Antiretroviral Therapy (Pedro Cahn)

8/7/2019 Antiretroviral Therapy (Pedro Cahn)

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STATE OF THE ART-A GLOBAL PERSPECTIVE

Pedro Cahn


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Outline: ARV Therapy in 2008

When to start

When to switch

What to use as cART

The global perspective

Research questions


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Increase in reported HIV cases in the Russian FederationIncrease in reported HIV cases in the Russian Federation

and Ukraine, 19872005and Ukraine, 19872005

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

0

50 000

100 000

150 000

200 000

250 000

300 000

350 000

400 000

30 000

45 000

60 000

75 000

90 000

105 000

120 000

15 000

0

Reported HIV cases

in the Russian Federation

Reported HIV cases

in Ukraine

Russian Federation

Newly reported casesCumulative (previous years)

Ukraine

Newly reported cases

Cumulative (previous years)

2.12Sources: Russian Federal AIDS Centre; Ukranian AIDS Centre and Ministry of Health of Ukraine


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

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

80

90

100


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0

5

10

15

20

25

30

35

40

1995 1996 1997 1998 1999 2000 2001

Deaths

per100

person-years

0

25

50

75

100 Percent a

ge

ofpatient-d

ayso

nART

DEATHS

USE OF ART

Mortality vs. ART utilization

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

AIDS Mortality Rates: 1996-2001


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39+/9 years

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

The Survival Benefits of AIDS Treatment in the United States


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Progress Report | April 20078 |

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

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

a2005 deaths annualized on basis of deaths until June 2005, reported by November 2005; ART programme data reporteduntil September 2005.

600

700P

D

D

2002estimated frommortality reports


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Progress Report | April 200710

AIDS 2008


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Antiretroviral Efficacy Rates Are

Improving in Clinical Practice

25

303134

3942

40

0

10

20

30

40

50

1996 1997 1998 1999 2000 2001 2002

Pa

tientsWith

HIV-1RN A

>500copies

/mL

(%)

Virologic failure of initial HAART in previously treatment-naive patients from5 observational cohorts (N = 4143)

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


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Clinical Outcome Improved by Starting

Therapy at Higher CD4+ Cell Count Timing of antiretroviral initiation

in treatment-naive subjects(N = 10,885) in AntiretroviralCohort Collaboration

HR for progression to AIDS or deathby CD4+ cell count at initiation oftherapy

< 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)

Results suggest a lower risk ofdisease progression/death whenstarting between 351-500 cells/mm3

Cumulative Probability of AIDS/Death byCD4+ Cell Count at HAART Initiation

Years Since Initiation of HAART1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

ProbabilityofA

IDSorDeath

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

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3


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The Problem of Late Diagnosis

CD4+ cell counts of treatment-naive patients firstpresenting for HIV care typically low

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

0

100

200

300350400450

500

CD4+

TLymp

hLeve

l

(cells/mm

3)

1996

Calendar Year

150

250

50

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006


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ACTG A5164: Immediate vs Deferred

ART in Patients With Acute OIs

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

Immediate Antiretroviral TherapyInitiation within 48 hours of randomization and

within 14 days of starting OI treatment(n = 141)

Deferred Antiretroviral TherapyInitiation between Weeks 4 and 32

(n = 141)

HIV-infectedpatients receiving

treatment forpresumed or

confirmed acute

OI/BI*

(N = 282)

Stratified by CD4+ cell count

< or 50 cells/mm3,

PCP, BI, or other OI

48 weeks

48 weeks

*Patients with TB excluded.


