HIV: Bench to Bedside

Jean Anderson M.D.

Director, The Johns Hopkins HIV Women’s Health Program

HIV History: 1981-2013

• 1981: PCP cluster – "Dr. Curran said there was

no apparent danger to non homosexuals from contagion. 'The best evidence against contagion', he said, 'is that no cases have been reported to date outside the homosexual community or in women"The New York Times (July 1981)

• July 1982: 24 cases of PCP,

KS, and other OIs in women reported to CDC

• December 1982: 1st case MTCT

• 1983: virus causing AIDS isolated

• 1985: serologic test • 1985: 1st case MTCT thru

breastfeeding • 1986: AZT is 1st ARV agent • 1987: Act-Up • 1990: Ryan White Act • 1991: Magic Johnson • 1994:ACTG 076 • 1996: HAART • 1997: Viral load accepted as

endpoint

HIV History: 1981-2013

• 2003: PEPFAR born

• 2008: 1st cure

• 2011-2012: ART as prevention

– HPTN 052

– PrEP

• 2013: “AIDS-free generation”

HIV/AIDS: The First Decade (1981-91)

• Patients: Most died – Wasting, dementia,

diarrhea

– Stigma and discrimination in society and in the health care setting

– Secrecy and abandonment

– Fear of contagion

– No treatment

• Science/Health Care Providers – Cause

– Epidemiology

– Natural history

– Diagnostics

– Drugs

Ryan White

• Child with hemophilia-

– HIV diagnosed in 1984 at 13 yr old

– Banned from school

– Advocacy by him and his family led to the passage of the Ryan White Care Act in 1990, 4 mo after his death

– Now $2 billion/yr for HIV drugs for 500,000

Magic Johnson

• Olympic hero and basketball star

• 1991: “I have AIDS”

• Trumped the efforts of millions to destigmatize HIV infection

President Bill Clinton: State of the Union Speech 2000

• “AIDS in Africa is so devastating-it threatens the social, political and economic stability of the world”

• Clinton Foundation 2001

– Low cost drugs

• 2002: $12,000/yr

• 2012: $100-200/yr

– Pediatric HIV

WHAT IT TOOK

• Care providers-core values, confronting stigma and fear, caring for the dying

• Science-

– Epidemiology

– Virology

– Immunology

– Infectious diseases

– Drug development/trials

• Activism-ACT-UP

• Leadership

– Science

– Government

– Regulation

• Political will and vision

– Clinton

– Bush

9

10

11

Viral-host Dynamics

• About 1010 (10 billion) virions are produced daily

• Average life-span of an HIV virion in plasma is ~6 hours

• Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days

• HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses

HIV Natural History

• HIV transmission – 2-4 wks

• Acute HIV (50-90%) – 1-3 wks

• Asymptomatic – 8 yrs

• AIDS – 1-2 yrs

• Death

13

Window Period: Untreated Clinical

Course

--------------------------------------------PCR P24 ELISA

0 2 3 4

Weeks since infection

a b Time from a to b is the window period

viremia

antibody Asymptomatic

Acute HIV syndrome

Primary

HIV

infection

Source: S Conway and J.G Bartlett, 2003

years

14

Laboratory Markers of HIV Infection

• Viral load

– Marker of HIV replication rate

– Number of HIV RNA copies/mm3 plasma

• CD4 count

– Marker of immunologic damage

– Number of CD4 T-lymphocytes cells/mm3

plasma

15

HIV RNA Set Point Predicts

Progression to AIDS

• HIV RNA viral loads after infection can be used in the following ways:

– To assess the viral set point

– To predict the likelihood of progression to AIDS in the next 5 years

• The higher the viral set point:

– The more rapid the CD4 count fall

– The more rapid the disease progression to AIDS

16

Natural History of HIV-1

Fauci As, 1996

17

General Mechanisms of HIV

Pathogenesis

• Direct injury

– Nervous (encephalopathy and peripheral neuropathy)

– Kidney (HIVAN = HIV-associated nephropathy)

– Cardiac (HIV cardiomyopathy)

– Endocrine (hypogonadism in both sexes)

– GI tract (dysmotility and malabsorption)

• Indirect injury

– Opportunistic infections and tumors as a consequence of immunosuppression

Key Studies

• 1987: AZT vs placebo (n=282); DSMB stopped study with 19 deaths in placebo arm vs 1 in AZT arm (NEJM 1987;317:185)

• 1994: ACTG 076: perinatal transmission rate 23% placebo vs 8% AZT (P=0.0006) (NEJM

1994;331:1173)

• 1997:HAART: IDV/AZT/3TC vs IDV vs AZT/3TC; at 52 wks 80% viral load suppression vs 0 (NEJM

1997;337:734)

