Current status and prospects of HIV treatment

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ScienceDirect Current status and prospects of HIV treatment Tomas Cihlar1 and Marshall Fordyce2 Current antiviral treatments can reduce HIV-associated morbidity, prolong survival, and prevent HIV transmission. Combination antiretroviral therapy (cART) containing preferably three active drugs from two or more classes is required for durable virologic suppression. Regimen selection is based on virologic efficacy, potential for adverse effects, pill burden and dosing frequency, drug–drug interaction potential, resistance test results, comorbid conditions, social status, and cost. With prolonged virologic suppression, improved clinical outcomes, and longer survival, patients will be exposed to antiretroviral agents for decades. Therefore, maximizing the safety and tolerability of cART is a high priority. Emergence of resistance and/or lack of tolerability in individual patients require availability of a range of treatment options. Development of new drugs is focused on improving safety (e.g. tenofovir alafenamide) and/or resistance profile (e.g. doravirine) within the existing drug classes, combination therapies with improved adherence (e.g. single-tablet regimens), novel mechanisms of action (e.g. attachment inhibitors, maturation inhibitors, broadly neutralizing antibodies), and treatment simplification with infrequent dosing (e.g. long-acting injectables). In parallel with cART innovations, research and development efforts focused on agents that target persistent HIV reservoirs may lead to prolonged drug-free remission and HIV cure. Addresses 1 Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA 2 HIV Clinical Development, Gilead Sciences, Inc., Foster City, CA, USA Corresponding author: Cihlar, Tomas ([email protected])

at suppressing plasma viremia, and significant progress has been made toward regimen simplification through the combination of three active drugs into single-tablet regimens (STRs) (Figure 1) and optimization of drug profiles that maximize long-term tolerability and safety. Lifelong, chronic therapy without treatment interruption is the standard of care, and the availability of multiple effective drugs in several classes with differing resistance, safety, and tolerability profiles provides choices after failure of first-line treatment. Herein, we review the current status of antiretroviral therapy and guidelines for HIV-infected adults, as well as prospects for further innovation in HIV treatment to benefit patients and optimize their long-term health.

Goals of antiretroviral therapy Eradication of HIV cannot be achieved with current cART due to the pool of latently infected CD4 T cells established early during acute infection. However, cART can reduce HIV-associated morbidity, prolong survival, and prevent HIV transmission [1–4]. Maximal and durable suppression of plasma viremia restores and preserves immunologic function, delays or prevents the development of drug-resistant mutations, and may also decrease the immune activation and inflammation thought to contribute to end-organ damage [5–7]. Suppressing plasma viremia below detection limits is possible within weeks of 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 Edited by Raymond Schinazi and Erik De Clercq

http://dx.doi.org/10.1016/j.coviro.2016.03.004 1879-6257/# 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Since the approval of zidovudine (AZT) in 1987, over 25 antiretroviral agents in six mechanistic classes have been approved to treat HIV infection (Figure 1). Combination antiretroviral therapy (cART) is the treatment paradigm established in the late 1990s responsible for the dramatic decline in AIDS deaths and is composed of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a third active drug from a different class. Contemporary HIV treatment is highly effective Current Opinion in Virology 2016, 18:50–56

Morbidity and mortality in HIV-infected subjects is increasingly 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 cART, aging patient populations with HIV-1 infection experience more age-related comorbidities, such as diabetes, and cardiovascular, renal, and bone disease, which manifest earlier than in HIV-uninfected peers [10]. With prolonged virologic suppression, improved clinical outcomes, and longer survival, patients may be exposed to antiretroviral agents for decades [11]. Thus, maximizing the safety and tolerability of cART regimens while maintaining strong clinical efficacy is a high priority.