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ACTG A5164: Improved Outcomes

With Immediate ART During Acute OI 92% treatment naive

Median baseline CD4+ cell count29 cells/mm3; HIV-1 RNA 5.07 log10

copies/mL

OIs with effective antimicrobialtherapy only: PCP, bacterialinfections, 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 similarbetween groups

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

Pa

tientsProgre

ssingto

AIDS

orDeath

atWee

k48(%)

100

80

60

40

20

0

14.2

24.1

Immediate Deferred

P= .035


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85.8%

75.9%


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HIV-Infected Patients in the HAART Era Have a10-Year Shorter Expected Survival than Age andGender-Matched Controls

Adapted from Lohse N, et al. Ann Intern Med2007;146:87-95

1

0.75

0.5

0.25

0

Pr

obab

ilityofSu

rviv

al

Pre-HAART (1995-1996)

Early HAART

(1997-1999)

25 30 35 40 45 50 55 60 65 70

Survival from age 25 years

Age, y

Late HAART(2000-2005)

Population controls


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SMART Substudy: Clinical Impact of

Immediate vs Deferred Therapy

Virologic Suppression StrategyContinuous therapy

(n = 249 not receiving ART at trial start)

Treatment Interruption StrategyDeferred therapy until CD4+ cell count< 250 cells/mm; discontinue therapywhen CD4+ cell count > 350 cells/mm(n = 228 not receiving ART at trial start)

Patients with CD4+ cellcount > 350 cells/mm

who are antiretroviral naive(n = 249) or have not

received ART

for 6 mos (n = 228)

(N = 477)

Mean

follow-up:

16 months

Study halted early

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


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SMART Substudy: Clinical Impact of

Continuous vs Interrupted Therapy

Event, n (Rate per 100 Person-Years)

Interrupted HAART Continuous HAART HR PValue

OI/death

Overall 15 (4.8) 4 (1.1) 4.4 .009

OI

Overall 11 (3.5) 3 (0.8) 4.4 .02

Serious non-AIDS

Overall 12 (3.9) 2 (0.5) 7.1 .01

Composite*

Overall 21 (7.0) 5 (1.3) 5.1 .001

*Includes OI and serious non-AIDS events.

Patients who initiated and remained on antiretroviral therapy at higher CD4+ cell counts(> 350 cells/mm) had better outcomes vs those who deferred and interrupted HAART

Caveat: small number of patients analyzed and not all treatment naive

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


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SMART: Effects of Therapy Reinitiation

on Morbidity and Mortality Significant decrease in excess risk

of OI/death in interruption arm afterstudy modification

Persistence of excess risk for

OI/death in interruption arm vscontinuous therapy arm related to:

Lower mean CD4+ cell count

Higher proportion with HIV-1 RNA> 400 copies/mL

Antiretroviral therapy interruptionassociated with long-termconsequences

Favors InterruptionFavors Continuous

OI or Death

Death

OI

Major CVD,Renal, orHepatic Disease

2.5

3.3

0.1 1 5

1.4

1.8

1.3

1.7

1.7

1.1

Premodification (n = 639)Postmodification (n = 195)

P= .03

El-Sadr W, et al. CROI 2008. Abstract 36.


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No new evidence has emerged to define

the optimal CD4 cell count that provides a

treatment-related survival advantage, and based onthe 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 well-conducted cohort studies.

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


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Where Do Treatment Guidelines Come

From?

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

Cohort studies compare outcomes of patients started ontherapy at various CD4+ cell count thresholds

Cohort studies in early HAART era supported startingbefore CD4+ cell count < 200 cells/mm3 but not earlier

More recent analyses suggest treatment outcomes betterwhen treatment is started with higher CD4+ cell counts

Newer therapies that are simpler and better tolerated thanthose in years past allow for question of earlier treatment tobe explored


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PISCIS Cohort: Time From Initiation of

Antiretroviral Therapy to AIDS/Death

Jaen A, et al. J Acquir Immune Defic Syndr. 2008;47:212-220.

