Npgmc Revision Course Hiv In Pregnancy, Sept 2005 Final

HIV IN PREGNANCY BY DR. J.U.E. ONAKEWHOR,

MBBS, M.SC, FWACS, FICS

(Consultant Ob-Gyn and Coordinator, PMTCT Program, UBTH, Benin City)

Presentation made at the Revision Course organised by the National Post Graduate Meidcal College of Nigeria ath the University of Benin Teaching Hospital ,Benin City, Nigeria September 5- 10 ,2005.

INTRODUCTION Since man fell from the throne of grace  Health Problems have become insurmountable  The Lord will strike you with the dxes of the Egyptians; boils, tumours, scab, itch, madness, blindness, confusion of heart from which you cannot be healed. - Deut, 28:27-28. 

OVERVIEW OF THE HIV BURDEN 

5 cases of P CP 1st reported from the University of California, Los Angeles, United States and published on June 5, 1981MMWR (24 years ago)

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Was initially called Gay men ( homosexual men) ’s disease

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HIV / AIDS has become a global pandemic

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Nigeria officially reported her first case of HIV/AIDS in a 13-year-old girl in 1986

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Curtailing this infection - the concern of everyone

Overview cont. In Africa:  Malaria infection –500 M /YR, HIV– 22M /YR:⇒ most common Dxes in Africa  HIV /AIDS epidemic + its ramification getting out of control  Spread of HIV/AIDS in Africa > worse than projection;  2.4M died of AIDS in sub-Saharan Africa in 2000 ( 80% of global AIDS deaths).  AIDS leading cause of death in Africa; 4th worldwide

GLOBAL PERSPECTIVE OF HIV/AIDS • HIV/AIDS is global problem- no continents is spared 

An estimated 37.8 million [34.6–42.3 million] people infected worldwide:

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Infected adults 35.7 million [32.7–39.8 million];

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Women most affected -17 million [15.8–18.8 million] infections world wide.

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Sub-Saharan Africa is home to 25 million people(70% of the world infected population). (UNAIDS 2004).

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Africa contributes only 11% to the world population of over 6billion.

GLOBAL PERSPECTIVE OF HIV/AIDS contd. 

New infections in 2003 - 4.8 million [4.2–6.3 million] people

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AIDS deaths in 2003 : Globally, there were 2.9 million.

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Adult deaths were put at 2.4 million.

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Deaths of children under 15yrs was about 490,000 (UNAIDS 2004)

GLOBAL PERSPECTIVE OF HIV/AIDS contd. 15,000 new infections occur every day.  9-10 infections per minute  ONE infection in 6 seconds  About 1 death every 10 seconds  > 95% of the infections occur in poor & developing countries • Africa remains the world’s burden. 

• The life expectancy in some African countries has dropped from 62 to 47 years. • Economically, the hardest hit countries could lose more than 20% of their Gross Domestic Product (GDP) by the year 2020 due to AIDS from ill-health and death of the work force.

HIV IN NIGERIA National prevalence; • 5.4% in 1999 (1.8% in 1991,3.8% in 1993,4.5% in 1996) • 5.8% in 2001 (`17. 0% in TB patients) In Benin City • 0.00% in1992 • 2.4% in 1997/98 • 8.5% in Dec.2001

• 1.8% in1993/94 • 5.8% in 2000 • 9.4% in June 2002

HIV in PREG _ in 2000 SPCH, B /C PREVALENCE FOR THE MILLENNIUM YEAR, 2000

QUARTER PREVALENCE (N=1,024 )

1st 9/59 (15.3 %)

2nd 13/59 (22.0 %)

Note increasing trend

3rd 16/59 (27.1 %)

4th 21/59 (35.6 %)

BAR CHART SHOWING QUARTERLY SEROPREVALENCE OF OBSTETRIC HIV AT THE SPCH, B/C in 2000. 25

20

15

10

5

0 1st Qtr

2nd Qtr

3rd Qtr

4th Qtr

PATHOPHYSIOLOGY :HIV Lifecycle 

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HIV is a retrovirus that uses its RNA and the host’s DNA to make viral DNA. It has a long incubation period. HIV consists of a cylindrical center surrounded by a sphere-shaped lipid envelope. The center consists of two single strands of RNA. HIV causes severe damage to and eventually destroys the immune system by utilizing the DNA of CD4+ lymphocytes to replicate itself, destroying the CD4+ lymphocyte.

PATHOPHYSIOLOGY contd Serotypes: HIV-1 and HIV-2.  HIV-1 more deadly and commoner and is more widely studied than HIV-2.  HIV-1and 2 are both present in West Africa;  HIV-1 is the commoner of the two.  HIV-2 commoner in West Africa than in any part of the world, HIV-2 is milder in its course than HIV-1; it does not seem to respond appropriately to the conventional drugs used in the treatment of HIV-1. Also, its laboratory (confirmatory) diagnosis is more strenuous.  Subtypes of HIV –1.

