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Early Infant Diagnosis HIV-1 PCR Cycle-threshold Predicts Infant Viral Load at Birth
Abstract
Background:
HIV-1 viral load (VL) has been found to be an independent predictor for disease progression among untreated HIV-infected children. However, qualitative polymerase chain reaction (PCR) assays are routinely used for early infant diagnosis (EID).
Objectives:
To predict HIV-1 VL at birth using qualitative EID real-time PCR cycle-threshold (Ct) values.
Study design:
This study was a secondary analysis of results from a cohort of intrauterine HIV-1 infected neonates. Neonates were enrolled at Rahima Moosa Mother & Child Hospital in Johannesburg, South Africa between June 2014 and November 2017. Laboratory EID HIV-1 PCR testing was performed at birth using COBAS AmpliPrep/COBAS TaqMan HIV-1 Qualitative Test v2.0 (EID CAP/CTM). Some infants had simultaneous EID point-of-care (POC) testing using Xpert HIV-1 Qualitative assay (EID Xpert). Neonates with a confirmed HIV-1 detected EID result and plasma HIV-1 RNA VL test were included in this analysis. Bland-Altman analysis was used to determine extent of agreement between Ct values of both EID assays. Multivariable linear regression models adjusting for time between EID and VL testing were used to describe the association between EID Ct values and VL and to predict VL at given EID Ct values.
Results:
Among 107 HIV-1 infected neonates included in the study, 59 had POC EID testing. Median VL was 28 400 copies per millilitre (cps/ml) (IQR: 1 918-218 358) - two neonates had VL < 100 cps/ml prior to antiretroviral therapy initiation. There was good correlation between Ct values of both EID assays (Spearman correlation coefficient 0.9, 95% CI: 0.8-1.0). The limits of agreement between EID CAP/CTM and Xpert Ct values were 4-11 cycles. For every one cycle increase in Ct value there was 0.3 log10 RNA decrease (95% CI: -0.3 to -0.2) for both EID assays. An EID CAP/CTM Ct value ≤ 23 and an EID Xpert Ct value ≤ 31 predicted a VL of > 5.0 log10 cps/ml in 82.2% (95% CI: 73.9-88.3) and 84.7% (95% CI: 73.7-91.8) of cases, respectively.
Conclusion:
EID Ct values at birth predict VL and accurately identify infants with VL > 5.0 log10 cps/ml.
... Proposed indeterminate cutoff criteria are based on laboratory findings of poor positive predictive value and irreproducible positive results associated with higher cycle threshold values of real-time PCR assays 34 . The cycle threshold refers to the number of thermal cycles required for the fluorescence signal to cross the assay's diagnostic intensity threshold and therefore should be inversely proportional to the amount of target nucleic acid present in the specimen tested 35 . However, whereas during the pre-ART era HIV-infected infants usually had high-level viremia, making a diagnosis straightforward 36 , there has been a significant decrease in pre-treatment viral load associated with PMTCT practices 37 . ...
... However, whereas during the pre-ART era HIV-infected infants usually had high-level viremia, making a diagnosis straightforward 36 , there has been a significant decrease in pre-treatment viral load associated with PMTCT practices 37 . Hence, HIV-infected infants increasingly present for testing with low-level viremia and may even be aviremic 35 . This in turn can result in a high number of HIV-infected infants who test indeterminate; South Africa reported around 3000 indeterminate results per annum between 2013 and 2015 38 , and birth cohorts found that half of infants with an indeterminate result were HIV-infected 29,39 . ...
Early diagnosis of HIV infection among infants and children is critical as prompt initiation of antiretroviral therapy prevents morbidity and death. Yet despite advances in the accuracy and availability of infant HIV diagnostic testing, there are increasing challenges with making an early definitive diagnosis. These challenges relate primarily to advances in prevention of mother-to-child transmission (PMTCT) of HIV. Although PMTCT programs have proven to be highly effective in reducing infant HIV infection, infants who are HIV-infected may achieve virological suppression and loss of detectability of HIV nucleic acid prior to diagnosis because of antiretroviral drug exposure. Hence, false-negative and indeterminate HIV polymerase chain reaction (PCR) results can occur, especially among high-risk infants given multi-drug prophylactic regimens. However, the infant HIV diagnostic landscape is also complicated by the inevitable decline in the positive predictive value of early infant diagnosis (EID) assays. As PMTCT programs successfully reduce the mother-to-child transmission rate, the proportion of false-positive EID results will increase. Consequently, false-negative and false-positive HIV PCR results are increasingly likely despite highly accurate diagnostic assays. The problem is compounded by the seemingly intractable prevalence of maternal HIV within some settings, resulting in a considerable absolute burden of HIV-infected infants despite a low mother-to-child transmission rate.
... This strategy entails providing ART to HIV-infected pregnant women, irrespective of the CD4 cell (T cell) count [10][11][12]. The WHO also recommends early detection of exposed infants using virological polymerase chain reaction (DNA-PCR) testing beginning at 6 weeks after birth to better tailor Infant exposed to HIV follow-up [13][14][15]. Some countries in Asia and sub-Saharan Africa have adopted this approach to enhance the performance of PMTCT programs [11,16,17]. ...
Introduction
Vertical transmission of HIV remains a major challenge in Guinea, especially, in low-resource rural areas. This paper presents the results of a pilot project designed to enhance the prevention of vertical transmission through a comprehensive improvement plan implemented across 66 large-cohort sites.
Methods
Data from 66 large-cohort of mother to child transmission prevention (PMTCT) sites from 2019 to 2022 were analysed to compare PMTCT metrics before (2019–2020) and after (2021–2022) the improvement initiative. Key indicators were reviewed, and trends were statistically analysed using Mann‒Whitney tests, with a p value less than 0.05 indicating statistical significance.
