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Diagnosis of lipodystrophy syndrome
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The benefits of long-term antiretroviral therapy (ART) are recognized all over the world with infected children maturing into adults and HIV infection becoming a chronic illness. However, the improved survival is associated with serious metabolic complications, including lipodystrophy (LD), dyslipidemia, insulin resistance, lactic acidosis and bone...
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Context 1
... distribution A variety of techniques can be used to diagnose LD (Table 2); however, clinical presentation remains the most commonly used method, especially in resource-limited settings. Sys- tematic objective measurements are required to detect abnormalities of fat distribution unless LD is severe enough to be recognized by the physician or caretaker. ...
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Citations
... With the introduction of combination antiretroviral therapy (cART), the incidence of severe HIV-or AIDS-related complications has declined and survival rates of children and adolescents with perinatally acquired HIV (PHIV) have significantly improved [1]. Despite adequate viral suppression with cART, long-term complications such as increased cardiovascular risk (CVD) and metabolic syndrome (MetS) are still eminent in HIV-infected individuals [2,3]. Furthermore, HIV is considered an independent risk factor for the development of CVD in HIV-infected adults, with lifelong treatment increasing this risk [3,4]. ...
Children with perinatally acquired human immunodeficiency virus (PHIV) are growing into adulthood with HIV and treatment-associated comorbidities, such as dyslipidemia and insulin resistance. HIV is identified as independent risk factor for cardiovascular disease (CVD). The hypothesis behind increased CVD risk associated with HIV includes vascular inflammation, dyslipidemia and combination antiretroviral therapy (cART) metabolomic toxicity. To investigate differences in lipid profiles and pathophysiological mechanisms of CVD risk in adolescents with PHIV, we compared the plasma lipidome of PHIV adolescents and HIV-negative controls. We additionally investigated the influence of current cART regimens and increased lipoprotein(a) (Lp(a)) levels on the plasma lipidome. We included 20 PHIV-infected adolescents and 20 HIV-negative controls matched for age, sex, ethnic origin and socio-economic status. Plasma lipidome was measured using Thermo Scientific Ultimate 3000 binary high-performance liquid chromatography (HPLC)–mass spectrometry. We evaluated the plasma lipidome in PHIV adolescents using different cART regimens (including those known to be associated with lipid alterations). The median age was 17.5 years (15.5–20.7) and 16.5 years (15.7–19.8) for PHIV adolescents and controls, respectively. Of PHIV adolescents, 45% used a non-nucleotide reverse transcriptase inhibitor (NNRTI)-based (25%) or protease inhibitor (PI)-based (20%) cART regimen. In this pilot study, we observed no significant differences between lipidomic profiles between PHIV adolescents and controls. We observed no differences in the plasma lipidome in participants with increased versus normal Lp(a) levels. Different cART regimens appear to influence chain length differences in the plasma lipidome of PHIV adolescents; however, the significance and causality of this observation remains undetermined. Further research on the influence of cART on lipid composition could further identify these alterations.
... While early ART initiation in children is common in high resource settings like Europe and North America, children in sub-Saharan Africa, who represent the majority of children living with HIV, typically begin ART during chronic HIV infection [50]. Initiation of ART during chronic infection in children results in a latent reservoir size comparable to that observed in adult populations [51], with long-term ART in children also associated with adverse health outcomes and increased immune activation [52][53][54]. Yet studies of the pediatric HIV reservoir, especially those related to its establishment during chronic HIV infection, remain limited compared to those in adults. ...
A cure for HIV-1 (HIV) remains unrealized due to a reservoir of latently infected cells that persist during antiretroviral therapy (ART), with reservoir size associated with adverse health outcomes and inversely with time to viral rebound upon ART cessation. Once established during ART, the HIV reservoir decays minimally over time; thus, understanding factors that impact the size of the HIV reservoir near its establishment is key to improving the health of people living with HIV and for the development of novel cure strategies. Yet, to date, few correlates of HIV reservoir size have been identified, particularly in pediatric populations. Here, we employed a cross-subtype intact proviral DNA assay (CS-IPDA) to quantify HIV provirus between one- and two-years post-ART initiation in a cohort of Kenyan children (n = 72), which had a median of 99 intact (range: 0–2469), 1340 defective (range: 172–3.84 × 104), and 1729 total (range: 178–5.11 × 104) HIV proviral copies per one million T cells. Additionally, pre-ART plasma was tested for HIV Env-specific antibody-dependent cellular cytotoxicity (ADCC) activity. We found that pre-ART gp120-specific ADCC activity inversely correlated with defective provirus levels (n = 68, r = −0.285, p = 0.0214) but not the intact reservoir (n = 68, r = −0.0321, p-value = 0.800). Pre-ART gp41-specific ADCC did not significantly correlate with either proviral population (n = 68; intact: r = −0.0512, p-value = 0.686; defective: r = −0.109, p-value = 0.389). This suggests specific host immune factors prior to ART initiation can impact proviruses that persist during ART.
