Perinatal hiv transmission update
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PERINATAL HIV TRANSMISSION UPDATE. JOAN M. DUGGAN, M.D. MCT. Objectives: Identify the CDC antiretroviral treatment strategies to prevent transmission of HIV from mother to child Identify the CDC labor and delivery strategies to prevent transmission of HIV from mother to child

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Perinatal hiv transmission update

PERINATAL HIV TRANSMISSIONUPDATE

JOAN M. DUGGAN, M.D.


Perinatal hiv transmission update

MCT

  • Objectives:

    • Identify the CDC antiretroviral treatment strategies to prevent transmission of HIV from mother to child

    • Identify the CDC labor and delivery strategies to prevent transmission of HIV from mother to child

    • July 8, 2008 CDC/ Public Health Service Task Force Statement on MCT – http:// AIDSinfo.nih.gov


The scope of the problem

The Scope of the Problem

  • HIV currently infects 33 million people worldwide (Dec 2008: UNAIDS) and millions have died from HIV and co-morbidities

    • 22 million people in sub-Sahara Africa

      • Up to 60% are women

    • 1.2 million in N. America + Europe

      • 370,000 are women


Perinatal hiv transmission update

70

Sub-Saharan Africa

60

GLOBAL

50

Percent

female

(%)

Caribbean

40

Asia

30

Latin America

20

Eastern Europe

& Central Asia

10

0

1990

‘91

‘92

‘93

‘94

‘95

‘96

‘97

‘98

‘99

2000

‘01

‘02

‘03

‘04

‘05

‘06

2007

Percent of adults (15+) living with HIV who are female

1990–2007

2.4


The scope of the problem1

The Scope of the Problem

  • Women infected with HIV (UNAIDS 2008)

    • 15.4 million women worldwide

    • The vast majority of these women are of childbearing age

      • age 15 – 49

    • > 2.0 million children (<15YO) now living with AIDS/HIV primarily by MCT (UNAIDS 2008)


The scope of the problem2

The Scope of the Problem

  • A significant number of HIV infected women are pregnant

    • For example, in 1998, 21% of pregnant women under age 20 in South Africa were HIV infected

      • In 2001, it was 15.4% for that age group, but over 30% for pregnant women ages 25 – 29

    • Approximately 370,000 infants and children are infected with HIV worldwide per year

      • Now, <250 HIV infected babies born/year in US

        • 1995 -- 16,000 HIV infected children born in US


Perinatal hiv transmission update

HIV prevalence (%) among pregnant women attending antenatal clinics in sub-Saharan Africa, 1997–2007

Southern Africa

Botswana

50

Burkina Faso

Lesotho

40

Mozambique

30

Namibia

NOTE: Analysis restricted to consistent surveillance sites for all countries except South Africa (by province) and Swaziland (by region)

Median HIV prevalence (%)

20

South Africa

Ghana

Swaziland

10

Zimbabwe

0

1997–

1998

1997–

1998

1997–

1998

1999–

2000

1999–

2000

1999–

2000

2001

2001

2001

2002

2002

2002

2003

2003

2003

2004

2004

2004

2005

2005

2005

2006

2006

2006

2007

2007

2007

Eastern Africa

West Africa

20

20

15

15

Ethiopia

10

10

Median HIV prevalence (%)

Median HIV prevalence (%)

Côte d'Ivoire

5

5

Kenya

Senegal

0

0

2.9

Source: National surveillance reports and UNAIDS/WHO/UNICEF, Epidemiological Fact Sheets on HIV and AIDS.  July 2008.


