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Antiretroviral Therapy (Pedro Cahn)

Antiretroviral Therapy (Pedro Cahn)

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STATE OF THE ARTA GLOBAL PERSPECTIVE

Pedro Cahn

Outline: ARV Therapy in 2008
 When to start  When to switch  What to use as cART  The global perspective  Research questions

Initial Reports
 June 5, 1981: 5 cases of PCP in gay men from UCLA (MMWR)

 July 3, 1981: 26 additional cases  Dec 10, 1981: 3 NEJM papers describe cases
Gottlieb MS NEJM 2001;344:1788-91

Increase in reported HIV cases in the Russian Federation and Ukraine, 1987–2005
Reported HIV cases in the Russian Federation 400 000 350 000 300 000 250 000 200 000 150 000 100 000 50 000 0 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 Ukraine Newly reported cases Cumulative (previous years) Russian Federation Newly reported cases Cumulative (previous years) Reported HIV cases in Ukraine 120 000 105 000 90 000 75 000 60 000 45 000 30 000 15 000 0

Sources: Russian Federal AIDS Centre; Ukranian AIDS Centre and Ministry of Health of Ukraine

2.12

Treatment access among injecting drug users (IDUs) in Eastern Europe, selected countries, 2004

100 90 80

AIDS Mortality Rates: 1996-2001
Mortality vs. ART utilization
40 100

Percentage of patient-days on ART

Deaths per 100 person-years

35 30 25 20 15 10 5 0 1995 1996 1997 1998 1999 2000 0 2001 25
DEATHS USE OF ART

75

50

Palella F et al. 8th CROI 2001; abstract 268b.

The Survival Benefits of AIDS Treatment in the United States

39+/9 years

Walensky et al: JID 2006;194:11-19

Institutional deaths per 100 000 population and programmatic data: patients currently receiving antiretroviral therapy and deaths on a therapy, Botswana 1994-2005a

estimated from 2002 mortality reports

700
2005 deaths annualized on basis of deaths until June 2005, reported by November 2005; ART programme data reported .until September 2005
a

Pa De

600
8|
Progress Report
| April 2007

De

AIDS 2008

10
|

Progress Report

| April 2007

Antiretroviral Efficacy Rates Are Improving in Clinical Practice
 Virologic failure of initial HAART in previously treatment-naive patients from 5 observational cohorts (N = 4143)
Patients With HIV-1 RNA > 500 copies/mL (%)
50 40 30 20 10 0 40 42 39 34 31 30 25

1996

1997

1998

1999

2000

2001

2002

Lampe F, et al. CROI 2005. Abstract 593.

Clinical Outcome Improved by Starting Therapy at Higher CD4+ Cell Count
 Timing of antiretroviral initiation in treatment-naive subjects (N = 10,885) in Antiretroviral Cohort Collaboration HR for progression to AIDS or death by CD4+ cell count at initiation of therapy
– < 200 vs 201-350 cells/mm3 HR: 2.93 (95% CI: 2.41-3.57) – < 350 vs 351-500 cells/mm3 HR: 1.26 (95% CI: 0.94-1.68) Cumulative Probability of AIDS/Death by CD4+ Cell Count at HAART Initiation 101-200 cells/mm3 201-350 cells/mm3 351-500 cells/mm3

Probability of AIDS or Death

0.12 0.10 0.08 0.06 0.04 0.02 0.00

Results suggest a lower risk of disease progression/death when starting between 351-500 cells/mm3

1 2 3 4 5 Years Since Initiation of HAART

Sterne J, et al. CROI 2006. Abstract 525.

The Problem of Late Diagnosis
 CD4+ cell counts of treatment-naive patients first presenting for HIV care typically low
500 450 400 350 300 250 200 150 100 50 0

CD4+ T Lymph Level (cells/mm3)

96 97 98 99 00 01 02 03 04 05 06 19 19 19 19 20 20 20 20 20 20 20 Calendar Year

Moore RD, et al. CROI 2008. Abstract 805.

ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs
Stratified by CD4+ cell count < or ≥ 50 cells/mm3, PCP, BI, or other OI Immediate Antiretroviral Therapy Initiation within 48 hours of randomization and within 14 days of starting OI treatment (n = 141)

HIV-infected patients receiving treatment for presumed or confirmed acute OI/BI* (N = 282) *Patients with TB excluded.

48 weeks

Deferred Antiretroviral Therapy Initiation between Weeks 4 and 32 (n = 141)

48 weeks

Zolopa A, et al. CROI 2008. Abstract 142.

ACTG A5164: Improved Outcomes With Immediate ART During Acute OI
– Median baseline CD4+ cell count 29 cells/mm3; HIV-1 RNA 5.07 log10 copies/mL

Patients Progressing to AIDS or Death at Week 48 (%)

92% treatment naive

100 80 60 40 20 0 14.2 Immediate Deferred P = .035 24.1

OIs with effective antimicrobial therapy only: PCP, bacterial infections, cryptococcal disease, MAC, toxoplasmosis Median duration from start of OI treatment to initiation of HAART
– Immediate group: 12 days – Deferred group: 45 days

 

Week 48 virologic outcomes similar between groups Safety and incidence of IRIS similar between groups

Zolopa A, et al. CROI 2008. Abstract 142.