Results
The implementation of this strategy significantly increased the antiretroviral therapy rate among HIV-positive pregnant women from 66 to 94%, and full antiretroviral prophylaxis coverage was achieved in infants. However, early infant diagnosis via polymerase chain reaction testing falls short of the national target, highlighting deficiencies in laboratory and specimen transport capacities. The study also revealed regional disparities in the use of PMTCT services.
Conclusion
The improvement plan effectively enhanced antiretroviral therapy and prophylaxis use, demonstrating the benefits of structured interventions and capacity development. Despite improvements, challenges such as insufficient polymerase chain reaction (PCR) testing and uneven access to services remain. Future initiatives should aim to equip PMTCT sites with essential resources and promote community-driven health-seeking behaviours in underserved areas.
... This strategy entails providing ART to HIV-infected pregnant women, irrespective of the CD4 cell (T cell) count [10][11][12]. The World Health Organization also recommends early detection of exposed infants using virological polymerase chain reaction (DNA-PCR) testing beginning at 6 weeks after birth to better tailor their follow-up [13][14][15]. Some countries in Asia and sub-Saharan Africa have adopted this approach to enhance the performance of PMTCT programmes [11,16,17]. ...
Introduction
This study assessed the prevention of mother‒to‒child transmission (PMTCT) in Guinea, focusing on the impact of the World Health Organization’s Option B + strategy for human immunodeficiency virus. This pilot study, conducted across 66 high-burden PMTCT sites, aimed to enhance service accessibility and utilization. The study evaluated the indicators of the mother-to-child transmission of human immunodeficiency virus before and after the implementation of the Option B + strategic plan.
Methods
Data from 66 large-cohort PMTCT sites from 2019 to 2022 were analysed to compare PMTCT metrics before (2019–2020) and after (2021–2022) the improvement initiative. Key indicators were reviewed, and trends were statistically analysed using Mann‒Whitney tests, with a p value less than 0.05 indicating statistical significance.
Results
The implementation of the strategy significantly increased the antiretroviral therapy rate among HIV-positive pregnant women from 66–94%, and full antiretroviral prophylaxis coverage was achieved in infants. However, early infant diagnosis via polymerase chain reaction testing fell short of the national target, highlighting deficiencies in laboratory and specimen transport capacities. The study also revealed regional disparities in the use of PMTCT services.
Conclusion
The improvement plan effectively enhanced antiretroviral therapy and prophylaxis use, demonstrating the benefits of structured interventions and capacity development. Despite improvements, challenges such as insufficient polymerase chain reaction (PCR) testing and uneven access to services remain. Future initiatives should aim to equip PMTCT sites with essential resources and promote community-driven health-seeking behaviours in underserved areas.
... Our findings concur with previously published studies. Importantly, the Ct value of an EID PCR result is inversely proportion to the plasma HIV viral load [23]. Hence, HIV-infected infants who have low-level viraemia will invariably have a high Ct value and therefore their HIV PCR results will likely be verified as indeterminate. ...
Objectives
We describe extent of, and variables associated with indeterminate HIV-PCR results and final HIV-status within South Africa’s early infant diagnosis (EID) programme between 2010–2019.
Methods
Retrospective analysis of routine paediatric HIV-PCR laboratory data from South Africa’s National Health Laboratory Service Data Warehouse between 2010–2019. Final HIV status was determined by linking patient results (including HIV-PCR, HIV viral load, HIV serology and CD4 counts) using a probabilistic matching algorithm. Multivariate logistic regression was performed to determine variables associated with final HIV-status among patients with an indeterminate HIV-PCR result.
Results
Among 4 429 742 specimens registered for HIV-PCR testing from 3 816 166 patients, 113 209 (2.97%) tested positive and 22 899 (0.6%) tested indeterminate. As a proportion of HIV-detected results, 15.7% (23 896/151 832) of total and 31.5% (4 900/15 566), 18.8% (11 400/60 794) and 10.1% (7 596/75 472) among patients aged <7 days, 7 days–3 months and ≥3 months, respectively, were reported as indeterminate. Overall, 39.7% of patients with an indeterminate result had a linked HIV test to determine HIV-status, of which 53.6% were positive with a median time to repeat testing of 30 days (IQR: 15–69). Among patients who tested indeterminate, variables associated with a significantly higher odds of having a positive HIV-status included testing indeterminate at birth (AOR: 0.63 [0.48-0.83] and 0.52 [0.39-0.69] for testing indeterminate at 7 days–3 months and ≥3 months respectively compared to birth), within a hospital (AOR: 2.45 [1.99-3.03]), and in districts with an IU-transmission rate ≥1.1% (AOR: 3.14 [1.84-5.35]) (P<0.001).
Conclusions
Indeterminate HIV-PCR results represent a considerable burden of missed diagnostic opportunities, diagnostic dilemmas and delays in making a definite diagnosis among HIV-infected infants within South Africa’s EID programme. Alternative EID verification practices are urgently needed.
Purpose
The Rahima Moosa Mother and Child Hospital (RMMCH) maternal HIV cohort originated from data systems that were developed to support HIV-related birth care and track outcomes of a complete birth cohort of HIV-exposed infants at Rahima Moosa Hospital and their mothers living with HIV.
Participants
Supported by the Empilweni Services and Research Unit, maternal and infant data from 13 654 pregnant women living with HIV who delivered their infants (and a subset also attended antenatal care) were collected at RMMCH in Johannesburg, South Africa since 2013. Maternal data were collected using counsellor-administered interviews and the 2013–2018 subset of this cohort was linked to the National Health Laboratory Services (NHLS) national HIV cohort—a longitudinal cohort of people living with HIV accessing care in the public sector antiretroviral therapy programme in South Africa that can observe national access to HIV care through laboratory testing data.
