Current Status and Prospects of HIV Treatment

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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

Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA the immune activation and inﬂammation thought to con-

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

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.

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 decreased community viral load and reduced rates of

poor adherence. new HIV diagnoses [25–27]. Recent clinical evidence

strongly supports the value of antiretroviral treatment

Recommended NRTIs are tenofovir disoproxil fumarate as prevention in sero-discordant couples; patients taking

(TDF) or abacavir (ABC) used in combination with cART had a 96% reduction in HIV transmission to their

emtricitabine (FTC) or lamivudine (3TC). Although uninfected partners [28].

potent and generally well tolerated, TDF may cause

clinically signiﬁcant renal toxicity and is associated with

Management of treatment-experienced

greater reductions in bone mineral density than other patients

antiretrovirals [12–15]. The novel prodrug tenofovir ala-

While current antiretroviral regimens for treatment-naı¨ve

fenamide (TAF) delivers approximately four-fold higher

patients are highly effective and well tolerated, a regimen

intracellular levels of the active metabolite tenofovir

change may be needed in individual patients because of a

diphosphate at one-tenth of a dose relative to TDF,

lack of virologic suppression, drug adverse effects, or

allowing for much lower doses of TAF versus TDF

avoidance of drug–drug interaction with other medica-

[16 ]. This lowers the plasma exposure of tenofovir by

tions [29]. Therapeutic goals for experienced patients

90% relative to TDF, thereby reducing the risk of teno-

remain the same as for naı¨ve patients: maintaining sup-

fovir-associated off-target effects. Another commonly

pression of virus replication while enabling immune

used NRTI, ABC, is a preferred NRTI when co-admin-

recovery and minimizing adverse drug effects. This

istered with 3TC and dolutegravir (DTG). ABC is also

requires a highly individualized approach and frequent

associated with drug hypersensitivity, requires testing for

monitoring as well as navigating the challenges of more

the HLA B*5701 allele, and may be linked to increased

limited treatment options.

rates of myocardial infarction [17–19]. Generally, selec-

tion of a regimen is centered on individual patients’ needs

Treatment guidelines are important sources of informa-

based on virologic efﬁcacy, potential adverse effects, pill

tion for the management of treatment-experienced sub-

burden, dosing frequency, drug–drug interaction poten-

jects and include recommendations for drug resistance

tial, resistance test results, comorbid conditions, and cost.

testing, management of drug-related adverse effects, and

drug–drug interactions (Federally approved HIV/AIDS

Treatment as prevention medical practice guidelines; URL: https://aidsinfo.nih.

Despite advances in the prevention and treatment of HIV gov/guidelines).

infection, the rate of new infections has remained rela-

tively unchanged over the past decade [20]. While sub- If a regimen change is needed due to resistance, ideally the

stantial efforts to prevent HIV transmission have focused new regimen should contain at least two or, preferably,

Current Opinion in Virology 2016, 18:50–56 www.sciencedirect.com

Treatment of HIV infection Cihlar and Fordyce 53

three fully active drugs [29]. New regimen construction administered subcutaneously or intramuscularly once every

requires careful review of patient treatment history and 4–8 weeks resulted in sufﬁcient systemic drug exposures

resistance testing. Genotypic resistance testing is routinely [42 ] and was effective as a long-acting therapy in combi-

used as it is faster and cheaper than phenotypic testing and nation with RPV (Margolis D et al., Abstract 31LB, CROI,

can quickly detect resistance due to the presence of known Boston, MA, February 2016). GS-9883 is another novel

well-characterized mutations in the target viral gene(s). unboosted INSTI currently being tested in treatment-

naı¨ve HIV-infected patients in combination with TAF

Virologic failure on the currently recommended ﬁrst-line and FTC (NCT02607930 and NCT02607956).

cART regimens due to emergence of drug resistance is

rare [30,31,32 ]. Resistance emergence could be more Among the antiretrovirals with novel mechanisms, BMS-

frequent in NNRTI-containing ﬁrst-line regimens com- 663068 (fostemsavir) is an oral prodrug of HIV attachment

pared with those containing boosted PIs [33] or INSTI inhibitor BMS-626529 [43]. BMS-626529 inhibits HIV

