HIV Infections Clinical Trial
Official title:
Presumptive and Definitive Virologic HIV Diagnosis in Hospitalized Malawian Infants
Purpose: The purpose of this research study is to learn about two HIV tests - a clinical
"presumptive diagnosis" (PD) that a trained healthcare provider can quickly use to determine
if a child is likely to be HIV-infected and in need of HIV medicines and an "expedited" gold
standard RNA-PCR test (expedited PCR) that is done at the UNC Project lab located at the
hospital and the result given within 48 hours. Both of these tests can obtain results
quickly while the current test called dried blood spot DNA-PCR goes to a lab and the result
may take up to one month. The performance of PD and expedited PCR will be compared to one
another with respect to HIV-infected infants correctly initiating life-saving antiretroviral
therapy.
Participants: Hospitalized children younger than 12 months of age who are HIV DNA-PCR
eligible at Kamuzu Central Hospital (KCH), in Lilongwe, Malawi. Other participants will be
patient caregivers and clinical officers who provide healthcare for children that could be
HIV-infected. Clinical officers will be trained to conduct the presumptive diagnosis test.
Procedures (methods): Patients will be randomized to either standard of care (PD and dried
blood spot DNA-PCR) or expedited PCR. A consultant pediatrician and a clinical officer will
perform the PD. If the PD or expedited PCR test results are positive, hospital care could
include HIV medicine.
Background A majority of HIV-infected children die by two years of age without
antiretroviral therapy (ART). Unfortunately, diagnosing HIV in this age group is complex as
it requires virologic testing. This has served as a barrier to younger HIV-infected (HIV+)
children accessing ART in resource-constrained generalized epidemic countries. Malawi, a
high HIV-prevalence country in sub-Saharan Africa, implemented a national early infant
diagnosis (EID) program utilizing virologic testing with dried blood spots (DBS) DNA PCR
technology in 2007 to address this gap.
In coordination with the national EID program in 2008, we implemented a routine HIV testing
strategy within the pediatric inpatient ward at Kamuzu Central Hospital (KCH) that
incorporated DBS. While our initial program results have been encouraging, we have observed
that only 50.2% of DBS recipients have returned for their test results after hospital
discharge, draining resources and reducing the potential impact of definitive virologic
testing and early diagnosis. DBS technology is a contributing factor to low patient
follow-up as it requires burdensome transport and lengthy processing by highly trained
laboratory personnel, requiring patients to return several weeks after testing for their
results. Currently in Malawi, as is the case throughout sub-Saharan Africa, definitive
virologic testing that provides test results prior to hospital discharge is not routinely
available.
Two alternatives that could potentially strengthen EID and pediatric ART access are the
routine use of presumptive diagnosis (PD), or a clinical HIV diagnostic algorithm in young
children, as an adjunct to DBS and definitive inpatient virologic testing that provides
results before hospital discharge ("expedited PCR") instead of PD and DBS. This research
proposal primarily aims to validate PD testing as well as assess the impact of PD and
expedited PCR upon patient outcomes within the established inpatient pediatric HIV testing
system at KCH.
RESEARCH QUESTION TO BE ADDRESSED BY THIS PROPOSAL Is presumptive diagnosis, as an adjunct
to dried blood spot DNA PCR, a valid approach for diagnosing HIV in hospitalized Malawian
children younger than 12 months of age, and how does this strategy, compared to an expedited
inpatient virologic diagnosis, affect patient outcomes?
RATIONALE FOR RESEARCH
Globally, an estimated 2.2 million children younger than 15 years of age were HIV-infected
in 2007, with approximately 90% living in sub-Saharan Africa. Malawi, a sub-Saharan African
country of 13.2 million people, reports an adult HIV prevalence of 11.9%. While 91,000 HIV+
children were estimated to be living in Malawi in 2007, less than 8% of all Malawian
children have ever been HIV tested. Additionally, HIV+ children comprised just 8% of all
national ART recipients, well below the 2014 goal of 15%. To address this gap, Malawi
approved the routine offering of HIV testing, or provider initiated HIV testing and
counseling (PITC), in line with global recommendations in 2007. While there is a high HIV
prevalence in hospitalized Malawian children and current guidelines support routine
inpatient HIV testing, no clear implementation strategy for hospitals has been offered.
Substantial percentages of HIV+ infants suffer from high mortality without early infant
diagnosis (EID) and ART initiation, irrespective of CD4%, leading to the recommendation that
all HIV+ children younger than 1 year of age should be universally initiated on ART. Despite
the simplification of ART eligibility in this age group, diagnosing HIV remains complex.
Maternal HIV antibodies can circulate in the blood stream of children until 12 months of
age, confounding HIV antibody test results unable to discriminate between the mother's and
child's antibodies. Accordingly, DNA PCR testing that detects HIV proviral DNA is the gold
standard for HIV diagnosis in this age group. To date the PCR technology utilized in EID
programs throughout sub-Saharan Africa, including Malawi, is DBS. Malawi piloted an EID
program starting in 2007 and approved a policy of universal ART for all HIV+ children
younger than 1 year of age in 2008. In Malawi, a uniform first line fixed-dose combination
ART regimen of stavudine, lamivudine, and nevirapine is provided free of charge by the
Malawian government for all eligible patients.The EID program has since expanded to 14 of 28
districts. Importantly, the national EID program identified the pediatric inpatient wards as
a critical access point for routine DBS testing, but recently reported that few EID sites
have established routine inpatient testing programs.