Aids in women

AIDS in Women

  • Ohio Data through December 2006

    • 11,631 people living with HIV/AIDS in Ohio

      • 3,066 are women (21%)

    • Counties with highest number of HIV/AIDS cases in women in Ohio

      • Cuyahoga (Cleveland) – 723 23%

      • Franklin (Columbus) – 515 19%

      • Hamilton (Cincinnati) – 361 19%

      • Montgomery (Dayton) 209 22%

      • Lucas (Toledo) – 218 29%


Mct of hiv

MCT of HIV

  • Perinatal transmission of HIV is a growing problem

    • Until there is a cure, MCT will occur

      • Undeveloped countries>>> developed countries

    • Transmission rates in developed countries are generally <2% in women diagnosed with HIV and receiving HAART

      • Transmission rates in undeveloped countries can range from 14% - 33% (up to 48% in one study)


Mct of hiv1

MCT of HIV

  • MCT HIV transmission occurs relatively frequently without treatment

    • There are no absolute parameters/thresholds for transmission or protection

      • Multiple risk factors contribute to a graded response to transmission (eg – viral load, maternal health)

    • When does perinatal HIV transmission occur during the course of pregnancy?

      • Important to understand in order to evaluate treatment strategies


Timing of hiv transmission

Timing of HIV Transmission

  • French CollaborativeStudy (Am J Epidem 1995:142:1330-7) evaluated non-breast feeding MCT

    • Analysis of 495 infants using the Markov model

    • 35% (i.e. – one-third) of infections occur in utero

      • Of these infections, 92% occur in the last 2 months

      • HIV can be detected in fetal tissues aborted at 8 weeks gestation

    • 65% (i.e. - two-thirds) of cases of MCT occur intrapartum

  • These are the usual quoted transmission rates


Timing of hiv transmission1

Timing of HIV Transmission

  • Kourtis, et al JAMA 2001 285: 709 –712

    • Analysis of ten treatment trials (PACTG 076, PETRA, SAINT, others) for non-breast feeding MCT challenged this view

    • Graphic depicts this in the next slide

      • Around 30% intrapartum transmission

      • Around 70% in utero transmission


Cd4 counts and viral loads

CD4 counts and Viral loads

  • Need to define two terms - CD4 count and HIV viral load - and understand their clinical use

    • CD4 count

      • “T-helper cell” - Coordinating cell for immune system function

      • initially the CD4 count falls after infection and then rebounds to levels slightly below those seen prior to infection

      • a variety of factors (eg: host genotype, virus genotype, viral load 6 - 12 months after infection) determine long term outcome

      • on average, the CD4 count falls by 10 cells/month: normal count>500 cells/mm


Cd4 counts

CD4 counts

  • CD4 Count > 500 (28%) often asymptomatic

  • CD4 Count 200 - 500 increasing incidence of thrush, shingles, pneumococcal pneumonia, etc.

  • CD4 Count <200 (14%) at risk for opportunistic infections (PCP, candida esophagitis, toxoplasmosis, etc.). Begin PCP prophylaxis. AIDS

  • CD4 Count <50 at risk for MAI, CMV. Begin MAC prophylaxis


Hiv viral load

HIV Viral Load

  • The amount of virus in blood (either proviral DNA or genomic RNA) can be measured using polymerase chain reaction (PCR) or other nucleic acid test

  • Quantities of HIV in plasma can be detected down to 20 copies of virus per cc of blood

    • This is a reasonable representation of the amount of virus in lymphoid tissue


Hiv viral load1

HIV Viral Load

  • 209 HIV + men enrolled in MACS study in Pittsburgh 4/84 - 3/85

  • Extensive information available on patients - blood samples, CD4 counts, clinical progression

  • Viral load is the best predictor of clinical outcome

  • Like a train heading towards a cliff - CD4 tells you where the train is - viral load tells you how fast it is traveling


Strategies to prevent mct

Strategies to Prevent MCT

  • PACTG 076:

    • In 1994, a landmark study was released which demonstrated for the first time a specific, effective therapy to decrease MCT

    • This study revolutionized the care of HIV infected women and set the gold standard for all subsequent care

      • Analysis of this study continues (eg. PACTG 219/076)


Pactg 076

PACTG 076

  • Connor, et al. Reduction of Maternal-Infant Transmission of HIV Type 1 with Zidovudine Treatment. NEJM Nov 3, 1994.

