“The TOP TEN” Important Issues of HIV Medicine in 2006

“The TOP TEN”Important Issues of HIV Medicine in 2006

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Faculty

Editor and Course DirectorEditor and Course Director

Harold A. Kessler, MDHarold A. Kessler, MDAssociate Dean, Post-Graduate Medical Associate Dean, Post-Graduate Medical

Education Director, Office of Continuing Medical Education Director, Office of Continuing Medical Education Rush University Medical CenterEducation Rush University Medical Center

Chicago, IllinoisChicago, Illinois

Presenter

Cyril K. GoshimaCyril K. Goshima, M.D, M.D

Director, AIDS Education ProjectDirector, AIDS Education ProjectHawaii AIDS Education & Training CenterHawaii AIDS Education & Training Center

Honolulu, HawaiiHonolulu, Hawaii

Learning Objectives (CME, CE, CPE)

At the completion of this educational activity, participants should be able to:

— Describe the most important recent developments regarding HIV treatment

— Identify key studies that can improve outcomes with HIV treatment

— Summarize the clinical data supporting methods for improving the health and management of HIV-infected patients

Disclosure Information

It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME. Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months. If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content.

Disclosure Information

Cyril K. Goshima, M.D.

Grants/Research Support: Abbott, Agouron, BI, BMS, Gilead, GSK, DuPont, Pfizer, Serono, Tibotec

Speakers’ Bureau: GSK, Gilead

Opinions & Off Label Discussion

The opinions or views expressed in this educational program are those of the participants and do not

necessarily reflect the opinions or recommendations of Gilead Sciences, Rush University Medical Center, University of Florida College of Pharmacy, ANAC or CCMC. The faculty may have included discussion on

unlabeled uses of a commercial product or an investigational use of a product not yet approved for

this purpose.

Please consult the full prescribing information before using any medication mentioned in this program.

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10. Developing World Treatment and Prevention


Developing WorldTreatment and Prevention 10

A Global View of HIV Infection38.6 million people living with HIV, 2005

UNAIDS Report on the global AIDS epidemic, 2006

"I just don't believe we can reverse this if we keep having more people infected every year than we are

increasing the number of people on medication.”

~William Jefferson Clinton, Head of Clinton Foundation

Survival in Africa with ART

HIV+ cohort followed since 1995 ART available since 2003 ART impact on mortality and causes of death assessed

Munderi P, et al. XVI IAC (2006). Abst. THLB0208

2003-20061995-20001819658Pt-yrs of F/U

Median CD4 cells at enrollment

Survival Probability after 2 yearsSurvival Probability after 1 yearMortality/1000 pt-yrsDeaths (%)

9375

93.8%27.5%95%54.7%34.1577.26%74%

Survival in Africa with ART

With ART there is a decrease in death With ART there is an increase in survival

Rapid Scale Up in India

Estimated 5.2 million people living with HIV/AIDS in India

April 2004: Free ART program started at 8 centers

June 2006: 34,620 pts on ART at 54 centers

Planned— 2007: 100,000 pts on ART— 2011: 300,000 pts on ART

at 250 centers

1%

73%

13%

13%

LTFU Died Stopped On ART

Outcomes at 24 mos. for Patients Started on ART

Khera A, et al. XVI IAC (2006). Abst. WEPE0096

Trials in Developing World

Open label, single arm study of TDF + FTC + EFV in Senegal1

40 ARV naïve pts: — median CD4 122/mm3

(3-310)— VL 5.3 log10 c/ml

At month 9:— 87.5% <400 c/ml— 77.5% < 50 c/ml— Median CD4 +242

cells/mm3

Safe and well tolerated— 3 Pts developed TB— 3 deaths (all with CD4 <5);

none drug related

0102030405060708090

100

%<400 c/mL %<50 c/mL

Month 1 Month 3 Month 6 Month 9

Landman R, et al. 13th CROI (2006). Abst. 543

TDF + FTC + EFV: HIV RNA Suppression

% P

atie

nts

Trials in Developing World

Success rates in developing countries are similar to those in the developed world

Promising HIV prevention approaches

1. Male circumcision: several consistent study results

2. Treatment as Prevention?

- ARVs to lower viral burden, decrease transmission

- Treat all infected patients?