Findings to date
Topics addressed by the cohort include antenatal care history, HIV treatment exposure, delivery/birth management, prophylaxis and maternal blood results relevant to HIV captured at delivery. The cohort was also one of the first to describe implementation of early infant diagnosis procedures in South Africa including evaluations of novel point-of-care testing strategies demonstrating improvements in uptake of HIV care among infants accessing point-of-care services.
Future plans
Annual linkage of infant delivery and testing data to longitudinal laboratory test data in the NHLS national HIV cohort is planned to allow for analysis of both infant continuity of care outcomes and as well as evaluation of maternal-infant pair treatment and mobility outcomes in the post partum and later period.
Introduction: HIV-1 polymerase chain reaction (PCR) testing at birth aims to facilitate earlier initiation of antiretroviral therapy (ART) for HIV-infected neonates. Data from two years of universal birth testing implementation in a high-burden South African urban setting are presented to demonstrate the prevalence and outcomes of diagnostic challenges in this context.
Methods: HIV-exposed neonates born at Rahima Moosa Mother and Child Hospital between 5 June 2014 and 31 August 2016 were routinely screened at birth for HIV-1 on whole blood samples using the COBAS® AmpliPrep/COBAS® TaqMan (CAP/CTM) HIV-1 Qualitative Test, version 2.0 (Roche Molecular Systems, Inc., Branchburg, NJ, USA). Virological results were interpreted according to standard operating procedures with the South African National Health Laboratory Service. All neonates with non-negative results were actively followed-up and categorized according to HIV infection status as positive, negative, uncertain and lost to follow-up (LTFU).
Results: 104 (1.8%) of 5743 HIV-exposed neonates received a non-negative birth PCR result, for which laboratory data were available for 102 (98%) cases – 78 (76%) tested positive and 24 (24%) indeterminate. HIV infection status was confirmed positive in 83 (81%) infants, negative in 8 (8%), uncertain in 5 (5%) and LTFU in 6 (6%) cases. The positive predictive value (excluding cases of uncertain diagnosis and inadequate testing) following a non-negative HIV-1 PCR screening test at birth was 0.91 (83/91; 95% confidence interval: 0.85–0.96). Neonates testing positive at birth had significantly higher viral load (VL) results than those testing indeterminate at birth of 4.5 and 3.0 log copies/ml (p = 0.0007), respectively. Similarly, mothers of neonates with positive as compared to indeterminate birth test results had higher VLs of 4.5 and 2.7 log copies/ml (p = 0.0013), respectively. Half of neonates with an indeterminate birth test were shown to be HIV-infected on subsequent confirmatory testing, with time to final diagnosis 30 days longer for these neonates (p
Background:
Outcomes of HIV-infected children before widespread use of antiretroviral therapy (ART) for treatment and prevention of mother-to-child transmission (PMTCT) have been well characterized but less is known about children who acquire HIV infection in the context of good ART access.
Methods:
We enrolled newly-diagnosed HIV-infected children <24 months (mos) of age at 3 hospitals and 2 clinics in Johannesburg, South Africa. We report ART initiation and mortality rates during 6 months from enrollment and factors associated with mortality.
Results:
Of 272 children enrolled, median age 6.1mos, 69.5% were diagnosed during hospitalization. By 6mos post-enrollment, 53(19.5%) died and 73(26.8%) were lost-to-follow-up. Using Kaplan-Meier analysis, the probability of death by 6mos after enrollment was 23.5%. The median age of death was 9.1mos (95% confidence interval[CI]: 8.6; 12.0). Overall, 226(83%) children initiated ART which was associated with a 71% reduction in risk of death (Hazard Ratio[HR] =0.29 [95%CI: 0.15; 0.58]). In multivariable analysis of infant factors, weight-for-age z-score <-2SD (HR=2.43[95%CI: 1.03-5.73]), CD4<20% (HR=3.29[95%CI: 1.60-6.76]) and identification during hospitalization (HR=2.89[95%CI: 1.16-7.25]) were independently associated with mortality. In multivariable analysis of maternal factors, CD4≤350/no maternal ART was associated with increased mortality risk (HR=2.57[95%CI: 1.19-5.59]) vs. CD4>350/no maternal ART; exposure to maternal/infant antiretrovirals for PMTCT was associated with reduced mortality risk (HR=0.53[95%CI: 0.28-0.99]) vs. no PMTCT.
Conclusions:
ART initiation is highly protective against death in young children. However, despite improved access to ART, young children remain at risk for early death; innovative approaches to rapidly diagnose and initiate treatment as early in life as possible are needed.