NCD4+ Cell Count (cells/mm3) HR (95% CI)

> 350

200-350, unadjusted

625

650

670

1.56

1.0 5.00.1

200-350, adjusted for lead time*

200-350

< 200, unadjusted

625

650

670< 200, adjusted for lead time*

1.85

2.81

2.97

*Lead time defined as time it took for patients who deferred therapy with early disease stage to reachlater disease stage

3427 treatment-naive patients assessed for progression to AIDS/death,stratified by CD4+ cell count when initiating antiretroviral therapy


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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-AIDSrelated 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. LangeCG, et al. AIDS. 2003;17:2015-2023. 3. Moyle GJ, et al. J Infect Dis.

2005;191:866-872.


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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 mayincrease the risk of serious non-AIDS events

SMART study: being off antiretroviral therapy raises risk ofserious non-AIDS diseaseseven when CD4+ cell count> 250 cells/mm3


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FIRST: More Non-AIDS Than AIDS

Events at Higher CD4+ Cell Counts

Baker J, et al. CROI 2007. Abstract 37.

Patient-years: 1288 | 1442 1324 | 1343 1238 | 1232 1940 | 1900

OD events Non-OD events

Latest CD4+ Cell Count (cells/mm3)

Rates decline at higher CD4 counts

Non-OD > OD at CD4+ cell counts > 200 cells/mm3

< 200 200-349 350-499 500

24

6

8

10

12

1416

18

Rate(Events/

1

00Pati

ent-Yrs)

0


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Immunosuppression Increases Risk of

HIV- and Non-HIVRelated Mortality Cohort study of > 23,000

patients in Europe, Australia,and US

76,577 patient-years offollow-up

1248 (5.3%) deaths from2000-2004

Both HIV- and non-HIVrelated mortality associatedwith CD4+ cell countdepletion

100

0.1

1.0

10

< 50 50-99 100-199

200-349

350-499

CD4+ Cell Count (cells/mm3)

RR

OverallHIVMalignancyHeartLiver

Weber R, et al. CROI 2005. Abstract 595.

500

AIDS i k t 6 th


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AIDS risk at 6 months

CASCADE Collaboration 2003


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CASCADE: Nadir CD4+ Cell Count

Predicts AIDS and Non-AIDS Events

Marin B, et al. IAS 2007. Abstract WEPEB019.

1.000.01 1.00 100.00

Nadir CD4+ Cell CountAIDS-Related Death

0.01 100.00

200-349 vs 35050-199 vs 350

< 50 vs 350

Non-AIDSRelated Death

1.000.01 100.00

Non-AIDS Cancer Death

1.000.01 100.00

Liver Disease Death

200-349 vs 350

50-199 vs 350< 50 vs 350

200-349 vs 350

50-199 vs 350< 50 vs 350

200-349 vs 350

50-199 vs 350

< 50 vs 350

CASCADE collaboration cohort (N = 9858)

Several clinical markers of HIV progression correlated with death due to AIDS-relatedcauses, non-AIDSrelated severe infection, liver diseases, and non-AIDSrelatedmalignancies including

Latest and nadir CD4+ cell counts

Time spent with CD4+ cell count < 350 cells/mm3


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Association Between Current CD4+

Cell Count & Non-AIDS ComplicationsStudy Lower Current CD4+ Cell Count Significantly

Associated With Increased Risk?

Non-AIDSmalignancies

Renaldisease/death

CVDevents/death

Liverdisease/death

FIRST Yes Yes Trend, NS No

D:A:D Yes Yes Trend, NS Yes

CASCADE Yes NA Yes Yes

SMART Trend, NS Trend, NS Trend, NS Yes

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


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Likelihood of Achieving Normal

CD4+ Cell Count Depends on BL Level

Moore RD, et al. Clin Infect Dis. 2007;44:441-446.

Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192.

ATHENA National CohortJohns Hopkins HIV Clinical Cohort

Years on HAART

MeanCD

4+CellCoun

t

(cells/mm

3)

1000

BL CD4+ Cell Count

0 48 96 144 192 240 288 336Weeks From Starting HAART

200

400

600

800

0

1000

> 500351-500

201-35051-200< 50

BL CD4+ Cell Count200

400

600

800

00

1 2 3 4 5

> 350

< 200

201-350

6


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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 > 500copies/mL

Zoufaly A, et al. CROI 2008. Abstract 16.

