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Research Advances in HIV Care

Research Advances in HIV Care

Joel E. Gallant, MD, MPH

Johns Hopkins University School of Medicine

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Cellular Reservoirs of HIV-1 Replication and Persistence

M. Stevenson, Nature Medicine. 2003

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0.00001

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

0 1 2 3 4 5 6 7 8

Time on HAART (years)

Fre

qu

ency

(IU

PM

)Frequency of Latently Infected CD4

Cells as a Function of Time on HAART

-

t ½ = 44.2 months73.4 years

Siliciano R, et al.

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Lipoatrophy

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Fat Accumulation

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Will We Return to Earlier Therapy?

• Availability of better, easier, less toxic regimens

– 2 pills qd without food restrictions

– No known long-term toxicity

• Long-term data may begin to demonstrate benefit with earlier therapy

• Risk of prolonged HIV exposure independent of CD4?

– e.g. dementia, NHL, PML

• Reduced transmission

• Potential for intermittent therapy

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Intermittent CD4-Guided TherapyThe BASTA Study

Maggiolo F, et al. 43rd ICAAC, Chicago, September 2003, H-448

• 18/76 (24%) restarted HAART at least once

• 95% in STI group have maintained CD4 >400 at 20 months of follow-up

• Only nadir CD4 <350 cells/mm3 predicted time to restart HAART

• Cost of care in STI group decreased by ~€300/month

114 patients:CD4 >800 cells/mm3

HIV RNA <50 c/mL

Continuous therapy(n=38)

Restart therapy when CD4 <400 cells/mm3

(n=76)

Characteristics:3.2 prior ARV regimens

57 mo of prior ARVPre-ARV RNA: ~100,000 c/mL

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Pulse TherapyC

D4

Cou

nt

CD4 Treatment threshold

= on HAART Time

Treatment interruption (mos-yrs)

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Stopping Drugs with Different Half-Lives

0 24 483612

Time (hours)

Dru

g c

on

cen

trat

ion

IC90

IC50

Last Dose

Day 1 Day 2

MONOTHERAPY

Zone of potential replication

Taylor S, et al. 11th CROI, San Francisco, 2004, #131

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Response to therapy in women receiving single-dose NVP for MTCT

• 255 women started d4T, 3TC, NVP postpartum

• 213 NVP-exposed, 42 not NVP-exposed intrapartum

• Genotype postpartum (median 12 days [range 10−14])

– K103N (21%)

– G190A (9%)

– Y181C (2%)

• 61 patients had detectable NVP levels up to 24 days postpartum

Jourdain G, et al. 11th CROI, San Francisco 2004, #41LB

Subsequent response to triple therapy (<50 c/mL)

No NVP 42 37 28NVP no mut 139 112 110NVP+mut 61 58 50

Chi2 for linear trend: p<0.001

59%

75%

0%1%

44%

53%

0%

43%

34%

0

30

60

90

Baseline 3 mo 6 mo

%

NonexposedExposed; no NNRTI mutationsExposed; NNRTI mutations

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Drug Resistance Among Treatment-Naive Patients

Little S, et al. 8th CROI; 2001; Chicago. Abstract 756.

Patients With >10-Fold Resistance (N = 408)

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2

4

6

8

10

12

14

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18

20

Any ARV NRTI NNRTI PI MDR

Iso

late

s W

ith

>10

-Fo

ld R

edu

ced

Su

scep

tib

ility

(%

)

1995-1998

1999-2000P = .001

P = .03P = .007 P = .0001

P = .002

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Targets for Antiretroviral Therapy

Reverse Reverse Transcriptase Transcriptase

InhibitorsInhibitors

Protease Protease InhibitorsInhibitors

Integrase Integrase InhibitorsInhibitors

EntryEntryInhibitorsInhibitors

Various PIVarious PI

NRTIs,NRTIs,NNRTIsNNRTIs

T-20T-20

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Antiretroviral Agents Approved in the U.S.(May 2004)