Guidelines and preferred regimens for firstline therapy Therapy used to be initiated based on decreasing CD4 cell count or clinical evidence of AIDS. More recently, therapy is being initiated regardless of the CD4 cell count, often immediately after a patient’s diagnosis, a www.sciencedirect.com

Treatment of HIV infection Cihlar and Fordyce 51

Figure 1

ddC AZT

ddI

zidovudine

didanosine

1986

1987

1988

nevirapine

DEL

IDV

RTV

NFV

EFV

nelfinavir

efavirenz

1997

1993

1994

1995

FTC emtricitabine

ATV atazanavir

ddIEC

APV

T-20 enfuviritide

amprenavir didanosineEC

1998

1999

2000

2001

2002

FPV

TPV

fosamprenavir

tipranavir

2003

2004

2005

3TC/AZT

LPV/RTV

ABC/3TC/AZT

ABC/3TC

TDF/FTC

Combivir

Kaletra

Trizivir

Epzicom

Truvada

MVC maraviroc

ETR RAL etravirine raltegravir

darunavir

2006

d4T

1992

abacavir

ritonavir

DRV

1991

ABC

delavirdine

1996

1990

saquinavir hard gel

lamivudine

stavudine

SQV* saquinavir soft gel

NVP indinavir

1989

SQV

3TC

zalcitabine

2007

2008

2009

NPVXR

RPV

nevirapine

rilpivirine

2010

2011

EVG DTG elvitegravir COBI** cobicistat

dolutegravir

2012

2013

2014

2015

TDF/FTC/RPV TDF/FTC/EFV

Complera(STR)

Atripla(STR)

TDF/FTC/ EVG/COBI

ATV/COBI

DRV/COBI

Evotaz

Prezcobix

Stribild(STR)

NRTI

PI

NNRTI

Entry inhibitor

INSTI

Pharmacokinetic booster

ABC/3TC/DTG

TAF/FTC/ EVG/COBI

Triumeq(STR)

Genvoya(STR)

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 tolerability and safety of contemporary cART drugs. Antiretroviral regimens that contain at least two and preferably three active drugs from two or more classes are recommended for virologic suppression. Initial therapy generally consists of two NRTIs combined with a third www.sciencedirect.com

agent such as an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a pharmacologically boosted protease inhibitor (PI). Global and regional guidelines have generally consistent recommendations for first-line therapy (Table 1); US and European guidelines have begun to Current Opinion in Virology 2016, 18:50–56

52 Antiviral strategies

Table 1 Recommended antiretroviral regimens for treatment-naı¨ve patients based on US DHHS guidelinesa Regimen

INSTI-based

PI-based

Components

STR available

NRTI

NRTI

Third agent

ABC TDF TDF TAF TDF

3TC FTC FTC FTC FTC

DTG DTG EVG/COBI EVG/COBI RAL

Yes (Triumeq) No Yes (Stribild) Yes (Genvoya) No

TDF

FTC

DRV/RTV

No

Comment

Only for patients who are HLA-B*5701 negative Only for patients with pre-antiretroviral therapy CrCl >70 mL/min Only for patients with pre-antiretroviral therapy CrCl 30 mL/min

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 and excellent safety and tolerability profiles (e.g. Federally approved HIV/AIDS medical practice guidelines; URL: https://aidsinfo.nih.gov/guidelines). Efavirenz and atazanavir are no longer recommended because of long-recognized tolerability and safety concerns and the availability of better alternatives. Boosted PI-based treatment maintains clinical value due to high genetic barrier to resistance in patients at high risk for intermittent therapy because of poor adherence. Recommended NRTIs are tenofovir disoproxil fumarate (TDF) or abacavir (ABC) used in combination with emtricitabine (FTC) or lamivudine (3TC). Although potent and generally well tolerated, TDF may cause clinically significant renal toxicity and is associated with greater reductions in bone mineral density than other antiretrovirals [12–15]. The novel prodrug tenofovir alafenamide (TAF) delivers approximately four-fold higher intracellular levels of the active metabolite tenofovir diphosphate at one-tenth of a dose relative to TDF, allowing for much lower doses of TAF versus TDF [16]. This lowers the plasma exposure of tenofovir by 90% relative to TDF, thereby reducing the risk of tenofovir-associated off-target effects. Another commonly used NRTI, ABC, is a preferred NRTI when co-administered with 3TC and dolutegravir (DTG). ABC is also associated with drug hypersensitivity, requires testing for the HLA B*5701 allele, and may be linked to increased rates of myocardial infarction [17–19]. Generally, selection of a regimen is centered on individual patients’ needs based on virologic efficacy, potential adverse effects, pill burden, dosing frequency, drug–drug interaction potential, resistance test results, comorbid conditions, and cost.