Viremia < 75% of timeViremia 75% of time

Influence of Cumulative log10 HIV-1 RNA

Days Since HAART Begun

.95

.975

1

Survival P

robabil

ity

WithoutL

ymphoma

40002000 300010000


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SMART Study: Stopping Therapy

Increases IL-6 and D-dimer Analysis of changes in inflammatory

and coagulation markers, IL-6 and D-dimer

IL-6 and D-dimer increased in

interruption arm (P < .0001) IL-6 and D-dimer levels related to all-

cause mortality and CVD (4th vs 1stquartile)

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)

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

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

Change in D-Dimer (g/mL)From Baseline to 1 Month

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

0

0.2

0.3

D-Dimer(g/mL

)

> 50,00010,000-50,000

401-10,000

400

0.28

0.11

0.40

0

0.1

P= .0005 for trend


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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-ARTHIV-1 RNA level in blood

1. Tuyama A, et al. CROI 2008. Abstract 57. 2. Letendre S. CROI 2008. Abstract 68.


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Treatment to Prevent

HIV Transmission


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The case for expanding access to


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The case for expanding access toHAART to curb the growth of the HIV

epidemic

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

HAARTHAART

CoverageCoverage


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HIV Treatment Reduces Heterosexual

Transmission 174 discordant, monogamous couples

in Raiki, Uganda, retrospectivelyanalyzed for factors associated withtransmission[1]

1. Gray RH, et al. Lancet. 2001;40:1149-1153.

2. Castilla J, et al. J Acquir Immune Defic Syndr. 2005;40:96-101.

30

1.0< 1700 1700-

12,49912,500-38,499

> 38,500

HIV-1 RNA (copies/mL)

Adjuste

dRateR

atioof

Transmission/C

oitalAc t

10

20

0.1

393 steady heterosexual couples[2]

HIV prevalence among partners declinedfrom 10.3% duringpre-HAART period to 1.9% duringlate HAART period (P= .0061)

EnrollmentPeriod

OR (95% CI) PValue

Pre-HAART(1991-1995)

1

Early HAART(1996-1998)

0.55(0.19-1.61)

.2763

Late HAART(1999-2003)

0.14(0.03-0.66)

.0127


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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

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

P

atients(%)

0

10

20

30

40

50

Baseline(n = 883)

4 Months(n = 779)

12 Months(n = 658)

24 Months(n = 463)

Risk behavior

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

Interruption

C

ontin

uous

Interru

ption

C

ontin

uous

Interru

ption

C

ontin

uous

Interruption

Con

tinuo

us


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ICONA study group

Median follow-up:45 weeks

Study population:862 ARV-naive patients

84.3% receivingunboosted PI + NRTIs

Discontinuations:n = 312 (36%)

Toxicity Is a Major Reason for

Discontinuation of First-Line HAART

58%

14%

8%

20%

Cause of Discontinuation

dArminio Monforte A, et al. AIDS. 2000;14:499-507.

Toxicity

Failure

Nonadherence

Other


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Safety and Tolerability of Select

Current Regimens Are ExcellentStudy Length Drug regimen Discontinuations Due to AEs,* %

AI424-089[1] 96 weeks ATV + d4T + 3TCATV/RTV + d4T + 3TC

38

GS934[2] 48 weeks EFV + TDF + FTCEFV + ZDV/3TC

511

KLEAN[3] 48 weeks FPV/RTV + ABC/3TCLPV/RTV + ABC/3TC

1210

ARTEMIS[4] 48 weeks DRV/RTV + TDF/FTCLPV/RTV + TDF/FTC

37

CASTLE[5] 48 weeks ATV/RTV + TDF/FTCLPV/RTV + TDF/FTC

23

HEAT[6] 48 weeks ABC/3TC + LPV/RTVTDF/FTC + LPV/RTV

46

GEMINI[7] 48 weeks SQV/RTV + TDF/FTCLPV/RTV + TDF/FTC

47

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.