[34]. Patients with multi-class resistance are undoubtedly entry into CD4 cells by binding to the gp120 envelope

the most challenging group to treat because of limited protein and preventing a conformational change that is

options. Depending on the nature and extent of the normally required to bind HIV co-receptor [44]. In a

resistance, the options may include drug classes not Phase 2b, randomized, active-controlled trial in treat-

generally recommended for initial therapy, such as entry ment-experienced subjects virologic response rates and

inhibitors maraviroc (CCR5 inhibitor) or enfuvirtide immunologic reconstitution were similar across the BMS-

(gp41 fusion inhibitor). Additional antiretroviral classes 663068 and ritonavir-boosted atazanavir (ATV/r) arms

such as Gag maturation inhibitors and gp120 entry inhi- through week 48 (Thompson M et al., Abstract 545,

bitors are in clinical testing and could become valuable CROI, Seattle, WA, February 2015).

options for individuals with multi-class resistance.

Maturation inhibitors represent another novel class of

Another reason for changing an existing regimen can be antiretrovirals that speciﬁcally interfere with processing

adverse effects and lack of tolerability. Examples include of the p24/p1 cleavage site in Gag polyprotein, a distinct

central nervous system (CNS) toxicity associated with mechanism of virus maturation inhibition from that

NNRTIs, particularly efavirenz, and lipid changes or gas- exerted by HIV PIs. BMS-955176 is an oral once-daily

trointestinal toxicity associated with boosted PIs [35]. After second-generation maturation inhibitor with improved

elimination of thymidine analogs from ﬁrst-line therapy potency against HIV variants with Gag polymorphism

and introduction of pre-screening for ABC hypersensitivi- over the ﬁrst-generation inhibitors (Protack Y et al., Ab-

ty, NRTI-associated toxicity is relatively rare and includes stract, 15th European AIDS Conference, Barcelona,

ABC-associated cardiovascular and lipid effects, and TDF- Spain, October 2015). In a proof-of-concept monotherapy

associated renal and bone effects. TAF, the novel prodrug study, 10-day dosing of BMS-955176 resulted in plasma

of tenofovir, signiﬁcantly reduces the renal and bone viral load reduction of up to 1.7 log10 copies/mL (Hwang

effects associated with TDF [36 ], and multiple switch C et al., Abstract 114LB, CROI, Seattle, WA, February

studies from TDF to TAF are in progress (ClinicalTrials.- 2015). In combination with ATV +/À ritonavir (RTV),

gov Identiﬁers: NCT02345252 and NCT02345226). An BMS-955176 was well tolerated and showed clinical

alternative strategy could be a switch to an NRTI-sparing efﬁcacy (Hwang C et al., Abstract PS10/5, 15th European

regimen. For example, an NRTI-sparing once-daily AIDS Conference, Barcelona, Spain, October 2015).

DTG + rilpivirine (RPV) regimen is being tested in Phase GSK2838232 is another second-generation maturation

3 switch studies (NCT02429791 and NCT02422797). inhibitor active against HIV isolates resistant to bevirimat

(Jeffrey J et al., Abstract 538, CROI, Seattle, WA, Febru-

New drugs in clinical development ary 2015). Its clinical development began by testing it

Several new drugs from clinically validated classes are in alone and in combination with RTV in healthy subjects

advanced stagesofdevelopment.Doravirine (formerly MK- (NCT02289495).

1439) is a potent novel NNRTI with a favorable resistance

proﬁle as it remains active against viruses with K103N and Broadly neutralizing antibodies (bNAbs) targeting the

Y181C mutations [37]. Doravirine reduced HIV viral load viral envelope have been tested in small proof-of-concept

by about 1.3 log in a 7-day monotherapy study [38]. Similar Phase 1 monotherapy studies. Antibodies 3BNC117 and

efﬁcacy to efavirenz was shown in a follow-up study, but VRC01 have shown HIV suppression in several subjects,

with fewer side effects, especially CNS-related, following but resistance emergence and/or preexisting HIV variants

treatment in combination with TDF/FTC [39]. Cabote- refractory to the treatment are among current concerns

gravir (formerly GSK1265744) is an orally bioavailable [45 ,46]. In contrast to bNAbs, the antibody PRO140