NRTIsNRTIs NNRTIsNNRTIs PIsPIs

zidovudine (AZT) – Retrovir nevirapine (NVP) – Viramune saquinavir (SQV) – Invirase, Fortovase

didanosine (ddI) – Videx, Videx EC

delavirdine (DLV) – Rescriptor indinavir (IDV) – Crixivan

zalcitabine (ddC) – Hivid efavirenz (EFV) - Sustiva ritonavir (RTV) – Norvir

stavudine (d4T) – Zerit Nucleotide RTIsNucleotide RTIs nelfinavir (NFV) – Viracept

lamivudine (3TC) – Epivir tenofovir DF (TDF) -Viread amprenavir (APV) – Agenerase

abacavir (ABC) – Ziagen Fusion InhibitorsFusion Inhibitors lopinavir/ritonavir (LPV/r) - Kaletra

emtricitabine (FTC) - Emtriva enfuvirtide (ENF, T20) - Fuzeon atazanavir (ATV) - Reyataz

fosamprenavir (FPV) - Lexiva

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Recommended regimens fortreatment-naïve patients: DHHS 3/04

Preferred regimens

PI-basedPI-based

ATV + (3TC or FTC) + (ZDV, d4T, or ABC)ATV + (3TC or FTC) + (ZDV, d4T, or ABC)

FPV + (3TC or FTC) + (ZDV, d4T, or ABC)FPV + (3TC or FTC) + (ZDV, d4T, or ABC)

FPV + RTV + (3TC or FTC) + (ZDV, d4T or FPV + RTV + (3TC or FTC) + (ZDV, d4T or ABC)ABC)

IDV + RTV + 3TC + (ZDV, d4T, or ABC)IDV + RTV + 3TC + (ZDV, d4T, or ABC)

LPV/r + FTC + (ZDV, d4T, or ABC)LPV/r + FTC + (ZDV, d4T, or ABC)

LPV + 3TC + ABCLPV + 3TC + ABC

NFV + 3TC + (ZDV, d4T, or ABC)NFV + 3TC + (ZDV, d4T, or ABC)

SQV + RTV + 3TC + (ZDV, d4T or ABC)SQV + RTV + 3TC + (ZDV, d4T or ABC)

*EFV safety in pregnancy not established – avoid in pregnant women or women with pregnancy potential**Only when an NNRTI- or a PI-based regimen cannot or should not be used as first-line therapy

Alternative regimens

NNRTI-basedNNRTI-based

EFV* + FTC + TDFEFV* + FTC + TDF

EFV* + (3TC or FTC) + (ddI or ABC)EFV* + (3TC or FTC) + (ddI or ABC)

NVP + (3TC or FTC) + (ZDV or d4T or ddI)NVP + (3TC or FTC) + (ZDV or d4T or ddI)

LPV/r +LPV/r +3TC + (ZDV or d4T) 3TC + (ZDV or d4T)

EFV* +EFV* +3TC + (ZDV or TDF or d4T)3TC + (ZDV or TDF or d4T)

Triple NRTI**Triple NRTI**

ABC + 3TC + (ZDV or d4T)

www.aidsinfo.nih.gov

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TDF or

ddI or

(ABC)

EFV or

ATV or

ATV/RTV or

FPV/RTV

Current Options for Once Daily Therapy

3TC or

FTC+ +

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The Move Toward Simpler Regimens

1996:

3-drug regimen: ddI + d4T + SQV

- 22 pills per day:

-SQV: 6 q8h with food

-ddI: 1 pill bid ½ hr ac or 2 hrs pc

-d4T: 1 pill bid

2004?:

3-drug regimen: TDF/FTC or ABC/3TC + EFV

– 2 pills qd

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Efavirenz Toxicity:Neuropsychiatric Effects

• Dizziness, dreams, insomnia, impaired concentration

• Management: Pre-treatment counseling, reassurance, altered dosing, short-term benzodiazepines, change drugs if persistent (e.g. > 2-3 weeks)

• Depression, hallucinations, psychosis

– Management: Change drugs

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The AIDS pandemicAdults and children living with HIV/AIDS, end 2003

• 5 M new HIV infections in 2003• 3 M deaths due to HIV/AIDS in 2003• 40 M living with HIV/AIDS; 50% females

North America790,000−1.2 M

North America790,000−1.2 M

Caribbean350,000−590,000

Caribbean350,000−590,000

Latin America1.3−1.9 M

Latin America1.3−1.9 M

North Africa& Middle East

470,000−730,000

North Africa& Middle East

470,000−730,000

Sub-Saharan Africa25−28.2 M

Sub-Saharan Africa25−28.2 M

East Asia & Pacific

700,000−1.3 M

East Asia & Pacific

700,000−1.3 M

S & SE Asia4.6−8.2 MS & SE Asia4.6−8.2 M

Australia& New Zealand

12,000−18,000

Australia& New Zealand

12,000−18,000

Western Europe

520,000−680,000

Western Europe

520,000−680,000

Eastern Europe& Central Asia1.2−1.8 M

Eastern Europe& Central Asia1.2−1.8 M

Source: UNAIDS

Prevalence (increase since 2002)

