Il trattamento precoce in funzione del beneficio clinico e della prevenzione della trasmissione secondaria

Andrea Antinori Dipartimento Clinico, INMI L Spallanzani, IRCCS, Roma Roma, 20 Aprile 2012

CNA-SIMIT: LG Italiane di terapia ARV

Quando iniziare in pazienti con infezione cronica

Evidenze a supporto dell’inizio precoce

Benefits of earlier treatment (>350 cells/mm 3 ) 1-3

• Reduction of opportunistic infections • Reduction of cancer and non-AIDS diseases (e.g. cardiovascular, hepatic and renal disease) • Reduction in HIV progression and death • Reduction in immune activation and inflammation • Reduced risk of HIV-1 transmission • Greater likelihood of achieving a normal CD4 count

Evidence

Randomized controlled studies including: • SMART sub-study 4 • Haiti Trial 5 • HPTN 052 sub-study 6 • Large observational studies including: • ART-Cohort Collaboration 7 • NA-ACCORD 8 • HIV-CAUSAL 9 Adapted from: 1. Gazzard BG, et al. HIV Medicine 2008;9:563–608. 2. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. December 1, 2009; 1–161.

3. Sax PE, Baden LR. N Engl J Med 2009;360(18):1897–1899.

4. SMART Study Group. J Infect Dis 2008;197:1133–1144.

5. Severe P, et al. NEJM 2010;363:257–65 6. Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. 7. When to Start Consortium. Lancet 2009;373:1352–1363.

8. Kitahata MM, et al. N Engl J Med 2009;360:1815–1826 9. The HIV-CAUSAL Collaboration, Ann Intern Med, 2011;154:509-515

SMART sub-study: Composite of opportunistic disease and serious non-AIDS events, including all-cause death

Hazard Ratio = 4.19 (95% CI: 1.69–10.4) P=0.002

Deferred episodic treatment Continuous treatment No. at Risk DC: VS: 228 249 188 209 157 178 125 144

Months

91 124 70 104 56 79 33 57 24 43 20 35 Adapted from SMART Study Group. J Infect Dis 2008;197:1133–1144.

Haiti: Earlier initiation of therapy leads to improved survival and lower rates of TB infection

Authors concluded that all HIV infected adults who have CD4+ <350 cells/mm 3 should be offered ART, including those who live in areas with limited resources Adapted from Severe P, et al. NEJM 2010;363:257–65.

•

HPTN 052: Primary Clinical Events During Follow-up

41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy – Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) 0.25

HR: 0.6 (95% CI: 0.4-0.9; P = .01) Delayed (n = 65) 0.20

0.15

0.10

0.05

0 877 886 701 700 317 333 86 85 32 36 0 1 2 3 4

Yrs Since Randomization

Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

Immediate (n = 40) 25 29 5 Number at risk

Risk of death associated with deferral of ART, according to CD4+ count at baseline, with adjustment for HIV-RNA level, age, and sex

Kitahata MM, et al. N Engl J Med, 2009

ART-CC: Prognosis based on CD4 count at initiation of ART

• ART Cohort Collaboration: 15 cohorts from Europe and US (N = 24,444)

HR for AIDS or death

Comparison 1-100 vs 101-200 101-200 vs 201-300 201-300 vs 301-400 251-350 vs 351-450 351-450 vs 451-550 HR* (95% CI) 3.35 (2.99-3.75) 2.21 (1.91-2.56) 1.34 (1.12-1.61) 1.28 (1.04-1.57) 0.99 (0.76-1.29) *Adjusted for lead-time and unobserved events.

When To Start Consortium, Lancet, 2009

Hazard Ratios of the Combined End Point of AIDS Defining Illness or Death, for cART Initiation at CD4 Cell Count Thresholds Ranging From 200 to 500 cells/mL

The HIV-CAUSAL Collaboration, Ann Intern Med, 2011

CASCADE. Time to combined end point of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (thin lines) or deferred (thick lines) cART stratified by CD4 cell count

Writing Committee for the CASCADE Collaboration, JAMA, 2011

Impact of timing of ART initiation on life expectancy

<100 cells/mm 3 Mortality rates (per 1000 person-years) 100-199 cells/mm

Overall Between the ages of 20 and 44 years 21.4 (20.1-22.8) 19.7 (18.1-21.3) 13.4 (12.2-14.8) 10.7 (9.4-12.2)

Potential years of life lost before age 65 years (per 1000 person-years)

20-64 years

Life expectancy (years;adjusted)

460.9

264.9

Exact age 20 years Exact age 35 years Percent surviving from 20 to 44 years 32.4 (SE1.09) 27.0 (SE0.37) 59.8% 42.0 (SE0.62) 30.4 (SE0.45) 80.6%

3

The Antiretroviral Therapy Cohort Collaboration. Lancet 2008, 372:293–99.