- Post Exposure prophylaxis?

- PreExposure prophylaxis?

"A vaccine's going to be critical in the long run to containing the epidemic. Unless there's some striking

breakthrough that we're not aware of, it's likely to be another 10 years before one is commercially available."

~Cate Hankins, chief HIV scientist at the United Nations

Developing WorldTreatment and Prevention

Continued transmission vexing across the world— Multiple reasons cited

Vaccines – still no leading candidate Treatment more available, consistent

responses Circumcision data consistently protective

"I just don't believe we can reverse this if we keep having more people

infected every year than we are increasing the number of people on medication.”

~William Jefferson Clinton, Head of Clinton Foundation

7.0

20.0

0

5

10

15

20

25

2003 2005

%

UNAIDS Report on the global AIDS epidemic, 2006

Coverage of ARV therapy

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3.

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7.

8.

9. Resistance in Naïve Patients



Resistance in Naïve Patients

“Drug resistance testing is recommended

for persons with chronic HIV infection prior

to initiation of therapy.”

~DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, October, 2006

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Resistance in Naïve Patients: A Global Study

WATCH: Worldwide Analysis of resistance Transmission over time of Chronically and acute infected HIV-1 Patients

6,054 naïve pts Country (n):

— Europe 3,252— Africa 1,162— Asia 653— Latin America 806— N America 290

Results: 8.9% ≥1 mutation0%

1%

2%

3%

4%

5%

6%

7%

8%

PI NRTI NNRTI

Bowles E, et al. XVI IAC (2006). Abst. MOPE0388

Resistance by ARV class

9Resistance in Naïve Patients

Pre treatment genotypic mutations Important in drug selection / options Noted worldwide Rates and trends vary across continents Especially high rate of NNRTI resistance in

recently infected US youth

“Drug resistance testing is recommended for persons

with chronic HIV infection prior to initiation of therapy.”

~DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, October, 2006

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8. The SMART Study




The SMART Study

“It was hypothesized that, over the longer term, a stratified treatment interruption will results in a

significant lower rate of serious toxicities than an uninterrupted treatment, while maintaining a low rate of disease progression.”

~http://www.smart-trial.org

Can We Ever Stop Treatment? Yes, but…

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Continuous ARV

(Viral Suppression)

Defer ARV until CD4 <250, then treat until CD4 >350,

then stop

(Drug Conservation)

N = 5,472Eligibility: CD4 >350

SMART Study: Design

Primary Endpoint: Powered to detect Clinical events / death

SMART Study Results:HIV and Clinical Events

Is stopping for < four months safer? Unclear yet.

Viral Suppression Group

Drug Conservation Group

444036322824201612840

Months

0.00

0.05

0.10

0.15

0.20

Hazard ratio, 2.6; 95% CI, 1.9-3.7; P<0.001

Cum

ulat

ive

Prob

abili

ty o

f Eve

nt

Opportunistic Disease or Death from Any Cause

No. at Risk

16228037244454068987010401301166620742720

17328838847457272490610771310169520812752

Drug conservation

Viral suppression

Drug Conservation Group

444036322824201612840

Months

0.00

0.05

0.10

0.15

0.20

Hazard ratio, 1.7; 95% CI, 1.1-2.5; P=0.009

15727337544354369386710411292166320742720

16528238046256371389910701307169220772752

Major Cardiovascular, Renal or Hepatic Disease

Viral Suppression Group

SMART Study Group NEJM 2006;355:2283-2296

The SMART Study: Conclusions

Stopping Suppressive ARVs – at any CD4 cell count – carries greater risk of OIs and other illnesses

Not just HIV-related OIs; — Other clinical conditions and all cause mortality were at higher rates

Increased risk explained by current CD4 cell counts— 250-350 has greater risk compared to >350

Increased Risk > 350 CD4 cell counts explained by viremia— Implications for when to start?