... PIs (saquinavir, ritonavir, indinavir, nelfinavir, lopinavir/reitonavir, atazanavir, fosamprenavir, tipranavir, and darunavir) can cause abnormal glucose metabolism and lead to IR, impaired glucose tolerance, impaired fasting glucose, DM2, dyslipidemias, or lipodystrophies (Dubé and Cadden, 2011;Lozano and Domingo, 2011;Barlow-Mosha et al., 2013;Lake and Currier, 2013;Jeerunda Santiprabhob et al., 2017). NNRTIs (nevirapine, efavirenz, and etravirine) usually cause hepatotoxicity, dyslipidemia, hypertriglyceridemia, and hyperinsulinemia (Worm et al., 2010;Lozano and Domingo, 2011;Jeerunda Santiprabhob et al., 2017). ...
Metabolic alterations, resulting from factors such as obesity or infections (HIV), generate inflammation in the body, affecting the immune system and causing oxidative stress. Prolonged exposure to antiretroviral therapy (ART) conditions the appearance of alterations considered risk factors for metabolic syndrome (MetS), affecting the quality of life in people living with HIV/AIDS (PLWHA). β-klotho is a protein that can counteract levels of oxidative stress. The aim was to determine the relation of β-klotho and oxidative stress with metabolic alterations in PLWHA. We hypothesized that levels of β-klotho and malondialdehyde (MDA) are related in PLWHA on ART with overweight/obesity. As a result of comparing cases versus controls, significant differences were obtained in levels of β-klotho (p = 0.011), MDA (p < 0.0001), body mass index (p = 0.001), and weight (p < 0.0001). The presence of MetS in PLWHA was 21.2% and 10.6% according to the World Health Organization and ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria, respectively. The founded correlations were of β-klotho (r = 0.019) and MDA (r = 0.0001), both with CD4+ cells in PLWHA. In controls, β-klotho was correlated with very low-density lipoprotein (r = 0.035) and atherogenic index (AI; r = 0.037), MDA with AI (r = 0.039), cholesterol, and low-density lipoprotein (r = 0.002). The increase of inflammation in the organism, owing to HIV infection and/or the presence of obesity, conditions metabolic disruption or depletion of elements needed for homeostasis in the human body.
... Only one study included a high proportion of treatment naïve patients (61%, 34/56) (22). Furthermore, two studies included patients exposed to didanosine and stavudine, two antiretroviral drugs that are no longer recommended for treatment of children and adolescents due to adverse events such as lipoatrophy, lactic acidosis, peripherical neuropathy and pancreatitis (35)(36)(37). As atazanavir has been used since 2004, several children and adolescents were exposed to antiretroviral regimens based on this protease inhibitor drug and two NRTIs, mainly zidovudine, lamivudine, stavudine, didanosine or tenofovir. ...
Background
Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents.
Methods
We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals.
Results
Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15–22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3–4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months.
Conclusion
Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3–4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen.
PROSPERO number
CRD42022309230
... In addition,~50% of the new infant HIV infections occur when a newly infected mother, who is not on therapy unknowingly transfers the virus to their offspring (127). Infants and children who are infected with HIV early in life from their mothers have to rely on lifelong ART to keep viral replication suppressed, and as a consequence, they are predisposed to ART-associated metabolic complications (128). Moreover, some ART regimens during pregnancy are associated with fetal complications such as neural tube disorders (129), preterm birth (130), hematological abnormalities (131), and mitochondrial dysfunction, later in life (129,131). ...
Pregnancy significantly elevates the risk of developing severe viral diseases, which can have a detrimental effect on fetal development and increases maternal mortality. In addition, certain viruses can be transmitted vertically from mother to babies, either in utero, during delivery, or postnatally during breastfeeding, resulting in congenital or neonatal diseases and associated sequelae. While neonates are highly susceptible to viral infections and severe disease outcomes, due to the immaturity of their developing immune system, virus-specific maternal antibodies transferred either trans-placentally or via breast milk provide protection to infants against intestinal, respiratory, or systemic infections, during the first months of life. Thus, maternal prenatal immunization is important not only to protect pregnant women from viral diseases, but also to prevent infection and/or improve disease outcomes for the fetuses and neonates via passively transferred antibodies. In this review, we discuss the protective role of maternal antibodies against three categories of viruses: (i) viruses that cause severe maternal disease outcomes with mainly indirect consequences to the fetus (e.g. SARS-CoV-2, influenza, DENV, filovirus), (ii) those that are vertically transmitted from mother to their infants and cause congenital diseases (e.g. HIV, ZIKV and CMV), and (iii) those that cause elevated disease severity among neonates and infants postnatally (e.g. RSV, Rotavirus, Norovirus, HSV and HBV). Furthermore, we review relevant pre-clinical animal models that can be employed to develop novel immunization strategies against these viruses to enhance protection of pregnant women and their babies.