≥200 cells/mm 3

7.0 (6.4-7.5) 5.0 (4.5-5.6) 138.3

50.4 (SE0.41) 37.2 (SE0.33) 89.9%

NA-ACCORD: Increasing Life Expectancy in North American HIV+ Pts on HAART

• Analysis of 23,730 HIV+ pts in NA ACCORD, on ART, with recent active data available – Estimated life expectancy at age 20 yrs increased in later periods 100 80 60 40 20 34.4

36.9

43.1

0 1996-9 2000-2 2003-5 Hogg R, et al. CROI 2012. Abstract 137.

47.1

2006-7

Life Expectancy at 20 Yrs of Age, 1996-2007, Yrs

Sex  Male  Female Race  Black  Hispanic  White Transmission category  Heterosexual  IDU  MSM

NA-ACCORD US Life Expectancy Data After Age 20

41.3

42.7

41.0

52.6

50.0

47.7

28.1

51.6

55.3

60.4

54.7

61.4

59.0

NR NR NR

Death rates in patients initiating ART with high CD4 count

1 0.1

Unadjusted Adjusted* 350-499 500-699

CD4 count (cells per µL)

≥700 • • • Pooled data from 23 European and North American cohorts For risk of death, data were analysed for 40 830 patients contributing 80 682 person-years of follow-up The death rate was lower in patients with CD4 counts greater than 500 cells/mm 3 compared with counts of 350–499 cells/mm 3 Risk of death according to CD4 count *Adjusted for sex, risk group, age, calendar year, and viral load Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients. Lancet 2010;376:340–345.

SMRs (standardized mortality ratio) according to gender, transmission group and time spent with CD4 count >500/mm3 among HIV infected individuals with CD4 count >500/mm3 after initiation of cART

The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Int J Epidemiol, 2011

Half of DHHS Panel Recommended ART Initiation at CD4+ Cell Count >500 c/mm

3

Arguments in Favor 

Cohort data showing survival benefit

  

Untreated HIV infection may be associated with higher risk of non-AIDS conditions

Availability of newer regimens with improved efficacy, convenience, and tolerability

Growing evidence that treatment reduces HIV transmission

Arguments Against 

Available data do not definitively establish benefit of ART in all patients with CD4+ cell count > 500 cells/mm 3

 Benefits of earlier initiation may be outweighed by • Risks of short- or long-term drug related adverse events • Risk of nonadherence in asymptomatic patients • Potential for development of drug resistance DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

Proportion of patients with a CD4+ cell count in the normal range (>500 cell/mmc) over 10 years, by CD4+ cell count before initiation of therapy

Kelley CF, et al. Clin Infect Dis, 2009

CD4 nadir is a predictor of HIV neurocognitive impairment

Ellis RJ, et al. AIDS, 2011 Across the range of values observed in the cohort, higher CD4 nadirs were associated with lower risk of neuropsychological impairment such that for every 5-unit increase in square-root CD4 nadir, the odds of neuropsychological impairment was reduced by 10%. This was true for all individuals (solid curve) as well as for HAND eligible patients (those without major confounding neurocognitive comorbidities; dashed curve).

Correlation between nadir CD4R T-cell count and measures of arterial stiffness

(r=-0.37, P=0.0009) AIx@75=augmentation index normalized for a heart rate of 75 bpm Ho J, et al. AIDS, 2010

Time From HIV Seroconversion to Reaching CD4+ Cell Count Thresholds <200, <350, and <500 Cells/mm3

Lodi S, et al. Clin Infect Dis, 2011

Components of annual cost of HIV care by CD4 count.

