Identification, Management, and Outcomes of Combination Antiretroviral Treatment Failure in Adolescents With Perinatal Human Immunodeficiency Virus Infection in Asia.

BACKGROUND: Combination antiretroviral therapy (cART) failure is a major threat to human immunodeficiency virus (HIV) programs, with implications for individual- and population-level outcomes. Adolescents with perinatally acquired HIV infection (PHIVA) should be a focus for treatment failure given their poorer outcomes compared to children and adults. METHODS: Data (2014-2018) from a regional cohort of Asian PHIVA who received at least 6 months of continuous cART were analyzed. Treatment failure was defined according to World Health Organization criteria. Descriptive analyses were used to report treatment failure and subsequent management and evaluate postfailure CD4 count and viral load trends. Kaplan-Meier survival analyses were used to compare the cumulative incidence of death and loss to follow-up (LTFU) by treatment failure status. RESULTS: A total 3196 PHIVA were included in the analysis with a median follow-up period of 3.0 years, of whom 230 (7.2%) had experienced 292 treatment failure events (161 virologic, 128 immunologic, 11 clinical) at a rate of 3.78 per 100 person-years. Of the 292 treatment failure events, 31 (10.6%) had a subsequent cART switch within 6 months, which resulted in better immunologic and virologic outcomes compared to those who did not switch cART. The 5-year cumulative incidence of death and LTFU following treatment failure was 18.5% compared to 10.1% without treatment failure. CONCLUSIONS: Improved implementation of virologic monitoring is required to realize the benefits of virologic determination of cART failure. There is a need to address issues related to accessibility to subsequent cART regimens, poor adherence limiting scope to switch regimens, and the role of antiretroviral resistance testing.

Early Height and Weight Changes in Children Using Cotrimoxazole Prophylaxis With Antiretroviral Therapy.

BACKGROUND: The growth benefits of cotrimoxazole during early antiretroviral therapy (ART) are not well characterized. METHODS: Individuals enrolled in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database were included if they started ART at ages 1 month-14 years and had both height and weight measurements available at ART initiation (baseline). Generalized estimating equations were used to identify factors associated with change in height-for-age z-score (HAZ), follow-up HAZ ≥ -2, change in weight-for-age z-score (WAZ), and follow-up WAZ ≥ -2. RESULTS: A total of 3217 children were eligible for analysis. The adjusted mean change in HAZ among cotrimoxazole and non-cotrimoxazole users did not differ significantly over the first 24 months of ART. In children who were stunted (HAZ < -2) at baseline, cotrimoxazole use was not associated with a follow-up HAZ ≥ -2. The adjusted mean change in WAZ among children with a baseline CD4 percentage (CD4%) >25% became significantly different between cotrimoxazole and non-cotrimoxazole users after 6 months of ART and remained significant after 24 months (overall P < .01). Similar changes in WAZ were observed in those with a baseline CD4% between 10% and 24% (overall P < .01). Cotrimoxazole use was not associated with a significant difference in follow-up WAZ in children with a baseline CD4% <10%. In those underweight (WAZ < -2) at baseline, cotrimoxazole use was associated with a follow-up WAZ ≥ -2 (adjusted odds ratio, 1.70 vs not using cotrimoxazole [95% confidence interval, 1.28-2.25], P < .01). This association was driven by children with a baseline CD4% ≥10%. CONCLUSIONS: Cotrimoxazole use is associated with benefits to WAZ but not HAZ during early ART in Asian children.

Transcriptome sequencing and comparative analysis of Schizochytrium mangrovei PQ6 at different cultivation times.