    • USPHS issued AZT guidelines August, 1994

    • Randomized, double-blind placebo controlled study

      • 477 HIV + pregnant women (14 to 34 week gestation) with CD4 >200 were enrolled

      • 409 women went to term (415 live births)


Pactg 0761

PACTG 076

  • Women received AZT or placebo

    • Ante partum: 100mg po 5x/day

    • Intrapartum: 2mg/kg IV AZT over 1 hour, then 1mg/kg/hr until delivery

    • Postpartum: for the neonate 2mg/kg q6hrs po X 6 weeks beginning 8 - 12 hours after birth : no breastfeeding

      • Infants were evaluated for HIV infection by peripheral blood mononuclear cell culture at weeks 12, 24, and 78

        • ELISA and Western Blot were also performed at weeks 72 and 78


Pactg 0762

PACTG 076

  • Results

    • No differences in demographics or pregnancy outcomes between the placebo and AZT groups

      • Placebo group: 25.5% infected infants at 72 weeks age

      • AZT group: 8.3% infected infants at 72 weeks age

      • NEARLY 70% REDUCTION IN MCT

      • Since publication of this study, use of AZT during pregnancy has been the standard of care

        • Intra-partum and post-partum aspects of PACTG 076 currently used as per the original study


How does azt work in mct

How does AZT work in MCT?

  • How did AZT cause the reduction in MCT?

    • Sperling RS, et al. NEJM Nov 28,1996.

      • 1) a high maternal viral load is a risk factor for HIV MCT

      • 2) AZT reduces the maternal viral load, but the reductions seen only partly explain the decreases in MCT

  • Role of AZT resistance in MCT

    • Eastman PS, et al. JID March 1998.

      • Conclusion: AZT resistance did not appear to be a significant factor in MCT/ AZT failure in this study


  • Beyond azt available agents

    NRTIs

    AZT (retrovir/zidovudine)

    Didanosine/Videx

    Stavudine/Zerit

    Lamivudine/Epivir

    Abacavir/Ziagen

    Tenofovir/Viread

    Emtricitabine/Emtriva

    NNRTIs

    Nevirapine/Viramune*

    Delavirdine/Rescriptor

    Efavirenz/Sustiva

    Etravirine/Intelence

    PIs

    Saquinavir (Invirase/Fortovase)

    Ritonavir/Norvir

    Indinavir/Crixivan

    Nelfinavir/Viracept

    Amprenavir/Agenerase

    Lopinavir+ritonavir/Kaletra

    Atazanavir/Reyataz

    Tipranavir/Aptivus

    Darunavir/Prezista

    Fosamprenavir/Lexiva

    Beyond AZT – available agents


    Beyond azt available agents1

    Beyond AZT – available agents

    • Entry inhihitors

      • Enfuvirtide/Fuzeon

      • Maraviroc/Selzentry

    • Integrase inhibitor

      • Raltegravir/Isentress


    Beyond azt recommended agents

    Beyond AZT – Recommended agents

    • NRTI

      • AZT

      • Lamivudine

        • AZT and lamivudine are usually used together as combivir one pill bid

    • NNRTI

      • Nevirapine if CD4 < 250

        • Viramune 200mg po qday X 2 weeks, then 200mg po bid

    • PI

      • Lopinavir/ritonavir (increased dose)

        • Kaletra three tabs po bid


    Beyond azt

    Beyond AZT

    • Combinations of Antiretrovirals are used in pregnant women

      • HAART – highly active antiretroviral therapy

        • In general, avoid 1) Zerit/Videx, 2) Sustiva 3) nevirapine with CD4 >250 4) oral amprenavir solution (dissolved in propylene glycol)

        • In general, preferred agents are AZT, epivir, nevirapine with CD< 250, lopinavir/ritonavir

          • Combivir (one bid) and Kaletra (three bid)


    For the hiv pregnant woman the cdc suggests

    For the HIV+ Pregnant woman, the CDC suggests...