The standard prophylactic regimen used as antiretroviral therapy (ART) for infants born to mothers in high-income and middle-income countries who are infected with human immunodeficiency virus (HIV) infection has been a 6-week course of zidovudine. Randomized controlled trials investigating postexposure prophylaxis for infants born to late-presenting women infected with HIV who did not receive ART in pregnancy have been conducted in breast-fed populations but not in non–breast-fed populations. Several trials showed that prophylaxis with combination ART (zidovudine plus ≥1 antiretroviral drugs) was effective in reducing viral transmission in high-risk breast-fed populations in low-income countries. However, it is unclear whether prophylaxis with combination ART would prevent intrapartum HIV-1 transmission in non–breast-fed infants of women who had not received antenatal ART. This randomized controlled study compared the efficacy and safety of ART prophylactic regimens in a population of solely formula-fed infants whose mothers had not received ART during pregnancy. In designing the study, the authors hypothesized that a 3-drug ART regimen would confer a higher level of protection against intrapartum HIV transmission than a 2-drug regimen. Both regimens were evaluated in this study. Formula-fed infants exposed to HIV-1 were randomly assigned to 1 of 3 ART regimens within 48 hours after birth. Infants in each of the 3 groups received zidovudine for 6 weeks. The first group was given only zidovudine (zidovudine-alone group, n = 566). In addition to zidovudine, the second group received 3 doses of nevirapine during the first 8 days of life (2-drug group, n = 562). The third group received zidovudine plus nelfinavir and lamivudine for 2 weeks (3-drug group, n = 556). The primary study outcome was HIV-1 infection at 3 months of age among infants uninfected at birth. The Kaplan-Meier method was used to estimate transmission rates. The study population included 1684 infants enrolled between 2004 and 2010 at 17 sites in Brazil, Argentina, the United States, and South Africa. The overall rate of in utero transmission of HIV-1 was 5.7% (93 infants); there were no significant differences among the groups. At 3 months, the overall rate of intrapartum transmission was 3.2%. Compared with the zidovudine-alone group, intrapartum transmission at 3 months was reduced by half in the 2- and 3-drug groups: The rate was 4.8% (24 infants) in the zidovudine-alone group versus 2.2% (11 infants) in the 2-drug group and 2.4% (12 infants) in the 3-drug group (P = 0.046 for both comparisons). The overall rate of HIV-1 infection in utero or intrapartum was 8.3% (140 infants). Transmission of infection was higher in the zidovudine-alone group (11.0%, 61 infants) than in the 2-drug group (7.1%, 39 infants) or the 3-drug group (7.4%, 40 infants); P = 0.03 for both comparisons. Multivariate analysis showed that zidovudine monotherapy, a higher maternal viral load at delivery, and maternal use of illegal substances during pregnancy were independent risk factors for transmission. Neutropenia occurred in 27.5% of infants in the 3-drug group versus 14.9% in the 2-drug group and 16.4% in the zidovudine-alone group (P < 0.001 for both comparisons). These findings support the prophylactic use of both the 2- and 3-drug combination ART regimens instead of zidovudine alone to prevent intrapartum HIV transmission in neonates whose mothers did not receive ART during pregnancy. However, the 3-drug regimen has more toxicity than the 2-drug regimen.
Nucleic acid detection for HIV-1 diagnosis, is strongly recommended in infants < 18 months in whom serology is unreliable. This study evaluated the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Qualitative Test, version 2.0 (TaqMan® HIV-1 Qual Test version 2.0), a dual-target total nucleic acid real-time PCR assay.
The limit of detection (LOD) of the new test in plasma and dried blood spots (DBS) was determined with the 2nd International HIV-1 RNA WHO Standard. The specificity of the assay was tested with EDTA Plasma (n=1301) and DBS from HIV-negative adults (n=1000). The sensitivity was determined using HIV-1 positive samples (n=169 adult EDTA Plasma, n=172 adult DBS, and 100 infant DBS) that included Group M, Subtypes A-H, CRF01_AE, CRF02_AG, and Groups O and N. All positive specimens and a subset of the negative specimens were also tested with the Abbott RealTi
m
e HIV-1 Qual assay (RealTi
m
e).
The LOD of the TaqMan® assay was 20 copies/mL in plasma and 300 copies/mL in DBS, with a specificity of 99.8% in plasma and 99.9% in DBS. TaqMan® assay was 100% concordant with RealTi
m
e in EDTA plasma samples and in 100 HIV-1 negative adult DBS. Out of 172 HIV-1 positive DBS from adults, the TaqMan® assay showed positive results for all DBS while RealTi
m
e missed five low-target DBS. Infant DBS results were 100% concordant.
The improved sensitivity of the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Qualitative Test, version 2.0, compared to current commercially available assays may enable earlier diagnosis and treatment in adults and infants. The dual target test may ensure HIV-1 detection even if a mutation in one of the two target regions is present. DBS sample matrix facilitates virological testing in remote areas.
Background Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. Methods We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. Findings 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. Interpretation This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.
Objective:
To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa.
Design:
This was a programmatic cohort study.
Methods:
Electronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t-test and Kaplan-Meier methods.
Results:
A total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2-9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% <25% or absolute CD4<1500 cells/mm(3) or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2-11.9) weeks in Cape Town and 8.6 (IQR: 7.7-10.0) weeks in Soweto infants (p<0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (p<0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36-0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05-2.71).
Conclusions:
ART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality.
Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored
sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%)
died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL,
and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was > 100,000 copies/mL
(95% confidence interval [CI], 1.4–3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2–4.0). If RNA levels
increased after baseline, the RR was 1.8 (95% CI, 1.3–2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95%
CI, 1.6–4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality
risk. In a time-dependent model, the RR per log10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1–3.6) and per 5 percentage
point decrement in CD4 cell percent was 1.3 (95% CI, 1.2–1.5). Both variables should be considered for in decision-making
regarding therapy and evaluation of antiretroviral response.
Background. The performance of ultra-sensitive, quantitative assays in the diagnosis of perinatal HIV has not been documented in a population with low perinatal transmission due to use of antiretroviral therapy. Methods: We studied 205 plasma samples from 71 perinatally-exposed infants for HIV diagnosis using a quantitative branched DNA (bDNA) assay with a detection range of 75-500,000 copies/mL. Results: Twelve (16.9%) infants had at least 1 positive bDNA result. Two (2.8%) infants had confirmed HIV-infections as determined by >= 2 subsequent positive bDNA results (range=1,818-500,000 copies/mL). The remaining 10 (14.5%) infants had 1 positive bDNA test (range=81-440 copies/mL) with 2 subsequent negative bDNA tests and/or a negative HIV ELISA test; these infants were considered to have a false-positive result. The performance of internal assay standards was within acceptable limits. Conclusions. Our study suggests caution is needed in the interpretation of single, low-level, positive results of the ultrasensitive, quantitative bDNA test for HIV diagnosis of perinatally-exposed infants.