OBJECTIVE: The heterotrophic marine microalga, Schizochytrium mangrovei PQ6, synthesizes large amounts of polyunsaturated fatty acids (PUFAs) with possible nutritional applications. We characterized the transcriptome of S. mangrovei PQ6, focusing on lipid metabolism pathways throughout growth. RESULT: Cell growth, total lipid, and docosahexaenoic acid (DHA, 22:6n-3) contents of S. mangrovei PQ6 in 500 ml batch cultures rapidly increased on day 1 in cultivation and reached their maximum levels on day 5. Maximum lipid accumulation in 500 ml batch cultures occurred on day 5, with total lipid and DHA contents reaching 33.2 ± 1.25% of dry cell weight (DCW) and 136 mg/g DCW, respectively. 11,025 unigenes, 28,617 unigenes and 18,480 unigenes from the transcriptomes of samples collected on day 1, 3, and 5 in cultivation were identified, respectively. These unigenes of the three samples were further assembled into 30,782 unigenes with an average size of 673 bp and N50 of 950 bp, and a total of 9,980 unigenes were annotated in public protein databases. 93 unigenes involved in lipid metabolism in which expression patterns corresponded with total lipid and DHA accumulation patterns were identified. CONCLUSION: The possible roles of PUFAs pathways, such as those mediated by fatty acid synthase, polyketide synthase, and desaturase/elongase, co-exist in S. mangrovei PQ6.

Molecular and cellular characterization of novel {alpha}-mannosidosis mutations.

α-Mannosidosis is a lysosomal storage disorder caused by mutations in the MAN2B1 gene. The clinical presentation of α-mannosidosis is variable, but typically includes mental retardation, skeletal abnormalities and immune deficiency. In order to understand the molecular aetiology of α-mannosidosis, we describe here the subcellular localization and intracellular processing of 35 MAN2B1 variants, including 29 novel missense mutations. In addition, we have analysed the impact of the individual mutations on the three-dimensional structure of the human MAN2B1. We categorize the MAN2B1 missense mutations into four different groups based on their intracellular processing, transport and secretion in cell culture. Impaired transport to the lysosomes is a frequent cause of pathogenicity and correlates with a lack of protein processing (groups 1 and 3). Mutant MAN2B1 proteins that find their way to the lysosomes are processed, but less efficiently than the wild-types (groups 2 and 4). The described four categories of missense mutations likely represent different pathogenic mechanisms. We demonstrate that the severity of individual mutations cannot be determined based only on their position in the sequence. Pathogenic mutations cluster into amino acids which have an important role on the domain interface (arginines) or on the folding of the enzyme (prolines, glycines, cysteines). Tolerated mutations generally include surface mutations and changes without drastic alteration of residue volume. The expression system and structural details presented here provide opportunities for the development of pharmacological therapy by screening or design of small molecules that might assist MAN2B1 folding and hence, transport and activity.

Long-Term Post-Transition Outcomes of Adolescents and Young Adults Living With Perinatally and Non-perinatally Acquired HIV in Southeast Asia.

PURPOSE: We assessed factors associated with clinical, social, and behavioral outcomes of adolescents and young adults with HIV (AYHIV) in Southeast Asia after transition from pediatric to adult HIV care. METHODS: AYHIV in Malaysia, Thailand, and Vietnam were prospectively followed through annual clinical assessments and laboratory testing. Data were described descriptively and a generalized estimating equation was used to calculate independent predictors for HIV viremia (>40 copies/mL). RESULTS: A total of 93 AYHIV were followed until February 2019: 60% female, 94% acquired HIV perinatally, 81% Thai, median age 20 (interquartile range, 18-21) years. The median follow-up time was 94 (91-100) weeks; 88% completed the study. At week 96, median CD4 was 557 cells/mm3 (interquartile range, 337-786), 77% had suppressed HIV viral load, 39% reported recent alcohol use, 49% had been sexually active, 53% of females and 36% of males intended to have children, and 23% screened positive for moderate depression (Patient Health Questionnaire-9 score ≥9) or reported suicidal ideation. HIV viremia was associated with <90% adherence to HIV treatment (adjusted incidence rate ratio [aIRR] 2.2 [1.28-3.78]), CD4 count ≤500 cells/mm3 (aIRR 4.75 [2.11-10.69]), and being on a nonnucleoside reverse transcriptase inhibitor regimen (vs. protease inhibitor aIRR 2.71 [1.13-6.49]). Having a trusted person to talk with about their feelings was protective (vs. never; usually or always, aIRR 0.41 [0.18-0.92]). DISCUSSION: After transition to adult HIV care, there were indications of social isolation and mental health problems that could prevent these AYHIV from maintaining control over their HIV infection and hinder progress toward social independence.