Drug Development

• 1987: AZT

• 1991-2: ddI, ddC

• 1995: d4T

• 1996: 3TC, SQV

• 1997: NVP, RTV, IDV, DLV, NFV

• 1998: EFV

• 1999: ABC, APV

• 2000:LPV

• 2001: TDF

• 2003:FTC, ATV, ENF

• 2005: TPV

• 2006: DRV

• 2007: MVC, RAL

• 2008: ETR

• 2011: RPV

• 2012: EVG

• 2013: DTG

What Was Learned About ART

• 1996: hit early, hit hard

• 1996: at least 2 drugs and 2 classes

• 1998: drug toxicity-lipodystrophy

• 1998: viral load <50 c/ml

• 2000: resistance

• 2000: adherence

• 2003: benefit of failed therapy

• 2006: once started, never stop

• 2006: non-OI complications

• 2007-8: salvage

• 2008: functional cure

• 2011: treatment=prevention

• 2012: hit hard, hit early

Change in MTCT in Resource-Rich Countries

ZDV Era Combination ARV Era

Tran

smis

sio

n (

%)

40

30

20

10

0 1993: WITS

1994: PACTG

076

1997: PACTG

185

1999: WITS

2001: PACTG

247

2002: PACTG

316

2003: WITS

2006: UK

24.5

7.6 5.0

3.3 2.0 1.5 1.2 0.8

Courtesy of Lynne Mofenson.

20-25% in utero (majority late)

35-50% peripartum

40-45% postpartum

Timing of Mother to Child HIV Transmission: ~Doubling of Risk with Breastfeeding

Overall cumulative risk MTCT (without antiretroviral drugs): 40-45% with prolonged breastfeeding

In Utero Peripartum Postpartum

Breastfeeding

The Numbers

2010: 162 children born with HIV infection The number of women with HIV giving birth

increased approximately 30% from 2000 to 2006 Nevertheless, the number of perinatal infections

continues to decline-since the mid-1990s there has been >90% reduction in perinatal transmissions

Perinatal transmission can be reduced to <1% with appropriate diagnosis and management in pregnancy

New USPHS Classification of Antiretroviral Drugs in Pregnancy-ARV

Naïve Women Considerations: efficacy, durability, toxicity, convenience, pregnancy PK data, adverse

outcomes for mother/fetus/infant

DHHS HIV Perinatal Guidelines. 2013

Drug Class Preferred Agents Alternative Agents Not Recommended Insufficient Data

NRTIs

ZDV/3TC,

ABC/3TC,

TDF/FTC

d4T, ddI n/a

NNRTIs NVP, EFV ETR RPV

PIs LPV/r, ATV/r SQV/r, DRV/r

IDV/r,

NFV, RTV (as single PI),

TPV/r

FPV/r

Entry inhibitors n/a n/a T20 MVC

Integrase

inhibitors n/a RAL n/a EVG/COBI

Barriers to Elimination of MTCT

• Failure to diagnose HIV in pregnancy • Acute infection in pregnancy • Adherence issues • ARV resistance • Mistakes in ARV management

– Stopping ART in the 1st trimester – Changing ART regimens in 1st trimester – Pharmacokinetic issues – Lack of infant prophylaxis

• Breastfeeding

Unanswered Questions

Should pregnant women stop ARV drugs after delivery? Evidence evolving on benefits of earlier

treatment in preventing harmful impact of ongoing HIV replication on AIDS and non-AIDS disease progression (Sterne 2009, Cain 2011, Severe 2010, Kitahata 2009)

Treatment interruption in nonpregnant adults associated with increased morbidity/mortality (El Sadr 2008, Phillips 2008, Lundgren 2008, Silverberg 2007)

HPTN 052: treatment as prevention. ~50% of HIV+ individuals have HIV- partners (NEJM 2011;365:493)

Unanswered Questions

What is the impact on short- or long-term maternal health for postpartum discontinuation of combination regimens used solely for PMTCT prophylaxis? Especially with multiple pregnancies? No increased risk of progression noted to date with

discontinuation after delivery with relatively high CD4 counts (HIV Med 2009; 10:157; JID 2007;196:1044; Infect Dis Obstet Gynecol 2009; 456717)

PROMISE Study

Must balance against adherence, resistance, toxicity concerns

Live Births Among HIV+ Women Before and After HAART Availability

• WIHS – Comparison of live birth rates 1994–1995 (pre-HAART era)

and 2001–2002 (HAART era) in HIV+ and HIV- women aged 15–44 years

– Women in HAART era were younger, with higher CD4 cell counts

– In HAART era, 150% increase in live birth rate among HIV+ women versus 5% increase among HIV- women • Live birth rate higher in all age categories with largest difference

(306%) seen in women >35 years

• Among HIV+ women with more than high school education, live birth rate was approximately half that of HIV- women in pre-HAART era but more than double the HIV- rate in HAART era

• Birth rate higher in HAART era within each category of CD4 cell count

• Women with history of intravenous drug use were the only group in both HIV+ and HIV- women who experienced a decline in birth rates

CD = cluster of differentiation. Sharma A et al. Am J Obstet Gynecol. 2007;196:541.e1-6.