KCH is a referral hospital with a 215 bed pediatric ward located in the capital of Lilongwe
with more than 10,000 pediatric admissions annually. In 2007, less than 10% of pediatric
inpatients at KCH were estimated to have accessed voluntary HIV counseling and testing (VCT)
services offered by lay counselors (Pediatric Department, KCH, unpublished data). In January
2008, we implemented a PITC program utilizing DBS testing in the KCH inpatient pediatric
department in collaboration with the Baylor International Pediatric AIDS Initiative (BIPAI),
KCH, and Lighthouse. The overall program objectives were to improve inpatient pediatric HIV
diagnosis and care, establish EID as a routine inpatient service, and provide national
guidance for inpatient pediatric PITC program expansion.
Over the first 12 months of implementation, the PITC program offered HIV testing to 45.2% of
admissions, or 10,245 mothers and their hospitalized children, representing a four-fold
increase in comparison to pre-PITC estimates1. 98.7% of mother-child pairs accepted testing,
and we observed the HIV prevalence of hospitalized children to be 8.5%, nearly two-fold
higher than the estimated community pediatric prevalence of 4.8% in Malawi. Furthermore,
73.9% of HIV+ hospitalized children had not yet accessed ART , despite over 70% of these
patients clinically or immunologically eligible. The program also completed 476 DBS tests
during the same time period, representing the highest volume EID site in Malawi, with 40.1%
testing positive.
Unfortunately, only 239 DBS recipients, or 50.2% of children tested, enrolled into
outpatient care at the Baylor College of Medicine-Abbott Fund Children's Clinical Centre of
Excellence clinic at KCH. Of these, 48.3% were initiated on ART a median of 2.4 months after
DBS collection. Low follow-up has been experienced at other EID sites throughout Malawi. One
contributing factor is the several weeks of processing time required for DBS samples. In
Malawi, DBS tests are transported to and from central laboratories to be processed in higher
volumes by sophisticated equipment and highly specialized laboratory personnel. Therefore,
counselors instruct caregivers to return in at least one month for their child's DBS test
results. If caregivers return for their child's results, they are then commonly re-referred
for HIV care at another site, often at an even later date, further delaying evaluation for
ART eligibility. Currently, a similar system exists at KCH. Despite substantial investment
into EID, the processing and transport delays inherent to DBS have lessened the impact of
EID and have resulted in a continued barrier to pediatric ART access in this age group.
Two diagnostic alternatives that could reduce the delays complicating the current DBS
systems are PD and point of care virologic testing. While PD is a less sensitive and
specific diagnostic alternative to PCR, it requires limited resources and provides a
strategy to immediately offer ART to hospitalized patients that fulfill PD criteria,
avoiding the one-month wait time and resultant losses to follow-up. Malawi National
guidelines recommend the use of PD to identify and initiate symptomatic HIV+ infants younger
than 12 months of age on ART when PCR is unavailable. While the sensitivity and specificity
of PD has been previously reported from Rwanda and Kenya, these studies are only partly
applicable to Malawi due to the lower estimated malaria burdens in Rwandese children, and
the mixture of inpatients and outpatients within the Kenyan study cohort. Both scenarios are
likely to alter the reported sensitivities and specificities of PD as compared to Malawi,
justifying the need to generate locally applicable data. To date, PD has not been widely
practiced in Malawi, and data generated from this research could provide guidance to
increase the usefulness of PD. The primary limitation to PD is that HIV-uninfected patients
could be incorrectly started on ART. However, it is possible that such patients might still
experience lower mortality and HIV transmission rates, with little adverse effects, as
suggested by the recent outcomes of extended post-natal antiretroviral prophylaxis studies.
Point of care virologic testing, on the other hand, has the potential to revolutionize
pediatric HIV care as HIV+ hospitalized infants could receive same day, accurate diagnostic
results, allowing immediate evaluation for ART eligibility and initiation. While no point of
care virologic test has yet been approved for routine use, the enhanced laboratory services
available at University of North Carolina Project (UNC Project) can offer HIV RNA PCR test
results in less than 48 hours. "Expedited" virologic testing is likely to provide definitive
HIV test results to nearly all hospitalized HIV-exposed infants prior to discharge,
therefore replicating the affect that point of care virologic testing will produce in the
hospitalized setting. Understanding how expedited PCR testing affects inpatient ART uptake,
outpatient follow-up, and longer term outcomes, compared to the current standard of care,
will be critical for further system development and strengthening in anticipation of future
point of care test availability.
This research proposal seeks to utilize the current inpatient pediatric PITC system
established at KCH to validate PD within the hospital setting, as well as investigate
patient outcomes utilizing current EID standard of care (PD and DBS) compared to expedited
PCR.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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