Treatment as prevention Despite advances in the prevention and treatment of HIV infection, the rate of new infections has remained relatively unchanged over the past decade [20]. While substantial efforts to prevent HIV transmission have focused Current Opinion in Virology 2016, 18:50–56

on individuals at risk of acquiring HIV, recent evidence has highlighted the strong impact of cART on secondary HIV transmission. In HIV-infected individuals, low plasma HIV RNA is associated with decreased concentration of virus in genital secretions [21–23], and HIV transmission risk is low when plasma viral loads are <400 copies/ mL [24]. In communities with high concentrations of HIV-infected individuals, the use of cART is associated with decreased community viral load and reduced rates of new HIV diagnoses [25–27]. Recent clinical evidence strongly supports the value of antiretroviral treatment as prevention in sero-discordant couples; patients taking cART had a 96% reduction in HIV transmission to their uninfected partners [28].

Management of treatment-experienced patients While current antiretroviral regimens for treatment-naı¨ve patients are highly effective and well tolerated, a regimen change may be needed in individual patients because of a lack of virologic suppression, drug adverse effects, or avoidance of drug–drug interaction with other medications [29]. Therapeutic goals for experienced patients remain the same as for naı¨ve patients: maintaining suppression of virus replication while enabling immune recovery and minimizing adverse drug effects. This requires a highly individualized approach and frequent monitoring as well as navigating the challenges of more limited treatment options. Treatment guidelines are important sources of information for the management of treatment-experienced subjects and include recommendations for drug resistance testing, management of drug-related adverse effects, and drug–drug interactions (Federally approved HIV/AIDS medical practice guidelines; URL: https://aidsinfo.nih. gov/guidelines). If a regimen change is needed due to resistance, ideally the new regimen should contain at least two or, preferably, www.sciencedirect.com

Treatment of HIV infection Cihlar and Fordyce 53

three fully active drugs [29]. New regimen construction requires careful review of patient treatment history and resistance testing. Genotypic resistance testing is routinely used as it is faster and cheaper than phenotypic testing and can quickly detect resistance due to the presence of known well-characterized mutations in the target viral gene(s). Virologic failure on the currently recommended first-line cART regimens due to emergence of drug resistance is rare [30,31,32]. Resistance emergence could be more frequent in NNRTI-containing first-line regimens compared with those containing boosted PIs [33] or INSTI [34]. Patients with multi-class resistance are undoubtedly the most challenging group to treat because of limited options. Depending on the nature and extent of the resistance, the options may include drug classes not generally recommended for initial therapy, such as entry inhibitors maraviroc (CCR5 inhibitor) or enfuvirtide (gp41 fusion inhibitor). Additional antiretroviral classes such as Gag maturation inhibitors and gp120 entry inhibitors are in clinical testing and could become valuable options for individuals with multi-class resistance. Another reason for changing an existing regimen can be adverse effects and lack of tolerability. Examples include central nervous system (CNS) toxicity associated with NNRTIs, particularly efavirenz, and lipid changes or gastrointestinal toxicity associated with boosted PIs [35]. After elimination of thymidine analogs from first-line therapy and introduction of pre-screening for ABC hypersensitivity, NRTI-associated toxicity is relatively rare and includes ABC-associated cardiovascular and lipid effects, and TDFassociated renal and bone effects. TAF, the novel prodrug of tenofovir, significantly reduces the renal and bone effects associated with TDF [36], and multiple switch studies from TDF to TAF are in progress (ClinicalTrials.gov Identifiers: NCT02345252 and NCT02345226). An alternative strategy could be a switch to an NRTI-sparing regimen. For example, an NRTI-sparing once-daily DTG + rilpivirine (RPV) regimen is being tested in Phase 3 switch studies (NCT02429791 and NCT02422797).

