Updates in HIV/AIDS Treatment- The Good, The Bad and the Ugly

Global Health Mini-UniversityOctober 9, 2009

Dr. Thomas Minior

Dr. Robert Ferris

USAID HIV/AIDS Treatment Advisors

Objectives

Define Antiretroviral (ARV) Treatment and review the different classes therapy

Understand the HIV life cycle and how it lends itself to ARV development

Review some interesting new issues in the field of HIV treatment and understand their potential impact on global HIV programs

Identify challenges in resource poor settings

Outline

HIV Life Cycle Antiretroviral Therapy 3 Hot Topics in HIV Treatment:

Links between HIV and Chronic disease When to Start antiretroviral therapy Treatment as Prevention

3 Important Public Health Implementation Issues: Challenges in Resource-Limited Settings The Treatment Time-Bomb Pediatric Issues

HIV Pathophysiology

The Life cycle of HIVImpact on the Immune

System

Human Immunodeficiency VirusA retrovirus

HIV Virus As a virus, HIV is dependent

on host cell machinery for its replication Needs to package its own enzymes to utilize the host machinery

HIV composition: Glycoprotein Envelope with

key transmembrane proteins: gp41 & gp120.

Largely made from human cell membrane lipoproteins

Viral capsid (inner shell) with p24 protein

RNA Genome (2 copies) Enzymes:

Reverse Transcriptase (2 copies)

Integrase (2 copies) Protease (2 copies)

High resolution light microscopy of HIV

Life cycle

HIV Life Cycle Summary

HIV attaches to & enters the T-Cell HIV Copies itself from RNA to DNA HIV DNA integrates into our genes Our T-Cells mistakenly copy the

virus HIV assembles itself and buds out of

the T-Cells to infect other cells

How HIV causes AIDS HIV virus enters the bloodstream HIV attaches to Host cell

Mediated through gp41, gp120 Host cells are CD4+ lymphocyte cells (T-Cells)

Can also infect other cells (macrophages, dendritic cells, kidney cells, etc.)

T-Cells are part of our immune systems Help facilitate cell-mediated immunity (regulates the

immune response; augments humoral immunity; particularly active againts viruses, fungi & protozoa)

Over time, significant HIV replication leads to CD4+ Cell destruction

This destruction impairs the immune system’s response to other pathogens

Natural History of HIV Infection

OIs, Clinical Staging, and CD4

WHO 1

WHO 2

WHO 3

WHO 4

Opportunistic Infections

Antiretroviral Therapy

(The Good)

The Birth of HIV/AIDS Therapeutics

0

5

10

15

20

25

Num

ber o

f Ava

ilabl

e Age

nts

1987 1990 1993 1996 1999 2002 2005 2008

RaltegravirEtravirineMaravirocDarunavirTipranavirEnfuviritideFosamprenavirAtazanavirFTCTenofovirLopinivirAmprenavirAbacavirEfavirenzDelavridineNeviripineNelfinivirIndinivirRitonivirSaquinivirDDCD4T3TCDDIAZT

HIV Life Cycle Summary HIV attaches to & enters the T-Cell

Entry Inhibitors

HIV Copies itself from RNA to DNANucleoside Reverse Transcriptase Inhibitors (NRTIs)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

HIV DNA integrates into our genesIntegrase Inhibitors

Our T-Cells mistakenly copy the virus

HIV assembles itself and buds out of the T-Cells to infect other cells

Protease InhibitorsViral Maturation Inhibitors

Efficacy in HIV Treatment: Decreased Mortality

What lead to the precipitous decline?

Multiple Drug Approach

Adult Resource Poor Settings

http://www.who.int/hiv/pub/guidelines/WHO%20Adult%20ART%20Guidelines.pdf

Pediatric Resource Poor Settings

http://www.who.int/hiv/pub/guidelines/WHOpaediatric.pdf

ART Works: HIV and life-expectancy

Over 40% of HIV positive individuals died of illnesses not attributable to HIV.

Survival was long – For 30 year old patients with CD4>500,

median survival ranges from 26.8-31.3 years For 50 year old patients with CD4>500,

median survival ranges from 21.1-22.3 years This may improve with improving therapies

Braithwaite, R, Justice, A, et al. “Estimating the proportion of patients with HIV who will die of comorbid diseases”. American Journal of Medicine (2005) 118, 890-898.

HIV and life-expectancy (2)

Mean life expectancy for individuals living with HIV in the US has improved from 10.5 years in 1996 to 22.5 years in 2005.

While improvements were seen in all groups, disparities still exist by gender, race.

Life expectancy still short of HIV negative peers.

Dependent on many factors.