Clinical Features and the Outcome Evaluations of Keloid and Hypertrophic Scar Treatment with Triamcinolone Injection in Mekong Delta, Vietnam - A Cross-Sectional Study.

Background: Excessive scarring is a common problem that can have significant cosmetic and psychological consequences for patients. Intralesional injection therapy, such as the use of triamcinolone, has emerged as an effective treatment option for hypertrophic scars. The objective of this study was to describe the morphological features of hypertrophic scars, categorize them, and evaluate the efficacy of triamcinolone injection therapy in treating these scars. Materials and Methods: A cross-sectional descriptive study of 80 patients with hypertrophic scars treated with triamcinolone intralesional injection at Can Tho University of Medicine and Pharmacy Hospital from 5/2018 to 5/2021. Results: There were 80 patients in all, with a male/female ratio of 1/1.05 and a median age of 15-35. There were 129 scars in all, with scar age >1 year accounting for 83%, keloid scars accounting for 64%, and hypertrophic scars accounting for the remaining 36%. Scars are most commonly seen on the trunk, accounting for 53.5% of all scars, particularly on the anterior chest wall. When the source of scars was discovered, trauma and acne accounted for 24% and 23%, respectively, while the rest were predominantly spontaneous scars, accounting for 49%. Scarring and discomfort of mild to moderate severity were common clinical symptoms; scars larger than 5cm in size had more symptoms than scars smaller than 5cm. Prior to the therapy, the mean Vancouver Score Scale-VSS was 6.55±2.13. After 24 weeks of the therapy, 96.7% of patients had entirely improved itching symptoms, 75% had completely improved pain, and 25% still had minimal pain. After therapy, the mean Vancouver Score Scale-VSS was 2.55±1.81 (p<0.05). At week 24, 3.75% of patients experienced skin shrinkage, 3.75% experienced depigmentation, and 13.75% experienced vasodilation. Conclusion: Triamcinolone intralesional injection should be utilized as a first-line therapy for hypertrophic scarring.

Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations.

The lysosomal storage disorder alpha-mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated alpha-mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants.

Successful treatment of two extremely premature infants with perinatal tuberculosis and severe sepsis.

Perinatal tuberculosis (TB) is a rare disease with severe clinical conditions that may spread to several organs. Early diagnosis to initiate an anti-TB regimen is key to saving patients. We report the successful treatment of two preterm babies with perinatal TB and sepsis at the National Children's Hospital (NCH), Vietnam.

Severe Recurrent Bacterial Pneumonia Among Children Living With HIV.

BACKGROUND: Bacterial pneumonia imparts a major morbidity and mortality burden on children living with HIV, yet effective prevention and treatment options are underutilized. We explored clinical factors associated with severe recurrent bacterial pneumonia among children living with HIV. METHODS: Children enrolled in the TREAT Asia Pediatric HIV Observational Database were included if they started antiretroviral therapy (ART) on or after January 1st, 2008. Factors associated with severe recurrent bacterial pneumonia were assessed using competing-risk regression. RESULTS: A total of 3,944 children were included in the analysis; 136 cases of severe recurrent bacterial pneumonia were reported at a rate of 6.5 [95% confidence interval (CI): 5.5-7.7] events per 1,000 patient-years. Clinical factors associated with severe recurrent bacterial pneumonia were younger age [adjusted subdistribution hazard ratio (aHR): 4.4 for <5 years versus ≥10 years, 95% CI: 2.2-8.4, P < 0.001], lower weight-for-age z-score (aHR: 1.5 for <-3.0 versus >-2.0, 95% CI: 1.1-2.3, P = 0.024), pre-ART diagnosis of severe recurrent bacterial pneumonia (aHR: 4.0 versus no pre-ART diagnosis, 95% CI: 2.7-5.8, P < 0.001), past diagnosis of symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease, including bronchiectasis (aHR: 4.8 versus no past diagnosis, 95% CI: 2.8-8.4, P < 0.001), low CD4% (aHR: 3.5 for <10% versus ≥25%, 95% CI: 1.9-6.4, P < 0.001) and detectable HIV viral load (aHR: 2.6 versus undetectable, 95% CI: 1.2-5.9, P = 0.018). CONCLUSIONS: Children <10-years-old and those with low weight-for-age, a history of respiratory illness, low CD4% or poorly controlled HIV are likely to gain the greatest benefit from targeted prevention and treatment programs to reduce the burden of bacterial pneumonia in children living with HIV.