“It was hypothesized that, over the longer term, a stratified treatment interruption will results in a significant lower rate of serious toxicities than an

uninterrupted treatment, while maintaining a low rate of disease progression.”

~http://www.smart-trial.org

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SMART Study Group NEJM 2006;355:2283-2296

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7. CCR5 Inhibitors

8. The SMART Study




CCR5 Inhibitors:The Good, The Bad, The Unknown

CXCR4 CCR5CD4

T-cell lines Lymphocytes Monocyte/macrophages

Coreceptor Usage of HIV-1 Variants

Based on slide from D. Kuritzkes.

R5(NSI)

X4(SI)

7

The Good

The Bad

The

Two agents on Phase III development; MVC on EAP 1st QTR 2007Short-term activity clear New class: no cross resistance to existing classesCD4 stability even in viremic dual tropic pts

Activity tied to tropism phenotype assay – unknown costTropism appears related to disease stagePotency and PK may present challenges

Uncertainty regarding safety of CCR5 inhibition Uncertain risk/benefit in patients with mixed infectionOptimal clinical use not defined Timing of FDA approval unclear

Unknown

CCR5 Inhibitors:The Good, The Bad, The Unknown 7

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6. Efavirenz Potency Further Validated ACTG 5095 and 5142

7. CCR5 Inhibitors

8. The SMART Study




ACTG 5095 and ACTG 5142:Efavirenz Potency Further Validated

What is the role of EFV + 2 NRTIs:— Compared to newer boosted PIs— At very high viral load levels / very low CD4 counts

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ACTG Protocol A5095

ZDV/3TC/ABC ZDV/3TC + EFVZDV/3TC/ABC

+ EFV

HIV+, ARV-naïve subjects, n=1,147

A phase III randomized, double-blind, placebo-matched, multicenter study with duration of follow-up planned for approximately 2 years after enrollment of last subject.

Baseline Characteristics

Median CD4+: 238 cells/mm3

Median HIV-1 RNA viral load: 78,825 copies/mL

<100,000 copies/mL 57%

100,000 copies/mL 43%

Gulick R, et al. 45th ICAAC (2005). Abst. H-416a

ACTG 5095: Similar Risk of Virologic Failure Across VL / CD4 Strata at Year 3

Ribaudo H, et al. XVI IAC (2006). Abst. THLB0211

By Baseline CD4 Cell Count

1.0 1.75 2.850.660.35

<50

50-199

200-349

350-499

≥500

By Baseline HIV RNA Level≥300,000

100,000-299,999

30,000-99,999

<30,000

1.0 1.75 2.850.660.35

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152

1.0

0.8

0.6

0.4

0.2

0.0

ACTG 5142:Time to Virologic Failure

Adjusted p values (threshold for significance <0.016)LPV/EFV vs LPV: 0.13LPV/EFV vs EFV: 0.5LPV vs EFV: 0.006

Pro

po

rtio

n N

ot

Fai

led

Time in Weeks From Randomization

LPV

EFV

LPV/ EFV

Riddler S, et al., XVI IAC (2006). Abst THLB0204

ACTG 5142:ARV Resistance Mutations (Preliminary Analysis)

Patient Samples LPV EFV LPV/ EFV

Observed VF 94 60 73

Genotypic assays+ 52 33 39

Any PI mutations 20 13 18

Major PI mutations++ 0 0 2

NNRTI mutations 2** (4%) 16 (48%) 27*

NRTI mutations 8 (15%) 11*** (33%) 4

Mutations in 2 classes 2** (4%) 10*** (30%) 2+some genotype assays pending++30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V,82A/F/L/S/T, 84V, 90M

*P < 0.05 compared to LPV; ** P<0.05 compared to EFV;*** P<0.05 compared to LPV/ EFV

% of Genotype results

Riddler S, et al., XVI IAC (2006). Abst THLB0204

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2.

3.

4.

