Evidence in effectiveness of HAART on transmission of HIV from mother to child during delivery and while breastfeeding
Gedamneh Fantaye
Saba University School of Medicine
Gedamneh Fantaye
937 Whittmore Drive Nashville, TN 37135
(615)-720-5022
fgedamneh@saba.edu
Dr. Bruzik
Article word count: 5447
Fantaye, Gedamneh 2
Abstract
The disease burden of HIV especially in resource limited area is enormous. Since the
invention of HAART this burden has turned around. UNAIDS and the world health
organization(WHO) estimate that in 2009 there were 230,000 to 510,000 new HIV
infections worldwide among children aged 0-15 years of age. The purpose of this study
is to determine the effectiveness of HAART in preventing mother-to-child transmission
and asses other factors that affect the effectiveness of HAART. Long term effect on
CNS of the child exposed to HAART in utero also been included in the research. The hypothesis of the study was The transmission of HIV from mother to a child during delivery and while breast feeding can be avoided if the mother viral load was controlled
well using HAART.
The method of the research included both inclusion and exclusion criteria. Initially, the
article selected for this research were published from the year 2011 to present. The
journal articles had to be related to prevention in HIV transmission from mother to child.
Fantaye, Gedamneh 3
Study Question
Are there any changes in HIV transmission from mother to child with the use of HAART?
Hypothesis
The transmission of HIV from mother to a child during delivery and while breast feeding
can be avoided if the mother viral load was controlled well using HAART.
Fantaye, Gedamneh 4
Introduction
HIV/AIDS has been a major threat for humanity since it was first recognized in the
United States in the summer of 1981. It is caused by an RNA virus which belongs to the
family of human retroviruses (retroviridae) and the subfamily of lentivirus. Once the virus
gets into human cells, it has a profound impact on the immunity of the host. This
manifest as acute HIV syndrome to symptomatic disease involving multiple systems of
the infected individual especially when the CD4 count of the host decreases. According
to WHO, around 35 million people were living with HIV in 2013 and since the start of
epidemic, 39 million people have died due to AIDS. Out of the estimated 35 million people living with HIV worldwide, 25 million living in sub-saharan Africa.8
HIV transmission is result from virus exposure at mucosal surface or from percutaneous
inoculation. According to united nations programme on HIV/AIDS(UNAIDS 2010),
heterosexual transmission is responsible for nearly 70% of HIV infection worldwide with
the remainder largely attributable to men who have sex with men(MSM), maternal
-infant infection, and injection drug use. The transmission probability per coital act are
also affected by other risk factors such as HIV disease stage (Viral load), presence of
genital ulcer, male circumcision, and exposure route. Socioeconomic factors can also
influence HIV transmission indirectly. UNAIDS and the world health organization(WHO)
estimate that in 2009 there were 230,000 to 510,000 new HIV infections worldwide
among children aged 0-15 years of age. Over 95% of these infections occurred in resource limited setting, primarily sub-saharan africa.3
Fantaye, Gedamneh 5
Once the the person is exposed to the virus from the many route of HIV transmission,
the virus attaches to CD4 molecules and CCR5(a chemokine co-receptor) then the virus
surface fuse with cellular membrane which allows it entry into a T-helper lymphocytes.