Knowledge of Antiretroviral Treatment and Associated Factors in HIV-Infected Patients.

This study aimed to assess the knowledge of antiretroviral (ARV) treatment and the associated factors in HIV-infected patients in Vietnam. We conducted a cross-sectional descriptive study of 350 human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients being treated with ARV at outpatient clinics at Soc Trang, Vietnam, from June 2019 to December 2019. Using an interview questionnaire, patients who answered at least eight out of nine questions correctly, including some required questions, were considered to have a general knowledge of ARV treatment. Using multivariate logistic regression to identify factors associated with knowledge of ARV treatment, we found that 62% of HIV-infected patients had a general knowledge of ARV treatment, with a mean score of 8.2 (SD 1.4) out of 9 correct. A higher education level (p < 0.001); working away from home (p = 0.013); getting HIV transmitted by injecting drugs or from mother-to-child contact (p = 0.023); the presence of tension, anxiety, or stress (p = 0.005); self-reminding to take medication (p = 0.024); and a high self-evaluated adherence (p < 0.001) were found to be significantly associated with an adequate knowledge of ARV treatment. In conclusion, education programs for patients, as well as the quality of medical services and support, should be strengthened.

Determinants of Viral Resuppression or Persistent Virologic Failure After Initial Failure With Second-Line Antiretroviral Treatment Among Asian Children and Adolescents With HIV.

Of 56 children with perinatally acquired human immunodeficiency virus (HIV) who had been prescribed second-line protease inhibitor-based antiretroviral therapy and had ≥1 previous episode of viral failure (HIV RNA, ≥1000 copies/mL), 46% had ≥1, 34% had ≥2, and 23% had ≥3 consecutive episodes of viral failure during the 2 years of follow-up. Two of these children experienced a major protease inhibitor mutation.

Peritransition Outcomes of Southeast Asian Adolescents and Young Adults With HIV Transferring From Pediatric to Adult Care.

PURPOSE: The aim of this article was to study the clinical and social outcomes of health care transition among Asian adolescents and young adults with HIV (AYHIV). METHODS: AYHIV who transferred from a pediatric to an adult clinic within the past year across five sites in Malaysia, Thailand, and Vietnam had clinical and laboratory evaluations and completed questionnaires about their health, socioeconomic factors, and transition experiences. Multiple logistic regression was used to assess associations with HIV viremia. RESULTS: Of 93 AYHIV enrolled between June 2016 and April 2017, 56% were female, 87% acquired HIV through perinatal exposure, median age was 20 years (interquartile range [IQR] 18.5-21). Two-thirds were in a formal education program, 43% were employed, 43% of females and 35% of males were sexually active. Median lifetime antiretroviral therapy duration was 6.2 years (IQR 3.3-10.7); 45% had received second-line therapy. Median CD4 was 601 cells/mm3 (IQR 477-800); 82% had HIV-RNA <40 copies/mL. Being in a relationship, a shorter posttransition duration, self-reported adherence of ≥95%, and higher CD4 were inversely associated with HIV viremia. Half felt very prepared for the transfer to adult care, and 20% frequently and 43% sometimes still met with pediatric providers. Two-thirds reported needing to keep their HIV a secret, and 23%-38% reported never or rarely having someone to discuss problems with. CONCLUSIONS: Asian AYHIV in our cohort were concerned about the negative social impact of having and disclosing HIV, and one-third lacked people they could trust with their personal problems, which could have negative implications for their ability to navigate adult life.