INSTI chemically related to DTG with potent activity targets CXCR5 co-receptor and provided sustained viro-

and a long half-life [40]. Oral cabotegravir has shown logic suppression in a Phase 2b study in HIV-infected

antiretroviral efﬁcacy in a short-term monotherapy trial subjects who switched from their suppressive antiretro-

[41], and an injectable nanosuspension-based formulation viral therapy to a subcutaneously self-administered

www.sciencedirect.com Current Opinion in Virology 2016, 18:50–56

54 Antiviral strategies

monotherapy with PRO140 once weekly for >1 year essential to achieve the ambitious goals in global imple-

(Cytodyn press release; URL: http://www.cytodyn.com/ mentation of antiretroviral therapy. In 2014, UNAIDS set a

media/press-releases/detail/223/cytodyn-reports-full- ‘90–90–90’ target aiming to diagnose 90% of all people

virologic-suppression-in-eleven-hiv). infected with HIV, provide treatment for 90% of those

diagnosed, and achieve full viral suppression in 90% of

Future directions of HIV treatment those on treatment by 2020 (UNAIDS; URL: http://www.

In addition to durable efﬁcacy, safety and tolerability will unaids.org/en/resources/documents/2014/90-90-90). This

continue to play an important role in the long-term translates into successfully treating >70% of all individuals

success of HIV therapies. In addition, further simpliﬁca- infected with HIV, representing almost 25 million people

tion of antiretroviral regimens will likely be a focus of worldwide.

future clinical development [47]. At least two 2-drug

STRs (DTG/RPV and 3TC/DTG) are being developed, In parallel with antiretroviral therapy innovations, re-

challenging the paradigm of two-NRTI backbone com- search and development efforts are expanding toward

bined with a third agent. 3TC/DTG combination has new therapeutic approaches for targeting persistent

shown promising results in a small proof-of-concept study HIV reservoirs that may lead to prolonged drug-free

in treatment-naı¨ve patients after 24 weeks of treatment remission of the infection and potentially to HIV cure

(Figueroa MI et al., abstract LBPS4/1, 15th European [48,49]. These new directions are focused on latency-

AIDS Conference, Barcelona, Spain, October 2015). Ad- reversing agents to activate the viral reservoirs, immu-

ditional once-daily NRTI-sparing regimens such as notherapies including innate immunity activators and

DTG + cobicistat-boosted darunavir (DRV) are planned effector antibodies, gene therapies, and therapeutic vac-

to be tested (NCT02499978 and NCT02486133). While cines to eliminate the persistent viral reservoirs or induce

encouraging results may be obtained from 24-week to 48- effective immune control of HIV infection [48,49]. All

week trials, it will be important to establish the longer- these efforts are in early stages of testing, and long-term

term durability of viral suppression without resistance systematic research and commitment will be necessary to

emergence of the 2-drug regimens side-by-side with the assess their true therapeutic potential. Ultimately, these

currently preferred 3-drug regimens. technologies may lead to fundamental changes in the

HIV healthcare.

Long-acting injectable formulations of drugs with estab-

lished oral efﬁcacy such as cabotegravir and RPV will be Acknowledgment

assessed in Phase 3 registrational trials and, if proven to Becky Norquist provided medical writing support.

show long-term safety and efﬁcacy, would provide addi-

tional options for simpliﬁed and potentially more conve- References and recommended reading

Papers of particular interest, published within the period of review,

nient maintenance therapy. However, long-term

have been highlighted as:

sustainability and tolerability of monthly/bi-monthly in-

of special interest

tramuscular injections needs to be established. Other

of outstanding interest

sustained-release drug delivery technologies may further

increase the convenience of antiretroviral therapy, but 1. Mocroft A, Vella S, Benﬁeld TL, Chiesi A, Miller V, Gargalianos P,

d’Arminio Monforte A, Yust I, Bruun JN, Phillips AN et al.:

these would likely require more potent drugs due to the

Changing patterns of mortality across Europe in patients

limited capacity of patches, implants and other currently

infected with HIV-1. EuroSIDA Study Group. Lancet 1998,

available drug delivery technologies. 352:1725-1730.

2. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J,

Satten GA, Aschman DJ, Holmberg SD: Declining morbidity and

Antiretroviral drugs with new mechanisms of action such

mortality among patients with advanced human

as the attachment and maturation inhibitors are in ad- immunodeﬁciency virus infection. HIV Outpatient Study

vanced stages of clinical testing and, if approved, would Investigators. N Engl J Med 1998, 338:853-860.

broaden treatment options especially for individuals with 3. Vittinghoff E, Scheer S, O’Malley P, Colfax G, Holmberg SD,

Buchbinder SP: Combination antiretroviral therapy and recent

multi-class resistance needing salvage therapy. Hopeful-

declines in AIDS incidence and mortality. J Infect Dis 1999,

ly, one or more of these new class agents will be suitable 179:717-720.

for co-formulation with existing antiretrovirals to generate

4. Antiretroviral Therapy Cohort Collaboration: Life expectancy of

STRs for second-line and third-line therapies. individuals on combination antiretroviral therapy in high-

income countries: a collaborative analysis of 14 cohort

studies. Lancet 2008, 372:293-299.

These advancements in the development of new antire-

5. O’Brien WA, Hartigan PM, Martin D, Esinhart J, Hill A, Benoit S,

troviral therapies and treatment paradigms will be happen-

Rubin M, Simberkoff MS, Hamilton JD: Changes in plasma HIV-1

ing in parallel with the increased availability of generic RNA and CD4+ lymphocyte counts and the risk of progression

to AIDS. Veterans Affairs Cooperative Study Group on AIDS.

antiretrovirals. In the absence of an efﬁcacious vaccine, the

N Engl J Med 1996, 334:426-431.

effective and widespread use of antiretrovirals for treat-

6. Garcia F, Plana M, Arnedo M, Brunet M, Castro P, Gil C, Vidal E,

ment and prevention is the key approach to curb the global

Millan O, Lopez A, Martorell J et al.: Effect of mycophenolate

AIDS epidemics. Therefore, these innovations will be mofetil on immune response and plasma and lymphatic tissue

Current Opinion in Virology 2016, 18:50–56 www.sciencedirect.com

Treatment of HIV infection Cihlar and Fordyce 55

viral load during and after interruption of highly active 19. Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG:

antiretroviral therapy for patients with chronic HIV infection: a Cardiovascular risks associated with abacavir and tenofovir

randomized pilot study. J Acquir Immune Deﬁc Syndr 2004, exposure in HIV-infected persons. AIDS 2011, 25:1289-1298.

36:823-830.

20. Prejean J, Song R, Hernandez A, Ziebell R, Green T, Walker F,

7. Yamashita TE, Phair JP, Munoz A, Margolick JB, Detels R, Lin LS, An Q, Mermin J, Lansky A et al.: Estimated HIV incidence

O’Brien SJ, Mellors JW, Wolinsky SM, Jacobson LP: in the United States, 2006–2009. PloS ONE 2011, 6:e17502.

Immunologic and virologic response to highly active

antiretroviral therapy in the Multicenter AIDS Cohort Study. 21. Baeten JM, Kahle E, Lingappa JR, Coombs RW, Delany-

AIDS 2001, 15:735-746. Moretlwe S, Nakku-Joloba E, Mugo NR, Wald A, Corey L,

Donnell D et al.: Genital HIV-1 RNA predicts risk of heterosexual

8. Center for Disease Control and Prevention: . Rev ed.. HIV/AIDS HIV-1 transmission. Sci Transl Med 2011, 3:77ra29.

Surveillance Report, 2005. U.S. Department of Health and

Human Services, Centers for Disease Control and Prevention; 22. Sheth PM, Kovacs C, Kemal KS, Jones RB, Raboud JM, Pilon R, la

2007: pp. 1–54. Also available at: http://www.cdc.gov/hiv/topics/ Porte C, Ostrowski M, Loutfy M, Burger H et al.: Persistent HIV

surveillance/resources/reports/. RNA shedding in semen despite effective antiretroviral

therapy. AIDS 2009, 23:2050-2054.