HIV-1 is the major cause of AIDS.  Like other retroviruses, it can make in the host cell nucleus a DNA copy of its RNA genome- a reversal of the normal direction of genetic flow.  mean plasma half-life of only 6 hours, a feature that is responsible for the very frequent mutation of the organism.  There are three genes in the RNA genome. ‘env’ gene encodes for envelope proteins including gp120. gp120 is responsible for ‘locking into the CD4 lymphocyte cell receptor. The ability of the virus to evade immune surveillance is based on the variability of this protein. CD4 Lymphocyte plays invaluable role in immune response of the host and is the main target of attack by the virus. Depletion of the host CD4 cells is a measure of the degree of spread of the infection within the host

Human Immunodeficiency Virus

HIV Structure

CD4+ T cell or macrophage

THE HIV LIFE CYCLE

Subtypes of the HIV-1 organism   

Subtypes A, B, C, D, E, F, G. The G subtype in Nigeria was first identified in Ibadan. The Clade AG virus present in Nigeria.

Implications of this genetic diversity may include -possible differences in natural history between subtypes, -shorter time to AIDS (in some cohorts), -difference in viral load pattern, -mutation resistance patterns to anti-viral drugs -the need for and difficulties in developing ‘cocktail’ vaccines that are effective against these various strains. -The natural history of the Clade AG virus, the viral load and mutation resistance patterns in Nigeria may be different – evaluated needed.

Incubation period One to three months to develop detectable antibodies after initial exposure.  median time may be less than four weeks,  seroconversion may take longer to occur.  During this asymptomatic phase of viraemia, billions of virions are produced,  infection transmission may be high and progressive attrition of the immune system takes place.  CD4 lymphocytes depletion rate of about 60 x 109 /L / year  Clinical AIDS in about ten years for some individuals ;  it may be shorter in some individuals - depending on the virulence of the offending organisms, - the genotype and phenotype of the virus - the viral load (plasma HIV RNA) - viral resistance. Other factors : maternal, obstetric, fetal and infant factors ( MTCT) 

In Africa Contd. Factors responsible for the HIV spread in sub-Saharan Africa:  Poverty; lack of resources  Denial  Stigma  Complacency  Life expectancy ↓ ; 67-→ 47 yrs (Nigeria – 52 yrs) 

Media For Transmission Of HIV

HIV can be transmitted through exchange of body fluid such as  Blood and blood products  Semen  Vagina fluid  Breast milk  Saliva  Donated organs for transplant 

Mode of transmission of HIV • Mother-to –Child transmission  Heterosexual intercourse (Semen, Vagina fluid)  Blood transfusion (blood and blood products)  Incidental needle punctures especially for medical staff,  Sharing of needles by intravenous drug abusers,  Sharing of other sharp unsterilized instruments for medical, social or cultural purposes (e.g. tattoos).  Sharing of Clippers, toothbrushes, etc.

Diagnosis of HIV/AIDS The diagnosis of HIV is based on 3. Detection of HIV- antibodies in the serum of an individual using i). Double ELISA (Enzyme-linked immuno-absorbent assay) test ii). Rapid test (Double/ Triple test) Algorithm (WHO) iii). Western Blot, iv). Immuno-precipitate assay v). Immuno-florescent assay 2. Detection of HIV - specific antigen for example the p24 antigen 3. Detection of HIV nucleic acid- using the Polymerase Chain Reaction (PCR) technique( RNA-PCR and DNA-PCR) 4. Viral culture. 5. Apart from laboratory, clinical diagnosis is also important when the patient is symptomatic. BUT Lab, confirmation mandatory Most diagnosis and classifications use a combination of the CD4 lymphocyte count and symptoms.

Others • Dry blood spot testing for viral antibodies (In rural hospitals or in resource–poor settings) is an acceptable method • Dual rapid tests for “same-day” rapid test results same day diagnosis in antenatal clinics provided the two kits have different working principles. advantage: -early results - enabling the antenatal women more access to antenatal strategies for the prevention of vertical transmission Voluntary counseling and confidential testing (VCCT) is universally recommended. Testing & Counseling( TC) now recommended for health facilities Routine screening with op-out option (practiced in some maternity centres worldwide).

T he CDC Classification of HIV disease

The CDC 1993 revised classification of HIV disease ( still widely in use) Three Categories; corresponds to three CD4 Lymphocyte categories A: CD4 >500 cells/mm3 (CD4% >28%), B: CD4 200-499 cells/mm3 (CD4% 14%-28%), C : CD4 <200 cells/mm3 (CD4% <14%). -These are symptom categories ; -recommended to “guide clinical and therapeutic management actions -in HIV-infected adolescent and adults”.