Sloan CE et al. AIDS, 2011

Cost-Effectiveness of Early Versus Standard ARV Therapy in HIV-Infected Adults in Haiti

Koenig SP, et al. PLoS Med, 2011

START study design

Has a patient recently presented with CD4 >500 cells/mm 3 ? Consider enrolling them in START HIV-infected treatment naïve participants with CD4 cell counts >500 cells/mm 3 Early ART group Immediately initiate ART N=450 for pilot phase N=2,000 (est.) for definitive study Deferred ART group Defer ART until CD4 <350 cells/mm 3 or AIDS symptoms develop N=450 for pilot phase N=2,000 (est.) for definitive study

Adapted from START Protocol Synopsis

CNA-SIMIT: LG Italiane di terapia ARV

Quando iniziare in pazienti con infezione cronica

In US only 43% of HIV prevalent population is currently treated by antiretrovirals

Seekins D, et al. IDSA 2010. Abstract 1064.

In Italy, 66,000 HIV individuals on ARVs among estimated 154,000 HIV infected people (42.8%)

Patients Starting ART at Higher CD4+ Cell Counts Overall, but Disparities Remain

 CD4+ cell count at start of ART (cells/mm 3 ), 2009 [1]

307 246

Low income Middle income High income

225 262 137 185 145-176 200 150 234 118 140 89 252 286

• In San Francisco study, overall trends of starting ART at higher CD4+ counts, but pts initiating ART at CD4+ counts > 350 cells/mm 3 significantly more likely to be white, older, MSM, nonpoor, and diagnosed by private provider [2] 1. Mugglin C, et al. CROI 2012. Abstract 100. 2. Truong HH, et al. CROI 2012. Abstract 139.

Late and very late diagnosis of HIV infection by prevention group and age group (UK, 2009)

Health Protection Agency, HIV in the United Kingdom. 2010 Report.

Addressing rates of undiagnosed infection in

•

Europe

Surveillance to identify the exact extent of the number of undiagnosed people living with HIV remains inconsistent across Europe. Different estimation approaches exist, using different sources of data 1 Country France 2 Germany 3 Italy 2 Spain 4 UK 2,5 Total EU + EEA/EFTA 2 Estimated proportion of HIV infections which are undiagnosed 30% 23% 25% – 26–30% 30% *Patients presenting to Madrid primary healthcare centres **Heterosexual patients presenting for STD screening † MSM patients presenting for STD screening Population prevalence of undiagnosed HIV infection – – – 0.35%* 0.25%**/2.4% – 1. http://www.hiveurope.eu/Project2Infectednotyetdiagnosed/tabid/71/Default.aspx

(accessed 16/4/11) 2. Hamers and Phillips HIV Medicine 2008;9(suppl 2):6–12.

3. Robert Koch Institut. Epidemiologisches Bulletin 2010;46:454–462.

4. Moreno S et al. IAC 2011. Vienna. Poster #LBPE 28. 5. Health Protection Agency. HIV in the United Kingdom: 2010 Report. Health Protection Report 2010 4(47).

†

Test offer at time of indicator condition

Kaposi's sarcoma Severe/recalc seb dermatitis –

280 (25.2%) of patients had had a missed opportunity for HIV testing

Pyrexia of unknown origin – Bacterial Pneumonia – Mononucleosis-like Oral candida/OHL Lymphadenopathy Blood dyscrasia STI Persistent diarrhoea/WL 0 ■ 20 Offered; ■ 40 not offered; ■ 60 80 not known whether offered 100

Tackling late diagnosis: test and treat

• • • Estimated rates of undiagnosed infection remain high across Europe 1 Transmission of HIV-1 has been associated with high viral load and undiagnosed infection in transmitter 2 Latest modeling of the US MSM population suggests that implementing the national testing strategy, coupled with initiation of treatment at CD4+ of 500 cells/mm 3 would have a significant impact: – – Decrease the transmission rate from 8.56% to 3.56%, Lead to 86.5% of HIV patients diagnosed and with an undetectable viral load 1. Hamers and Phillips HIV Medicine 2008;9(suppl 2):6–12.

