other-to-child transmission (MTCT) accounts for
90% of HIV infections in children under the age of 15 years [1]. Without
any intervention, the infant born to an HIV-infected pregnant woman has
25-45% risk of HIV infection during pregnancy, delivery, and
breastfeeding [2]. In the absence of breastfeeding, intrauterine (transplacental)
infection and peripartum infection account for 25-40% and 60-75%,
respectively, of vertical infection. Breastfeeding carries an 8-25% risk
of vertical transmission in the developing countries [3,4].
In 2000, there was a global surge in the new cases of
HIV infections, and the world was staring at an HIV epidemic [5]. The
alarm bells were enough to arouse the United Nations and its member
states, and they became a signatory to the Millennium Declaration in
September 2000 wherein they resolved to take terse measures to combat
HIV by 2015 (Millennium Development Goal-6). The United Nations General
Assembly Special Session on HIV/AIDS, held in June 2001, set the goal of
reducing the proportion of infants infected with HIV by 20% by 2005, and
by 50% by 2010 [6]. Scaling up of Prevention of Mother-to-Child
Transmission (PMTCT) of HIV services and increased access to
anti-retroviral therapy were the major armamentaria to attain this goal.
Over the next fifteen years, much was achieved due to sustained efforts
of all member states, and HIV-infection rates and AIDS-related deaths
decreased by 40% [5].
PMTCT of HIV has been at the helm of all research in
HIV. Ever since the Pediatric AIDS Clinical Trials Group demonstrated
that administration of zidovudine (AZT) to pregnant women and their
infants could reduce risk of perinatal transmission by nearly 70% [7],
several clinical trials have used single, dual, or triple Anti
Retroviral Therapy (ART) with or without breastfeeding, with different
modes of delivery to reduce the risk of transmission from mother to
child. Clinical trials initially focused on shortened zidovudine-alone
prophylaxis regimens and moved to evaluating whether combination ARV
regimens, such as short-course zidovudine combined with lamivudine,
might have improved efficacy over zidovudine alone. Studies also
evaluated whether even simpler, less expensive, single-drug regimens,
such as single-dose intrapartum/neonatal nevirapine (NVP), would be
effective, and whether combining such regimens with other short-course
regimens might result in improved efficacy. The HIVNET 012 regimen
advocated administration of single dose oral nevirapine (200 mg) to the
mother during labour and also to the neonate (2 mg/kg) soon after birth
[8]. The mothers were advised to exclusively breastfeed their babies
till 6 months unless replacement feeding was acceptable, feasible,
affordable, sustainable and safe. This regimen resulted in lesser
chances of infant deaths and lesser HIV transmission during labour, and
was well accepted in resource-poor countries as it was quite economical
and convenient. However, it totally neglected the maternal health, and
was not shown to be useful in preventing risk of HIV transmission
antenatally or during the breastfeeding period. The rates of vertical
transmission using this regimen were reported upto 10% [9,10]. Avoidance
of breastfeeding was not a feasible option in several developing
countries. In conditions where the mothers chose to breastfeed, it was
not clear whether this option was made due to compulsion or by choice.
In addition, there was a problem of acquisition of viral resistance to
non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs [11].
In 2010, the WHO laid down new PMTCT ARV guidance
[12] wherein countries had the option to choose between two prophylaxis
regimens for pregnant women living with HIV with CD4 greater than 350
cells/mm3: Option A and Option B. Under Option A, women received
antenatal (AZT starting at 14th week of gestation) and intrapartum
(single dose NVP at onset of labour with first dose of AZT/3TC)
antiretroviral prophylaxis along with an antiretroviral postpartum tail
regimen (AZT/3TC for 7 days postpartum) to reduce risk of drug
resistance, while infants receive daily nevirapine starting from birth
until 1 week after cessation of all breastfeeding; or, if not
breastfeeding or if mother is on treatment, through age 4-6 weeks. Under
Option B, all pregnant and lactating women with HIV initially are
offered triple ART – beginning in the antenatal period and continued
throughout the duration of breastfeeding. At the end of breastfeeding,
women who do not yet require ART for their own health would discontinue
the prophylaxis and continue to monitor their CD4 count, eventually
re-starting ART when the CD4 falls below 350 cells/mm
.
Infants would be offered daily NVP or AZT from birth through age 4-6
weeks regardless of infant feeding method.
In 2011, a systematic review published clearly
advocated that triple ART for all expectant and breastfeeding mothers
along with NVP prophylaxis to the baby for 6 weeks duration is the best
approach to mitigate MTCT of HIV [13]. In 2013, a third more efficacious
approach was recommended by WHO i.e., Option B+, in which all pregnant
women living with HIV are offered life-long triple-drug ART, regardless
of their CD4 count or clinical staging and all HIV-exposed infants are
offered 4-6 weeks of NVP/AZT regardless of feeding method [14]. This new
regimen was shown to be associated with less than 2% risk of HIV
transmission by vertical route. The WHO emphasized that whereever
possible Option B+ be adopted as it was shown to reduce HIV-related
mortality and also ensure better maternal health. Based on the new
guidelines from WHO (June 2013), the National AIDS Control Organization
(NACO) decided to provide life-long ART (triple drug regimen) for all
pregnant and breastfeeding women living with HIV, in which all pregnant
women living with HIV receive a triple drug ART regimen regardless of
CD4 count or WHO clinical stage, with effect from January 1, 2014 [15].
This would not only ensure better maternal health, but also prevent
stopping and starting ARV drugs with repeat pregnancies, reduce vertical
transmission in future pregnancies and avoid drug resistance. In
addition, infants would be administered 6 weeks of daily oral nevirapine
therapy.