The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants.
Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth.
A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups).
In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.).
To examine false-positive HIV DNA polymerase chain reaction (PCR) test results in children, and the potential implications for the paediatric HIV epidemic in sub-Saharan Africa.
A review was done of records over a 6-year period of children less than 18 months old at an HIV treatment site in South Africa, to evaluate those with an initial 'false'-positive HIV DNA PCR result, but later proven to be HIV-uninfected with HIV DNA PCR and/or quantitative HIV RNA PCR tests. We calculated the influence of changing HIV transmission rates on predictive values (PV) of HIV DNA PCR tests in a hypothetical population of all HIV-exposed infants over a 1-year period. (Positive PV: proportion of individuals with a positive test with disease; negative PV: proportion of individuals with negative test and no disease).
Of 718 children, 40 with an initial positive HIV DNA PCR test were subsequently proven to be HIV-uninfected, resulting in a positive PV of 94.4%. Most (75%) uninfected children had PMTCT interventions and were asymptomatic or mildly symptomatic (77.5%). Calculations using a test specificity of 99.4%, as reported previously, show a decrease in positive PV using a single-test strategy from 98.6% at 30% HIV transmission rate, to 94.8% at 10% transmission, to 62.5% at 1% transmission. Reduction in test specificity further decreases positive PV at low transmission rates.
Decreasing mother-to-child HIV transmission rates reduce the positive predictive value of a single HIV DNA PCR test result, necessitating adaptations to diagnostic algorithms to avoid misdiagnosis and inappropriate treatment, especially with early initiation of antiretroviral therapy in asymptomatic infants.
Previously, HIV epidemic models have used a double Weibull curve to represent high initial and late mortality of HIV-infected children, without distinguishing timing of infection (peri- or post-natally). With more data on timing of infection, which may be associated with disease progression, a separate representation of children infected early and late was proposed.
Paediatric survival post-HIV infection without anti-retroviral treatment was calculated using pooled data from 12 studies with known timing of HIV infection. Children were grouped into perinatally or post-natally infected. Net mortality was calculated using cause-deleted life tables to give survival as if HIV was the only competing cause of death. To extend the curve beyond the available data, children surviving beyond 2.5 years post infection were assumed to have the same survival as young adults. Double Weibull curves were fitted to both extended survival curves to represent survival of children infected perinatally or through breastfeeding.
Those children infected perinatally had a much higher risk of dying than those infected through breastfeeding, even allowing for background mortality. The final-fitted double Weibull curves gave 75% survival at 5 months after infection for perinatally infected, and 1.1 years for post-natally infected children. An estimated 25% of the early infected children would still be alive at 10.6 years compared with 16.9 years for those infected through breastfeeding.
The increase in available data has enabled separation of child mortality patterns by timing of infection allowing improvement and more flexibility in modelling of paediatric HIV infection and survival.
Despite FDA approval and CE marking of commercial tests, manufacturer-independent testing of the technical aspects of newly
developed tests is important. To evaluate the analytical performance and explore the clinical applicability of the new Roche
COBAS AmpliPrep COBAS TaqMan HIV-1 test, version 2.0 (CAP/CTM v2.0), platform comparison was performed with the Roche CAP/CTM
test, version 2.0, the COBAS Amplicor HIV-1 Monitor Test, version 1.5 (CAP/CA v1.5), the COBAS AmpliPrep COBAS TaqMan HIV-1
Test (CAP/CTM v1.0), and the Abbott m2000 RealTime HIV-1 assay on panels and diagnostic samples. Specificity was tested for HIV-2 samples. Furthermore, samples from HIV-1-seropositive
individuals with CAP/CA v1.5-measured viral loads below 50 HIV-1 RNA copies per ml (cp/ml) and replicates of HIV-1-seronegative
plasma were tested in a checkerboard analysis. CAP/CTM v2.0 is HIV-1 specific, with broad genotype inclusivity and no serious
underquantification of viral load relative to the other assays used. Low viral loads below the threshold of quantification
for CAP/CA v1.5 are observed with CAP/CTM v2.0. A CAP/CTM v2.0-measured viral load of >50 copies/ml in these samples correlated
with therapy failure. In conclusion, CAP/CTM v2.0 is an accurate and reliable test for HIV-1 viral load measurement relative
to the other assays used with respect to specificity, sensitivity, and genotype inclusivity.
The implementation of antiretroviral therapy demands the need for increased access to viral load (VL) monitoring. Newer real-time
VL testing technologies are faster and have larger dynamic ranges and fully automated extraction to benefit higher throughputs
in resource-poor environments. The Abbott RealTime human immunodeficiency virus type 1 (HIV-1) assay was evaluated as a new option for testing for HIV-1 subtype C in South
Africa, and its performance was compared to the performance of existing assays (the Cobas AmpliPrep-Cobas TaqMan HIV-1, version
1, assay; the AmpliPrep-Cobas Monitor standard HIV-1 assay; and the NucliSENS EasyQ-EasyMag HIV-1 assay) in a high-throughput
laboratory. The total precision of the RealTime HIV-1 assay was acceptable over all viral load ranges. This assay compared most favorably with the Cobas AmpliPrep-Cobas
TaqMan HIV-1 assay (R2 = 0.904), with a low standard deviation of difference being detected (0.323 copies/ml). The bias against comparator assays
ranged from −0.001 copies/ml to −0.228 copies/ml. Variability in the reporting of VLs for a 20-member subtype panel compared
to the variability of other assays was noted with subtypes G and CRF02-AG. The RealTime HIV-1 assay can test 93 samples per day with minimal manual preparation, less staff, and the minimization of contamination
through automation. This assay is suitable for HIV-1 subtype C VL quantification in South Africa.