9. Selik RM, Byers RH Jr, Dworkin MS: Trends in diseases reported

on U.S. death certiﬁcates that mentioned HIV infection, 1987– 23. Graham SM, Holte SE, Peshu NM, Richardson BA, Panteleeff DD,

1999. J Acquir Immune Deﬁc Syndr 2002, 29:378-387. Jaoko WG, Ndinya-Achola JO, Mandaliya KN, Overbaugh JM,

McClelland RS: Initiation of antiretroviral therapy leads to a

10. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, rapid decline in cervical and vaginal HIV-1 shedding.

Berti A, Rossi E, Roverato A, Palella F: Premature age-related AIDS 2007, 21:501-507.

comorbidities among HIV-infected persons compared with

the general population. Clin Infect Dis 2011, 53:1120-1126. 24. Attia S, Egger M, Muller M, Zwahlen M, Low N: Sexual

This article identiﬁes age related comorbidities that are more common transmission of HIV according to viral load and antiretroviral

among HIV-infected patients and tend to occur 10 years earlier than the therapy: systematic review and meta-analysis. AIDS 2009,

general population. Risk factors include lower nadir CD4 cell count and 23:1397-1404.

longer exposure to antiretroviral therapies.

25. Das M, Chu PL, Santos GM, Scheer S, Vittinghoff E, McFarland W,

11. Lewden C, Chene G, Morlat P, Rafﬁ F, Dupon M, Dellamonica P, Colfax GN: Decreases in community viral load are

Pellegrin JL, Katlama C, Dabis F, Leport C et al.: HIV-infected accompanied by reductions in new HIV infections in San

adults with a CD4 cell count greater than 500 cells/mm on Francisco. PloS ONE 2010, 5:e11068.

long-term combination antiretroviral therapy reach same

mortality rates as the general population. J Acquir Immune 26. Montaner JS, Lima VD, Barrios R, Yip B, Wood E, Kerr T,

Association of

Deﬁc Syndr 2007, 46:72-77. Shannon K, Harrigan PR, Hogg RS, Daly P et al.:

highly active antiretroviral therapy coverage, population viral

Report describing a subset of HIV-infected individuals on cART who

load, and yearly new HIV diagnoses in British Columbia,

achieved a CD4 count 500 cells/mm with a resultant life expectancy

Canada: a population-based study similar to the general population. . Lancet 2010,

376:532-539.

12. Mocroft A, Kirk O, Reiss P, De Wit S, Sedlacek D, Beniowski M,

Gatell J, Phillips AN, Ledergerber B, Lundgren JD et al.: Estimated 27. Porco TC, Martin JN, Page-Shafer KA, Cheng A, Charlebois E,

glomerular ﬁltration rate, chronic kidney disease and Grant RM, Osmond DH: Decline in HIV infectivity following the

antiretroviral drug use in HIV-positive patients. AIDS 2010, introduction of highly active antiretroviral therapy. AIDS 2004,

24:1667-1678. 18:81-88.

13. Morlat P, Vivot A, Vandenhende MA, Dauchy FA, Asselineau J, 28. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC,

Deti E, Gerard Y, Lazaro E, Duffau P, Neau D et al.: Role of Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH

traditional risk factors and antiretroviral drugs in the incidence et al.: Prevention of HIV-1 infection with early antiretroviral

of chronic kidney disease, ANRS CO3 Aquitaine cohort, therapy. N Engl J Med 2011, 365:493-505.

France, 2004–2012. PloS ONE 2013, 8:e66223.