Clinical and Immunologic Staging Laboratory axis

Clinical Axis

CD4

Stage 1 Asymptomatic PGL

Stage 2 Early HIV

Stage 3 Intermediate

Stage 4 Late AIDS

A

>500

1A

2A

3A

4A

B

200-500

1B

2B

3B

4B

C

<200

1C

2C

3C

4C

• Hashed area represents those with case definition of AIDS (stages 1C, 2C, 3C, 4A, 4B, 4C)

Vulnerable group • Young persons most predominant vulnerable group (15-49; the younger the age the more likely the risk of infection). 

Women

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children

WHO ARE AT RISK OF HIV ?          

All unmarried sexually active persons Married but unfaithful couples ( ↑ sero- Discordances) Blood transfusions MTCT; over 90% of vertical transmission Homosexuals I.V Drug abusers Health hazards (medical / health workers) Persons with STIs Low social economic class, esp.20-39 yrs(78%) Sharing sharp unsterilized objects (harmful traditional practices- scarifications , tattooing, ear piercing, circumcision, manicure, pedicure, clippers, etc.)

INTERVENTIONS  

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HIV -developed countries ; now a treatable chronic dx Developing countries; a major health problems -2nd most killer after malaria Microbicidal agents - 60 candidates AVRS / HAART-currently the mainstay of MX Vaccines –over 30 types under clinical trials vs HIV- 1 Sub-type B&E in phase 3 clinical trial

Predominant sub-types in S.S.Africa are A, C, D  Recombinant viruses-AG in Nigeria.  Prevent new infections- PMTCT in pregnancy  Cocktail Vaccine – the most appropriate

Intergenerational sex and HIV infection of young women 

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Transmission of HIV from older to younger people is necessary to maintain virus in population- without sex between older and younger populations epidemic would fade as infected persons age Pressures on young women to have sex or marry older men  Dominance

of older males in society  Family pressure  Economic  Social status

PMTCT Using Antiretroviral (ARV) Treatment versus Prophylaxis 

ARV Treatment Long-term

use of antiretroviral drugs to treat maternal HIV/AIDS and prevent PMTCT

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ARV Prophylaxis Short-term

use of antiretroviral drugs to reduce HIV transmission from mother to infant

Challenges in PMTCT      

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Preventing HIV in young women Preventing unintended pregnancy in HIV+ women Diagnosing HIV early in pregnant women Getting ARV prophylaxis started before transmission can take place Reducing transmission risk at term Preventing transmission from breast milk while protecting child against diarrhea and malnutrition Avoiding ARV resistance

PMTCT: Four targets for a comprehensive approach Prevent young women from becoming infected  Prevent unintended pregnancy in HIVinfected women  Prevent HIV-infected women from transmitting HIV to their infant  Provide HIV care, treatment, and support to HIV+ women, their infants, and their families 

Risk of mother-to-child transmission of HIV without intervention* Exposure 1st trimester

Transmission risk (%) <1

Cumulative risk (%) <1

2nd trimester

2

2

3rd trimester

5

7

Labor & delivery

12-14

19-21

24 months breastfeeding

12-18

31-39

*Consensus estimates from multiple studies

Risk of mother-to-child transmission of HIV during pregnancy, delivery, and breastfeeding

1st trimester 2nd trimester 3rd trimester Labor & delivery

Uninfected

24 months breastfeeding

Goals of Antiretroviral Therapy in Pregnancy PMTCT • Improve maternal health status .prevent mother to child transmission of HIV Achievable through : - Maximal long-term viral suppression Optimal immune reconstitution, Reducing the risk of resistance and cross-resistance to the antiretroviral agents, -

Minimizing drug toxicity to the mother avoiding drugs with fetal teratogenic effects.

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Enhancing the quality of life and the overall clinical outcome for both mother and baby at affordable cost of care.

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Finally the objective of this care is to integrate with long-term public health efforts.

modalities ANC  LABOR, Vag. Deliv &C/S  POST NATAL 

Enrolling and retaining women and children in PMTCT 

Follow up of infants  Must

monitor infants to measure program outcome  Nutritional support  Testing for HIV  TMP/SMX (Bactrim) prophylaxis  An avenue to getting mothers, fathers, & siblings tested or into care

Monitoring ARV therapy Laboratory data 

Absolute minimum tests per WHO • HIV test • hemoglobin or hematocrit level

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Basic tests WBC or FBC • Total lymphocyte count • Liver function tests (LFTs) • Renal function tests (RFTs) • Blood sugar •

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Desirable tests • CD4 • Amylase • Bilirubin