South Africa has among the highest levels of HIV prevalence in the world. Our objectives are to describe the distribution of South African infant and child mortality by age at fine resolution, to identify any trends over recent time and to examine these trends for HIV-associated and non HIV-associated causes of mortality.
A retrospective review of vital registration data was conducted. All registered postneonatal deaths under 1 year of age in South Africa for the period 1997-2002 were analysed by age in months using a generalized linear model with a log link and Poisson family.
Postneonatal mortality increased each year over the period 1997-2002. A peak in HIV-related deaths was observed, centred at 2-3 months of age, rising monotonically over time.
We interpret the peak in mortality at 2-3 months as an indicator for paediatric AIDS in a South African population with high HIV prevalence and where other causes of death are not sufficiently high to mask HIV effects. Intrauterine and intrapartum infection may contribute to this peak. It is potentially a useful surveillance tool, not requiring an exact cause of death. The findings also illustrate the need for early treatment of mother and child in settings with very high HIV prevalence.
In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. We investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial.
HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir-ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). We report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy.
At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI], 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy.
Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%. (ClinicalTrials.gov number, NCT00102960.)
This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive
value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression—HIV-1
RNA level, CD4 cell count, and CD4 percentage—for weight growth failure, cognitive decline, and survival in HIV-infected children.
Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment,
with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors,
higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival,
whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The
finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation
of treatment effects in children.
We describe the extent of and variables associated with irreproducible HIV-1 PCR positive results within South Africa's Early Infant Diagnosis (EID) program from 2010 to 2015 and propose criteria for differentiating indeterminate from clearly positive results using the COBAS® AmpliPrep/COBAS® TaqMan HIV-1 Qualitative Test version 2.0 (CAP/CTM Qual v2.0). Fourteen percent of specimens with an instrument-positive result that were repeat tested yielded a negative result for which cycle threshold (Ct) proved to be the only predictive variable. A Ct <33.0 was found to be the most accurate threshold value for differentiating clearly positive from irreproducible cases, correctly predicting 96.8% of results. Among 70 patients with an irreproducible positive result linked to a follow up HIV-1 PCR test, 67 (95.7%) were negative and 3 (4.3%) were instrument-positive. Criteria differentiating clearly positive from indeterminate results need to be retained within EID services and infants with indeterminate results closely monitored and final HIV status determined.
Background:
South Africa represents the first high-burden setting to introduce routine virological testing at birth within its early infant diagnosis program, implemented in June 2015. National HIV birth testing coverage, intra-uterine transmission rates and case rates for the first year since introduction of universal birth testing are reported.
Methods:
HIV polymerase chain reaction (PCR) test data from June 2015 to May 2016 were extracted from the National Health Laboratory Service's central data repository by year, month, age, result and geographic location. Birth testing was defined as all HIV PCR tests performed at <7 days of life; coverage as the proportion of all HIV-exposed neonates born who were tested at birth; estimated intra-uterine transmission rate as the percentage of HIV PCR positive tests in HIV-exposed neonates tested and case rates as the number of HIV PCR positive tests per 100 000 total live births.
Results:
Between June 2015 to May 2016, the South African national monthly birth testing coverage increased from 39% (8 636 tests) to 93% (20 479 tests). During this period the number of positive tests at birth increased from 114 to 234 per month, equating to a national intra-uterine transmission rate of 1.1% and a birth case rate of 247 per 100 000 live births.
Conclusion:
Universal birth testing for all HIV-exposed neonates is rapidly being achieved in South Africa, facilitating earlier detection of intra-uterine infected neonates. However, the successful linkage into care of HIV-infected neonates and their treatment outcomes remain to be assessed.
Objective:
To describe baseline HIV-1 RNA viral load (VL) trends within South Africa's Early Infant Diagnosis (EID) program 2010-2016, with reference to prevention of mother-to-child transmission (PMTCT) guidelines.
Methods:
HIV-1 total nucleic acid polymerase chain reaction (TNA PCR) and RNA VL data from 2010-2016 were extracted from the South African National Health Laboratory Service's central data repository. Infants with a positive TNA PCR and subsequent baseline RNA VL taken at age <7 months were included. Descriptive statistics were performed for quantified and lower-than-quantification limit (LQL) results per annum and age in months. Trend analyses were performed using log likelihood ratio tests. Multivariable linear regression was used to model the relationship between RNA VL and predictor variables whilst logistic regression was used to identify predictors associated with LQL RNA VL results.
Results:
Amongst 13 606 infants with a positive HIV-1 TNA PCR linked to a baseline RNA VL, median age of first PCR was 57 days and VL was 98 days. 13 195 (97.0%) infants had a quantified VL and 411 (3.0%) had an LQL result. A significant decline in median VL was observed between 2010-2016, from 6.3 log10 (IQR:5.6-6.8) to 5.6 log10 (IQR:4.2-6.5) RNA copies/ml, after controlling for age (P<0.001), with younger age associated with lower VL (P<0.001). The proportion of infants with a baseline VL <4 Log10 RNA copies/ml increased from 5.4%-21.8%. Subsequent to PMTCT Option B implementation in 2013, the proportion of infants with an LQL baseline VL increased from 1.5%-6.1% (P<0.001).