2. Fisher et al. AIDS 2010;24:1739–1747.

3. Sorensen S and Sansom S. CROI 2011. Boston. #1010. U.S. National HIV/AIDS Strategy. Available at: www.AIDS.gov .Accessed: March 11, 2011

CDC urban MSM modeling study: Implementing a test and treat strategy could lead to a reduction in transmission

Results for each intervention New infections per year Transmission rate* % MSM living with HIV and aware* % newly diagnosed linked to care per year % diagnosed & undetectable VL Current practice Goal based on current practice  testing (24% to 48%)  testing notification (80% to 90%) 2,657 1,993 2,290 2,635 8.56% 5.99% 7.64% 8.50% 65.3% 90.0% 81.0% 66.1% 70.0% 85.0% 70.0% 70.0% 51.7% 62.0% 46.6% 51.5%  linkage (70% to 85%) 2,616 8.41% 65.7% 85.0% 53.3%  VL suppression (80% to 90%) 2,407 8.03% 66.6% 70.0% Treat at CD4 of 500 cells/mm 3 All of the above All of the above, plus treating at diagnosis 2,461 1,707 923 7.90% 5.93% 3.56% 67.1% 84.5% 93.6% 70.0% 85.0% 100% 58.8% 59.1% 63.2% 86.3%

* Based on total # infected

Sorensen S and Sansom S. CROI 2011. Boston. #1010. U.S. National HIV/AIDS Strategy. Available at: www.AIDS.gov

.Accessed: March 11, 2011

•

Projected effect of ART in injecting drug users (IDUs) stratified by CD4 count

Effect of ART on HIV incidence after 5 years for different eligibility criteria 100 80 Treat all HIV-positive IDUs CD4 count <350 cells per µL CD4 count <200 cells per µL Treat only AIDS cases 60 40 20 0 10% 25% 50% 75%

Proportion of IDUs meeting ART eligibility criteria recruited per year

Adapted from Degenhardt L, et al. Lancet 2010;376:285–301.

• •

Expanded HAART coverage decreases new HIV diagnoses

New HIV diagnoses (all) Active on HAART New HIV diagnoses (ever IDU) 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 p=0.003

p=0.026

p=0.954

January 2004

p=0.002

p<0.0001

0 1996 1997 1998 1999 2000 2001 2002 2003 2004

Year

2005 2006 2007 2008 2009 HAART significantly decreased new HIV diagnoses in 1996–1999 (P=0.027) and in 2004–2009 (P=0.001) 750 700 650 600 550 500 450 400 350 300 250 200 150 100 50 0 New HIV diagnoses among IDU decreased ~50% after 2007 Adapted from Montaner JSG, et al. Lancet 2010;376:532–39.

Earlier HIV diagnosis and initiation of therapy associated with reduced transmission 45,000 1000

864

Minimum CVL (p = 0.003) Most recent CVL (p < 0.001) Maximum CVL (p = 0.010) Newly diagnosed HIV cases (p < 0.001) 800

737

30,000 600

590 588 506 540

400 15,000 200 0 0 2004 2005 2006 Year 2007 2008 2009 Irrespective of CVL measure, the number of diagnosed HIV cases decreased over time (p < 0.001)

Adapted from Das M, et al. CROI 2011. Boston. Abstract #1022

“Test and treat” reduced incidence of HIV in IDU, 1988–2009

•

Temporal changes in HIV incidence, % injecting, % on HAART & cVL, 1988-2009 80 60 40 20 0 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 Calendar year % on HAART Log mean cVL % Injecting HIV incidence 4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

• • • Injection drug user (IDU) cohort – HIV+ (n=1103); HIV- (n=3443) – – Median baseline age: 36 years Subjects enrolled 1988–2009 Community Viral Load (cVL) peaked at 25,000 copies/ml in 1992 and declined to 2,500 copies/ml in 2009

Over the entire study period, HIV incidence decreased by 44% for each log decline in cVL

During the HAART era (since 1997) HIV incidence declined by: – 74% for each log decline in cVL – 5% for each 1% increase in the proportion of HIV+ participants on HAART Adapted from Kirk G, et al. CROI 2011. Boston. #484

• •

The Effect of Expanded Antiretroviral Treatment Strategies on the HIV Epidemic Among MSMs in San Francisco

Despite advancements in treatment and expanded outreach efforts, 600 incident HIV infections occurred in San Francisco in 2008.

The San Francisco Department of Public Health estimates that 78% of all known HIV-infected persons were receiving care in 2008.