    • AZT should be part of antiretroviral therapy during pregnancy when feasible

      • PACTG 076 should be followed for intra-partum and post-partum management

      • HAART should be routinely used with preferred agents

        • Goal of therapy is an undetectable viral load before labor and delivery

        • HAART should be given for MCT regardless of viral load or need for treatment of the mother


    For the hiv pregnant woman the cdc suggests1

    For the HIV+ Pregnant woman, the CDC suggests...

    • Recommendations are outlined in clinical scenarios – July 8, 2008 Public Health Service Task Force – http:// AIDSinfo.nih.gov

      • 6 Clinic scenarios for HAART use in pregnancy to decrease MTCT

      • 4 Clinical scenarios for mode of delivery to decrease MTCT


    Cdc scenario 1

    CDC Scenario #1

    • HIV infected woman receiving HAART who becomes pregnancy

      • Continue HAART if successfully suppressing viremia (<50 copies/cc)

        • Avoid EFV, D4T/ddI , other potential teratogens and adjust antiretroviral therapy as needed

        • If stable on NVP, can continue

        • Consider adding AZT

      • HIV resistance testing if viral load >1,000


    Cdc scenario 2

    CDC Scenario #2

    • HIV infected pregnant woman who is antiretroviral naïve and has indications for HAART

      • AIDS, CD4<350, Hx of OI, HIVAN

      • HIV resistance testing

      • Initiate HAART regimen

        • Use preferred agents including AZT if feasible

        • Repeat HIV resistance testing if viral load suppression sub-optimal


    Cdc scenario 3

    CDC Scenario #3

    • HIV infected pregnant woman who is antiretroviral naïve and does not require treatment for her own health

      • HIV resistance testing

      • Consider HAART after first trimester complete

        • Use preferred agents including AZT if feasible

        • Repeat HIV resistance testing if viral load suppression sub-optimal


    Cdc scenario 3 con t

    CDC Scenario #3 (con’t)

    • HAART to prevent MCT only

      • Can consider use of AZT alone if HIV VL < 1,000

        • Controversial and many doctors (including myself) do not agree with this strategy

      • Consider D/C of HAART after delivery


    Cdc scenario 4

    CDC Scenario #4

    • HIV infected pregnant woman who is HAART experienced but not currently receiving antiretrovirals

      • Begin HAART based on resistance testing and treatment history and information about potential medication teratogenicity

        • Use preferred agents including AZT if feasible

        • Repeat HIV resistance testing if viral load suppression sub-optimal


    Cdc scenario 5

    CDC Scenario #5

    • HIV-infected woman who has received no HAART prior to labor

      • 1) Give IV AZT during labor and give AZT to the infant postpartum as per PACTG 076

      • 2) Give IV AZT and single dose nevirapine at onset of labor followed by single dose nevirapine to newborn at 48 - 72 hours

        • Consider 3-7 days AZT/3TC starting intra-partum or post-partum to decrease nevirapine resistance

      • Other “short course” options exist


    Cdc scenario 6

    CDC Scenario #6

    • Infants born to mothers who have received no antiretroviral therapy during pregnancy or labor and delivery

      • Initiate post-partum AZT as soon as possible (preferably within 6 - 12 hours of birth)

        • AZT may be used in combination with other antiretrovirals particularly if the mother has known or suspected AZT resistant virus


    Cdc recommendations

    CDC Recommendations

    • The following are included in all the scenarios

      • Resistance testing at start of therapy and if failure to suppress viral load

      • Continue oral regimen during labor and delivery and add IV AZT as per PACTG 076


    Cdc recommendations con t

    CDC Recommendations con’t

    • No increased monitoring is recommended for viral load and CD4 counts

    • Discussion of antiretroviral therapy should be noncoercive and the woman makes the final decision about medical therapy

    • Refusal to accept medical care (AZT/other drugs) should not result in punitive action or denial of care

      • All pregnant women who have received antiretroviral therapy during pregnancy should be reported to the Antiretroviral Pregnancy Registry