... IR is defined as lower capacity of insulin to instigate use of glucose by adipose tissue and muscles, or which leads to expansion of pancreatic insulin formation. 4 HIV and continued use of ART are considered to be facilitators for development of IR in the pediatric population. 4 HIV infection, opportunistic infections and intestinal inflammation can culminate in changes to inflammatory cytokines, such as soluble tumor necrosis factor and hormones such as adiponectin and reduced leptin, which impairs glucose homeostasis. ...
... 4 HIV and continued use of ART are considered to be facilitators for development of IR in the pediatric population. 4 HIV infection, opportunistic infections and intestinal inflammation can culminate in changes to inflammatory cytokines, such as soluble tumor necrosis factor and hormones such as adiponectin and reduced leptin, which impairs glucose homeostasis. 5,6 In addition, changes to CD4+ and CD8+ T-cell functions may impair glycolysis, which may adversely influence glucose metabolism. ...
... 29 Although there is no consensus on the association between different lipodystrophy phenotypes and IR in pediatric patients diagnosed with HIV, high insulin concentrations were found previously in children with lipohypertrophy, and less consistently in children with lipoatrophy. 4 The skinfolds associated with IR differed according to sex (male/ female). This may be explained by the existence of sexual dimorphism. ...
Background:
Studies that test associations between anthropometric indicators and insulin resistance (IR) need to provide better evidence in the context of the pediatric population (children and adolescents) with human immunodeficiency virus (HIV), as anthropometric indicators present a better explanation of the distribution of body fat.
Objective:
To test the associations between anthropometric indicators and insulin resistance (IR) among children and adolescents diagnosed with HIV.
Design and setting:
Cross-sectional study on 65 children and adolescents (8-15 years) infected with HIV through vertical transmission conducted at the Joana de Gusmão Children's Hospital, Florianópolis, Brazil.
Methods:
The anthropometric indicators measured were the abdominal (ASF), triceps (TSF), subscapular (SSF) and calf (CSF) skinfolds. The relaxed arm (RAC), waist (WC) and neck (NC) circumferences were also measured. Body mass index (BMI) was calculated from the relationship between body mass and height. IR was calculated through the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Simple and multiple linear regression analyses were used.
Results:
After adjustment for covariates (sex, bone age, CD4+ T lymphocytes, CD8+ T lymphocytes, viral load, and physical activity), associations between IR and models with SSF and CSF remained. Each of these explained 20% of IR variability. For females, in the adjusted analyses, direct associations between IR and models with ASF (R² = 0.26) and TSF (R² = 0.31) were observed.
Conclusions:
SSF and CSF in males and ASF and TSF in females were associated with IR in HIV-infected children and adolescents.
... Due to effective life-long combination antiretroviral therapy (cART), perinatally HIVinfected (PHIV) children and adolescents are expected to have a near normal life expectancy [1]. However, non-communicable disease manifestations such as metabolic syndrome and cardiovascular disease (CVD) are more likely to occur in people living with HIV compared to the general population [2,3]. In PHIV children and adolescents, cardiovascular complications are also apparent, including structural and functional myocardial dysfunction, increased intima-media thickness and endothelial dysfunction [4]. ...
HIV is an independent risk factor of cardiovascular disease (CVD); therefore, perinatally HIV-infected (PHIV) children potentially have a greater CVD risk at older age. Lipoprotein(a) (Lp(a)) is an established risk factor for CVD in the general population. To evaluate a potential increased CVD risk for PHIV children, we determined their lipid profiles including Lp(a). In the first substudy, we assessed the lipid profiles of 36 PHIV children visiting the outpatient clinic in Amsterdam between 2012 and 2020. In the second substudy, we enrolled 21 PHIV adolescents and 23 controls matched for age, sex and ethnic background on two occasions with a mean follow-up time of 4.6 years. We assessed trends of lipid profiles and their determinants, including patient and disease characteristics, using mixed models. In the first substudy, the majority of PHIV children were Black (92%) with a median age of 8.0y (5.7–10.8) at first assessment. Persistent elevated Lp(a) levels were present in 21/36 (58%) children (median: 374 mg/L (209–747); cut off = 300). In the second substudy, the median age of PHIV adolescents was 17.5y (15.5–20.7) and of matched controls 16.4y (15.8–19.5) at the second assessment. We found comparable lipid profiles between groups. In both studies, increases in LDL-cholesterol and total cholesterol were associated with higher Lp(a) levels. A majority of PHIV children and adolescents exhibited elevated Lp(a) levels, probably associated with ethnic background. Nonetheless, these elevated Lp(a) levels may additionally contribute to an increased CVD risk.