In accordance with Shaw et al., there is generally an orderly and reproducible
appearance in the blood of viral and host marker of infection following a clinically
productive transmission event. The initial period between the moment when the first cell
is infected and when virus is first detectable in the blood is termed the eclipse period which has been estimated to be approximately 7-21 days.11 The clinical manifestation of HIV infected patient can be varied depending on the
degree of immunodeficiency that arise with progression of HIV infection. Laboratory
measurement of CD4 T-cells and plasma HIV viral load are commonly used to establish
patient degree of immunosuppression and the rate of destruction of immune system in area with adequate resources. However in resource limited area which are regions hard-hit by the HIV/AIDS epidemic, rather than measuring CD4 T-cells and viral loads
clinicians must rely on clinical parameters when assessing a patient disease status. The
WHO has developed clinical staging and immunological classification of HIV-related
disease in adult and children using standardized clinical parameters based on solely
patient clinical feature to accommodate facilities with no or limited access to laboratory
testing. The WHO clinical staging system for adults sorts patients into one of four
hierarchical clinical stages ranging from stage 1(asymptomatic) to stage 4(AIDS). The
WHO clinical staging system system allow for efficient identification of early infection
Fantaye, Gedamneh 6
and aggressive management when clinicians are equipped with the knowledge to apply them. Therefore be useful tools for improving access to and implementation of care.12 Azidothymidine(Zidovudin) was introduced as the first treatment of HIV in 1987. Then
followed by new class of drugs in 1995-1996 leads to combination ARV therapy(HAART)
possible for HIV treatment. As of 2010, more than 20 ARV agents been approved. According to the WHO Clinical Staging System for HIV/AIDS, the effect on plasma HIV RNA concentration and clinical efficacy were taken in consideration while approving ARV agents. HIV activity can
be measured with plasma HIV RNA concentration that will be also altered with HAART
treatment. The success of HAART changed the course of one a deadly disease to now being a
chronic illness. In Addition, suppression of HIV with HAART prevents virus transmission from
infected women to their new born babies. However, the life long dependency on it makes delayed drug toxicity inevitable. 12 The 2009 data from UNAIDS and WHO estimated 230,000 to 510,000 new HIV infection of children aged 0-15 years. According to Chibwesha et al., more than 400,000 new pediatric infections in 2008.1 And 95% of this infections are from sub-saharan africa countries and maternal to child transmission(MTCT) is the most common cause of infection.3 In accordance of Stevens et al, MTCT occurs during in utero(10%), perinatal (15%), and postnatal through breastfeeding(10%).8 Plasma viral load, CD4 count, and the stage of HIV disease of the mother affect risk of transmission. The lower maternal viral load, the lesser the probability of
MTCT. mode of delivery, premature delivery, duration of membrane rupture, and infection in the
birth canal also determine the probability MTCT during delivery. Mixed feeding and mastitis are
related as postnatal risk factors once the child delivered. This three distinct periods should be
considered and targeted when one planning intervention strategy for prevention of MTCT. according to Chibwesha et al. , MTCT has been dramatically reduced since highly antiretroviral
Fantaye, Gedamneh 7
therapy(HAART) been introduced.1 The lowering ability of maternal viral load of HAART during pregnancy as well as during breastfeeding been the main reason for the decline in MTCT.
Hence suppression of maternal viral load is the main target of therapy plan while approaching
for prevention of MTCT The Office of AIDS Research Advisory Council guideline recommends that all
pregnant women with HIV should initiate antiretroviral therapy (ART) as early in
pregnancy as possible, regardless of their plasma HIV RNA copy number or CD4 T
lymphocyte count to prevent perinatal transmission. In addition, ARV helps reduce the
rate of disease progression, reduce the risk of opportunistic disease and maternal
death. The medications should be administered at all time points (antepartum,
intrapartum) and postnatally to the neonate. It is also recommended that their viral load
be maintained below the limit of detection during and after pregnancy. Although having
undetectable plasma HIV RNA levels may appear to reduce the risk of perinatal
transmission, there has been reports of perinatal transmission among women on ART.
(AIDS Guideline). Conducting this research is critical in determining the effectiveness of
HAART in prevention of MTCH and maximizing the benefit by identifying factors that can affect MTCH.
Fantaye, Gedamneh 8
Methods
Search Strategy
Database to be searched using Pubmed (https: //www.ncbi.nlm.nih.gov/pubmed). Among the search terms used from MeSH databases includes“antiretroviral therapy OR highly active” OR “pregnancy”
AND “children” AND “Transmission prevention OR generic names of antiretroviral drugs (“zidovudine”, “efavirenz”, “lopinavir” and so on) AND “Breastfeeding” .
