51

Initiation Progression Complication

hsCRP, MCP-1 OPG, IL-6

TNF-alpha, IL-10

ICAM-1, VCAM-1 E-Selectin, P-Selectin Insulin, Adiponectin

D-dimer

Inflammation Endothelial dysfunction

Insulin resistance Hypercoagulability

Chronic inflamation Immuneactivation/senescence

CD38+HLA-DR+CD8 T cells CD28-CD57+ CD8 T cells, resit. to apoptosis, shortened telomers

Switching strategies (monotherapy & double therapy) in suppressed patients usually consist on:

In the past and now: Replacing 2NRTI+1IP/r by

LPV/r monotherapy (OKT4, PIVOT) DRV/r monotherapy (MONET, MONOI, PROTEA, PIVOT)

LPV/r+3TC (OLE)

ATV/r+3TC (SALT)

DRV/r+3TC (DUAL) DTG +3TC (DOLAM,…..)

A. The HIV infected individual B. The pandemic C. In summary….

Approaches to HIV management: Horizon 2020

B. The pandemic Towards an AIDS free generation ….

in 2030 …… ?

Approaches to HIV management: Horizon 2020

clinicaloptions.com/hiv Starting Antiretroviral Therapy in 2012: A Compendium of Interactive Cases

HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples

Single transmission in patient in immediate HAART arm believed to have occurred close to time therapy began and prior to suppression of genital tract HIV

Total HIV-1 Transmission Events: 39 (4 in immediate arm and

35 in delayed arm; P < .001)

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

P < .001

Immediate Arm: 1

Delayed Arm: 27

Cohen MS, et al. N Engl J Med. 2011;365:493-505.

•  “Modelling  by  UNAIDS  indicates  that  the  world  has  a  brief,  five-­‐year  window  of  opportunity  to  lay  the  founda?on  to  end  the  AIDS  epidemic  as  a  public  health  threat.”  

Cascade of HIV care – Switzerland 2012

81%   80%   79%  71%   68%  

0%  

20%  

40%  

60%  

80%  

100%  

HIV  Posi?ve  People   Diagnosed   Linked  to  care   Retained  in  Care   On  ART   Viral  Supression  <200  copies/ml  

12,700   12,300  

10,700  11,200  

15,700  

12,600  

Breakpoint 1 Breakpoint

2

Cascade of HIV care, Switzerland 2012

Slide 60 of 44

SIVES, Catalunya june 2013

20% Lack of adherence to general health recommendations

7% Lack of adherence to prescribed ART

25% Lack of diagnosis

61

individuals in care required antiretroviral therapy, but !27%

declined or failed to initiate therapy [47]. We estimate that 80%

of in-care HIV-infected individuals in the United States should

be receiving antiretroviral therapy but that 25% of these in-

dividuals are not receiving therapy. Recent guidelines recom-

mend considering antiretroviral therapy initiation when CD4

cell counts decrease to ,500 cells/lL, which would increase the

proportion of in-care individuals eligible for treatment [48, 49].

Persistence with Antiretroviral TherapyNonpersistence occurs when therapy is halted prematurely.

Patients may stop their medications as a result of medication

adverse effects or competing priorities [50, 51], and providers

may recommend cessation of therapy in response to clinical or

laboratory adverse events or barriers to adherence [52, 53]. In 3

large cohort studies, 4%–6% of individuals who remained in

care discontinued their antiretroviral regimen each year [52, 54,

55].

Adherence to Antiretroviral TherapyA meta-analysis of 31 North American adherence studies found

that 55% of HIV-infected individuals achieve adequate adher-

ence [56]. Because antiretroviral therapy has become more po-

tent, better treatment outcomes can be achieved despite lower

adherence. With modern initial antiretroviral regimens, 70%–

80% adherence leads to durable viral suppression in most

individuals [57, 58]. In 2 recent studies from large North

American cohorts, 60%–80% of individuals achieved adequate

levels of adherence by this new standard [59, 60]. As a consequence

of successful viral suppression at lower levels of adherence, the

population effectiveness of antiretroviral therapy has increased.