... When it comes to children and adolescents, these disorders must be observed more carefully since some drugs have a cumulative effect, which is an independent risk factor, others have only a transitory effect [6]. Thus, complications can generate acute, serious, and permanent problems, especially in those infected vertically [8]. ...
We analyze the influence of dietary counseling and physical activity on biochemical and metabolic parameters in children and adolescents with HIV. A longitudinal experimental study, including three analyses: At the beginning, 4th month, and 8th month. A sample of 18 subjects with HIV of both sexes, mean age 10.4 ± 4.50 years. Usual food intake (24 h recall and food intake marker), level of habitual physical activity, biochemical parameters, resting metabolic rate, as well as body composition (dual-energy X-ray absorptiometry), biological maturation, and anamnesis with clinical data and socioeconomic were evaluated. There was an effect of time on the reduction of blood glucose and triglycerides and the resting metabolic rate. There was a significant increase in fruit consumption throughout the study. The consumption of soft drinks decreased when comparing analysis periods 1 and 2, however, it increased again in analysis period 3. There was no significant effect of time on the set of variables related to a food recall. Counseling healthy habits and regular clinical follow-up were relevant for improving biochemical parameters (glucose, triglyceride, HDL cholesterol), maintaining the resting metabolic rate, increasing fruit consumption, and decreasing the consumption of soft drinks, in part of the time, of children and adolescents with HIV. Finally, we emphasize that counseling positively influenced healthy habits, and these, in turn, improved health-related parameters.
... Acquiring HIV in the peripartum period or during breastfeeding commits infants to a life-long sentence of daily ART, as interruption of treatment is universally associated with the rebound of replicating virus and repopulation of viral reservoirs. Moreover, prolonged drug exposure in children who initiate ART at a young age can have long-term metabolic consequences (28), and children are at a higher risk than adults of developing triple class virologic failure (29). Thus, novel interventions to universally prevent pediatric HIV infections that do not rely on daily adherence to medications will be needed to end the pediatric HIV epidemic. ...
Widespread availability of antiretroviral therapy among pregnant women living with HIV has greatly reduced the rate of mother-to-child transmission (MTCT) of HIV across the globe. However, while Joint United Nations Programme on HIV/AIDS has set targets to reduce the annual number of new pediatric HIV infections to fewer than 40,000 in 2018 and fewer than 20,000 in 2020, progress towards these targets has plateaued at an unacceptably high global estimate of greater than 160,000 children newly infected with HIV in 2018. Moreover, it has become clear that expansion of maternal antiretroviral therapy alone will not be sufficient to close the remaining gap and eliminate MTCT of HIV. Additional strategies such as maternal or infant passive and/or active immunization that synergize with maternal antiretroviral therapy will be required to end the pediatric HIV epidemic. In this review, we outline the landscape of existing maternal interventions and emerging maternal immune-based approaches to prevent MTCT of HIV.
... While ART inactivates replicating virus, the drugs cannot abolish the latent viral reservoir that results from infection, causing lifelong dependence on this drug. While ART in HIV-infected children prevents disease progression to AIDS, ART has been associated with metabolic complications including lipodystrophy, dyslipidemia, insulin resistance, lactic acidosis, and loss of bone density (208). Thus, additional options to support current prevention strategies against perinatal HIV transmission are needed to eliminate the pediatric HIV epidemic. ...
Congenital and perinatal infections are transmitted from mother to infant during pregnancy across the placenta or during delivery. These infections not only cause pregnancy complications and still birth, but also result in an array of pediatric morbidities caused by physical deformities, neurodevelopmental delays, and impaired vision, mobility and hearing. Due to the burden of these conditions, congenital and perinatal infections may result in lifelong disability and profoundly impact an individual's ability to live to their fullest capacity. While there are vaccines to prevent congenital and perinatal rubella, varicella, and hepatitis B infections, many more are currently in development at various stages of progress. The spectrum of our efforts to understand and address these infections includes observational studies of natural history of disease, epidemiological evaluation of risk factors, immunogen design, preclinical research of protective immunity in animal models, and evaluation of promising candidates in vaccine trials. In this review we summarize this progress in vaccine development research for Cytomegalovirus, Group B Streptococcus, Herpes simplex virus, Human Immunodeficiency Virus, Toxoplasma, Syphilis, and Zika virus congenital and perinatal infections. We then synthesize this evidence to examine how close we are to developing a vaccine for these infections, and highlight areas where research is still needed.