Harrison K, Song R, Zhang X. “Life Expectancy after HIV diagnosis based on National HIV Surveillance Data from 25 States, United States”. JAIDS. Pre-print 2009.

clinicaloptions.com/hiv

Stay Tuned: Evolving Concepts in Antiretroviral Therapy

Reduced Mortality After First 3 Mos of ART in Developing Countries ART-LINC dataset[1] (N =

2725 with active follow-up) Botswana National HIV

Treatment Program[2] (N = 53,423 with adequate follow-up data)

47.8% of patients who died received HAART for < 3 mos

If patients survived > 3 mos, 94.3% likelihood of survival for > 5 yrs0 50 100 150 200

Mos 3-4

Mos 7-12

Mortality/1000 Pt-Yrs

27

51

Mo 2 106

147Mo 1

51Mos 5-6

1. Braitstein P, et al. Lancet. 2006;367:817-824. 2. Puvimanasinghe JP, et al. IAC 2008. Abstract MOAB0204.

Hot Topics in HIV Treatment

HIV & Chronic DiseaseWhen to Start HIV treatment

Treatment as Prevention

HIV and Chronic Disease (1)

Early on the major causes of morbidity were Opportunistic Infections and HIV wasting

As ART became more effective, causes of death began to switch to chronic diseases: cardiovascular disease, liver disease, kidney disease

This was initially presumed due to metabolic toxicities of the antiretroviral therapy.

However, recent research suggests that uncontrolled viral replication has long term complications as well. HIV has reservoirs other than CD4+ lymphocytes:

Macrophages, CNS Glial Cells, and Kidney cells. Ongoing HIV replication leads to diffuse immune system

activation and inflammation – which can have harmful consequences.

clinicaloptions.com/hiv

Optimal Timing of Antiretroviral Therapy

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

1248 (5.3%) deaths from 2000-2004

Both HIV- and non-HIV–related mortality associated with CD4+ cell count depletion

1.0

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

500

100

0.1

10

< 50 50-99 100-199

200-349

350-499

CD4+ Cell Count (cells/mm3)

RR

OverallHIVMalignancyHeartLiver

clinicaloptions.com/hiv

When to Start Antiretroviral Therapy

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-AIDS–Related Death

1.000.01 100.00

Non-AIDS Cancer Death

1.000.01 100.00

Liver Disease Death

200-349 vs ≥ 35050-199 vs ≥ 350

< 50 vs ≥ 350

200-349 vs ≥ 35050-199 vs ≥ 350

< 50 vs ≥ 350

200-349 vs ≥ 35050-199 vs ≥ 350

< 50 vs ≥ 350

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

HIV & Chronic Disease (2)

HIV+ individuals have higher rates of heart disease, cancer, renal disease even when accounting for known factors. General rule: unchecked HIV infection

makes any unrelated chronic disease worse... (there are exceptions, of course)

Hypothesized why overall life expectancy (even for those on treatment) doesn’t reach HIV- peers

When to Initiate Therapy Initiation of antiretroviral therapy is a balancing

act When treatment is initiated it is presumed to be

lifelong We must balance the benefits with long-term

toxicities, cost, pill burden, and resistance Until recently, clinicians have tried to wait until

the immune system is weaker to start ARV treatment:

Resource-Limited Settings typically wait until CD4+ falls to <200-250

Resource-Rich Settings typically wait until CD4+ falls to <350

This saves money and prevents toxicities from medicines.

But is this approach still the most effective? ART is easier to take and less toxic now We’ve already seen that unchecked HIV can worsen chronic

disease…

clinicaloptions.com/hiv

HIV/AIDS Annual Update 2006

CD4+ Count Response Based on Baseline CD4+ Count

Magnitude of CD4+ increase greatest if therapy started at low CD4+ counts, but greater likelihood of CD4+ count normalization with earlier therapy

Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

Johns Hopkins HIV Clinical Cohort

Mea

n C

D4+

Co

un

t (c

ells

/mm

3 )

1000

800

600

400

200

00 48 96 144 192 240 288 336

ATHENA National Cohort

0 1 2 3 4 5

200

400

600

800

0

1000

Years on HAART Weeks From Starting HAART

clinicaloptions.com/hiv

Answering the Questions: Initiating Antiretroviral Therapy

HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort

Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs excluded from model

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

CD4+ < 200 vs 201-350

CD4+ < 350 vs 351-500

Hazard ratio for AIDS (95% CI)

3.68 (3.01-4.51)

1.52 (1.10-2.10)

Hazard ratio for AIDS or death (95% CI)

2.93 (2.41-3.57)

1.26 (0.94-1.68)

Cumulative Probability of AIDS/Death According to CD4+ Count at Initiation

of HAART

Years Since Initiation of HAART

0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Pro

bab

ility

of

AID

S o

r D

eath

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

HIV Treatment as Prevention

Transmission only occurs from people infected with HIV

HIV viral load (amount of HIV measurable in the blood) is the biggest predictor of transmission

ART lowers viral load Proof of concept: HIV

treatment prevents mother to child transmission

Advantages: Easily measurable Few other prevention

trials have been successful

CDC HIV Testing Recs

PACTG 076 & USPHS ZDV Recs

HIV Treatment Reduces Heterosexual Transmission

174 discordant, monogamous couples in Raiki, Uganda, retrospectively analyzed for factors associated with transmission[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)

Ad

just

ed R

ate

Rat

io o

f Tr

ansm

issi

on

/Co

ital

Act

10

20

0.1

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)

Enrollment Period

OR (95% CI) P Value

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

Universal Testing & Treatment?