5. New Data with Boosted Protease Inhibitors: Naïve Patients


7. CCR5 Inhibitors

8. The SMART Study




New Data with Boosted Protease Inhibitors:Clinical Trials in Naïve Patients

Hyperbilirubinemia

Separate timing of ARA use

Do not use with PPI

Decreased risk hyperlipidemia

QD

Lowest pill burden

ATV/r

Interim Data set presentedFewer lipid effects than LPV/rSQV/r

Rash

Dose flexibility

No food restrictions

QD or BID for Tx naïve

FPV/r

Hyperlipidemia

Insulin Resistance

Substantial clinical trial data

Heat stable reformulation

QD or BID for Tx naïve

LPV/r

Component Considerations Major Toxic Effects and Cautions

Note: TPV/r NOT recommended for use in ARV naïve pts Adapted from Hammer S, et al. JAMA 2006;296:827-843.

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Parade of Boosted Protease InhibitorsClinical Trials in Naïve Patients

More PI options to select from Similar Efficacy data for most boosted PIs

— Hepatic Safety data avoid TPV use (naïve pts)

Promising initial data: lower RTV dose— Tradeoff of rare PI resistance?— Lipid data show small differences remain

Induction maintenance promising for— Boosted PIs (LPV) without NRTIs— Unboosted ATV with NRTIs

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1.

2.

3.

4. Newest Protease Inhibitors: Experienced Patients



7. CCR5 Inhibitors

8. The SMART Study




Newest Protease Inhibitorsfor Experienced Patients

Two new boosted PIs available in the past year Which one do we pick? And with what regimen?

4

50

1

(94)

42

2

(113)

22

3

(58)

10

≥4

(41)

42

All

(373)

Virologic Response by DRV Associated Mutations

De Meyer S, et al. XV Int’l HIV Drug Resistance Wkshp (2006). Poster 73

Number of TMC114 mutations(Number of Patients)

Patie

nts

with

VL

HIV

RN

A <

50 c

opie

s/m

L at

Wee

k 24

(%)

64

0

(67)

100

80

40

60

20

0

* V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V

7 8 8 9 10 8

Median number of IAS-USA PI resistance-associated mutations

Treatment Response by TPV Resistance

Number of PI Mutations (TPV list)

BaselineTPV Susceptibility

(Q25,Q75)

Change in VL*at 2 Weeks(Q25,Q75)

0 to 10.8

(0.5, 1.1)

-1.25

(-0.91, -1.78)

2 to 31.2

(0.7, 2.2)

-1.37

(-0.79, -1.83)

4 to 52.4

(1.2, 5.0)

-1.40

(-0.57, -1.87)

6 to 73.6

(2.1, 12.0)

-1.27

(-0.23, -1.81)

8+16.3

(4.9, 50.3)

-0.33

(+0.11, -0.83)

*Change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log10 copies/mL.Tipranavir FDA Review (May 19, 2005); Available at www.fda.govValdez H et al. Antiviral Ther 2005;10:S29

Change in VL*at 24 Weeks(Q25,Q75)

-2.10

(-0.82, -2.77)

-0.89

(-0.21, -2.35)

-0.45

(-0.03, -2.15)-0.49

(-0.03, -1.60)-0.08

(+0.01, -0.18)

How to Pick a PIRole for Resistance Testing

REDUCED RESPONSE96.93.471.5Darunavir/r

REDUCED RESPONSE5.41.21.5Tipranavir/r

RESISTANT2.449.0Atazanavir

MINIMAL RESPONSE56.19.783.6Lopinavir/r

RESISTANT2.277.4Fosamprenavir

MINIMAL RESPONSE9.61.277.4Amprenavir/r

MINIMAL RESPONSE2.00.977.4Amprenavir

REDUCED RESPONSE26.57.19.0Saquinavir/r

MINIMAL RESPONSE7.31.334.7Nelfinavir

MAXIMAL RESPONSE40.110.69.7Indinavir/r

MINIMAL RESPONSE4.50.99.7Indinavir

PI mutations: 10I, 13V, 32I, 33F, 46I/L, 54L, 63P, 71V, 76wt/V, 82I, 84V, 90M

PI

Newest Protease Inhibitorsfor Experienced Patients

Two new boosted PIs available in the past year— Which one do we pick?— Resistance pattern can guide choice

And with what regimen?— At least one fully active drug from a new ARV class

4

1.