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Fixed-Dose Combinations

+

+=

=

=

ABC

TDF

ZDV

3TC

FTCFTC

++EFV

+ =LPVLPV RTVRTV

TDF FTC

Fixed-dose combinations

ZDV/3TC

ABC/3TC

TDF/FTC

EFV/EFV/

TDF/TDF/

FTCFTC

LPV/RTV

Individual Agents


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When to Start: 2008 vs. 2006

Guideline Recommendation to BeginImmediate Therapy Optimal Time Not Well Defined orRecommendation to Delay Therapy

DHHS 2008[1] CD4+ cell count < 350 cells/mm3

Previous AIDS-defining illnessPregnant women

HIV-associated nephropathyHBV-coinfection, when HBV treatment

indicated

CD4+ cell count > 350 cells/mm3

EACS 2007[2] CD4+ cell count < 350 cells/mm3

CD4+ cell count from 350-500 cells/mm3 with high HIV-1 RNA

Opportunistic infection


IAS-USA2006[3] *

Active AIDSNo history of active AIDS, butCD4+ cell count 200 cells/mm3

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


1. US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx.2. European AIDS Clinical Society.

Available at: http://www.eacs.eu/guide/1_Treatment_of_HIV_Infected_Adults.pdf.

3. Hammer SM, et al. JAMA. 2006;296:827-843.*See updated version in JAMA Aug 2008


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164

187

102

181

200

192

87 239

163

97134

179

97100

125

12386

122

103 53157 206

95

72

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 atapproximately 150-200 cells/mm3, increasing in sub-Saharan Africa from50-100 cells/mm3

When Is Antiretroviral Therapy

Started?

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


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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-AIDSrelated complicationsall of themincreasingin 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 nowthan in years past


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When to Start: Summary

Prospective clinical trials, cohort studies, retrospectivedata, and consensus guidelines support startingantiretroviral 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


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Timeline of ARV Development

87 91 92 94 95 96 97 98 99 0088 89 90 01 02 0393 0504 06

ZDV

07


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87 91 92 94 95 96 97 98 99 0088 89 90 01 02 0393 0504 06

ddC

3TC

NNRTI

NRTI

PIEntry

inhibitor

ddI

IDV

SQR LPV/r

TDFNVP

DRV

TPVT-20

ZDV d4TABC

DLV

EFV FTC

RTV

NFV ATV

FPV

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

07

MVC

Timeline of ARV Development

APV

RTGV

08

ETV

Integraseinhibitor

NNRTI

NRTI

PI

NRTI

Entryinhibitor

PI

NRTI


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Retrovirus life cycleRetrovirus life cycle

Entry inhibitorsENF MRV

VCV TNX355AMD11070

Reversetranscriptase

inhibitorsZDV NVPddI DLVTDF EFVd4T ABCFTC 3TC

ETV TMC 278RCV APC

IntegraseinhibitorsGS9137

Raltegravirothers

Maturationinhibitor

Bevirimat

Proteaseinhibitors

SQV IDVRTV NFVFPV LPVATV TPVDRV

Recommended Regimens forRecommended Regimens for


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Recommended Regimens forRecommended Regimens forTreatment-Nave Patients: DHHS 2008Treatment-Nave Patients: DHHS 2008

Column A Column B

PI or NNRTI + 2 NRTIs

Preferred Lopinavir/ritonavir bid*Fosamprenavir + ritonavir

Atazanavir + ritonavir

Efavirenz Tenofovir DF/emtricitabine

Abacavir/lamivudine

Alternative Lopinavir/ritonavir qdFosamprenavir (unboosted)Atazanavir (unboosted)

Fosamprenavir + ritonavir qd

Nevirapine

Zidovudine/lamivudineDidanosine + lamivudine

Adapted from: http://aidsinfo.nih.gov/Default.aspx.