85.8% 75.9%

HIV-Infected Patients in the HAART Era Have a 10-Year Shorter Expected Survival than Age and Gender-Matched Controls
Survival from age 25 years 1 Population controls

Probability of Survival

0.75 Late HAART (2000-2005)

0.5

0.25

Early HAART (1997-1999) Pre-HAART (1995-1996) 25 30 35 40 45 50 55 60 65 70

0

Age, y
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87-95

SMART Substudy: Clinical Impact of Immediate vs Deferred Therapy
Study halted early

Patients with CD4+ cell count > 350 cells/mm³ who are antiretroviral naive (n = 249) or have not received ART for ≥ 6 mos (n = 228) (N = 477)

Virologic Suppression Strategy Continuous therapy (n = 249 not receiving ART at trial start) Mean follow-up: 16 months

Treatment Interruption Strategy Deferred therapy until CD4+ cell count < 250 cells/mm³; discontinue therapy when CD4+ cell count > 350 cells/mm³ (n = 228 not receiving ART at trial start)

Emery S, et al. IAS 2007. Abstract WEPEB018.

SMART Substudy: Clinical Impact of Continuous vs Interrupted Therapy
  Patients who initiated and remained on antiretroviral therapy at higher CD4+ cell counts (> 350 cells/mm³) had better outcomes vs those who deferred and interrupted HAART Caveat: small number of patients analyzed and not all treatment naive
Event, n (Rate per 100 Person-Years) Interrupted HAART OI/death  Overall OI  Overall Serious non-AIDS  Overall Composite*  Overall 21 (7.0) 5 (1.3) 5.1 .001 12 (3.9) 2 (0.5) 7.1 .01 11 (3.5) 3 (0.8) 4.4 .02 15 (4.8) 4 (1.1) 4.4 .009 Continuous HAART HR P Value

*Includes OI and serious non-AIDS events. Emery S, et al. IAS 2007. Abstract WEPEB018.

SMART: Effects of Therapy Reinitiation on Morbidity and Mortality
 Significant decrease in excess risk of OI/death in interruption arm after study modification Persistence of excess risk for OI/death in interruption arm vs continuous therapy arm related to:
– Lower mean CD4+ cell count – Higher proportion with HIV-1 RNA > 400 copies/mL OI 1.7 Major CVD, Renal, or Hepatic Disease 1.7 1.1 Premodification (n = 639) Postmodification (n = 195) OI or Death 2.5 1.4 1.8 1.3 3.3 P = .03

Death

Antiretroviral therapy interruption associated with long-term consequences

0.1 1 5 Favors Interruption Favors Continuous
El-Sadr W, et al. CROI 2008. Abstract 36.

“No new evidence has emerged to define the optimal CD4 cell count that provides a treatment-related survival advantage, and based on the inherent difficulty with designing and executing such studies, it is unlikely that a randomized, controlled trial will be conducted to answer this question. Rather, recommendations rely on wellconducted cohort studies.”

Hammer SM, et al. JAMA. 2006;296:827-843.

Where Do Treatment Guidelines Come From?
 Cohort studies compare outcomes of patients started on therapy at various CD4+ cell count thresholds  Cohort studies in early HAART era supported starting before CD4+ cell count < 200 cells/mm3 but not earlier  More recent analyses suggest treatment outcomes better when treatment is started with higher CD4+ cell counts
– Newer therapies that are simpler and better tolerated than those in years past allow for question of earlier treatment to be explored

Egger M, et al. Lancet. 2002;360:119-129.

PISCIS Cohort: Time From Initiation of Antiretroviral Therapy to AIDS/Death
 3427 treatment-naive patients assessed for progression to AIDS/death, stratified by CD4+ cell count when initiating antiretroviral therapy
CD4+ Cell Count (cells/mm3) 200-350 < 200, unadjusted < 200, adjusted for lead time* > 350 200-350, unadjusted N 625 650 670 625 650 1.56 1.85 1.0 5.0 2.81 2.97 HR (95% CI)

200-350, adjusted for lead time* 670 0.1

*Lead time defined as time it took for patients who deferred therapy with early disease stage to reach later disease stage Jaen A, et al. J Acquir Immune Defic Syndr. 2008;47:212-220.

Problems With Data From Cohort Studies
 Studies may underestimate the benefits of deferring therapy
– – – Not randomized (confounding) Treatment-related toxicity or resistance not considered an endpoint Lead-time bias

Studies may underestimate the benefits of early therapy
– – – – – – – Short follow-up Treatment improving Higher risk of toxicity with advanced disease[1] Prevention of “subclinical” immunodeficiency[2] May preempt R5 to X4 switch associated with more rapid disease progression[3] Prevention of non-AIDS–related diseases and reduction in inflammatory markers Possible prevention of HIV-related neurologic disease

1. Lichtenstein K, et al. J Acquir Immune Defic Syndr. 2003;32:48-56. 2. Lange CG, et al. AIDS. 2003;17:2015-2023. 3. Moyle GJ, et al. J Infect Dis. 2005;191:866-872.

