HIV Early Antiretroviral Therapy Research Articles

High mortality following early initiation of antiretroviral therapy in infants living with HIV from three African countries

Even with increasing access to rapid HIV diagnosis and early antiretroviral therapy (ART) initiation, infants living with HIV seem to have adverse outcomes. We assessed the probability of death, viral suppression, and other HIV-related events in the first three years of life among early-treated children with perinatally-acquired HIV in South Africa, Mozambique, and Mali. We enrolled a cohort of infants who initiated ART within the initial 6 months of life and within 3 months of diagnosis. These children were monitored 2, 6, 12 and 24 weeks after enrolment, followed by biannual check-ups up to 4 years after enrolment. We assessed the probability of death, viral load (VL) suppression, severe immunosuppression (according to WHO guidelines), and engagement in care using Kaplan-Meier plots, and hazard ratios for these outcomes using multivariable Cox regression models. Two hundred and fifteen infants were enrolled and monitored for a median of 34 months [IQR, 16.3; 44.1]. ART initiation occurred at a median of 34 days of age [IQR, 26.0; 73.0]. The probability of death at 1 year of ART was 10% (95% CI, 6-14), increased to 12% (95% CI, 8-17) at 2 and remained in 12% at 3 years. The main risk factor for HIV/AIDS-related mortality was baseline viral load [HR: 2.98 (95% CI, 1.25-7.12)]. Sixty-one of 146 (42%) children achieved sustained virological control below lower limit of detection for any ≥1 year period between enrolment and 4 years after enrolment. Viral suppression during follow-up was inversely associated with baseline viral load [Hazard Ratio (HR): 0.72 (95% CI, 0.58-0.89] and adverse maternal social events [HR: 0.26 (95% CI, 0.15-0.45)]. Adherence to ART was assessed as optimal in 81% of the visits. Female sex at birth, lower age at diagnosis and maternal adverse social life events were risk factors for low adherence [Odds ratio, OR 1.25 (95% CI, 1.00-1.56); 1.12 (95% CI, 1.01-1.27) and 2.52 (95% CI, 2.16-12.37), respectively]. Despite early ART, mortality remains high in infants. High baseline VL and adverse maternal social environment increased the risk of poor outcomes. Sustained supportive strategies are essential during and after pregnancy, to achieve better survival. Early Treated Perinatally HIV Infected Individuals: Improving Children's Actual Life (EPIICAL) is a research consortium funded by ViiV Healthcare and led by Penta Foundation. The funder was not involved in the analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. The corresponding authors had access to all data and take final responsibility for the decision to submit.

Similar cortical morphometry trajectories from 5 to 9 years in children with perinatal HIV who started treatment before age 2 years and uninfected controls

BackgroundLife-long early ART (started before age 2 years), often with periods of treatment interruption, is now the standard of care in pediatric HIV infection. Although cross-sectional studies have investigated HIV-related differences in cortical morphology in the setting of early ART and ART interruption, the long-term impact on cortical developmental trajectories is unclear. This study compares the longitudinal trajectories of cortical thickness and folding (gyrification) from age 5 to 9 years in a subset of children perinatally infected with HIV (CPHIV) from the Children with HIV Early antiRetroviral therapy (CHER) trial to age-matched children without HIV infection.Methods75 CHER participants in follow-up care at FAMCRU (Family Centre for Research with Ubuntu), as well as 66 age-matched controls, received magnetic resonance imaging (MRI) on a 3 T Siemens Allegra at ages 5, 7 and/or 9 years. MR images were processed, and cortical surfaces reconstructed using the FreeSurfer longitudinal processing stream. Vertex-wise linear mixed effects (LME) analyses were performed across the whole brain to compare the means and linear rates of change of cortical thickness and gyrification from 5 to 9 years between CPHIV and controls, as well as to examine effects of ART interruption.ResultsChildren without HIV demonstrated generalized cortical thinning from 5 to 9 years, with the rate of thinning varying by region, as well as regional age-related gyrification increases. Overall, the means and developmental trajectories of cortical thickness and gyrification were similar in CPHIV. However, at an uncorrected p < 0.005, 6 regions were identified where the cortex of CPHIV was thicker than in uninfected children, namely bilateral insula, left supramarginal, lateral orbitofrontal and superior temporal, and right medial superior frontal regions. Planned ART interruption did not affect development of cortical morphometry.ConclusionsAlthough our results suggest that normal development of cortical morphometry between the ages of 5 and 9 years is preserved in CPHIV who started ART early, these findings require further confirmation with longitudinal follow-up through the vulnerable adolescent period.