Choose a PI or NNRTI plus 2 NRTIs.

*The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred component was basedon twice-daily dosing. A smaller study has shown similar efficacy with once-daily dosing but also showeda 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 womenwith 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.

Ri k f d f i it h i


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SCOPE cohort ofART-experiencedsubjects (n=106)

Stable ART for >120days

HIV RNA >1000 c/mL

>1 resistance

mutation Resistance testing Q4

months until ARTmodification

Hatano H, CROI 2006, #615

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

0

0.25

0.50

0.75

1.00

0 4 8 12 16 20 24

Time (months)

Time to loss of 1drug equivalent

1 new major PI mutation*

1 new NRTI mutationAny new mutation

*Data are forPI-treatedsubjects (n=71)

0

0.25

0.50

0.75

1.00

%

without

new

mutatio

n

0 4 8 12 16 20 24Time (months)

Time to development

of new mutation

Risks of deferring switch infailing patients


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55

0

10

20

30

40

UK CHIC Study

Time Since Starting HAART (Years)Time Since Starting HAART (Years)2 4 6 8 10

Cumulative Risk of Extensive Failure

Cumula

tive

Risk(%)

NRTI

PI

NNRTI

3-class resistance

Extensive 3-class resistance

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


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Mortality After First HAART Failure By

Time to Regimen Modification

23261619

Conditiona

lHazard

0

Among subjectsfailing a NNRTI-

based regimen.

0.009

Time since failure (months)

Among subjectsfailing a PI-based

regimen.

0.0080.0070.0060.005

0.0040.0030.0020.001

0

0.0090.0080.0070.0060.0050.0040.0030.0020.001

1 4 7 1013 293234374043464952

Condition

alHazard

Switch at 1 month Switch at 6 months Switch at 12 months Switch at 18 months

Modeling study using datafrom 2 clinical cohorts

Model suggests delayedmodification may beassociated with greaterincrease in mortality followingfirst-line failure of NNRTI-based regimen vs PI-basedregimen

HR for death: 1.21 per 3-modelay in switch from failingNNRTI regimen; P = .002

CD4+ decline may be slowerafter PI failure

Modification of failed PIregimens less dependent onimmediate vs later timing

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

R l ti hi B t Vi l S iRelationship Between Viral Suppression


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Relationship Between Viral Suppressionand Mortality

Relationship Between Viral Suppressionand Mortality

Prospective, population-based DanishHIV Cohort Study

N = 3919 HIV-infected patients

On HAART 18 months

Stratified based on proportion ofdetectable 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

Lohse N, et al. ICAAC 2005. Abstract H-515

CID2006;42:136-144.

100% (all values VL 400)

1%-99% (of values VL 400)

0% (all values VL < 400)0.25

0.20

0.15

0.10

0.05

0.00

0 18 36 54 72

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

Cumu

lat i

veMort

ality

Proportion of Detectable Viral Loads Over6-18 Months After Initiation of HAART

BENCHMRK 1 & 2 Combined EfficacyBENCHMRK 1 & 2 Combined Efficacy


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BENCHMRK-1 & 2 Combined EfficacyBENCHMRK-1 & 2 Combined EfficacyPercent of Patients With HIV RNA


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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


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WHO - CD4 criteria for initiation of ART inAdults and Adolescents

CD4 (cell /mm3) a Treatmentrecommendation b

< 200 Treat irrespective of clinical stagec[A-III]

200 - 350 Consider treatment [B-III] and initiate ARTbefore dropbelow 200 cell/mm3

c

[A-III]

>350 Defer treatment in asymptomatic persons [A-III]

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 withclinical staging in decision makingc 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


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WHO - Recommendations for initiating ART inadults and adolescents based on clinical stage

and availability of immunological markers

WHO ClinicalStaging

CD4 testingnot available

CD4 testing available

1 Do not treat[A-III]

Treat if CD4 cell count < 200/mm3 a

[A-III]