A Major Reason to Treat Earlier: Risk of Non-AIDS Diseases and Death
 Higher risk of CV, neoplastic, hepatic, renal diseases in HIV-infected vs HIV-uninfected people  Lower CD4+ cell count and/or higher HIV-1 RNA may increase the risk of serious non-AIDS events  SMART study: being off antiretroviral therapy raises risk of serious non-AIDS diseases—even when CD4+ cell count > 250 cells/mm3

FIRST: More Non-AIDS Than AIDS Events at Higher CD4+ Cell Counts
  Rates decline at higher CD4 counts Non-OD > OD at CD4+ cell counts > 200 cells/mm3
18 16 14 12 10 8 6 4 2 0

Rate (Events/ 100 Patient-Yrs)

OD events

Non-OD events

< 200
1288 | 1442

200-349
1324 | 1343

350-499
1238 | 1232

≥ 500
1940 | 1900

Latest CD4+ Cell Count (cells/mm3)
Patient-years: Baker J, et al. CROI 2007. Abstract 37.

Immunosuppression Increases Risk of HIV- and Non-HIV–Related Mortality
 Cohort study of > 23,000 patients in Europe, Australia, and US
– 76,577 patient-years of follow-up
100 Overall HIV Malignancy Heart Liver

10

 1248 (5.3%) deaths from 2000-2004  Both HIV- and non-HIV– related mortality associated with CD4+ cell count depletion
Weber R, et al. CROI 2005. Abstract 595.

RR
1.0 < 50 50-99 100199 200349 350499 ≥ 500

CD4+ Cell Count (cells/mm3) 0.1

AIDS risk at 6 months

CASCADE Collaboration 2003

CASCADE: Nadir CD4+ Cell Count Predicts AIDS and Non-AIDS Events
  CASCADE collaboration cohort (N = 9858) Several clinical markers of HIV progression correlated with death due to AIDS-related causes, non-AIDS–related severe infection, liver diseases, and non-AIDS–related malignancies including
– – Latest and nadir CD4+ cell counts

Time spent with CD4+ cell count < 350 cells/mm3 AIDS-Related Death Non-AIDS–Related Death Nadir CD4+ Cell Count 200-349 vs ≥ 350 200-349 vs ≥ 350 50-199 vs ≥ 350 50-199 vs ≥ 350 < 50 vs ≥ 350 < 50 vs ≥ 350 0.01 1.00 100.00 0.01 1.00 100.00 Liver Disease Death 200-349 vs ≥ 350 50-199 vs ≥ 350 < 50 vs ≥ 350 0.01 1.00 100.00 Marin B, et al. IAS 2007. Abstract WEPEB019. Non-AIDS Cancer Death 200-349 vs ≥ 350 50-199 vs ≥ 350 < 50 vs ≥ 350 0.01 1.00 100.00

Association Between Current CD4+ Cell Count & Non-AIDS Complications
Study Lower Current CD4+ Cell Count Significantly Associated With Increased Risk? Non-AIDS malignancies FIRST D:A:D CASCADE SMART Yes Yes Yes Trend, NS Renal disease/death Yes Yes NA Trend, NS CVD events/death Trend, NS Trend, NS Yes Trend, NS Liver disease/death No Yes Yes Yes

Phillips A, et al. CROI 2008. Abstract 8.

Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level
Johns Hopkins HIV Clinical Cohort BL CD4+ Cell Count > 350 1000 201-350 < 200 800 600 400 200 0 0 1 2 3 4 Years on HAART 5 6 ATHENA National Cohort 1000 800 600 400 200 0 BL CD4+ Cell Count 201-350 > 500 51-200 351-500 < 50 0 48 96 144 192 240 288 336 Weeks From Starting HAART

Mean CD4+ Cell Count (cells/mm3)

Moore RD, et al. Clin Infect Dis. 2007;44:441-446. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192.

Virologic Control Associated With Lower Risk of Lymphoma
    Retrospective cohort analysis (N = 6458) Inclusion criteria: initiation of antiretroviral therapy until development of lymphoma or December 31, 2006 94 lymphomas: 78 NHL and 16 primary CNS lymphoma Independent risks for lymphoma: MSM, older age, CD4+ cell count < 200 cells/mm3, ≥ 75% of HIV-1 RNA > 500 copies/mL

Survival Probability Without Lymphoma

1

Influence of Cumulative log10 HIV-1 RNA

.975 Viremia < 75% of time Viremia ≥ 75% of time 0 4000

.95

1000 2000 3000 Days Since HAART Begun Zoufaly A, et al. CROI 2008. Abstract 16.

SMART Study: Stopping Therapy Increases IL-6 and D-dimer
 Analysis of changes in inflammatory and coagulation markers, IL-6 and Ddimer
D-Dimer (µg/mL)
Change in D-Dimer (µg/mL) From Baseline to 1 Month 0.3 0.28

 

IL-6 and D-dimer increased in interruption arm (P < .0001) IL-6 and D-dimer levels related to allcause mortality and CVD (4th vs 1st quartile)
– IL-6: all-cause OR 12.6 (P < .0001); CVD OR 2.8 (P = .003) – D-dimer: all-cause OR 13.3 (P < .00001); CVD OR 2.0 (P = .06)

0.2 0.11 0.1 0 0 ≤ 400 40110,000 10,00050,000 > 50,000 0.40 P = .0005 for trend

Possible mechanism: increased HIV-1 RNA may stimulate coagulation cascade in vascular endothelium

Month 1 HIV-1 RNA Level (copies/mL)

Kuller L, et al. CROI 2008. Abstract 139.