Determining standardized causes of death of infants, children, and adolescents living with HIV in Asia.

OBJECTIVE: To implement a standardized cause of death reporting and review process to systematically disaggregate causes of HIV-related deaths in a cohort of Asian children and adolescents. DESIGN: Death-related data were retrospectively and prospectively assessed in a longitudinal regional cohort study. METHODS: Children under routine HIV care at sites in Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam between 2008 and 2017 were followed. Causes of death were reported and then independently and centrally reviewed. Predictors were compared using competing risks survival regression analyses. RESULTS: Among 5918 children, 5523 (93%; 52% male) had ever been on combination antiretroviral therapy. Of 371 (6.3%) deaths, 312 (84%) occurred in those with a history of combination antiretroviral therapy (crude all-cause mortality 9.6 per 1000 person-years; total follow-up time 32 361 person-years). In this group, median age at death was 7.0 (2.9-13) years; median CD4 cell count was 73 (16-325) cells/µl. The most common underlying causes of death were pneumonia due to unspecified pathogens (17%), tuberculosis (16%), sepsis (8.0%), and AIDS (6.7%); 12% of causes were unknown. These clinical diagnoses were further grouped into AIDS-related infections (22%) and noninfections (5.8%), and non-AIDS-related infections (47%) and noninfections (11%); with 12% unknown, 2.2% not reviewed. Higher CD4 cell count and better weight-for-age z-score were protective against death. CONCLUSION: Our standardized cause of death assessment provides robust data to inform regional resource allocation for pediatric diagnostic evaluations and prioritization of clinical interventions, and highlight the continued importance of opportunistic and nonopportunistic infections as causes of death in our cohort.

Mycobacterial Blood Culture for Diagnosis of Tuberculosis in Vietnamese Children.

Diagnosis of pediatric tuberculosis is notoriously difficult. We investigated the additional yield of blood culture in hospitalized children in Vietnam. Among 554 enrolled clinically suspected patients, an additional 6 cases were diagnosed, while the incremental cost per case was USD500. Addition of blood culture is therefore not recommended for our total patient population, but may be considered in specific groups.

A Longitudinal Study of Behavioral Risk, Adherence, and Virologic Control in Adolescents Living With HIV in Asia.

BACKGROUND: Adolescents living with HIV (ALHIV) have poorer adherence and clinical outcomes than adults. We conducted a study to assess behavioral risks and antiretroviral therapy outcomes among ALHIV in Asia. METHODS: A prospective cohort study among ALHIV and matched HIV-uninfected controls aged 12-18 years was conducted at 9 sites in Malaysia, Thailand, and Vietnam from July 2013 to March 2017. Participants completed an audio computer-assisted self-interview at weeks 0, 48, 96, and 144. Virologic failure (VF) was defined as ≥1 viral load (VL) measurement >1000 copies/mL. Generalized estimating equations were used to identify predictors for VF. RESULTS: Of 250 ALHIV and 59 HIV-uninfected controls, 58% were Thai and 51% females. The median age was 14 years at enrollment; 93% of ALHIV were perinatally infected. At week 144, 66% of ALHIV were orphans vs. 28% of controls (P < 0.01); similar proportions of ALHIV and controls drank alcohol (58% vs. 65%), used inhalants (1% vs. 2%), had been sexually active (31% vs. 21%), and consistently used condoms (42% vs. 44%). Of the 73% of ALHIV with week 144 VL testing, median log VL was 1.60 (interquartile range 1.30-1.70) and 19% had VF. Over 70% of ALHIV had not disclosed their HIV status. Self-reported adherence ≥95% was 60% at week 144. Smoking cigarettes, >1 sexual partner, and living with nonparent relatives, a partner or alone, were associated with VF at any time. CONCLUSIONS: The subset of ALHIV with poorer adherence and VF require comprehensive interventions that address sexual risk, substance use, and HIV-status disclosure.