Pulse wave velocity in early-treated children living with perinatal HIV infection is similar to uninfected children.

HIV is associated with accelerated cardiovascular disease, due to HIV-associated metabolic abnormalities, antiretroviral therapy (ART), and HIV itself. Carotid-femoral pulse wave velocity (PWV) is the noninvasive gold standard measurement of arterial stiffness, and associated with incident vascular events in adults. It is unclear if arterial stiffness is accelerated in children living with perinatal HIV (CHIV) who initiate ART early in life. We compared the longitudinal trajectory of PWV in CHIV to children unexposed to HIV. A secondary comparison compared HIV exposed uninfected children (CHEU) to unexposed children. Four hundred and sixty-five children (141 CHIV, 160 CHEU, 164 unexposed) previously in the children with HIV early antiretroviral therapy (ART) (CHER) and P1060 trials were followed annually at Tygerberg Children's Hospital, South Africa between 2014 and 2020. CHIV initiated ART in infancy or early childhood, with excellent ART adherence and largely sustained viral suppression. The primary outcome was PWV, measured using the Vicorder system, and evaluated using linear mixed effects models. Median (interquartile range) age at first PWV measurement was 8.64 (7.7-9.1) years, and median follow-up time 2.9 (1.6-4.0) years. Adjusted analyses showed no significant mean difference in PWV in CHIV and CHEU compared to unexposed [CHIV: 0.101 m/s, 95% confidence interval (CI) -0.012 to 0.214; CHEU: 0.068 m/s, 95% CI -0.047 to 0.183], after adjusting for gender, age, ethnicity, mean arterial pressure, resting average heart rate and family history of cardiovascular disease. Early-treated CHIV with sustained viral suppression have similar PWV to unexposed children. Excellent adherence and early ART initiation may protect against cardiovascular disease.

Childhood lung function following perinatal HIV infection and early antiretroviral therapy initiation: a cross-sectional study.

Despite the introduction of antiretroviral therapy (ART), HIV-associated pulmonary complications remain prevalent in children following perinatal HIV infection. In the post-ART era the incidence of opportunistic infections has decreased; however, non-infectious complications including diminished lung function are common. It is unclear whether early initiation of ART influences lung function later in life.We performed a cross-sectional study examining pulmonary function tests (PFT) (spirometry, plethysmography, carbon monoxide diffusing capacity) in HIV-unexposed (HU), HIV-exposed-uninfected (HEU) and perinatally HIV-infected children on early ART (HIV+) recruited from the Cape Town arms of the CHER and IMPAACT 1060 trials. PFT was performed once children could participate (October 2013 to January 2020). Global Lung Initiative reference software was used for Z-standardisation of lung function by sex, age and height.In total 394 children (HU n=90, HEU n=162, HIV+ n=142) underwent PFT, median age 8.7 (IQR 7.7–9.8) years. HIV+ had ART initiated at a median age of 17.6 (8.0–36.7) weeks. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC Z-scores were similar in all groups. Plethysmography demonstrated air-trapping with increased total lung capacity (TLC), functional residual capacity, residual volume (RV) and RV/TLC Z-scores in HIV+. There were no differences in alveolar volume; however, diffusing capacity was increased in HIV+.Our findings indicate that following perinatal HIV infection, early ART may attenuate HIV-associated lung disease and is associated with normal childhood spirometry. However plethysmography demonstrates that small airway dysfunction is more pronounced in HIV+. Longitudinal follow-up is required to assess if these children are at risk of obstructive airway disease later in life.

Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial

BackgroundReduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial.MethodsInfants with HIV < 12 weeks old with CD4% ≥ 25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4% < 25%. In 229 participants, HIV-1 proviral DNA was quantified by PCR from stored peripheral blood mononuclear cells from children who had received ≥ 24 weeks ART and two consecutive undetectable HIV-1 RNA 12–24 weeks apart. HIV-1 proviral DNA was compared between ART-Def and ART-96 W at week 96, and in all arms at week 248. Factors associated with HIV-1 proviral DNA levels were evaluated using linear regression.FindingsLonger duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p = 0.0003) and 248 weeks (p = 0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p = 0.0225) and 248 weeks (p = 0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p = 0.0042).IntepretationLonger ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure.FundingWellcome Trust, National Institutes of Health, Medical Research Council.

Cortical structural changes related to early antiretroviral therapy (ART) interruption in perinatally HIV-infected children at 5 years of age.