Other Risks of Ongoing Virus Replication
 Accelerated fibrosis in patients with HIV/HCV-coinfection[1]
– HSC mediate fibrosis in patients with HCV – HIV infects HSC in vitro by CD4-independent pathways – Result: activation of HSC by HIV increases collagen gene expression, potentially explaining the rate of fibrosis in HIV/HCV coinfection

 Increased HIV-associated dementia[2]
– In patients with neurocognitive dysfunction starting or changing ART, 60% fail to normalize neuropsychiatric function after 24 weeks – Factors associated with incomplete recovery: CD4+ cell count nadir ≤ 350 cells/mm3, higher pre-ART HIV RNA level in CSF, lower pre-ART HIV-1 RNA level in blood
1. Tuyama A, et al. CROI 2008. Abstract 57. 2. Letendre S. CROI 2008. Abstract 68.

Treatment to Prevent HIV Transmission

The case for expanding access to HAART to curb the growth of the HIV epidemic

HAART Coverage

Julio SG Montaner, Robert Hogg, Evan Wood, Thomas Kerr, Mark Tyndall, Adrian R Levy, P Richard Harrigan – Lancet 2006;368:531-36

HIV Treatment Reduces Heterosexual Transmission
 174 discordant, monogamous couples in Raiki, Uganda, retrospectively analyzed for factors associated with transmission[1] 30   393 steady heterosexual couples[2] HIV prevalence among partners declined from 10.3% during pre-HAART period to 1.9% during late HAART period (P = .0061) OR (95% CI) 1 0.55 (0.19-1.61) 0.14 (0.03-0.66) .2763 .0127 P Value

Adjusted Rate Ratio of Transmission/Coital Act

20 10 1.0 < 1700 0.1 1700- 12,500- > 38,500 12,499 38,499

Enrollment Period Pre-HAART (1991-1995) Early HAART (1996-1998) Late HAART (1999-2003)

HIV-1 RNA (copies/mL)

1. Gray RH, et al. Lancet. 2001;40:1149-1153. 2. Castilla J, et al. J Acquir Immune Defic Syndr. 2005;40:96-101.

SMART Study: Being on Treatment Does Not Increase High-Risk Behavior
 Higher transmission risk among patients in interruption arm
– Unchanged sexual activity but higher HIV-1 RNA levels throughout follow-up

50 40

Risk behavior Risk behavior with HIV-1 RNA > 1500 copies/mL

Patients (%)

30 20 10 0

n s s n tio ou ou tio p u u p rru tin ru tin te er on on In nt C C I

n s n s tio ou t io p ou u p u tin rru rru tin n e te t n In Co In Co

Baseline (n = 883)

4 Months (n = 779)

12 Months (n = 658)

24 Months (n = 463)

Burman W, et al. CROI 2007. Abstract 979.

Toxicity Is a Major Reason for Discontinuation of First-Line HAART
 ICONA study group
– Median follow-up: 45 weeks – Study population: 862 ARV-naive patients – 84.3% receiving unboosted PI + NRTIs – Discontinuations: n = 312 (36%)
20% 58% 14% Cause of Discontinuation
Toxicity Failure Nonadherence Other

8%

d’Arminio Monforte A, et al. AIDS. 2000;14:499-507.

Safety and Tolerability of Select Current Regimens Are Excellent
Study AI424-089[1] GS934[2] KLEAN[3] ARTEMIS[4] CASTLE[5] HEAT[6] GEMINI[7] Length 96 weeks 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks Drug regimen ATV + d4T + 3TC ATV/RTV + d4T + 3TC EFV + TDF + FTC EFV + ZDV/3TC FPV/RTV + ABC/3TC LPV/RTV + ABC/3TC DRV/RTV + TDF/FTC LPV/RTV + TDF/FTC ATV/RTV + TDF/FTC LPV/RTV + TDF/FTC ABC/3TC + LPV/RTV TDF/FTC + LPV/RTV SQV/RTV + TDF/FTC LPV/RTV + TDF/FTC Discontinuations Due to AEs,* % 3 8 5 11 12 10 3 7 2 3 4 6 4 7

1. Malan N, et al. IAS 2007. Abstract WEPEB024. 2. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 3. Eron J Jr, et al. Lancet. 2006;368:476-482. 4. DeJesus E, et al. ICAAC 2007. Abstract 718-b. 5. Molina JM, et al. CROI 2008. Abstract 37. 6. Smith K, et al. CROI 2008. Abstract 774. 7. Walmsley SL, et al. EACS 2007. Abstract PS1.4.