Inclusion Criteria
Women who began HAART either prior to or during pregnancy infants had been PCR tested between 3 and 12 weeks of life Exclusion Criteria Infants with HIV-1 infection
Data Analysis
The most common data analysis used in the studies is Kaplan-Meier. Kaplan-Meier
method was used to to compare differences in the primary outcome b/w groups, to
estimate HIV-transmission and death rates from delivery to 24 months. For
neurodevelopment analysis, the review article used random effects meta analysis
model.
Fantaye, Gedamneh 9
Results
After screening multiple articles, a total of 10 studies were assessed and met
the inclusion criteria for this review. The characteristics of the studies are provided in
the appendix below. Five of the studies are randomized control clinical trial. There were
one retrospective cohort study, one observational study, one non-randomized control
trial, and three meta-analysis review article. Study Design Summary
Study Design Number of Studies Randomized control trial 5 Cohort study 2 Review articles 3
Among the articles, the population used were similar, in which all were pregnant
women with HIV-1 positive in resource-limited setting. The study settings were all in
Africa such as Zambia, Kenya, Botswana and Sub-saharan Africa and one study
included india and haiti. The majority of the studies were in Kenya. The objectives and
findings of the studies varies from each other, therefore, the results section will be
divided out into different sections: pharmacological, and non-pharmacological. The
pharmacological section will consist of results from studies discussing the safety,
efficacy and tolerance of HAART in pregnant women and their children as well as a
study looking further in ways to suppress medication resistance, and two studies looking
at the medications impact in long term survival rate and impact of medication duration in
Fantaye, Gedamneh 10 reduction of HIV transmission mother to child. The non-pharmacological section will
consist of results from studies discussing impact of exclusive breastfeeding among
women taking HAART and the effect of integrated HIV Care in prenatal clinics.
Pharmacological
Safety, Efficacy and Tolerance 3,6,9
In the Kisumu Breastfeeding Study, a phase IIB open-label single-arm clinical trial,
conducted by Thomas et al. wanted to assess whether triple-antiretroviral prophylaxis regimen
given to HIV-infected pregnant women was feasible, well tolerated, safe and achieved a lower
transmission rate compared to other short-course regimens evaluated such as a single dose
nevirapine(NVP) regimen. In the study, triple-ARV regimen was given to pregnant women in late
pregnancy (34-36 weeks gestation) and continuing up to 6 months postpartum while exclusively
breastfeeding. The participants must have no previous ARV exposure, hemoglobin > 7 g/dl,
absolute neutrophil count > 1,000 cells/mm3, platelets > 50,000/ml, Scr < 1.55 mg/dl, and ALT <
2.5 times upper limit of normal. The initial regimen consisted of two nucleoside reverse
transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor. The mothers
received zidovudine (ZDV) 300mg and lamivudine 150 mg in a fixed-dose combination pill
(Combivir) taken twice daily and NVP 200 mg once daily for the 1st two weeks and then twice
daily thereafter. The infants received a single dose NVP (2mg/kg) within 72 hours of birth. In
addition to the medication the women received, they were advised to exclusively breastfeed for
the first 5.5 months and then wean off over 2 weeks with complete cessation of breastfeeding
by 6 months. Out of 522 women enrolled, 416 mothers completed these study. The study used
Kaplan-Meier methods to estimate HIV-transmission and death rates from delivery to 24 months
which is shown on Figure 1 below. Among 487 live-born, singletons and first-born infants of
Fantaye, Gedamneh 11 mothers , HIV-transmission rates at birth, 6 weeks, and 6, 12 and 24 months were 2.5%, 4.2%, 5.0%, 5.7% and 7.0% respectively. 3
Figure 1. Kaplan-Meier estimates of HIV-transmission rates
When the HIV-transmission rates were stratified over a 2 year period using the mother’s CD4
cell count and viral load, transmission was at a lower rate with CD4 cell count >500 and viral load <10,000 compared to CD4 cell count <500 and Viral load > 10,000. Refer to table 2 below to see the percentage difference. The result shows there is no significant