(34−54,000)

(45−80,000)

(120-180,000)

(30−40,000)

(43−67,000)

(3.0−3.4 M)

(180−280,000)

(150−270,000)

(610,000−1.1 M)

(700−1,000)

Source: UNAIDS

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Current level of risk maintained

Risk halved over next 15 years

UNAIDS. Report on the global HIV/AIDS epidemic. June 2000; Source: Zaba B, 2000 (unpublished data)

Ris

k o

f d

yin

g o

f A

IDS

(%

)

Current adult HIV prevalence rate (%)

Cambodia

Côte d’Ivoire

Kenya

South Africa

Zambia

Zimbabwe

Botswana

Burkina Faso

Cambodia

Côte d’Ivoire

Kenya

South Africa

Zambia

Zimbabwe

Botswana

0

10

20

30

40

50

60

70

80

90

100

5 10 15 20 25 30 35 400

Burkina Faso

Lifetime Risk of AIDS Death:15-Year-old Boys Infected with HIV

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Classification of HIV

HIV-1 HIV-2

Group M* Group N Group O

Clades A, B**, C, D, F, F2, G, H, J, K

RecombinantsCommon: AE, AG

Uncommon: AGHK, FD, AFGHJK, AB, BC

• Genetic composition differs, allowing assessment of the geographic distribution

• Viruses may combine, creating circulating recombinant forms (CRFs)

• HIV-1 is most common, but HIV-2 now circulating outside Africa, especially India

* Most infections due to Group M viruses ** Clade B: 98–99% USA, 90% Europe

McCutchan F. 2nd IAS, Paris 2003, #23; Peeters M. ibid, #24

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A global view of HIV-1 infection 50% of all new HIV-1 cases worldwide are caused by HIV-1 subtype C

B

B

B , F

B F

C

C

CE

E

C

B

B

B

A D C C

A G, H, O

C, E

F

B

C

I

B

C

A/C/D

COJFAdult prevalence rate

15.0% – 36.0% 5.0% – 15.0% 1.0% – 5.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1% not available

HIV-1 group M (main) viruses includes several subtypes A through K

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All Vaccine Placebo

Total 5009 191/3330 (5.7%) 98/1679 (5.8%)

Men 4741 190/3155 (6.3%) 94/1586 (5.9%)

Women 268 1/175 (0.6%) 4/93 (4.3%)

White 4185 211/2994 (5.4%) 98/2994 (6.0%)

Black* 314 4/203 (2.0%) 9/111 (8.1%)

Men 168 4/111 (3.6%) 5/57 (7.5%)

Women 146 0/93 (0.0%) 4/53 (7.5%)

Hispanic 326 11/212 (5.2%) 6/114 (5.3%)

Asian 73 2/53 (3.8%) 2/20 (10.0%)

Other 111 6/71 (8.5%) 6/40 (15.0%)

VaxGen B/B Phase III: Preliminary results

• Multivariate analysis: No differences seen after controlling for age, education, geographic region, and risk behavior.

Graham BS. 43rd ICAAC, Chicago, September 2003, #637b; Popovic V. ibid, #H-1942

• Univariate analysis: Vaccine effectiveness statistically higher in blacks and women

*p<0.01

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Obstacles to HIV vaccine development

• Enormous clade and sequence variability

• Natural immune response to HIV infection is <5% effective

• Promising animal vaccine approaches with homologous sequences have completely failed (e.g., SIV 239)

• Naturally controlled infections do not protect against pathogenic superinfection (reinfection with different HIV strain)

Desrosiers R. 11th CROI, San Francisco 2004, #109

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SIV in nonhuman primatesPotential for new strains of HIV

• HIV-1 and -2 crossed species from nonhuman primates

• Assay of meat derived from 17 species of butchered primates for SIV-type viruses (>1000 samples)

• 14/17 species found to contain SIV-like viruses

• Potential for human exposure and resulting in HIV-3, HIV-4, HIV-5…

Peeters M, et al. 2nd IAS, Paris 2003, #24

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