Fixed-Dose Combinations
Individual Agents ZDV ABC TDF Fixed-dose combinations

+ +
TDF

3TC

= =
FTC

ZDV/3TC ABC/3TC TDF/FTC

FTC

EFV LPV

+ +

+
RTV

= =

EFV/ TDF/ FTC LPV/RTV

When to Start: 2008 vs. 2006
Guideline DHHS 2008[1] Recommendation to Begin Immediate Therapy CD4+ cell count < 350 cells/mm3 Previous AIDS-defining illness Pregnant women HIV-associated nephropathy HBV-coinfection, when HBV treatment indicated CD4+ cell count < 350 cells/mm3 CD4+ cell count from 350500 cells/mm3 with high HIV-1 RNA Opportunistic infection Active AIDS No history of active AIDS, but CD4+ cell count ≤ 200 cells/mm3 Optimal Time Not Well Defined or Recommendation to Delay Therapy CD4+ cell count > 350 cells/mm3

EACS 2007[2]

CD4+ cell count > 500 cells/mm3

IAS-USA 2006[3] *

No history of active AIDS, but CD4+ cell count from 200-350 cells/mm3 CD4+ cell count > 350 cells/mm3

1. 2. 3.

US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. European AIDS Clinical Society. Available at: http://www.eacs.eu/guide/1_Treatment_of_HIV_Infected_Adults.pdf. Hammer SM, et al. JAMA. 2006;296:827-843.

*See updated version in JAMA Aug 2008

When Is Antiretroviral Therapy Started?
  Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008) Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from 50-100 cells/mm3
164 187 102

200 123

179

181

86 125 122 100 97 97 87

163 192 157 206 95 103 53 72 134 239

Egger M, et al. CROI 2007. Abstract 62.

Summary: Why should we start earlier
 Treatment reduces AIDS-related morbidity and mortality  Treatment reduces markers of systemic inflammation and immune activation  Treatment reduces non-AIDS–related complications—all of them increasing in an aging HIV population
– Cardiovascular disease – Malignancies – Hepatic disease – Renal disease

 Treatment reduces risk of transmission to others  Treatment is more user friendly, more effective and better tolerated now than in years past

When to Start: Summary
 Prospective clinical trials, cohort studies, retrospective data, and consensus guidelines support starting antiretroviral therapy at a CD4+ cell count of 350 cells/mm3 and perhaps higher  Continued efforts at earlier diagnosis of HIV are critical to continue reductions in HIV morbidity and new infections

Timeline of ARV Development

ZDV ’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07

Timeline of ARV Development
DLV ZDV ddC ddI NVP d4T 3TC ABC EFV TDF FTC ETV
RTGV

’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 08

NRTI
NNRTI PI
Entry inhibitor
Integrase inhibitor

SQR RTV IDV

NFV

LPV/r APV

ATV FPV TPV T-20 MVC DRV

25 unique ARV agents, at the first year of FDA approval

Retrovirus life cycle
Entry inhibitors ENF MRV VCV TNX355 AMD11070 Reverse transcriptase inhibitors ZDV NVP ddI DLV TDF EFV d4T ABC FTC 3TC ETV TMC 278 RCV APC Integrase inhibitors GS9137 Raltegravir others Maturation inhibitor Bevirimat

Protease inhibitors SQV IDV RTV NFV FPV LPV ATV TPV DRV

Recommended Regimens for Treatment-Naïve Patients: DHHS 2008
Column A PI
Preferred

Column B + 2 NRTIs
Tenofovir DF/emtricitabine‡ Abacavir/lamivudine

or

NNRTI
Efavirenz†

Lopinavir/ritonavir bid* Fosamprenavir + ritonavir Atazanavir + ritonavir Lopinavir/ritonavir qd Fosamprenavir (unboosted) Atazanavir (unboosted)║ Fosamprenavir + ritonavir qd

Alternative

Nevirapine§

Zidovudine/lamivudine Didanosine + lamivudine

Choose a PI or NNRTI plus 2 NRTIs. *The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred component was based on twice-daily dosing. A smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate-to-severe diarrhea with the once-daily regimen (16% vs 5%). † Efavirenz is not recommended for use in the first trimester of pregnancy or in sexually active women with childbearing potential who are not using effective contraception. ‡ Emtricitabine may be used in place of lamivudine and vice versa. § Nevirapine should not be initiated in women with CD4 cell count >250 cells/mm3 or in men with CD4 cell count >400 cells/mm3 because of increased risk of symptomatic hepatic events in these patients. ║ Atazanavir must be boosted with ritonavir if used in combination with tenofovir DF.
Adapted from: http://aidsinfo.nih.gov/Default.aspx.

% without new mutation

Risks of deferring switch in failing patients • SCOPE cohort of ART-experienced subjects (n=106)
1.00 0.75 0.50
Data are for PI-treated subjects (n=71)
*

Time to development of new mutation

– Stable ART for >120 days – HIV RNA >1000 c/mL – >1 resistance mutation – Resistance testing Q4 months until ART modification
Hatano H, CROI 2006, #615

0.25

1 new major PI mutation* 1 new NRTI mutation Any new mutation 0 4 8 12 16 Time (months) 20 24

0

1.00

Time to loss of 1 drug equivalent

0.75

0.50

0.25
Number of available antiretrovirals from the following: ZDV, 3TC, ddI, ABC, TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV.