New drugs in clinical development Several new drugs from clinically validated classes are in advanced stages of development. Doravirine (formerly MK1439) is a potent novel NNRTI with a favorable resistance profile as it remains active against viruses with K103N and Y181C mutations [37]. Doravirine reduced HIV viral load by about 1.3 log in a 7-day monotherapy study [38]. Similar efficacy to efavirenz was shown in a follow-up study, but with fewer side effects, especially CNS-related, following treatment in combination with TDF/FTC [39]. Cabotegravir (formerly GSK1265744) is an orally bioavailable INSTI chemically related to DTG with potent activity and a long half-life [40]. Oral cabotegravir has shown antiretroviral efficacy in a short-term monotherapy trial [41], and an injectable nanosuspension-based formulation www.sciencedirect.com

administered subcutaneously or intramuscularly once every 4–8 weeks resulted in sufficient systemic drug exposures [42] and was effective as a long-acting therapy in combination with RPV (Margolis D et al., Abstract 31LB, CROI, Boston, MA, February 2016). GS-9883 is another novel unboosted INSTI currently being tested in treatmentnaı¨ve HIV-infected patients in combination with TAF and FTC (NCT02607930 and NCT02607956). Among the antiretrovirals with novel mechanisms, BMS663068 (fostemsavir) is an oral prodrug of HIV attachment inhibitor BMS-626529 [43]. BMS-626529 inhibits HIV entry into CD4 cells by binding to the gp120 envelope protein and preventing a conformational change that is normally required to bind HIV co-receptor [44]. In a Phase 2b, randomized, active-controlled trial in treatment-experienced subjects virologic response rates and immunologic reconstitution were similar across the BMS663068 and ritonavir-boosted atazanavir (ATV/r) arms through week 48 (Thompson M et al., Abstract 545, CROI, Seattle, WA, February 2015). Maturation inhibitors represent another novel class of antiretrovirals that specifically interfere with processing of the p24/p1 cleavage site in Gag polyprotein, a distinct mechanism of virus maturation inhibition from that exerted by HIV PIs. BMS-955176 is an oral once-daily second-generation maturation inhibitor with improved potency against HIV variants with Gag polymorphism over the first-generation inhibitors (Protack Y et al., Abstract, 15th European AIDS Conference, Barcelona, Spain, October 2015). In a proof-of-concept monotherapy study, 10-day dosing of BMS-955176 resulted in plasma viral load reduction of up to 1.7 log10 copies/mL (Hwang C et al., Abstract 114LB, CROI, Seattle, WA, February 2015). In combination with ATV +/ ritonavir (RTV), BMS-955176 was well tolerated and showed clinical efficacy (Hwang C et al., Abstract PS10/5, 15th European AIDS Conference, Barcelona, Spain, October 2015). GSK2838232 is another second-generation maturation inhibitor active against HIV isolates resistant to bevirimat (Jeffrey J et al., Abstract 538, CROI, Seattle, WA, February 2015). Its clinical development began by testing it alone and in combination with RTV in healthy subjects (NCT02289495). Broadly neutralizing antibodies (bNAbs) targeting the viral envelope have been tested in small proof-of-concept Phase 1 monotherapy studies. Antibodies 3BNC117 and VRC01 have shown HIV suppression in several subjects, but resistance emergence and/or preexisting HIV variants refractory to the treatment are among current concerns [45,46]. In contrast to bNAbs, the antibody PRO140 targets CXCR5 co-receptor and provided sustained virologic suppression in a Phase 2b study in HIV-infected subjects who switched from their suppressive antiretroviral therapy to a subcutaneously self-administered Current Opinion in Virology 2016, 18:50–56

54 Antiviral strategies

monotherapy with PRO140 once weekly for >1 year (Cytodyn press release; URL: http://www.cytodyn.com/ media/press-releases/detail/223/cytodyn-reports-fullvirologic-suppression-in-eleven-hiv).