    Short course therapy for mct

    “Short Course” Therapy for MCT

    • HIVNET 012 :

      • Single dose nevirapine to mother in labor and single dose nevirapine a day to infant 2 -3 days later and breast feeding allowed: 47% reduction in MCT

        • 65% of women in this study developed nevirapine resistance (CROI,2005)

        • Use of nevirapine in subsequent pregnancies being studied

    • Thailand

      • AZT 2x/day starting at 36 weeks and every three hours orally during labor and no breast feeding: 50% reduction in MCT


    Short course therapy for mct1

    “Short Course” Therapy for MCT

    • Cote d’Ivoire

      • AZT 2x/day starting at 36 weeks and every three hours orally during labor and breast feeding allowed: 37% reduction in MCT

    • PETRA trial

      • AZT 300 mg given every three hours and lamivudine 150mg given every 12 hours during labor, and then AZT/lamivudine given for one week to mother and child (all meds given orally): 37% reduction in MCT to date


    Cdc scenario 1 delivery

    CDC Scenario #1 – Delivery

    • HIV infected woman presenting > 36 weeks gestation, no HAART, no labs available before delivery

      • Start HAART or PACTG 076

      • Consider C-section at 38 weeks to reduce MCT

        • If scheduled c-section, give AZT beginning 3 hours before surgery (loading dose and 3 hours infusion)

        • Prophylactic antibiotic therapy

          • Cefotetan, cefoxitin, cefazolin, amp-sulbactam, clinda/FQ, etc

        • Post-partum PACTG 076


    Cdc scenario 2 delivery

    CDC Scenario #2 - Delivery

    • HIV infected woman who is on HAART, but has a viral load >1,000 at 36 weeks

      • Continue HAART

      • Consider C-section at 38 weeks to reduce MCT

        • If scheduled c-section, give AZT beginning 3 hours before surgery (loading dose and 3 hours infusion)

        • Prophylactic antibiotic therapy prior to C-section

        • Post-partum PACTG 076


    Cdc scenario 3 delivery

    CDC Scenario #3 - Delivery

    • HIV infected woman who is on HAART, and has an undetectable viral load at 36 weeks

      • No information on elective C-section reducing the <2% MCT when VL undetectable to an even further level

        • Study in CID Feb 2005 challenges that view

        • Vaginal delivery if feasible


    Cdc scenario 4 delivery

    CDC Scenario #4 - Delivery

    • HIV infected woman scheduled for elective C-section who presents with early labor or rupture of membranes

      • Start IV AZT immediately

      • Labor progressing rapidly, deliver vaginally

        • If minimal cervical dilation, can administer loading dose AZT and proceed with C-section

        • Can use pitocin to expedite delivery

        • Avoid scalp electrodes, other invasive monitoring procedures

        • Post-partum PACTG 076


    Hiv testing in pregnancy

    HIV Testing in Pregnancy

    • CDC is recommending “adoption of simplified HIV testing procedures….CDC will promote recommendations for routine HIV testing of all pregnant women, and, as a safety net, for the routine screening of any infant whose mother was not screened.”

      • MMWR April 18, 2003/vol 52/no. 15


    Conclusions

    Conclusions

    • HIV MCT is largely preventable

      • PACTG 076 rates @25% without treatment

        • Most centers treating HIV in pregnancy report <1%

      • Need to get testing during pregnancy

        • If testing not done in pregnancy, test neonate/child ASAP

        • Consider testing in the second and third trimester in selected areas and patients

      • Need to institute appropriate therapy and plan for appropriate mode of delivery

      • Antiretroviral agents recommended for use in pregnancy are relatively safe


    Conclusions1

    Conclusions

    • HIV MCT is largely preventable

      • Three antiretroviral agents recommended

      • C-section for VL> 1,000

      • No breast-feeding

      • Diagnosis of HIV during pregnancy

        • Test older children

      • Birth of an HIV infected infant is a sentinel event representing missed testing and treatment opportunities


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