2.

3. Integrase Inhibitors




7. CCR5 Inhibitors

8. The SMART Study




Integrase Inhibitors

Initial data sets of these drugs show great promise

What lessons are we learning?

3

MK-0518: A Novel HIV-1 Integrase Inhibitor

HIV integrase inhibition: a new mechanism of action— Active against WT, MDR HIV, CCR5 and CXCR4

Potent activity in ART-naive pts after 10 days of monotherapy

— HIV RNA of 1.7 – 2.2 log10 copies/mL

Predominantly metabolized via glucuronidation (UGT1A1)

— No (known) ARV drug interactions

— Not an inhibitor/inducer of CYP3A4

— No RTV boosting

Integrase Inhibitors

Initial Data Sets Show Great PromiseWhat lessons are we learning?

1. Highly active across naïve and experienced pt spectrum

2. Encouraging safety profile in short term use3. However, observe incomplete suppression at week 244. An important component to a new regimen

— But must still avoid functional monotherapy (EAP?)

5. Unknowns:— Future implications of faster suppression?— Cost?

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1.

2. Single Tablet Therapy: EFV/FTC/TDF





7. CCR5 Inhibitors

8. The SMART Study




Single Tablet Therapy(EFV/FTC/TDF)

Yes, it’s a single pill How strong are the data versus other options?

2

GS 934:Proportion < 400 c/mL (TLOVR)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

10 0

Weeks

TDF+FTC+EFV 75%*

ZDV/3TC+EFV 62%

p = 0.004

*95% CI: (+4.3%, +21.1%)% R

espo

nder

Gallant J, et al. XVI IAC (2006). Abst. TUPE0064

BL 8 16 24 32 40 48 60 72 84 96

BL 8 16 24 32 40 48 60 72 84 96

GS 934:Proportion < 50 c/mL (TLOVR)

0

10

20

30

40

50

60

70

80

90

TDF+FTC+EFV 67%*ZDV/3TC+EFV 61%*

p = 0.16

*95% CI: (-2.3%, +15.0%)

Weeks

% R

espo

nder

CD4 Mean Change: 270 TDF+FTC+EFV 237 ZDV/3TC+EFV p = 0.036

Gallant J, et al. XVI IAC (2006). Abst. TUPE0064

GS 934:Resistance Development through Week 96

TDF+FTC+EFV(n = 244)

ZDV/3TC+EFV(n = 243)

Viremic / Genotype 14 (6%) 29 (12%)

Wild Type 4 7

Any Resistance 10 (4%) 20 (8%)

EFV-R 10 (4%) 18 (7%)

M184V/I 2 (1%) 9 (4%)

TAMs 0 1

K65R 0 0

Excludes patients with baseline NNRTI-R mutations (n = 487)Gallant J, et al. XVI IAC (2006). Abst. TUPE0064

p = 0.017

p = 0.036

% of total enrolled

P<0.001

5.5

8.1

Week 96

GS 934:Week 96 Total Limb Fat (DXA)*

*For subset who had week 48 DataGallant J, et al. XVI IAC (2006). Abst. TUPE0064

P=0.034

Tota

l Lim

b Fa

t (K

g)

6

7.4

0

1

2

3

4

5

6

7

8

9

10

Week 48

EFV + ZDV/3TC

EFV + TDF + FTC

P=0.001

P=0.01

N 49 51 44 49

Single Tablet Therapy(EFV/FTC/TDF)

Yes it’s a single pill

How strong are the data versus other options?

Unsurpassed Efficacy Unique in simplicity Supportive Long term safety data

— ~2% have increases in Creatinine – stable over years

— Small degree of hip demineralization

2

1. The Progress of Initial Treatment






7. CCR5 Inhibitors

8. The SMART Study




The Progress of Initial Treatment

An abundance of data over a decade narrows down our choices to a few best

Within these few, are there ways to distinguish the “front runners”?

