highlighted the strong impact of cART on secondary approved HIV/AIDS medical practice guidelines; URL: HIV transmission. In HIV-infected individuals, low plas- https://aidsinfo.nih.gov/guidelines). Efavirenz and ataza- ma HIV RNA is associated with decreased concentration navir are no longer recommended because of long-recog- of virus in genital secretions [21–23], and HIV transmis- nized tolerability and safety concerns and the availability of sion risk is low when plasma viral loads are <400 copies/ better alternatives. Boosted PI-based treatment maintains mL [24]. In communities with high concentrations of clinical value due to high genetic barrier to resistance in HIV-infected individuals, the use of cART is associated patients at high risk for intermittent therapy because of with
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