difference in overall HIV transmission when stratified by maternal baseline CD4 count
with p-value of 0.06 but there is a difference in HIV-transmission when stratified by maternal baseline viral load categories (p=0.01)3
Fantaye, Gedamneh 12
Maternal HIV-transmission rates 95% Confidence interval CD4 cell count <500 CD4 cell count >500 8.4% 4.1% 5.8%-12.0% 1.8%-8.8% p=0.06 Viral load <10,000 Viral load >10,000 3.0% 8.7% 1.1%-7.8% 6.1%-12.3% p=0.01 Table 2: HIV transmission rates when stratified using maternal CD4 cell count and viral load
The most associated side effects with the study regimen included anemia,
neutropenia, hepatotoxicity and rash. All rash side effects did resolve after discontinuation of NVP.3 Although the study above shows great benefit of ART regimen in reducing HIV
transmission and viral load of mother, there has been some concern of neurological
effects of ART exposure in utero. A meta analysis review conducted by Coelho et al,
describes the mechanism of action of ARTs side effect and discuss the possible
neurological impairment of children exposed in utero. The study performed literature
search through PubMed and selected for review only studies involving HIV-1 exposed
uninfected children that were exposed to antiretroviral drugs in utero, which underwent
neurological evaluations. They included 6 studies in their meta-analysis (refer to Table 3 below).9 Four of the studies in the meta-analysis were prospective cohort while the remaining two were cross-sectional. To rule out the effect of the virus over CNS, ART
unexposed children were used as a control and compared with uninfected children born
from HIV-1 infected mother who have been on ART during pregnancy.
Fantaye, Gedamneh 13 Neurodevelopmental function of both groups were assessed using Bayles Scale Of
Infant Development second and third editions (BSID 2,3) or Full-Scale Developmental
Quotient(FSDQ). Age between 3-36 months of a total of 2210 HIV-1 and ART exposed
uninfected group verses 414 ART unexposed in utero as control were included in the
meta-analysis. Since the children were exposed for different class of ART in the utero,
random effect meta-analysis model were considered in the study. Also the sample size
variability of the study were high which makes the heterogeneity of the result to be quite
high (I2=72.8%,95% CI=37%-88.2%). And the pooled SMD was very low(-0.04; 95%
CI=-0.3-0.2, p=0.78). This indicate no significant difference between in utero ART
exposed children of HIV-1 uninfected children and ART unexposed children in neurodevelopmental function.9
Table 3: Summary of the six studies characteristics included in meta-analysis
Fantaye, Gedamneh 14 In another study done by Coovadia et al. looked at the efficacy and safety of an extended once daily nevirapine(NVP) regimen in infant children of breastfeeding
mothers with HIV-1 infection. NVP regimen is used as a prevention of postnatal HIV
transmission. The study is a phase 3, randomised, double-blind and placebo-controlled
HPTN 046 trial. The study population were enrolled from 4 african countries.They wanted to assess the benefit of extending NVP treatment to 6 months from birth who had already received 6 weeks of once daily nevirapine. Post 6 week, the infants were
tested for HIV infection. If they were HIV negative, they would continue receiving
nevirapine prophylaxis or placebo until 6 months. The primary endpoint of the study is to look at transmission rate at 6 months and safety of the medication between the groups.6 The findings show on Table 3 below, that 1.1% (125 of 758) of infants taking the
extended nevirapine developed HIV-1 compared to 2.4% (116 of 761) infants of
controls between 6 weeks and 6 months with p-value of 0.049 which is statistically
significant. As far as side effects, there is no significant difference between the
treatment groups (16% of infants receiving extended nevirapine vs 15% of controls had
serious adverse events). This result indicates extending nevirapine prophylaxis up to 6 months of age has 54% reduction in HIV transmission and safe to be used in infants.6
Fantaye, Gedamneh 15
Table 3: Cumulative incidence of HIV-infection or death in infants uninfected at age 6
weeks.