1

Recommended ComponentsNRTI NNRTI PITDF or AZT and FTC or 3TC

FTC and ddIEFVor NVP*

LPV/r SQV/rATV/r IDV/r

Alternate ComponentsABC and 3TC

ddI and TDF

ddI and 3TC

AZT and ABC

d4T and 3TC

FPV/rATVNFV

Special Circumstances Only (3-NRTI Regimen)AZT-3TC-ABC**

*In selected patients** No longer recommended for initial therapy except when use of NNRTIs or PIs is precludedAdapted from Yeni PG et al. JAMA 2004;292:251-265.

Initial ARV Regimens:IAS-USA Treatment Guidelines (2004)

Initial ARV Regimens:IAS-USA Treatment Guidelines (2006)

Recommended

NRTI NNRTI PI

TDF/FTC or ZDV/3TC or ABC/3TC EFV(or NVP†)

LPV/r SQV/rATV/r FPV/r

Alternate

No specific alternatives listed‡

†In selected patients‡Triple-NRTI regimens are no longer recommended as initial therapy because of insufficient antiretroviral potency compared with a regimen containing efavirenz. However, for patients requiring treatment with regimens that preclude use of NNRTIs or protease inhibitors, a combination consisting of zidovudine, abacavir, and lamivudine may be considered.

Adapted from Hammer S, et al. JAMA 2006;296:827-843.

Preferred regimens

PI-basedATV + (3TC or FTC) + (AZT, d4T, ABC or ddI) or (TDF+RTV

100mg/d)

FPV + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

FPV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

IDV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

LPV/r + (3TC or FTC) + (d4T, ABC, TDF or ddI)

NFV + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

SQV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

Alternative regimens

EFV +(3TC or FTC) + (AZT or TDF)

LPV/r +(3TC or FTC) + AZT

3 NRTI-basedABC + AZT + 3TC – only when a preferred or an alternative NNRTI- or PI-based regimen

cannot or should not be used

DHHS Recommended Regimens forTreatment-Naїve Patients (2005)

NNRTI-based

EFV + (3TC or FTC) + (ABC, ddI or d4T)

NVP + (3TC or FTC) + (AZT, d4T, ddI, ABC or TDF)

DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, July, 2005.

1 Efavirenz is not recommended for use in the 1st trimester of pregnancy or in sexually active women with child-bearing potential who are not using effective contraception.2 The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred PI component was based on twice-daily dosing [NEJM 2002]. 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%) [JAIDS 2006].3 Emtricitabine may be used in place of lamivudine and vice versa.4 Nevirapine should not be initiated in women with CD4+ T cell count >250 cells/mm3 or in men with CD4+ T cell count >400 cells/mm3 because of increased risk of symptomatic

hepatic events in these patients.5 Atazanavir must be boosted with ritonavir if used in combination with tenofovir.

Select 1 Component from Column A + 1 from Column B

Column A (NNRTI or PI) Column B (Dual-NRTIs)

Preferred components

NNRTI or PIEFV1 ATV/r

FPV/r (BID)LPV/r2 (BID)

TDF/FTC3 (co-formulated); orAZT/3TC3 (co-formulated)

Alternative Components

NNRTI or PINVP4 ATV5

FPVFPV/r (QD)LPV/r (QD)

ABC/3TC3 (co-formulated)DDI + (FTC or 3TC)

www.aidsinfo.nih.gov DHHS Guidelines, October 10, 2006

DHHS Recommended Regimens forTreatment-Naїve Patients (2006)

The Progress of Initial Treatment

An abundance of data over a decade narrows down our choices to a few best

Within these few, are there ways to distinguish the front runners?

Balancing Success / Simplicity / Safety getting easier to do…

1

1. The Progress of Initial Treatment






7. CCR5 Inhibitors

8. The SMART Study




Documents

“The TOP TEN” Important Issues of HIV Medicine in 2006