ART interruption in children can occur especially in resource-limited settings for reasons including poor adherence, stock-outs, ART intolerance of non-pediatric formulas and pill size, as well as ultimately to test for HIV remission. Although early ART initiation is now standard of care in pediatric HIV management, very little is known on the effect of early ART initiation or subsequent interruption on brain development. This study aimed to investigate the effect of ART interruption on brain cortical thickness (CT) and folding in a subset of children from the Children with HIV Early antiRetroviral therapy (CHER) trial cohort who all started ART before 18 months of age. CHER participants in the neuroimaging follow-up study had magnetic resonance (MRI) scans on a 3T Siemens Allegra brain scanner at age 5.44 ± 0.37 years. MR images were processed using the automated cross-sectional stream in FreeSurfer v6.0 and vertex wise comparisons of CT and local gyrification indices (LGIs) were performed between HIV+ children and HIV- controls, as well as between HIV+ children on interrupted or continuous ART and controls. HIV+ children (n = 46) showed thicker cortex than HIV- children (n = 29) in bilateral frontal and left temporo-insular regions but lower LGIs in left superior and bilateral medial orbitofrontal cortex extending into rostral anterior cingulate. Children on interrupted ART (n = 21) had thicker cortex than HIV- controls in left frontal and right insular regions, but children on continuous treatment (n = 25) showed no difference from controls. Children on both interrupted and continuous ART showed region-specific alterations in LGI relative to controls. Cortical folding appears more sensitive than CT to early life events including early ART and interruption. However, immune health resilience in children can translate to long term preservation of morphometric brain development, especially for those on early and continuous treatment.

Impact of Acute HIV Infection and Early Antiretroviral Therapy on the Human Gut Microbiome.

Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1-5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation

Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.

Naive B Cell Output in HIV-Infected and HIV-Uninfected Children.

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks–12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks–8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children.

The cost-effectiveness of oral HIV pre-exposure prophylaxis and early antiretroviral therapy in the presence of drug resistance among men who have sex with men in San Francisco

BackgroundPoor adherence to either antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) can promote drug resistance, though this risk is thought to be considerably higher for ART. In the population of men who have sex with men (MSM) in San Francisco, PrEP coverage reached 9.6% in 2014 and has continued to rise. Given the risk of drug resistance and high cost of second-line drugs, the costs and benefits of initiating ART earlier while expanding PrEP coverage remain unclear.MethodsWe develop an infection–age-structured mathematical model and fit this model to the annual incidence of AIDS cases and deaths directly, and to resistance and demographic data indirectly. We investigate the impact of six various intervention scenarios (low, medium, or high PrEP coverage, with or without earlier ART) over the next 20 years.ResultsLow (medium, high) PrEP coverage with earlier ART could prevent 22% (42%, 57%) of a projected 44,508 total new infections and 8% (26%, 41%) of a projected 18,426 new drug-resistant infections, and result in a gain of 43,649 (74,048, 103,270) QALYs over 20 years compared to the status quo, at a cost of $4745 ($78,811, $115,320) per QALY gained, respectively.ConclusionsHigh PrEP coverage with earlier ART is expected to provide the greatest benefit but also entail the highest costs among the strategies considered. This strategy is cost-effective for the San Francisco MSM population, even considering the acquisition and transmission of ART-mediated drug resistance. However, without a substantial increase to San Francisco’s annual HIV budget, the most advisable strategy may be initiating ART earlier, while maintaining current strategies of PrEP enrollment.

Functional Connectivity Alterations between Networks and Associations with Infant Immune Health within Networks in HIV Infected Children on Early Treatment: A Study at 7 Years.

Although HIV has been shown to impact brain connectivity in adults and youth, it is not yet known to what extent long-term early antiretroviral therapy (ART) may alter these effects, especially during rapid brain development in early childhood. Using both independent component analysis (ICA) and seed-based correlation analysis (SCA), we examine the effects of HIV infection in conjunction with early ART on resting state functional connectivity (FC) in 7 year old children. HIV infected (HIV+) children were from the Children with HIV Early Antiretroviral Therapy (CHER) trial and all initiated ART before 18 months; uninfected children were recruited from an interlinking vaccine trial. To better understand the effects of current and early immune health on the developing brain, we also investigated among HIV+ children the association of FC at 7 years with CD4 count and CD4%, both in infancy (6–8 weeks) and at scan. Although we found no differences within any ICA-generated resting state networks (RSNs) between HIV+ and uninfected children (27 HIV+, 18 uninfected), whole brain connectivity to seeds located at RSN connectivity peaks revealed several loci of FC differences, predominantly from seeds in midline regions (posterior cingulate cortex, paracentral lobule, cuneus, and anterior cingulate). Reduced long-range connectivity and increased short-range connectivity suggest developmental delay. Within the HIV+ children, clinical measures at age 7 years were not associated with FC values in any of the RSNs; however, poor immune health during infancy was associated with localized FC increases in the somatosensory, salience and basal ganglia networks. Together these findings suggest that HIV may affect brain development from its earliest stages and persist into childhood, despite early ART.