0 0

4

8

12 16 Time (months)

20

24

UK CHIC Study
40

Cumulative Risk of Extensive Failure
NRTI PI NNRTI 3-class resistance Extensive 3-class resistance

Cumulative Risk (%)

30

20

10

0

2

Time Since Starting HAART (Years)

4

6

8

10

Virologic failure: HIV RNA >400 copies/mL despite >4 months on HAART. Extensive failure by drug class: NRTI: virologic failure of >1 subclass: ZDV and d4T, 3TC and FTC, ddI and TDF and ABC. PI: virologic failure of >1 ritonavir-boosted PI. NNRTI: virologic failure of EFV or NVP. 55

Phillips A, et al. 14th CROI, 2007. Abstract 532.

Mortality After First HAART Failure By Time to Regimen Modification
Switch at 1 month Switch at 6 months 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0 1 4 7 10131619232629323437404346 49 52 Time since failure (months) Switch at 12 months Switch at 18 months

Conditional Hazard

 

Modeling study using data from 2 clinical cohorts Model suggests delayed modification may be associated with greater increase in mortality following first-line failure of NNRTIbased regimen vs PI-based regimen
– HR for death: 1.21 per 3-mo delay in switch from failing NNRTI regimen; P = .002 CD4+ decline may be slower after PI failure Modification of failed PI regimens less dependent on immediate vs later timing

Among subjects failing a NNRTIbased regimen.

Among subjects failing a PI-based regimen.

Conditional Hazard

– –

Petersen M, et al. CROI 2008. Abstract 798.

Relationship Between Viral Suppression and Mortality
• Prospective, population-based Danish HIV Cohort Study
– N = 3919 HIV-infected patients – On HAART ≥ 18 months
100% (all values VL ≥ 400) 1%-99% (of values VL ≥ 400) 0% (all values VL < 400)

Proportion of Detectable Viral Loads Over 6-18 Months After Initiation of HAART

Cumulative Mortality

• Stratified based on proportion of detectable VL (> 400 copies/mL) during the period 6 to 18 months after initiation of HAART • Higher risk of death with transient or lack of viral suppression
– Consistent with shorter-term studies

0.25 0.20 0.15 0.10 0.05 0.00 0

18

36

54

72

Lohse N, et al. ICAAC 2005. Abstract H-515 CID2006;42:136-144 .

Months After Baseline (baseline = 18 months after HAART initiation)

BENCHMRK-1 & 2 Combined Efficacy† Percent of Patients With HIV RNA <50 copies/mL at Week 48 by Selected ARTs in OBT

CROI 2008 Abstract # J-117 Poster #789

CONFRONTING FAILURE: NEW DRUGS, HOW TO USE IT
• • • •     Goal: Virological supression < 50 copies How: Use at least 2 active drugs, one new class if possible When: Switch as early as possible Why: Avoid accumulation of resistance mutations (GSS) Avoid increases in fold changes (PSS) Preserve active drugs for OBR Preserve CD4 levels

WHO - CD4 criteria for initiation of ART in Adults and Adolescents

CD4 (cell /mm3)

a

Treatment recommendation

b

< 200 200 - 350 >350

Treat irrespective of clinical stage c [A-III]

Consider treatment [B-III] and initiate ART before drop below 200 cell/mm3 c [A-III]

Defer treatment in asymptomatic persons [AIII]

a CD4 cell count should be measured after stabilization of any intercurrent condition b CD4 cell count supplement clinical assessment and should therefore be used in combination with clinical staging in decision making c A drop of CD4 cell count below 200 cells/mm3 is associated with a significant increase of opportunistic infections and death

WHO - Recommendations for initiating ART in adults and adolescents based on clinical stage and availability of immunological markers
WHO Clinical CD4 testing Staging not available CD4 testing available

1 2 3 4
a

Do not treat
[A-III] [B-III]

Treat if CD4 cell count < 200/mm3
[A-III]
c

a

Do not treat Treat
[A-III]

Treat irrespective of CD4 cell count, with consideration of CD4< 350/mm3 in some situations b [A-III] Treat irrespective of CD4 cell count

Treat

[A-III]

[A-III]

The precise CD4 cell level above 200/mm3 at which ARV treatment should be started has not been established. b CD4 cell count advisable to assist with determining need for immediate therapy for situations as pulmonary TB and severe bacterial infections, which may occur at any CD4 level. c A total lymphocyte count of ≤ 1200/mm3 can be substituted for the CD4 count when the latter is unavailable and mild HIV disease exist. It is not useful in the asymptomatic patients. Thus, in the absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2

WHO: First Line ARV Drugs in Adults and Adolescents
Preferential 2 NRTI/NNRTI approach

AZT* or d4T 3TC or FTC TDF* or ABC
Triple NRTI alternative approach#

EFV NVP

* Preferential NRTI to be combined with 3TC or FTC. # Triple NRTI should be considered as an alternative strategy for first-line in situations where NNRTI options provide additional complications and to preserve the PI class for second line(e.g., pregnancy, viral hepatitis co-infection, TB confection, women who wish to fall pregnant or who have CD4 count > 250 cells /mm3; severe reactions to NVP or EFV and HIV-2 infection).