To determine the optimal time to start HAART to prevent MTCT, one retrospective cohort analysis were conducted by Chibwesha et al. at Lusaka, Zambia.1 Women on HAART whose infants been PCR tested between 3-12 weeks of life were included on
this analysis. The duration on HAART was categorized as < 4 weeks, 5-8 weeks, 9-12
weeks, or >13 weeks prior to delivery. And Infant HIV assessed using Abbott M2000 assay PCR on dried blood spots.1 In the 3 years period of the study in the clinics, 4254 live birth were recorded from HIV infected mother on HAART. Out of this, 1813
mother-infant pair met the inclusion criteria for the analysis. And the result indicated that
the odd of mother to child transmission markedly elevated in those women categorized
< 4 weeks or fewer weeks compared to at least 13 weeks on HAART prior to delivery(
OR 4.3; 95% CI 2.3-8.1). The locally generated weighted regression line( as shown in
figure 2 below) indicated that a 14% (OR 0.86; 95% CI 0.77-0.96) reduction in MTCT for
Fantaye, Gedamneh 16 women on HAART for fewer than 13 weeks for each additional week on HAART prior to
delivery. But limited benefit beyond 13 weeks on HAART prior to delivery was seen from the locally generated weighted regression line.1
Figure 2: Probability of transmission
Beside determining the optimal time to start HAART, the same study by Chibwesha et al
conducted univariable analysis on education status, hemoglobin concentration, CD4 count, and
maternal syphilis screen result on MTCT. And the univariable analysis indicated elevated odd of
transmission among women of unknown education status(OR 2.3; 95% CI 1.1-4.8), hemoglobin concentration <8-9.9 g/dL(OR 2.5; 95% CI 1.2-5.0), CD4 cell count<200 cells/uL( OR 3.5; 95% CI 1.2-10.2), and positive syphilis screen result( OR 4.4; 95% CI 1.7-11.9)1
Fantaye, Gedamneh 17 In another study by Shapiro et al. of HAART in prevention of MTCT during pregnancy and breastfeeding and also 24 month survival was studied at Botswana, Africa.4 The study was a randomized trial of assing women in two randomized arms(arm A and arm B) and one
observational arms depending on CD4 and AIDS defining illness. Arm A receive
abacavir(300mg)/zidovudine(300mg)/lamivudine(150mg) twice daily and arm B receive
lopinavir(400mg)/ritonavir(100mg)/zidovudine(300mg). For both arm A and B HAART started
between 26-34 weeks and continued through weaning or 6 months postpartum. Inclusion
criteria for the randomized arm of the study was CD4>200 and no AIDS defining illness where
as CD4<200 or AIDS defining illness assigned to the observation arm. A total of 730 women
participated in the study. 285 in arm A, 275 in arm B, and 170 in observational arm. Women in
all arms were counseled to exclusively to breastfeed to 6 months. Infants were enrolled and
evaluated at birth and HIV DNA PCR tested at birth, 1,6, 12 months, and HIV ELISA at 18
months. Poisson regression and kaplan-meier estimator were used to analyze event rate and
time-to-event respectively. The result of the study indicated out of the 709 live born infants, 24
month survival was available for 691(97%) children. 687(97%) out of the 709 live born infants
were breastfed. Form this breastfed, 173(25%) stopped prior to 5 months and only 3(1%) was
breastfed beyond 7 month. 1 child reported positive from breast milk at 18 month ELISA test
while it turn to be negative on the subsequent ELISA test. During the study period, 37 child were
died. 9 children before breastfeeding started, 6 during breastfeeding, and the other 22 post
weaning. There is no statistically significant difference in child survival among the assigned
arms(p=0.71 between randomized arms and p=0.69 between randomized and observational
arm). However, the study found statistically significant difference in child mortality during
breastfeeding period, 3 months post weaning, and beyond 3 months post weaning. Child
mortality was 2.1/100 person-years for breastfeeding period compare with 7.9/100 person-years
Fantaye, Gedamneh 18 for 3 months post weaning(RR=3.7, 95% CI=1.3,12.0; p=0.007). And child mortality decline to
1.0/100 person-years for beyond 3 months post weaning compared with 3 months post weaning(RR=7.5, 95% CI=3.2, 18.4; p<0.001)4
Non-pharmacological
Breastfeeding, HIV CARE 2,5
As far as effective non-pharmacological use to prevent HIV transmission from mother to
child is encouraging HIV-positive mothers to practice exclusive breastfeeding for the first 6
months. A study conducted by Okanda in the Kisumu Breastfeeding Study trial in Kenya