Dual Analysis of Loss to Follow-up for Perinatally HIV-Infected Adolescents Receiving Combination Antiretroviral Therapy in Asia.

BACKGROUND: Perinatally HIV-infected adolescents (PHIVA) are an expanding population vulnerable to loss to follow-up (LTFU). Understanding the epidemiology and factors for LTFU is complicated by varying LTFU definitions. SETTING: Asian regional cohort incorporating 16 pediatric HIV services across 6 countries. METHODS: Data from PHIVA (aged 10-19 years) who received combination antiretroviral therapy 2007-2016 were used to analyze LTFU through (1) an International epidemiology Databases to Evaluate AIDS (IeDEA) method that determined LTFU as >90 days late for an estimated next scheduled appointment without returning to care and (2) the absence of patient-level data for >365 days before the last data transfer from clinic sites. Descriptive analyses and competing-risk survival and regression analyses were used to evaluate LTFU epidemiology and associated factors when analyzed using each method. RESULTS: Of 3509 included PHIVA, 275 (7.8%) met IeDEA and 149 (4.3%) met 365-day absence LTFU criteria. Cumulative incidence of LTFU was 19.9% and 11.8% using IeDEA and 365-day absence criteria, respectively. Risk factors for LTFU across both criteria included the following: age at combination antiretroviral therapy initiation <5 years compared with age ≥5 years, rural clinic settings compared with urban clinic settings, and high viral loads compared with undetectable viral loads. Age 10-14 years compared with age 15-19 years was another risk factor identified using 365-day absence criteria but not IeDEA LTFU criteria. CONCLUSIONS: Between 12% and 20% of PHIVA were determined LTFU with treatment fatigue and rural treatment settings consistent risk factors. Better tracking of adolescents is required to provide a definitive understanding of LTFU and optimize evidence-based models of care.

Time to First-Line ART Failure and Time to Second-Line ART Switch in the IeDEA Pediatric Cohort.

BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second-line. METHODS: Children initiating their first ART regimen between 2 and 14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis. Outcomes of interest were: first-line ART failure (clinical, immunologic, or virologic), change to second-line, and attrition (death or loss to program ). Cumulative incidence was computed for first-line failure and second-line initiation, with attrition as a competing event. RESULTS: In 27,031 children, median age at ART initiation was 6.7 years. Median baseline CD4% for children ≤5 years of age was 13.2% and CD4 count for those >5 years was 258 cells per microliter. Almost all (94.4%) initiated a nonnucleoside reverse transcriptase inhibitor; 5.3% a protease inhibitor, and 0.3% a triple nucleoside reverse transcriptase inhibitor-based regimen. At 1 year, 7.7% had failed and 14.4% had experienced attrition; by 5 years, the cumulative incidence was 25.9% and 29.4%, respectively. At 1 year after ART failure, 13.7% had transitioned to second-line and 11.2% had experienced attrition; by 5 years, the cumulative incidence was 31.6% and 25.9%, respectively. CONCLUSIONS: High rates of first-line failure and attrition were identified in children within 5 years after ART initiation. Of children meeting failure criteria, only one-third were transitioned to second-line ART within 5 years.

Final Height and Associated Factors in Perinatally HIV-infected Asian Adolescents.

We analyzed final height of 273 perinatally HIV-infected Asian adolescents older than 18 years at their last clinic visit. By the World Health Organization child growth reference, 30% were stunted, but by the Thai child growth reference, 19% were stunted. Half of those who were stunted at antiretroviral therapy initiation remained stunted over time. Being male and having a low baseline height-for-age Z score of less than -1.0 were associated with low final height Z score.