Egger, 2007

Response to HIV therapy in resource-poor and resource-rich regions
Virologic responses after initiating therapy

• Virologic response to first ART: Switzerland vs South Africa:
– 967 pts in Swiss HIV Cohort (median CD4+ = 212 cells/mm3) – 1856 pts in Cape Town (median CD4+ = 81 cells/mm3)

• Similar virologic responses when adjusted for age, gender, CD4+ cell
count, year of starting therapy, and disease stage tolerability

• More ART modifications among Swiss, often to improve convenience and

Mortality during the first year of HAART

• Estimated mortality of 15% in sub-Saharan Africa vs 5% in Europe and
North America

• Early mortality seen after initiation of ART possibly due to pre-existing
condition or immune restoration

Egger M, et al. 14th CROI, Los Angeles 2007, #62

Lancet 2006:367(9513);817-21

Suboptimal Initial Response/First Failure in Resource Unconstrained Settings

• Typically picked up early through VL monitoring • All potential reasons evaluated • Goal of therapy remains maximal virologic suppression
– i.e., VL <50 copies/ml, achievable in ~90% of patients

• Tailoring regimens to individual needs
– Resistance testing used to assist with choice recognizing its limitations [amplification at low virus loads, mixtures (importance of low-frequency variants) – TDM

Treatment Failure in Resource Limited Settings

• Lack of widespread availability of CD4 and VL testing

implies that completeness of response to any line of therapy may not be fully assessed and treatment failure will be picked up later
– Greater degree of drug resistance will occur

• Lack of individualized drug resistance testing • Need for a public health approach, while pushing for
wider availabilty of appropriate monitoring tools • Goal of therapy is to reduce morbidity
and mortality, so CD4 conservation and maximal virologic suppression should be persued

Limited use of second-line
• Only 40,000 (2%) on 2nd line at end 2006
– limited provision in public sector – high cost: $1000 – 2500 pa – only some countries have universal access – HIV-TB co-management – ?? switch rates (4% annual in DART)
900'000 800'000 700'000 600'000 500'000 400'000 300'000 200'000 100'000 2006 2007 2008 2009 2010
To ta l n u m b e r o f p e o p le n e e d in g 2 n d lin e AR Vs (lo w e s tim a te ) To ta l n u m b e r o f p e o p le n e e d in g 2 n d lin e AR Vs (h ig h e s tim a te )

Much more focus on scaling up first-line
– Clear what to use; many FDCs – Price competition: d4T/3TC/NVP for $121 pa

Need for second-line will rise
- Universal access includes second-line - Significant pressure from activist communities - Earmarked resources: UNITAID; GFATM; PEPFAR - Action of Clinton Foundation and others -Only 40,000 (2%) on 2nd line at end 2006
9 0 0 '0 0 0 8 0 0 '0 0 0 7 0 0 '0 0 0 6 0 0 '0 0 0 5 0 0 '0 0 0 4 0 0 '0 0 0 3 0 0 '0 0 0 2 0 0 '0 0 0 1 0 0 '0 0 0 2006 2007 2008 2009 2010
T o ta l n u m b e r o f p e o p le n e e d in g 2 n d lin e AR Vs (lo w e s tim a te ) T o ta l n u m b e r o f p e o p le n e e d in g 2 n d lin e AR Vs (h ig h e s tim a te )

The number of people is forecast to grow at a compound rate of around 40% between 2006 and 2010 Depending on the switch rate – at which patients develop resistance to 1st line ARVs and therefore need to change to 2nd line therapies – between 500,000 and 800,000 people could need 2nd line ARVs by 2010

Challenges in HAART in 2008 and Onwards
• Quantitative:  Earlier initiation  Wider roll-out without matching monitoring capacity  > life expectancy  Evidence for treating upfront newborns  CART for pregnant women • Qualitative:  Ageing population  Stigma, discrimination and denialism  Pediatric formulations  Co-infected patients  Chronic toxicity  Late detection  Wrong approach to budget allocation

The Face of the Global Health Workforce Crisis Countries with a critical shortage of health service providers (doctors, nurses and midwives)

Source: World Health Report 2006 – Working Together for Heath

Countries in the tropics lag behind those in temperate zones in innovation, markets, and intellectual property rights

Different resources: Indicators of global science

% of world totals (1995)

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Population

GDP

Publications

Patents (EU)

Patents (US) Pharma Sales

Advance Economies

Rest of the World

Sources: J. Sachs: UNESCO: The Economist, 14 August 1999

Projected reduction in African agricultural labour force due to HIV and AIDS by 2020
Namibia Botswana Zimbabwe Mozambique South Africa Kenya Malawi Uganda UR Tanzania Central African Republic Côte d’Ivoire Cameroon 0 5 10 15 20 25 30 2020 2000

Projected labor force loss (%) by year

Sources: ILO (2004). HIV/AIDS and work: global estimates, impact and responses

4.8

Wealth, poverty and HIV: countries grouped by region and HIV prevalence
80 70 60 50 % 40 30 20 10 0
All (48) Africa Asia* Latin America and Caribbean 1-5 5-10 10-20 over 20

Industrialized countries

Countries with HIV prevalence over 1.9% in 2002

Countries according to level of HIV prevalence in 2001 (%)

% of population living on less that $1 per day Relative income of richest 10% to poorest 10% *except Japan

Source: UN Population Division( 2005a). Most figures relate to 2002, or earlier.