Altered brain morphometry in 7-year old HIV-infected children on early ART.

Even with the increased roll out of combination antiretroviral therapy (cART), paediatric HIV infection is associated with neurodevelopmental delays and neurocognitive deficits that may be accompanied by alterations in brain structure. Few neuroimaging studies have been done in children initiating ART before 2years of age, and even fewer in children within the critical stage of brain development between 5 and 11years. We hypothesized that early ART would limit HIV-related brain morphometric deficits at age 7. Study participants were 7-year old HIV-infected (HIV+) children from the Children with HIV Early Antiretroviral Therapy (CHER) trial whose viral loads were supressed at a young age, and age-matched uninfected controls. We used structural magnetic resonance imaging (MRI) and FreeSurfer ( http://www.freesurfer.net/ ) software to investigate effects of HIV and age at ART initiation on cortical thickness, gyrification and regional brain volumes. HIV+ children showed reduced gyrification compared to controls in bilateral medial parietal regions, as well as reduced volumes of the right putamen, left hippocampus, and global white and gray matter and thicker cortex in small lateral occipital region. Earlier ART initiation was associated with lower gyrification and thicker cortex in medial frontal regions. Although early ART appears to preserve cortical thickness and volumes of certain brain structures, HIV infection is nevertheless associated with reduced gyrification in the parietal cortex, and lower putamen and hippocampus volumes. Our results indicate that in early childhood gyrification is more sensitive than cortical thickness to timing of ART initiation. Future work will clarify the implications of these morphometric effects for neuropsychological function.

Thymic Output and CD4 T-Cell Reconstitution in HIV-Infected Children on Early and Interrupted Antiretroviral Treatment: Evidence from the Children with HIV Early Antiretroviral Therapy Trial.

Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants' immune systems are more plastic and dynamic than older children's or adults', and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart. Data from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children's CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART. Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption. Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children's CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children's CD4 levels.

Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis

Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART. We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7-12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960. The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6-93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133-13 129]) than in the ART-Def group (6870 μg/μL [1706-53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1-60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1-2·3]) adjusted for ART initiation age. About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests. Wellcome Trust, Medical Research Council, and National Institutes of Health.

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.

Antiretroviral therapy during the neonatal period.

No abstract available

Utility of clinical parameters to identify HIV infection in infants below ten weeks of age in South Africa: a prospective cohort study

BackgroundAs HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa.HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings.Results417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50th centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression.ConclusionsA combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.

Early versus deferred antiretroviral therapy in children in low-income and middle-income countries

We reviewed current literatures on early and deferred initiation of antiretroviral therapy in HIV-infected infants and children in low-income and middle-income countries. Data from children with HIV antiretroviral (Children with HIV Early Antiretroviral Therapy) study showed a significant reduction of 76% in mortality among infants who received antiretroviral therapy within 3 months of their life as opposed to those on deferred therapy. These data led World Health Organization to promptly revise the guideline to recommend initiation of antiretroviral therapy in all HIV-infected infants regardless of clinical or immunological status. The recommendation for older children is differed between guidelines of developed and developing countries. In general, higher CD4 cell count threshold is used for younger children and similar criteria to those used for adults are used once children are above 5 years of age. The randomized study of when to start antiretroviral therapy in children older than 1 year is ongoing. The current trend is to move toward early treatment to reduce morbidity and mortality, achieve immune recovery, normal growth, and development. Even though the antiretroviral rollout program has been successful in Asia and Africa, the challenges lie in diagnosing infants in a timely manner and maintaining infrastructure and resources to support life-long treatment.

Guidance for antiretroviral therapy in HIV-infected infants less than 1 year of age

No abstract available.

Lessons from a multicentre paediatric HIV trial

A major hindrance in the paediatric HIV field is the limited evidence-base to guide practice. Large randomised paediatric studies are difficult to do, because of the complex medical and social issues and limited global expertise. The randomised Children with HIV Early Antiretroviral Therapy Study showed benefit with the early treatment of children under 1 year of age,1 but no randomised study results are available for children older than this.2 The Thai and Cambodian guidelines follow those of WHO, which are based on data from non-randomised large cohorts, and expert advice.