Two recent studies found that 78%–87% of individuals receiving

antiretroviral therapy, including individuals receiving initial and

subsequent regimens, had an undetectable viral load [1, 2].

Resistance to Antiretroviral MedicationsAntiretroviral resistance accumulates during virological failure.

Antiretroviral resistance also contributes to the failure of anti-

retroviral therapy. The contribution of antiretroviral medication

resistance to regimen failure is unclear but appears to be small,

particularly with the advent of new antiretroviral medications

and classes. On a population level, rates of transmitted and

prevalent resistance are stable or decreasing in some resource-

rich settings [1, 61, 62]. This is likely attributable to the high

genetic barrier to resistance and/or high potency of the most

frequently used regimens [63]. In a large US study from 2006,

15% of individuals with newly diagnosed HIV infection had

transmitted antiretroviral resistance—a slightly higher percent-

age than in prior studies [64].

Nonpersistence, nonadherence, and antiretroviral resistance

are barriers to effective antiretroviral therapy, contributing to

detectable HIV viremia in 15%–25% of individuals receiving

therapy. However, the majority of individuals receiving anti-

retroviral therapy in 2010 have undetectable viral loads. Thus,

most HIV-infected individuals receiving therapy are at low risk

for clinical progression and low risk to transmit HIV to others.

The Spectrum of Engagement in Care: By the

Numbers

In Figures 2 and 3a, we synthesize these findings to estimate the

spectrum of engagement in HIV care in the United States and

the proportion of the HIV-infected population who have an

HIV load ,50 copies/mL. Approximately 79% of HIV-infected

individuals are aware of their HIV infection, but !50% are not

adequately engaged in HIV care. Thus, 60% of HIV-infected

individuals in the United States are not receiving regular HIV

care because of deficits in diagnosis of HIV infection, linkage to

care, or retention in care. Of the remaining 40% of individuals,

!80% require antiretroviral therapy, 75% of whom receive it.

Finally, !80% of treated individuals have an undetectable viral

load (defined as , 50 copies/mL). These 210,000 HIV-infected

individuals with undetectable viral loads constitute just 19% of

the HIV-infected population in the United States. With .80%

of HIV-infected individuals in the United States having detect-

able HIV viremia, it is not surprising that the incidence of HIV

infection has not decreased in the United States despite almost

15 years of widespread access to combination antiretroviral

therapy. The model in Figure 2 is simplistic, but we are unaware

of data from cohorts of individuals tracked over the engage-

ment-in-care continuum that can more precisely determine the

true proportion of HIV-infected individuals in the United States

with an undetectable HIV load.

These estimates can be used to explore the potential impact of

interventions to improve engagement in care on the proportion

of HIV-infected individuals with an undetectable HIV load.

These simple simulations will also help demonstrate the impact

of uncertainty in our engagement-in-care estimates on the

projected proportion of HIV-infected individuals in the United

States with undetectable HIV loads.

Test-and-Treat Implications

Although there is now a burgeoning interest in the impact of

widespread antiretroviral therapy on HIV prevention, this is not

new. Approximately 10 years ago, mathematical models were

first published to suggest that widespread use of antiretroviral

therapy in HIV-infected individuals could reduce the incidence

of HIV infection [65–67]. Since that time, epidemiological data

have suggested that antiretroviral therapy reduces the risk of

HIV transmission in heterosexual sero-discordant couples by

92%–98% [7, 8, 68, 69]. In addition, ecological data have

revealed that the incidence of HIV infection may be decreasing

HIV/AIDS d CID 2011:52 (15 March) d 795

by guest on March 8, 2012

http://cid.oxfordjournals.org/Downloaded from

19%

↵80%

20%

EECA:  90-­‐90-­‐90  

881 149

90%

90%

90%

235 670?