Conclusion:
Between 2010-2016 a significant decline in baseline viraemia within South Africa's EID program was observed, with loss of detectability amongst some HIV-infected infants.
Background:
Earlier diagnosis of HIV-infected infants facilitates earlier access to therapy and improved clinical outcomes.
Aim:
The aim of this study was describe the management of infants who started antiretroviral therapy in the first month of life.
Methods:
A retrospective review was performed on HIV-infected neonates who started ART within the first month of life between January 2013 and March 2015.
Results:
997 neonates had one HIV PCR test. 26 (2.6%) tested positive for HIV and 22 initiated therapy in the first month of life. The median age of first HIV PCR test was 7 days. Neonates were started on ART within a median of 7 days of their first HIV test which equated to a median age of 13.5 (IQR 7-20) days of life. Median gestational age was 35 weeks (IQR 33-38 weeks) and birth weight was 2170 grams (IQR 1773-2480). Nineteen (86.4%) had low birth weight (less than 2.5 kilograms) and 16 (72.7%) were premature. Median baseline HIV viral loads were log 4.444 copies/ml (IQR 3.457-5.125), median CD4 counts of 1338 (IQR 803-1928) and CD4% percentages of 36.1% (22.2-45.4).All children initiated zidovudine and lamivudine, 10 with lopinavir/ritonavir and 12 with nevirapine. All children in care are now receiving lopinavir/ritonavir. Of the 22 neonates initiated on treatment, 11 are in care (mean age of 2.1 years). 2 of these infants had a viral load of <50copies/ml when last measured.
Conclusions:
Early ART initiation in neonates is feasible. Challenges include safe, palatable regimens and continued close follow up of mothers and infants.
Context.—
Pediatric human immunodeficiency virus (HIV) infection has unique viral
pathogenetic features that preclude routine extrapolation from adult studies
and require specific analysis.Objectives.—
To evaluate the prognostic value of 2 key laboratory markers—plasma
RNA and CD4+ lymphocyte count—for HIV disease progression
in infants and children and to establish targeted values for optimal outcome.Design.—
Data from a cohort of 566 infants and children who participated in a
randomized, placebo-controlled trial of nucleoside reverse transcriptase inhibitors
(ACTG 152) were analyzed. The trial was conducted between 1991 and 1995 and
enrolled a heterogenous cohort of antiretroviral therapy–naive children
(age, 3 months to 18 years); patients had a median follow-up of 32 months.Main Outcome Measures.—
The trial clinical end points consisted of time to first HIV disease
progression (growth failure, decline in neurologic or neurodevelopmental function,
opportunistic infections) or death.Results.—
Baseline plasma RNA levels were high (age group medians, 5×104 to >106 copies/mL), and both baseline RNA and CD4+ lymphocyte count were independently predictive of subsequent clinical
course. Risk reduction for disease progression between 49% and 64% was observed
for each log10 reduction in baseline RNA and was linear without
suggestion of a threshold or age effect. Disease progression predictive power
was enhanced by the combined use of plasma RNA and CD4+ cell count.
Marker values of less than 10000 copies/mL for plasma RNA and greater than
500×106/L (<6.5 years of age) or greater than 200×106/L (>6.5 years) for CD4+ cell count were associated with
a 2-year disease progression rate of less than 5%.Conclusions.—
Two key laboratory markers—plasma RNA and CD4+ lymphocyte
count—are independent predictors of clinical course among HIV-infected
infants and children. The linear, age-independent relationship between log10 plasma RNA and relative risk of disease progression strongly supports
therapeutic efforts to achieve plasma virus levels as low as possible.
Figures in this Article
THE TREATMENT of human immunodeficiency virus (HIV) infection with antiretroviral
compounds has recently undergone rapid progress. In parallel, the quantitation
of plasma viral RNA and CD4+ lymphocytes has become the foundation
on which prediction of clinical course and response to therapy is based. Most
of this rapid change has resulted from clinical studies conducted in adult
populations. Aggressive, multidrug regimens are currently being introduced
into pediatric populations both in clinical practice as well as in controlled
trials.1- 4
While plasma RNA and CD4+ lymphocyte quantitation data are being
generated in children, it is unclear whether the experience and guidelines
developed for adults5- 7
will be applicable to infants and children. Special issues that underscore
this concern include the presence of a developing immune system at the time
of infection followed by high levels of proliferating target cells and immune
activation8- 9 and persistently
high levels of plasma virus for extended periods in young children.10- 12
This article focuses on analyses using the large plasma RNA and CD4+ lymphocyte database obtained before and during therapy in 566 infants
and children who participated in a large treatment trial, ACTG 152.13- 14 Plasma RNA and CD4+ lymphocyte
levels associated with a low risk of disease progression in HIV-infected infants
and children are described.
To compare performance of testing for human immunodeficiency virus (HIV)-1 DNA and HIV-1 RNA for diagnosis of HIV-1 infection in infants receiving preventive antiretroviral therapy.
This substudy of the French multicenter prospective cohort of neonates born to HIV-infected mothers, included 1567 infants tested for HIV with polymerase chain reaction (PCR) in a single laboratory, receiving post-natal prophylaxis, not breastfed, and having simultaneous HIV-1 DNA and RNA results before 45 days. The performance of PCR was assessed in reference to the 6-month HIV-1 RNA result.