29. Calvo KR, Daar ES: Antiretroviral therapy: treatment-

14. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, experienced individuals. Infect Dis Clin North Am 2014,

Myers L, Melbourne K, Ha B, Sax PE: Bone mineral density and 28:439-456.

fractures in antiretroviral-naive persons randomized to

30. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D,

receive abacavir-lamivudine or tenofovir disoproxil fumarate-

Gallant JE, Liu HC, Zhong L, Yale K et al.: Co-formulated

emtricitabine along with efavirenz or atazanavir-ritonavir: Aids

elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-

Clinical Trials Group A5224s, a substudy of ACTG A5202.

formulated efavirenz, emtricitabine, and tenofovir for initial

J Infect Dis 2011, 203:1791-1801.

treatment of HIV-1 infection: a randomised, double-blind,

15. Gilead Sciences Inc: VIREAD (tenofovir disoproxil fumarate) phase 3 trial, analysis of results after 48 weeks. Lancet 2012,

tablets, for oral use VIREAD (tenofovir disoproxil fumarate) 379:2439-2448.

powder, for oral use. U.S. Prescribing Information; 2013.

31. DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J,

16. Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K et al.:

Callebaut C, Zhong L, Ramanathan S, Rhee MS, Fordyce MW Co-formulated elvitegravir, cobicistat, emtricitabine, and

et al.: Antiviral activity, safety, and pharmacokinetics/ tenofovir disoproxil fumarate versus ritonavir-boosted

pharmacodynamics of tenofovir alafenamide as 10-day atazanavir plus co-formulated emtricitabine and tenofovir

monotherapy in HIV-1-positive adults. J Acquir Immune Deﬁc disoproxil fumarate for initial treatment of HIV-1 infection: a

Syndr 2013, 63:449-455. randomised, double-blind, phase 3, non-inferiority trial. Lancet

This report of a Phase 1b monotherapy trial provides initial evidence of 2012, 379:2429-2438.

superior efﬁcacy of TAF over TDF at 1/10th the dose level.

32. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A,

17. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Gutierrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C

Wit S, Law M, D’Arminio Monforte A, Friis-Moller N et al.: Use of et al.: Dolutegravir plus abacavir-lamivudine for the treatment

nucleoside reverse transcriptase inhibitors and risk of of HIV-1 infection. N Engl J Med 2013, 369:1807-1818.

myocardial infarction in HIV-infected patients enrolled in the Report of a Phase 3 clinical study demontrating higher efﬁcacy and fewer

D:A:D study: a multi-cohort collaboration. Lancet 2008, discontinuations due to side effects of DTG/ABC/3TC regimen compared

371:1417-1426. with EFV/TDF/FTC regimen in treatment-naı¨ve HIV-infected patients after

48 weeks.

18. Obel N, Farkas DK, Kronborg G, Larsen CS, Pedersen G, Riis A,

Pedersen C, Gerstoft J, Sorensen HT: Abacavir and risk of 33. Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C,

myocardial infarction in HIV-infected patients on highly active Godfrey C, Jahed NC, Myers L, Katzenstein D et al.: Atazanavir

antiretroviral therapy: a population-based nationwide cohort plus ritonavir or efavirenz as part of a 3-drug regimen for initial

study. HIV Med 2010, 11:130-136. treatment of HIV-1. Ann Intern Med 2011, 154:445-456.

www.sciencedirect.com Current Opinion in Virology 2016, 18:50–56

56 Antiviral strategies

34. Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, integrase strand transfer inhibitor. HIV Clin Trials 2013,

Khuong-Josses MA, Kilby JM, Lutz T, Podzamczer D, Portilla J 14:192-203.

et al.: Brief report: dolutegravir plus abacavir/lamivudine for

the treatment of HIV-1 infection in antiretroviral therapy-naive 42. Trezza C, Ford SL, Spreen W, Pan R, Piscitelli S: Formulation and

patients: week 96 and week 144 results from the SINGLE pharmacology of long-acting cabotegravir. Curr Opin HIV AIDS

randomized clinical trial. J Acquir Immune Deﬁc Syndr 2015, 2015, 10:239-245.

70:515-519. This report describes the pharmacokinetics after intramuscular and

subcutaneous administration of long-acting formulations of cabotegravir.

35. Margolis AM, Heverling H, Pham PA, Stolbach A: A review of the The data indicate that clinically relevant concentrations for HIV main-

toxicity of HIV medications. J Med Toxicol 2014, 10:26-39. tenance therapy may occur with monthly or bi-monthly dosing.

36. Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, Pozniak A,

43. Nowicka-Sans B, Gong YF, McAuliffe B, Dicker I, Ho HT, Zhou N,

Thompson M, Podzamczer D, Molina JM et al.: Tenofovir

Eggers B, Lin PF, Ray N, Wind-Rotolo M et al.: In vitro antiviral

alafenamide versus tenofovir disoproxil fumarate,

characteristics of HIV-1 attachment inhibitor BMS-626529, the

coformulated with elvitegravir, cobicistat, and emtricitabine,

active component of the prodrug BMS-663068. Antimicrob

for initial treatment of HIV-1 infection: two randomised,

Agents Chemother 2012, 56:3498-3507.

double-blind, phase 3, non-inferiority trials. Lancet 2015,

385:2606-2615. 44. Langley DR, Kimura SR, Sivaprakasam P, Zhou N, Dicker I,

Report describing two Phase 3 registrational studies for TAF-containing McAuliffe B, Wang T, Kadow JF, Meanwell NA, Krystal M:

STR. The results demonstrated the same efﬁcacy, but signiﬁcantly Homology models of the HIV-1 attachment inhibitor BMS-

reduced renal and bone effects of TAF-containing STR versus TDF- 626529 bound to gp120 suggest a unique mechanism of

containing STR. action. Proteins 2015, 83:331-350.

37. Lai MT, Feng M, Falgueyret JP, Tawa P, Witmer M, DiStefano D,

45. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr,

Li Y, Burch J, Sachs N, Lu M et al.: In vitro characterization of

Buckley N, Kremer G, Nogueira L, Braunschweig M, Scheid JF

MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase

et al.: Viraemia suppressed in HIV-1-infected humans by

inhibitor. Antimicrob Agents Chemother 2014, 58:1652-1663.

broadly neutralizing antibody 3BNC117. Nature 2015,

522(7557):487-491.

38. Schurmann D, Sobotha C, Gilmartin J, Robberechts M, De

This is the ﬁrst report of a Phase 1 clinical testing of a broadly neutralizing

Lepeleire I, Yee KL, Guo Y, Liu R, Wagner F, Wagner JA et al.: A

antibody in HIV-infected subjects. The study provides initial evidence of

randomized, double-blind, placebo-controlled, short-term

antiviral activity of broadly neutralizing antibody 3BNC117 in a subset of

monotherapy study of doravirine in treatment-naive HIV-

treated individuals. The data also emphasize the potential for pre-existing

infected individuals. AIDS 2016, 30:57-63.

and acquired resistance to monoclonal antibodies.

39. Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M,

46. Lynch RM, Boritz E, Coates EE, DeZure A, Madden P, Costner P,

Keikawus A, Hoffmann C, Rugina S, Osiyemi O, Escoriu S,

Enama ME, Plummer S, Holman L, Hendel CS et al.: Virologic

Dretler R et al.: Forty-eight-week efﬁcacy and safety and early

effects of broadly neutralizing antibody VRC01 administration

CNS tolerability of doravirine (MK-1439), a novel NNRTI, with

during chronic HIV-1 infection. Sci Transl Med 2015, 7:319ra206.

TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc

2014, 17(Suppl. 3):19532.

47. Gulick R: HIV treatment 2020: what will it look like? J Int AIDS

Soc 2014, 17(Suppl. 3):19528.

40. Ford SL, Gould E, Chen S, Margolis D, Spreen W, Crauwels H,

Piscitelli S: Lack of pharmacokinetic interaction between

48. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM:

rilpivirine and integrase inhibitors dolutegravir and

Eradicating HIV-1 infection: seeking to clear a persistent

GSK1265744. Antimicrob Agents Chemother 2013, 57:5472-5477.

pathogen. Nat Rev Microbiol 2014, 12:750-764.

41. Spreen W, Min S, Ford SL, Chen S, Lou Y, Bomar M, St Clair M,

49. Chun TW, Moir S, Fauci AS: HIV reservoirs as obstacles and

Piscitelli S, Fujiwara T: Pharmacokinetics, safety, and

opportunities for an HIV cure. Nat Immunol 2015, 16:584-589.

monotherapy antiviral activity of GSK1265744, an HIV

Current Opinion in Virology 2016, 18:50–56 www.sciencedirect.com