Charlebois ED, et al. Clin Infect Dis, 2011

HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples

HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm 3 Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm 3 (n = 886 couples) (N = 1763 couples) Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm 3 * (n = 877 couples) • • *Based on 2 consecutive values ≤ 250 cells/mm 3 . Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms

DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

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

Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P < .0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 Immediate Arm: 1 P < .001

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

HPTN 052: Multivariate Analysis of Factors Associated With Linked Transmissions

Variable

Treatment, immediate vs delayed Baseline CD4+ count, per 100 cells/mm 3 decrease Baseline HIV-1 RNA, per 1 log 10 copies/mL increase Baseline condom use, 100% vs < 100% Sex of infected partner, male vs female

HR

0.04

1.24

2.85

0.33

0.73

   61% of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm 3 All transmissions occurred prior to starting ART 82% of transmissions occurred in African patients Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

95% CI

0.01-0.28

1.00-1.54

1.51-5.41

0.12-0.91

0.33-1.65

Relative Risks in Per-Act Probability of HIV-1 Transmission

3297 serodiscordant African couples experiencing 86 linked HIV-1 transmissions The unadjusted per-act risks of unprotected male-to-female (MTF) and female-to male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010–.0037) and 0.0010 (95% CI, .00060–.0017).

Per-act probability of transmission (infectivity) vs log10 plasma HIV-1 RNA (copies/mL) from a model that includes plasma human immunodeficiency virus type 1 RNA and condom use only. Solid line is without reported condom use and dashed line is with reported condom use. Vertical lines represent 95% confidence intervals Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1–uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision.

Hughes JP, et al. J Infect Dis, 2012

Efficacy of HIV Prevention Strategies From Randomized Clinical Trials

Study

ART for prevention; HPTN 052, Africa, Asia, Americas PrEP for discordant couples; Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu PrEP for MSMs; iPrEX, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV144, Thailand 0 20 40 60

Efficacy (%)

Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print]. 80 100

Effect Size, % (95% CI)

96 (73-99) 73 (49-85) 63 (21-84) 54 (38-66) 44 (15-63) 42 (21-58) 39 (6-60) 31 (1-51)

Return on increased investment resulting from implementation of the Status Quo approach versus 50% and 75% expansion scenarios

Lima VD, et al. PLoS One, 2010

When to start ART? 2010-2011 Guidelines Update Clinical category AIDS-defining or symptoms NAD diseases, HBV, pregnancy CD4 cells/mm Any value Any value 3 DHHS 11 Treat (AI) 1 Treat (AI/III) IAS-USA 10 Treat (AI) 2 Treat (BII/AI) EACS 11 3 Treat Treat or consider only if CD4 <500/mm 3 Treat CNA-SIMIT 11 Treat (AI) Treat (AI-II/BII) 4 # Asymptomatic <350 Treat (AI) Treat (AI) Treat (AI) Asymptomatic Asymptomatic 350–500 >500 Treat (A/BII) Treat (AII) Treat or consider only on individual basis § Treat as moderate or optional * Consider treatment (CIII)° Generally defer Treat all (AII) Treat on individual basis (AII/BIII)

1.

2.

3.

4.

# Including as recommend to treat HAND (NMD/HAD), non AIDS malignancies (AII), high risk of HIV secondary transmission (BII) § Recommend if HCV/HBV coinfection, HIV-AN or other organ deficiency; consider if HIV-RNA >10 5 , CD4 decline > 50-100 cells/mm 3 per year, >50 years, pregnancy, high CV risk or malignancy ^ Treat if HIV-RNA >100.000, CD4 decline >50 cells/mm •50% favor starting antiretroviral therapy at this stage of HIV disease (BIII); 50% view initiating therapy at this stage as optional (CIII) ° 3 per year, >50 years, HCV coinfection (AII), consider if high CV risk (BIII) ART should be cosidered unless patient is an elite controller (HIV-1 RNA <50 c/mL) or has stable CD4 cell count and low-level viremia in the absence of ART DHHS Guidelines 2011. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 2010.

ARV Treatment of Adult HIV Infection. 2010 Recommendation of the IAS-USA panel. JAMA 2010;304:321-333.

EACS Guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf

.

Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf

Initiation of ART: UK Collaborative HIV Cohort (UK CHIC)

100 80 Initial CD4 > 500 (cells/mm 3 ) Initial CD4 > 400 (cells/mm 3 ) 60 40 20 0 500 400 300 200

CD4 cell count (cells/µl)

100 0 • • • Estimated proportion of patients starting ART before a given CD4 count, restricted to persons presenting with a CD4 count >400 or >500 cell/mm 3 UK Collaborative HIV cohort initiating ART 1997–2003: n=10,820 34% of patients having presented early, initiated therapy at CD4 count <200 cell/mm 3 Adapted from Stohr W, et al. HIV Medicine 2007,8:135–141.

Do still persist all the risk evaluations associated with early therapy strategies?

Panel on Antiretroviral Guidelines for Adults and Adolescents. DHHS. March 23, 2004; 1–97 .

Do still persist all the risk evaluations associated with early therapy strategies?

Panel on Antiretroviral Guidelines for Adults and Adolescents. DHHS. January 10, 2011; 1–166.

Guideline recommended regimens have an improved risk:benefit ratio

• Previous concerns about earlier initiation of therapy are now less relevant due to availability of antiretroviral regimens with: 1,2 – More options in event of virological failure – Lower toxicity – – Better tolerability Improved pharmacokinetic profiles – Simpler dosing/improved adherence 1. Gazzard BG, et al. HIV Med 2008;9:563–608.

2. Thompson MA, et al. JAMA 2010;304;321–333 .

Guideline recommended regimens have an improved risk:benefit ratio

• Initiating treatment at higher CD4 cell counts may decrease the risk of developing treatment-limiting antiretroviral resistance 1 • Triple class resistance to the three main classes of drugs occurs slowly in routine clinical practice 2,3 – Newer regimens have demonstrated durable efficacy, with virological and immunological responses being maintained for several years 4 – The risk of viral failure decreases with duration of HAART 5 1. Uy J, et al. J Acquir Immune Defic Syndr 2009;51(4):450–453.

2. Phillips AN, et al. AIDS 2007; 21: 1717-1721. 3. Lima VD, et al. Am J Epidemiol 2010;172:460–68 4. Maggiolo F. J Antimicrob Chemother 2009;64:910–968.

5. Lima VD, et al. J Acquir Immune Defic Syndr 2010 Sep 10. [Epub ahead of print]

Incidence per 1000 person-years of follow-up of TCVF over calendar time (2000-2009) among patients who started ART since 1998

TCVF: triple-class virologic failure The Pursuing Later Treatment Options II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Group. J Acquir Immune Defic Syndr, 2012

2000–09 trends in virological and clinical outcomes in people with TCVF

PLATO-II Collaboration: 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000–09.

Individuals with plasma HIV-1 RNA <50 copies per mL.

Incidence of new AIDS event.

The Pursuing Later Treatment Option II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Group. Lancet Infect Dis, 2012

Risk of Viral Failure Declines With Duration of Suppression on cART Irrespective of Adherence Level

Lima VD, et al. J Acquir Immune Defic Syndr, 2010

Guideline recommended regimens have an improved risk:benefit ratio

• • • Starting therapy at progressively higher CD4 counts has been shown to lower the risk of some toxic side effects associated with antiretroviral therapy 1 The risk of lipoatrophy has been reduced by the use of newer antiretroviral agents 2,3 – Low CD4 cell count is the strongest risk factor for lipoatrophy 3 – Other most common statistically significant risk factors were: exposure and duration of therapy, presence of markers of disease severity, age and white race 3 Potential risks and benefits should be considered and discussed with the patient before initiating therapy 4,5 1. Kitahata MM, et al. N Engl J Med 2009;360:1815–1826. 2. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. December 1, 2009;1–161.

3. Lichtenstein KA. J Acquir Immune Defic Syndr. 2005;39:395–400.

4. Thompson MA, et al. JAMA. 2010;304;321–333.

5. European AIDS Clinical Society (EACS), 2011.

500 350 200

350 vs. 500: significance over the lifetime of an HIV-infected adult

• • • • Assume 25 year old with 550 CD4 cells and VL 40,000 Untreated, expect annual loss of ~80 cells Delay until 350 cells would take ~2.5 years

If assume he will remain treated for at least 40 years, immediate therapy adds ~7% time on treatment Age 25

Gallant JE, personal observation, 2010

65

Ringraziamo Gilead per il supporto a questa iniziativa