The study by Seenivasan, et al. [16] published
in the current issue of Indian Pediatrics shows a vertical
transmission rate of 6.7% amongst breastfed groups despite use of ARV
prophylactic regimen using single dose NVP for mother-infant pairs.
There was no HIV transmission detected amongst neonates born to mothers
receiving triple ART. This study comes at a time when there is
sufficient evidence to prove the superiority of triple ART for pregnant
and breastfeeding mothers over the regimens using shorter regimens using
fewer ARVs. All the same, it does add weight to the current
recommendations of NACO on lifelong use of triple ARV in all pregnant
women living with HIV and ARV prophylaxis with NVP in infants. However,
it remains to be seen whether triple/dual ARV will replace nevirapine
monotherapy for ARV prophylaxis in neonates exposed to HIV in the times
to come. Till then the PMTCT centers should work in close conjunction
with the ART centers to monitor both mothers and infants receiving
anti-retroviral therapy/prophylaxis.
We must accept that changing guidelines is not a
piece of cake and the entire health system needs to be refurbished. More
healthcare workers, drugs, costs, laboratory set-ups, and better
monitoring will be needed to enforce the revised guidelines. Only time
will tell if resource-poor countries will be able to cope with the
increased demands of these new guidelines and show positive results.
1. Kourtis AP, Bulterys M. Mother-to-child
transmission of HIV: Pathogenesis, mechanisms and pathways. Clin
Perinatol. 2010;37:721-37.
2. Kourtis AP, Lee FK, Ebrams EJ, Jamieson DJ,
Buttery M. Mother to child transmission of HIV: Timing and implications
for prevention. Lancet Infect Dis. 2006; 6:726-32.
3. Watts DH. Drug therapy: Management of human
immunodeficiency virus infection in pregnancy. N Eng J
Med. 2002;346:1879-91.
4. Mor Z, Chemtob D, Pessach N, Nitzan-Kaluski D.
Human immunodeficiency virus in new born of infected mothers: Pregnancy,
breastfeeding and prevention. Harefua. 2006;145:682-6.
5. UNAIDS. UNAIDS announces that the goal of 15
million people on life-saving HIV treatment by 2015 has been met nine
months ahead of schedule. Available from:
http://www.unaids.org/en/resources/presscentre/pressrelease
andstatementarchive/2015/july/20150714_PR_MDG 6report. Accessed
August 5, 2015.
6. United Nations General Assembly. Declaration of
commitment on HIV/AIDS: Five years later. Follow-up to the outcome of
the twenty-sixth special session: Implementation of the declaration of
commitment on HIV/AIDS. Report of the Secretary General. Agenda
45. 2006. Available from:
http://www.unaids.org/sites/default/files/sub_landing/files/20060324_sgreport_ga_a60737_
en.pdf. Accessed August 12, 2015.
7. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott
G, O’Sullivan MJ, et al. Reduction of maternal-infant
transmission of human immunodeficiency virus type 1 with zidovudine
treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study
Group. N Engl J Med. 1994;331:1173-80.
8. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda
D, Allen M, et al. Intrapartum and neonatal single-dose
nevirapine compared with zidovudine for prevention of mother-to-child
transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the
HIVNET 012 randomised trial. Lancet. 2003;362:859-68.
9. Arora D, Gupta RM, Kochar SP. Efficacy of single
dose nevirapine in reducing viral load in HIV positive mother in labour
and transmission of HIV infection to new born babies as part of
prevention of parent to child transmission. Med J Armed Forces India.
2014;70:309-14.
10. Kesho Bora Study Group, de Vincenzi I. Triple
antiretroviral compared with zidovudine and single-dose nevirapine
prophylaxis during pregnancy and breastfeeding for prevention of
mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised
controlled trial. Lancet Infect Dis. 2011;11:171-80.
11. Flys T, Nissley DV, Claasen CW, Jones D, Shi C,
Guay LA, et al. Sensitive drug-resistance assays reveal long-term
persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance
mutation in some women and infants after the administration of
single-dose NVP: HIVNET 012. J Infect Dis. 2005;192:24-9.
12. World Health Organization. Antiretroviral drugs
for treating pregnant women and preventing HIV infection in infants.
Recommendations for a public health approach 2010 version. Available
from: http://apps.who.int/iris/bitstream/10665/75236/1/9789241599818_eng.pdf.
Accessed August 12, 2015.
13. Siegfried N, van der Merwe L, Brocklehurst P,
Sint TT. Antiretrovirals for reducing the risk of mother-to-child
transmission of HIV infection. Cochrane Database Syst Rev.
2011;7:CD003510.
14. Global Network of People living with HIV.
Understanding the perspectives and/ or experiences of women living with
HIV regarding Option B+ in Uganda and Malawi. Available from:
www.gnpplus.net/assets/wbb_file_up
down/2793/Option-B+%20Understanding%20 perspectives
%20experiences%20of%20women% 20 living%20with% 20HIV.pdf. Accessed
August 12, 2015.
15. National AIDS Control Organization. Updated
Guidelines for Prevention of Parent to Child Transmission (PPTCT) of HIV
using Multi Drug Anti-retroviral Regimen in India. December, 2013.
Available from:
http://naco.gov.in/upload/NACP%20-%20IV/18022014%20BSD/National_
Guidelines_for_PPTCT.pdf. Accessed August 12, 2015.
16. Seenivasan S, Vaitheeswaran N, Seetha V,
Anbalagan S, Karunaianantham R, Swaminathan S. Outcome of prevention of
parent to child transmission of HIV in an urban population in Southern
India. Indian Pediatr. 2015;52:759-62