2 Do not treatc

[B-III]

3 Treat[A-III]

Treat irrespective of CD4 cell count,with consideration of CD4< 350/mm3

in some situations b[A-III]

4 Treat[A-III]Treat irrespective of CD4 cell count

[A-III]a 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


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TDF* or ABC

AZT* or d4T

NVP

EFV3TC or FTC

Triple NRTI alternative

approach#

Preferential 2 NRTI/NNRTI approach

* Preferential NRTI to be combined with 3TC or FTC.

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

WHO: First Line ARV Drugs in Adults and Adolescents


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Egger, 2007

Response to HIV therapy in resource-poor


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p py pand resource-rich regionsVirologic 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+ cellcount, year of starting therapy, and disease stage

More ART modifications among Swiss, often to improve convenience andtolerability

Mortality during the first year of HAART

Estimated mortality of15% in sub-Saharan Africa vs 5% in Europe andNorth America

Early mortality seen after initiation of ART possibly due to pre-existingcondition or immune restoration

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


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Lancet2006:367(9513);817-21

S b ti l I iti l R /Fi t F il


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Suboptimal Initial Response/First Failurein Resource Unconstrained Settings

Typically picked up early through VL monitoring All potential reasons evaluated

Goal of therapy remains maximal virologic suppression i.e., VL


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Treatment Failurein Resource Limited Settings

Lack of widespread availability of CD4 and VL testingimplies that completeness of response to any line oftherapy may not be fully assessed and treatment failurewill 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 morbidityand mortality, so CD4 conservation and

maximal virologic suppression should be

persued


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Limited use of second-line

Only 40,000 (2%) on 2nd line atend 2006

limited provision in public sector

high cost: $1000 2500 pa

only some countries haveuniversal access

HIV-TB co-management ?? switch rates (4% annual in

DART)

Much more focus on scalingup first-line

Clear what to use; many FDCs Price competition: d4T/3TC/NVP

for $121 pa

-

100'000

200'000

300'000

400'000

500'000

600'000

700'000

800'000

900'000

2006 2007 2008 2009 2010

Tota l num ber

peop le need in

2nd l i ne ARVs

(h igh e st im ate

Tota l num ber

peop le need in

2nd l i ne ARVs

(low es tim ate)

N d f d li ill i


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Need for second-line will rise

-

100 '000

200 '000

300 '000

400 '000

500 '000

600 '000

700 '000

800 '000

900 '000

2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0

To ta l n u m b e

p e o p le n e e d i

2 n d l in e A R V

(h ig h e s tim a t

To ta l n u m b e

p e o p le n e e d i

2 n d l in e A R V

(lo w e s tim ate

The number of people is

forecast to grow at a compoundrate of around 40% between2006 and 2010

Depending on the switch rate at which patients developresistance to 1st line ARVs andtherefore need to change to 2ndline therapies between500,000 and 800,000 peoplecould need 2nd line ARVs by2010

- 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

Challenges in HAART in 2008 and Onwards


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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


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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


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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Population GDP Publications Patents (EU) Patents (US) Pharma Sales

Advance Economies Rest of the World

%ofworldtota

ls(1995)

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

Different resources: Indicators of global

science

zones in innovation, markets, and intellectual propertyrights


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Projected reduction in African agricultural labour forceProjected reduction in African agricultural labour force

due to HIV and AIDS by 2020due to HIV and AIDS by 2020

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

Projected labor force loss (%) by year

Namibia

Botswana

Zimbabwe

Mozambique

South Africa

Kenya

Malawi

Uganda

UR Tanzania

Central African Republic

Cte dIvoire

Cameroon

0 5 10 15 20 25 30

2020 2000

4.8


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Wealth, poverty and HIV:Wealth, poverty and HIV:

countries grouped by region and HIV prevalencecountries grouped by region and HIV prevalence

0

10

20

30

40

50

60

70

80

over 20

%

10-205-101-5LatinAmerica

andCaribbean

Asia*AfricaAll (48)

% of population living on less that $1 per day

Relative income of richest 10% to poorest 10%*except Japan

Industrializedcountries

Countries with HIV prevalenceover 1.9% in 2002

Countries according to level ofHIV prevalence in 2001 (%)

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

4.3

Is cost the main obstacle?