Future directions of HIV treatment In addition to durable efficacy, safety and tolerability will continue to play an important role in the long-term success of HIV therapies. In addition, further simplification of antiretroviral regimens will likely be a focus of future clinical development [47]. At least two 2-drug STRs (DTG/RPV and 3TC/DTG) are being developed, challenging the paradigm of two-NRTI backbone combined with a third agent. 3TC/DTG combination has shown promising results in a small proof-of-concept study in treatment-naı¨ve patients after 24 weeks of treatment (Figueroa MI et al., abstract LBPS4/1, 15th European AIDS Conference, Barcelona, Spain, October 2015). Additional once-daily NRTI-sparing regimens such as DTG + cobicistat-boosted darunavir (DRV) are planned to be tested (NCT02499978 and NCT02486133). While encouraging results may be obtained from 24-week to 48week trials, it will be important to establish the longerterm durability of viral suppression without resistance emergence of the 2-drug regimens side-by-side with the currently preferred 3-drug regimens. Long-acting injectable formulations of drugs with established oral efficacy such as cabotegravir and RPV will be assessed in Phase 3 registrational trials and, if proven to show long-term safety and efficacy, would provide additional options for simplified and potentially more convenient maintenance therapy. However, long-term sustainability and tolerability of monthly/bi-monthly intramuscular injections needs to be established. Other sustained-release drug delivery technologies may further increase the convenience of antiretroviral therapy, but these would likely require more potent drugs due to the limited capacity of patches, implants and other currently available drug delivery technologies. Antiretroviral drugs with new mechanisms of action such as the attachment and maturation inhibitors are in advanced stages of clinical testing and, if approved, would broaden treatment options especially for individuals with multi-class resistance needing salvage therapy. Hopefully, one or more of these new class agents will be suitable for co-formulation with existing antiretrovirals to generate STRs for second-line and third-line therapies. These advancements in the development of new antiretroviral therapies and treatment paradigms will be happening in parallel with the increased availability of generic antiretrovirals. In the absence of an efficacious vaccine, the effective and widespread use of antiretrovirals for treatment and prevention is the key approach to curb the global AIDS epidemics. Therefore, these innovations will be Current Opinion in Virology 2016, 18:50–56

essential to achieve the ambitious goals in global implementation of antiretroviral therapy. In 2014, UNAIDS set a ‘90–90–90’ target aiming to diagnose 90% of all people infected with HIV, provide treatment for 90% of those diagnosed, and achieve full viral suppression in 90% of those on treatment by 2020 (UNAIDS; URL: http://www. unaids.org/en/resources/documents/2014/90-90-90). This translates into successfully treating >70% of all individuals infected with HIV, representing almost 25 million people worldwide. In parallel with antiretroviral therapy innovations, research and development efforts are expanding toward new therapeutic approaches for targeting persistent HIV reservoirs that may lead to prolonged drug-free remission of the infection and potentially to HIV cure [48,49]. These new directions are focused on latencyreversing agents to activate the viral reservoirs, immunotherapies including innate immunity activators and effector antibodies, gene therapies, and therapeutic vaccines to eliminate the persistent viral reservoirs or induce effective immune control of HIV infection [48,49]. All these efforts are in early stages of testing, and long-term systematic research and commitment will be necessary to assess their true therapeutic potential. Ultimately, these technologies may lead to fundamental changes in the HIV healthcare.

Acknowledgment Becky Norquist provided medical writing support.

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