Why is Preconception Care Important?

High rates of unintended pregnancy

Occurs in approx 50% of all pregnancies in US; about half of these occur in women using contraception and over half of unintended pregnancies are aborted (Fam Plann Perspect 1998;30:24;

Contraception 2011;84:478)

Information from HIV+ women suggests rates of unintended pregnancy as high or higher: 56% (Canada) (HIV Med 2012; 13:107); 83% (US adolescents) (Am J Obstet Gynecol 2007;197:S123); 77% while using contraception (US-WIHS) (AIDS 2004;18:281)

Why is Preconception Care Important?

High rates of HIV serodiscordance (SDC) among sexual partnerships

Approximately 50% of HIV+ individuals are in SDC relationships and ~20% in relationships with partner of unknown HIV status (Fam Plann Perspect 2001; 33:144)

Estimated ~140,000 HIV SDC heterosexual couples in US, about half of whom want more children (Am J

Obstet Gynecol 2011;204:488)

Why is Preconception Care Important?

HIV has an adverse effect on fertility and there is potential improvement in fertility with ART

HIV associated with decrease in pregnancy rates and increase in pregnancy loss (JAIDS 2000;25:345; Lancet

1998;351:9096; Am J Epidemiol 2000; 151:1020; Int J STDs/AIDS 2006; 17:842)

Effective ART restores or improves fertility (PLoS

Medicine 2010;7:e1000229; AIDS Res Treat 2011;2011:519492; AIDS Behav 2012; Feb)

Why is Preconception Care Important?

High rates of comorbidities potentially affecting maternal or fetal health

43% of Canadian HIV+ women report current or history of domestic violence (AIDS Pt Care STDs 2010;24:763)

WIHS: Depression present in 53% of HIV+ women (JAIDS 2009; 51:399)

Substance abuse: 20% of new HIV infections in women due to IDU (CDC); WIHS-27% reported crack, cocaine, IDU (wilson 1999)

Hepatitis: approx 10% of HIV+ pts have chronic HBV infection and 16% have HCV (JAIDS 1991;4:416; J Infect Dis 1991;163:1138; Clin Infect Dis 2002;34:831)

Palefsky. Curr Opin Oncol 2003

+++ ++ +/-

Research Questions

• What are the long term effects of HAART on HPV-related lower genital tract disease?

• What is the most appropriate screening strategy for HIV+ women?

• What is the role of an HPV vaccine in prevention or treatment of HPV-related disease in HIV+ individuals?

Life Expectancy in HIV-infected Patients

< 100

100-200

>200

Life expectancy (at age 20)

32 42 50

ART-CC1: Depending on when ART is started, life expectancy is 10-30 years less than that in uninfected patients

CD4 Nadir

1. ART-Cohort Collaboration. Lancet.; 2. Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-7. 3. Van Sighem A, et al. AIDS 201;24:1527

AQUITAINE cohort2: Mortality same as that of general population in patients with CD4 >500 after 6th year of ART

ATHENA cohort3: Modeled life expectancy for asymptomatic pts who remained naive and without AIDS at Wk 24 after Dx similar to age- and sex-matched uninfected controls: 52.7 vs 53.1 years

ISIS/HPTN 064: High HIV Incidence Among At-Risk Women in US

• 2099 women recruited from US communities with high HIV prevalence[1]

– 88% black, 12% Hispanic, 8% white

– 1.5% of women newly diagnosed with HIV at baseline

1. Hodder S, et al. CROI 2012. Abstract 1048. 2. Prejean J, et al. PLoS One. 2011;6:e17502. 3. UNAIDS Report on the Global AIDS Epidemic. 2010.

Annual HIV incidence 5 x higher than CDC’s 0.05% estimate for black women[2]

– Comparable to adult incidence rates in sub-Saharan Africa (0.28% for Congo and 0.53% for Kenya)[3]

Events Analyzed Women

Analyzed,

n

Events, n Window

Period

Annual

Incidence

Estimates, %

95% CI

Acute infection at

enrollment 2064 2 2 wks 2.52 0.60-10.7

Seroconversion 1951 4 -- 0.24 0.09-0.65

Updating the Guidelines

How Monthly conference calls

Complete review of all sections and updating yearly

Significant new information is rapidly disseminated via website (http://www.aidsinfo.nih.gov)

Why New information becomes available

Longer experience with ARV drugs re: safety, PK

HIV: The Future • HIV treatment cascade:

– Diagnosis

– Linkage to care

– Initiation of ART

– Retention in care

– Undetectable viral load (28% in US)

• Prevention bundle: T&T, PrEP, circumcision, condoms

• Treatment: test and treat everyone

• Research: vaccine and cure

• Challenge: global economy