analyzes the rate of adherence to exclusive breastfeeding for the first 6 months postpartum
while receiving antiretroviral therapy. The enrolled 522 HIV-infected pregnant women received
nutrition and infant feeding counseling. And 491 women delivered 502 live infants. The majority
of the participant (43%) were between 20-24 years, 74% married, 72% completed primary
education. The result indicated 80.4% of the participant exclusively breastfed at 5.25 months
postpartum. 89.8% of women who had 3 and more children breastfeed compared to 77.4% for
women who had less than 3 children(p<0.001). In addition the study found single mothers
breastfed more than mother living with the children father. And also female child more breastfed than male child(84.5% vs 76.9%, p=0.04)2 In another study by Washington et al at Nyanza, Kenya was conducted to see the effect of
integration HIV care at antenatal clinic to see infants outcome. The study was a clustered
randomized trial into 2 arms- integrated and control arms. 1172 HIV positive pregnant women
older than 18 years of ages were participated in the study. From this. 569 were assigned at the
integrated arm whereas 603 on the control arm. The result was interpreted by blind investigator.
Fantaye, Gedamneh 19 The result indicated slight number of infants turned to be positive on the integrated arm compared with the control arm at 6 weeks PCR test however it was not statistically significant. 5
Fantaye, Gedamneh 20
Discussion
The research question that was being investigated was if there are any changes in HIV
transmission from mother to child with the use of HAART. On the other hand, the hypothesis guiding the study was the transmission of HIV from mother to a child during delivery and while breast feeding can be avoided if the mother viral load was controlled
well using HAART. The findings from the study confirms this hypothesis. The findings
depicts that there exists lack of enough literature on the question conducted in the United States. All of the studies and trials reviewed for this topic were done in resource-limited settings. In some of the studies, the health-care facility did not have the
equipment to check the mothers viral load while on ART treatment which is a valuable
information missing to support my hypothesis. Instead, most of the studies provided
CD4 counts of the patients. Of the studies that provided Viral load, the results supported
the hypothesis that pregnant mothers with low viral load has lower percentage of
HIV-transmission rate from mother to child. Other limitations would be patients’ lack of
access to some medications such as zidovudine. In some of the studies, they did not
least the name of medications and dosing given to pregnant mothers. It is vital to know
which medication is given because certain medications such as Efavirenz should be
avoided in pregnant women. Efavirenz has been associated with neural tube defects in
the first trimester, in some but not all studies.
In addition to the supported hypothesis, the research indicates there are also
other contributions in reducing transmission: infant prophylaxis, exclusive breastfeeding
while on ART treatment for 6 months, and access to HIV care clinic. Although
Fantaye, Gedamneh 21 breastfeeding is not recommended in the USA, it is recommended in resource limited
settings due being prefered over lack of clean water. There had been infants infected
after 6 months postpartum which is believed to be due late infection caused by
unreported continued breastfeeding. Further studies are still need to determine the most
appropriate strategy regarding recommendation of either triple ARVs or infant receiving
ARV prophylaxis, and optimal length of breastfeeding. The long term effect of HAART
on child neurodevelopment was been studied and no effect on child neurodevelopment
was found.
For effective benefit of HAART for reducing transmission from mother-to child,
the time to start treatment prior to delivery also has effect. A maximized benefit were
observed starting HAART 13 weeks prior to delivery. In addition, maternal
socioeconamic status and othersexual transmission diseas also implicated in the
successful prevention of maternal to child transmission
The limitation observed in this review include a higher attrition rate in participant in the
randomized trials and lack of exact timing when they start treatment in the
meta-analysis data.
Fantaye, Gedamneh 22
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