4.3

Is cost the main obstacle?

1.4% GLOBAL INCOME 82,7%

Richest 20%

Poorest 20%

1.3 billion people live with less than 1 u$s a day

The World Bank

45% of Eligible US Patients Not On HAART

PLWHA Eligible In care On HAART
CROI 2005: Teshale E, et al. Abstract 167.

820,000
746,000 – 894,000

480,000
441,000 – 519,000

340,000
320,000 – 860,000

268,000
253,000 – 283,000

Survival Benefits: Life-Years Saved With Antiretroviral Therapy and/or Medical Interventions to Prevent Opportunistic Infections[1] Year Intervention Per-Person Benefit # Patients Entering Care Total Survival Benefit (Months) (Years) 1989-92 1993-95 1996-97 1998-99 2000-02 2003 1989-2003 1994-2003 1989-2003 PCP prophylaxis PCP & MAC prophylaxis Prophylaxis + HAART-1 Prophylaxis + HAART-2 Prophylaxis + HAART-3 Prophylaxis + HAART-4 All prophylaxis + HAART pMTCT All interventions Infections averted = 2945 3.1 24.4 93.7 132.6 138.8 159.9 158,370 226,458 72,716 52,702 71,946 24,780 40,912 460,465 567,788 582,359 832,179 330,189 2,813,892 137,479 2,951,371

HAART-1, HAART-2, HAART-3, and HAART-4 reflect incremental improvements in HAART MAC = Mycobacterium avium complex; PCP = Pneumocystis carinii pneumonia

Walensky R et al. The survival benefits of AIDS treatment in the US J Infect Dis. 2006;194:1-5

Survival Gains in Resulting From Medical/Surgical Advances in Various Diseases

Condition

Treatment

Per-person survival gains (months) Chemotherapy Adjuvant chemotherapy Bypass surgery Marrow transplant 7 29 50 92

Non-small-cell lung cancer Node and breast cancer Coronary artery disease Relapsed nonHodgkin's lymphoma Prophylaxis in persons with HIV/AIDS HIV/AIDS

Opportunistic infection prophylaxis: trimethoprim/sulfamethoxazole, azithromycin Antiretroviral therapy
Walensky R et al. The survival benefits of AIDS treatment in the US. J Infect Dis. 2006;194:1-5

3

160

Table 1. Estimated number of people receiving antiretroviral therapy, people needing antiretroviral therapy and percentage coverage in low- and middle-income countries according to region, December 2006

Geographical region

Sub-Saharan Africa Latin America and the Caribbean East, South and South-East Asia Europe and Central Asia North Africa and the Middle East Total

% 0 6 >
80
|
Progress Report

d e d lu c x le il t s
Estimated number of people receiving ARV therapy Estimated need Coverage 1 340 000 355 000 280 000 4 800 000 28% 72% 19% 15% 6% 490 000 1 500 000 32 000 4 000 230 000 77 000 [1.8 – 2.2 million]

2 015 000

[6.0 – 8.4 million]

7 100 000

[24 – 34%]

28%

| April 2007

HAART MAKES THE DIFFERENCE

APRIL
Courtesy Joep Lange

NOVEMBER

Uno termina siendo cómplice de lo que no intentó evitar

JP Sartre

ONE WORLD TWO STANDARDS OF CARE

• • • •

FDC (TDF/EMT/EFV) Resistance testing Baseline check-up Frequent CD4 & VL monitoring • Rtv-boosted PI’s • 3rd and 4th line regimens

FDC (d4T/3TC/NVP) Not available Limited CD4 in some settings, VL low % • Limited availability • • • • • Almost not availble

ONE WORLD TWO STANDARDS OF CARE • • • • ARV can be delivered all over the world Success rates comparable to 1st world Early mortality higher, due to late start Guidelines compromised by cost, procurement, lack of political will and stigmatization of vulnerable populations • The majority of patients in need still lack access to WHO recommended ARVs • While expanding access to 1st line, push for proven 2nd line therapies

Summary: Choosing an Initial Regimen
 Most effective initial antiretroviral regimens
– DHHS
– NNRTI-based regimen with EFV or – Boosted PI-based regimen with LPV/RTV

– IAS-USA
– NNRTI-based regimen with EFV or – Boosted PI regimen with LPV/RTV, FPV/RTV, SQV/RTV, or ATV/RTV

 Factors in choosing initial regimen
– Efficacy – Tolerability – Resistance – Convenience

We know how to prevent and how to treat HIV/AIDS

The epidemic can be curbed

There is enough money around

Poverty and uneven distribution of wealth is a majo

driving force of the epidemic

Lack of political will is killing 2.8 million people a ye

The best moment to plant a tree was 20 years ago. The second best option is today…

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