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Optional*

Viral load 

Resistance testing

*not available in Nigeria routinely at this time

Effectiveness of antiretrovirals for PMTCT: Infection rates at 1 month 

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Effectiveness depends on DURATION- how early in pregnancy treatment started, and on INTENSITY- how many drugs used No intervention: 20 % infected Single-dose NVP: 12 % infected ZDV from 28 weeks: 7 % infected 2 drugs: 1-4 % infected HAART: <1 % infected

Thai randomized trial of PMTCT in nonbreastfeeding women & infants Gestational age ZDV started

Duration of infant ZDV

% Infants infected at 6 mo

90% Confidence interval

28

3 days

4.7%

2.4-7.0

28

6 weeks

6.5%

4.1-8.9

35

3 days

10.5%

6.4-14.4

35

6 weeks

8.6%

5.6-11.6

Summary of Efficacy of ARVs for PMTCT Intervention (IP = intrapartum)

% HIV+ at 1 month

None

~18-22%

Neonatal NVP or ZDV

13-21, 9.3-16.6

Neonatal ZDV/3TC or ZDV/NVP

14.2-15.3

Intrapartum/neonatal NVP

10.4-11.9

Intrapartum/neonatal ZDV

10-20

Intrapartum/neonatal ZDV/3TC

7.9-8.9

ZDV start 36-37 wk + IP + neonatal

9.6-15.1

ZDV start 35 wk + IP + neonatal

8.6-10.4

ZDV start 23-28 wk + IP + neonatal

4.3-8.3

ZDV/3TC start 36, 34, 23-32 wk

5.9, 2.8, 1.6

ZDV 28 wk + IP NVP and/or neonatal NVP

1.1-2.0

HAART 34 wk

3.6

Early HAART

<1

Effectiveness of antiretrovirals for PMTCT: Infection rates at 1 month 

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Effectiveness depends on DURATION- how early in pregnancy treatment started, and on INTENSITY- how many drugs used No intervention: 20 % infected Single-dose NVP: 12 % infected ZDV from 28 weeks: 7 % infected 2 drugs: 1-4 % infected HAART: <1 % infected

Caesarian delivery for PMTCT 

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Scheduled Caesarian delivery reduces MTCT in infants at risk of HIV transmission because mother is on no prophylaxis or inadequate prophylaxis (ZDV monotherapy) No evidence of efficacy after onset labor Increased morbidity in women with HIV Under conditions where safe, scheduled C/S can be performed, adequate ARV prophylaxis should be feasible

THE NIGERIAN PMTCT PROGRAM:HAART 1ST Line : ZVD+NVP+ Lamivudine 2nd Line : ZVD+Efaverenz+ Lamivudine Outside tertiary centers: NVP ± Lamivudine ZDV ± Lamivudine

Antiretrovirals in pregnancy Drug Pros

Cons

ZDV Lots of experience

Anemia

3TC

Resistance if not HAART

Lots of experience

D4T

? Mitochondrial toxicity Do not use with DDI

DDI

? Mitochondrial toxicity Do not use with D4T

ABC Potent

Less experience

TDF

? Bone toxicity

Antiretrovirals in pregnancy Drug NVP

Pros Experience

EFV

OK with rifampin

NFV

Experience Well-tolerated

Cons Hepatic toxicity Resistance if not HAART ? 1st trimester teratogen Resistance if not HAART Not as potent as LPV/r

IDV/r

? Bilirubin

SQV/r

Little experience; GI

LPV/r

Potent

GI intolerance

Safety of antiretrovirals in pregnancymaternal toxicity   

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GI upset: most protease inhibitors (except nelfinavir) Anemia: zidovudine Hepatic toxicity  Nevirapine, especially if CD4 >250 and female  Other ARVs  Hepatic steatosis, hepatic failure around term: combination of D4T+DDI. Contraindicated in pregnancy Glucose intolerance: PIs (except atazanavir)

Resistance to ARVs after prophylaxis against MTCT  

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ZDV monotherapy from 2nd trimester: little resistance NVP single dose  20-40% of mothers with detectable resistance  46% of infants who fail prophylaxis have resistant virus ZDV from 28 weeks & in labor + single dose NVP- rate of NVP resistance similar to single dose NVP without ZDV ZDV/3TC: 3TC resistance depending on duration (about 30% after 3 months exposure) HAART regimens  No resistance if full suppression achieved  Varies according to regimen: NNRTI failure associated with rapid resistance

% of patients with HIV RNA <400 copies/mL

Correlation Between Optimal Therapeutic Response at 3 Months and Adherence to Protease Inhibitor Therapy 100 90 80 70 60 50 40 30 20 10 0

78

45 33

29 18

>95

90-95

80-90

70-80

<70

% of prescribed doses taken -- MEMS cap data Paterson D, et al. Ann Intern Med. 2000;133:21-30.

GOAL: Take ARV meds exactly as prescribed so there is enough medicine in blood at all times.

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THANK YOU