Estimated PLHIV PLHIV who knowtheir status

On ART 2013 VL = 0

1 673 500

PLHIV do not knowtheir status

47%

PLHIVwho know their status

are not on ART

73%

86%

Estimated PLHIV are not on ART

Figure 2. Lack of access to key services for PLHIV in EECA

Source: See Annex 1

PLHIV do not know their status

1 673 500Estimated PLHIV

881 149PLHIV who know

their status

235 670On ART 2013

Figure 2. Lack of access to key services for PLHIV in EECA

Source: See Annex 1

PLHIV who know their status are not on ART

Estimated PLHIV are not on ART

47%

86%

73%

Source: UNAIDS

Source: UNAIDS

KM Estimates of Time to HIV-1 Infection (mITT Population)

Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 per 100 PY), 2 in TDF/FTC arm (incidence: 0.94 per 100 PY)

86% relative reduction in the incidence of HIV-1 (95% CI: 40-99, p=0.002) NNT for one year to prevent one infection : 18

CROI 2015, Seattle, WA. #23LB.

A. The HIV infected individual B. The pandemic C. In summary….

Facing the challenge of the HIV patient in the near future / co-morbidities

In summary…. For HIV infected individuals …

-  Ultimate goal of ART is an ajusted life expectancy close/identical to the general population. This would require managing the non-AIDS co-morbidities

-  Achieving an sustaining an undetectable plasma VL is mandatory. II´s like Dolutegravir have an important role

-  Objectives beyond undetectable plasma viral load should be considered

-  The situation of many stable & suppressed patients can be potentially improved (including lowering the costs) without increasing the risk of loosing the virological suppression

-  Functional cure may be an achievable goal

In summary…. For the AIDS pandemic

-  Ultimate goal is an AIDS free generation in 2030…..?

-  A combination of preventive strategies will be required including:

Classical prevention approaches More testing and more treating Likely PrEP (intermittent ?) in selected settings Possibly a preventative vaccine (even one only partially

effective)

Clinical Group JL Blanco M Laguno C Cáceres M López-Diéguez P Callau J Mallolas M Calvo C Manzardo S Corral D Martínez F Etcheverri E Martínez E Fernández M Martínez JM Gatell C Mensa F García A Milinkovic M Larrousse JM Miró E Lazzari A Moreno A León I Pérez M Loncà L Zamora

Virology Lab M Arnedo N Boulanger T Escribá C García M García C Gil C Hurtado S Lyonnais A Merino G Mirambeau L Muñoz

Immunology Lab C Alvarez L Miralles N Climent M Plana R Fernández C Rovira T Gallart S Sánchez A García V Sánchez J Joseph N Saubí MJ Maleno S Varea

E Yuste

Clinical Trials Coordination JA Arnaiz X Carné A Cruceta J Pich M Sarasa S Varea

Clinical Institute of Medicine & Dermatology Infectious Diseases & AIDS Division

External Colaborators J Alcamí B Autran M Lederman D Nixon G Pantaleo B Walker

ISCIII

Pharma companies

Infectious Diseases & AIDS Units. Hospital Clinic. Barcelona. Spain

www.escofetzamora.com

Attachment

Fusion

CD4

Chemokine co-receptor

Reverse transcription

Viral DNA Human genomic DNA

Integration (strand transfer) Transcription

Translation

Accessory viral proteins

Gag Pol Gag

Assembly/ cleavage

Release

Maturation

gp120

Budding

The need for novel drugs and novel classes

1. Dau et al. Drugs 2009;1:31–50. 2. Andrieux-Meyer et al. J Int AIDS Soc 2012;15:17986.

New drugs targeting different stages of the HIV-1 life cycle are needed to1,2

Improve tolerability and

toxicity

Reduce pill burden

Provide options for treatment-

experienced and -naive patients

Reduce drug–drug interactions

Provide novel formulations/

delivery systems

Figure from Lataillade et al. CROI 2015, Abstract 114LB.