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Richest 20% Poorest 20%

GLOBAL INCOME

82,7%82,7%

1.4%1.4%

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

The World Bank
http://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpghttp://www.unaids.org/bangkok2004/photos/C-2624_768.jpg


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45% of Eligible US Patients Not On HAART

CROI 2005: Teshale E, et al. Abstract 167.

820,000746,000 894,000

PLWHA

480,000441,000 519,000Eligible

340,000320,000 860,000In care

268,000253,000 283,000On HAART

Survival Benefits: Life-Years Saved With Antiretroviral Therapy and/or Medical Interventions


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to Prevent Opportunistic Infections[1]

Year Intervention Per-Person Benefit(Months)

# Patients Entering Care Total Survival Benefit(Years)

1989-92 PCP prophylaxis 3.1 158,370 40,9121993-95 PCP & MAC

prophylaxis24.4 226,458 460,465

1996-97 Prophylaxis + HAART-1 93.7 72,716 567,788



2003 Prophylaxis + HAART-4 159.9 24,780 330,189

1989-2003 All prophylaxis +HAART

2,813,892

1994-2003 pMTCT Infections averted = 2945 137,479

1989-2003 All interventions 2,951,371

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

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


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

Condition Treatment Per-person

survival gains(months)

Non-small-cell lungcancer

Chemotherapy 7

Node and breast

cancer

Adjuvant chemotherapy 29

Coronary arterydisease

Bypass surgery 50

Relapsed non-Hodgkin's lymphoma

Marrow transplant 92

Prophylaxis inpersons withHIV/AIDS

Opportunistic infection prophylaxis:trimethoprim/sulfamethoxazole, azithromycin

3

HIV/AIDS Antiretroviral therapy 160

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

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

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


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Progress Report | April 200780

Geographical region Estimated number of people receiving

ARV therapy

Estimatedneed

Coverage

Sub-Saharan Africa 1 340 000 4 800 000 28%

Latin America and the Caribbean 355 000 490 000 72%

East, South and South-East Asia 280 000 1 500 000 19%

Europe and Central Asia 32 000 230 000 15%

North Africa and the Middle East 4 000 77 000 6%

Total2 015 000[1.8 2.2 million] 7 100 000[6.0 8.4 million] 28%[24 34%]

>60%st

illexclu

ded

>60%

stillexclu

ded

HAART MAKES THE DIFFERENCE


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HAART MAKES THE DIFFERENCE

APRIL NOVEMBER

Courtesy Joep Lange


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Uno termina siendo cmplicede lo que no intent evitar

JP Sartre

ONE WORLD


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ONE WORLDTWO STANDARDS OF CARE

FDC (TDF/EMT/EFV)

Resistance testing

Baseline check-up Frequent CD4 & VL

monitoring

Rtv-boosted PIs

3rd and 4th lineregimens

FDC (d4T/3TC/NVP)

Not available

Limited

CD4 in some settings,VL low %

Limited availability

Almost not availble

ONE WORLD


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ONE WORLDTWO 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 andstigmatization of vulnerable populations

The majority of patients in need still lackaccess to WHO recommended ARVs

While expanding access to 1st line, push forproven 2nd line therapies


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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


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

he epidemic can be curbedhere is enough money around

overty and uneven distribution of wealth is a maj

riving force of the epidemic

ack of political will is killing 2.8 million people a y

The best moment to plant a tree was 20 years ago.

Antiretroviral Therapy (Pedro Cahn)

Documents