Mathematical modeling suggests that identification of ~90% of HIV+ patients through VCT coupled with immediate lifelong treatment in Southern Africa could reduce HIV incidence to < 1/1000 in 10 years. Would even realize

cost-savings by 2030. How realistic is this?

Global Health Implications:

Taking the Public Health Approach

Challenges in Resource Limited Settings

The Treatment Time-BombPediatric Issues

Public Health Approach

All these recent controversies highlight the importance to get people on treatment: Earlier treatment

improves outcomes ART leads to few

chronic and opportunistic diseases

ART can prevent new infections

Is this feasible??

Challenges: Human Resources

Infrastructure

Supplies

Transport

Challenges: Cost

The “Treatment Timebomb”(The UGLY)

HIV/AIDS Funding

2003 2004 2005 2006 2007 20080

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

18,000

20,000

$4,200

$13,765

Philan-thropicMultilateralBilateral

US

$ M

illi

on

+ 62% Multilateral

+ 112%Bilateral

+ 616%Domestic

+ 244% Philanthrop.

Slide Adapted from Implementers Meeting Presentation by Stefano Bertozzi, 2009

UNAIDS estimates

$8.1 billion funding gap

for 2007

Sample Costing Exercises:

Resource Availability and Needs

Slide adapted courtesy of John Stover & Rachel Sanders, HPI/Futures Group

0

50

100

150

200

Hea

lth B

enefi

t

Global AIDS Expenditures

Health benefit from investing in HIV prevention, care and treatment

ARV becomes available in developing countries

M O N E Y

VA

LU

E

0

50

100

150

200

Hea

lth B

enefi

t

Global AIDS Expenditures

ECONOMIC CRISIS

??

ARV becomes available in developing countries

Two obvious responses:1. Strategies to

maintain/increase funding levels

2. Improve efficiency

Health benefit from investing in HIV prevention, care and treatment

0

50

100

150

200

Hea

lth B

enefi

t

Global AIDS Expenditures

Health benefit from investing in HIV prevention, care and treatment

Two obvious responses:1. Strategies to

maintain/increase funding levels

2. Improve efficiency

Special Pediatric Challenges

HIV Progression in Children is BiModal

20-25% rapidly develop profound immunosuppression and opportunistic infections.– Without treatment

few of these children survive 2 years

– Many die within the first 6 months of life

75-80% may have a slower progression – Mean time to AIDS is

6-9years – Still more rapid

progression than adults (8-11yrs)

Early Diagnosis is Essential!

< 18 months Persistence of maternal

antibody No EIA, Western Blot Tests for viral components:

HIV DNA or RNA PCR, Immune Complex Dissociated

(ICD) p24 antigen Dried Blood Spots (DBS)

> 18 months Can use EIA, Western Blot

Clinical Identification of HIV+ Children is Difficult

Signs often non-specific Respiratory distress Poor weight gain weight or

abnormal growth Missed milestones in

development crawling, walking and speaking

Poor school performance, seizures, and other symptoms of HIV encephalopathy

Why are children more vulnerable to the symptoms

of HIV? It is during the first few years of life that

the immune system is developing. Untreated HIV infection will stunt the overall

maturation of the immune system Adults have already developed immunologic

memory and are therefore less prone to infections

Children are frequently unable to express health needs, or comprehend the need for medications Also have frequently changing dosing

requirements Children are dependent on adults for food

choices and good nutrition, which impacts growth, development, and efficacy of medications

More Pediatric Challenges

Pediatric expertise and experience

Misperceptions that all infected children will die early in childhood

Caretaker dependence ART Issues for children:

Drug availability Taste Appropriate formulations (FDCs,

liquids, etc.) Dosing Affordable prices http://www.who.int/3by5/en/finalreport.pdf

“The Pearls” 1. HIV Treatment Works! 2. Evidence supports earlier

initiation of treatment! Lower mortality Fewer Ois and less chronic disease

3. Without adequate prevention, we face serious challenges in being able to meet the need for treatment!

Discussion

• www.usaid.gov• www.pepfar.gov • www.globalhealthlearning.org• http://depts.washington.edu/hivaids/index.html• www.who.int/hiv/pub/guidelines/en/