Specificity of both HIV-1 RNA and HIV-1 DNA PCR was 100% at all ages (except 99.8% for DNA at birth); sensitivity was 58% (RNA) and 55% (DNA) at birth, and 89% at 1 month, 100% at 3 months for both, and 100% at 6 months (DNA). Concordance between HIV-1 DNA and RNA results was 0.78 and 0.81 (Kappa) at birth and 1 month and 100% at 3 and 6 months. Type of maternal and neonatal prophylaxis had no effect on sensitivity, but influenced viral load.
The performances of testing for HIV-1 DNA and RNA were similar with 100% sensitivity at 3 months. At 1 month during prophylaxis, 11% of infected children had negative PCR results.
Pediatric human immunodeficiency virus (HIV) infection has unique viral pathogenetic features that preclude routine extrapolation from adult studies and require specific analysis.
To evaluate the prognostic value of 2 key laboratory markers-plasma RNA and CD4+ lymphocyte count-for HIV disease progression in infants and children and to establish targeted values for optimal outcome.
Data from a cohort of 566 infants and children who participated in a randomized, placebo-controlled trial of nucleoside reverse transcriptase inhibitors (ACTG 152) were analyzed. The trial was conducted between 1991 and 1995 and enrolled a heterogeneous cohort of antiretroviral therapy-naive children (age, 3 months to 18 years); patients had a median follow-up of 32 months.
The trial clinical end points consisted of time to first HIV disease progression (growth failure, decline in neurologic or neurodevelopmental function, opportunistic infections) or death.
Baseline plasma RNA levels were high (age group medians, 5 x 10(4) to >10(6) copies/mL), and both baseline RNA and CD4+ lymphocyte count were independently predictive of subsequent clinical course. Risk reduction for disease progression between 49% and 64% was observed for each log10 reduction in baseline RNA and was linear without suggestion of a threshold or age effect. Disease progression predictive power was enhanced by the combined use of plasma RNA and CD4+ cell count. Marker values of less than 10000 copies/mL for plasma RNA and greater than 500 x 10(6)/L (<6.5 years of age) or greater than 200 x 10(6)/L (>6.5 years) for CD4+ cell count were associated with a 2-year disease progression rate of less than 5%.
Two key laboratory markers--plasma RNA and CD4+ lymphocyte count-are independent predictors of clinical course among HIV-infected infants and children. The linear, age-independent relationship between log10 plasma RNA and relative risk of disease progression strongly supports therapeutic efforts to achieve plasma virus levels as low as possible.
More routine laboratories in South Africa are equipped to perform quantitative than qualitative HIV viral detection assays. The accessibility of early infant diagnosis would be improved if a quantitative viral load (VL) assay performed on dried blood spots (DBS) could accurately diagnose HIV-infection. The VL assay routinely used in the country has not previously been assessed on DBS for early infant diagnosis.
To determine the accuracy of the NucliSens EasyQ assay (bioMerieux, Lyon, France) on DBS for early infant diagnosis of HIV in a subtype C-infected population.
Stored DBS samples collected from children presenting for HIV testing were analyzed. DBS EasyQ VL results were compared to the child's HIV status as determined by a whole blood HIV DNA PCR result.
The EasyQ assay was performed on 235 stored DBS samples from 71 HIV-infected and 164 HIV-uninfected children. Of the 216 infants (children aged 12 months or less) tested, all 52 HIV-infected infants were detected (sensitivity of 100%). Six of 164 HIV-uninfected infants yielded false positive results (specificity 96.3%). All false positive and six of the true positive infants had VL<3.7 log IU/ml. These 12 (5.6%) infants would require repeat testing to differentiate true from false positives. Using a threshold above 3.7 log IU/ml (equivalent to 4 log copies/ml) to define a positive result would yield an accurate diagnosis in 204 (94.4%) infants.
DBS EasyQ VL assays provide an accurate option for early infant diagnosis in low resource settings.
Summary:
Background: Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only.
Methods: We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models.
Findings: 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 105 copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor.
Interpretation: This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.
HIV contributes substantially to child mortality, but factors underlying these deaths are inadequately described. With individual data from seven randomised mother-to-child transmission (MTCT) intervention trials, we estimate mortality in African children born to HIV-infected mothers and analyse selected risk factors.
Early HIV infection was defined as a positive HIV-PCR test before 4 weeks of age; and late infection by a negative PCR test at or after 4 weeks of age, followed by a positive test. Mortality rate was expressed per 1000 child-years. We investigated the effect of maternal health, infant HIV infection, feeding practices, and age at acquisition of infection on mortality assessed with Cox proportional hazards models, and allowed for random effects for trials grouped geographically.
378 (11%) of 3468 children died. By age 1 year, an estimated 35.2% infected and 4.9% uninfected children will have died; by 2 years of age, 52.5% and 7.6% will have died, respectively. Mortality varied by geographical region, and was associated with maternal death (adjusted odds ratio 2.27, 95% CI 1.62-3.19), CD4+ cell counts <200 per microL (1.91, 1.39-2.62), and infant HIV infection (8.16, 6.43-10.33). Mortality was not associated with either ever breastfeeding and never breastfeeding in either infected or uninfected children. In infected children, mortality was significantly lower for those with late infection than those with early infection (0.52, 0.39-0.70). This effect was also seen in analyses of survival from the age at infection (0.74, 0.55-0.99).
These findings highlight the necessity for timely antiretroviral care, for support for HIV-infected women and children in developing countries, and for assessment of prophylactic programmes to prevent MTCT, including child mortality and infection averted.
- A Haeri Mazanderani
A. Haeri Mazanderani, et al.
Journal of Clinical Virology 114 (2019) 21-25
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Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, WHO, Geneva
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http://www.who.int/hiv/pub/arv/arv-2016/en/. Accessed February 21, 2017.