Triple Antiretroviral Therapy Research Articles

Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.

Effects of preterm birth, maternal ART and breastfeeding on 24-month infant HIV-free survival in a randomized trial.

IMPAACT 1077BF/FF compared the safety/efficacy of two HIV antiretroviral therapy (ART) regimens to zidovudine (ZDV) alone during pregnancy for HIV prevention. PROMISE found an increased risk of preterm delivery (<37 weeks) with antepartum triple ART (TDF/FTC/LPV+r or ZDV/3TC/LPV+r) compared to ZDV alone. We assessed the impact of preterm birth, breastfeeding and antepartum ART regimen on 24-month infant survival. We compared HIV-free and overall survival at 24-months for liveborn infants by gestational age, time-varying breastfeeding status, and antepartum ART arm at 14 sites in Africa and India. Kaplan-Meier survival probabilities and Cox proportional hazards ratios (HR) were estimated. 3,482 live-born infants (568 [16 3%] preterm and 2,914 [83 7%] term) were included. Preterm birth was significantly associated with lower HIV-free survival (0·85; 95% CI: 0·82-0·88) and lower overall survival (0·89; 95% CI: 0·86-0·91) versus term birth (0·96; 95% CI: 0·95-0·96). Very preterm birth (<34 weeks) was associated with low HIV-free survival (0·65; 95% CI: 0·54-0·73) and low overall survival (0·66; 95% CI: 0·56-0·74). Risk of HIV infection or death at 24-months was higher with TDF-ART than ZDV-ART (adjusted HR 2·37; 95% CI: 1·21-4·64). Breastfeeding initiated near birth decreased risk of infection or death at 24 months (adjusted HR 0·05; 95% CI: 0·03-0·08) compared to not breastfeeding. Preterm birth and antepartum TDF-ART were associated with lower 24-month HIV-free survival compared to term birth and ZDV-ART. Any breastfeeding strongly promoted HIV-free survival, especially if initiated close to birth. Reducing preterm birth and promoting infant feeding with breastmilk among HIV/ARV-exposed infants remain global health priorities.

Emotional and behavioural difficulties among children and adolescents attending “ART teen clubs” in Mzuzu City in northern Malawi: a cross-sectional study

BackgroundWhile triple anti-retroviral therapy (ART) has improved HIV-infected children surviving into adolescence and adulthood, these children remain vulnerable to HIV-related psychological disturbance due to both the direct HIV infection effects on the brain and indirect effects related to coping with a range of medical, psychological and social stresses associated with HIV, which makes it vital to identify their mental health needs. This study assessed the emotional and behavioural challenges of HIV perinatally infected children and adolescents with a completed disclosure process attending “ART teen club” in Malawi.MethodsA cross-sectional descriptive study design was conducted to obtain quantitative descriptive descriptions of emotional and behavioural challenges among HIV-infected children and adolescents between 10 and 22 years of age. They were interviewed on their family socio-demographic characteristics, clinical characteristics as well as emotional, conduct, hyperactivity, peer and prosocial problems using the Chichewa version of the Strengths and Difficulties Questionnaire. Data were analyzed using descriptive analysis and logistic regression.ResultsBased on the four-band categorization of the SDQ, higher scores for total difficulties score were observed in 72.9% of the children. According to the subscales of the SDQ, results show that children had higher scores in peer problems (62.8%), emotional (68.2%), conduct (68.6%) and prosocial (57.8%) subscales while lower scores were identified in the hyperactivity (16.6%) subscale. Results show that within each level, males are having lower frequencies as compared to females. Results from multivariate binary logistic regression indicate that those with a single parent or not as well as the WHO HIV clinical stage had an impact on the mental health status of the children. Children who do not have a single parent (AOR 3.404; 95% CI:1.563–7.416, p = 0.002) had 3.404 odds of having abnormal mental health status unlike those children with a single parent and children who were in WHO HIV clinical stage 2 (AOR 2.536; 95% CI:1.005–6.395, p = 0.049) or 3 and 4 (AOR 8.459; 95% CI:1.5.820-10.544, p < 0.001) had more odds of having the mental disorder as compared with those children in WHO HIV clinical stage 1.ConclusionThe findings of this research underscore the multifaceted nature of mental well-being among children and adolescents living with HIV. Elevated scores in total difficulties, emotional, conduct, and peer problems signify areas of concern, while disparities in hyperactivity and prosocial behavior highlight the nuanced nature of their behavioral challenges. Recognizing the inadequacy of a one-size-fits-all approach, the research emphasizes the necessity of a comprehensive strategy, incorporating factors like religious background, family structure, and clinical HIV stage. Furthermore, the role of “ART teen clubs” in this context is pivotal. Beyond addressing identified risk factors, these clubs must actively foster resilience. Creating an inclusive environment, tapping into individual strengths, and nurturing a sense of community are vital components. By adopting such a holistic approach, Teen support clubs can significantly contribute to the overall mental well-being of adolescents living with HIV, enabling them to navigate challenges effectively and thrive amidst their circumstances.

EE359 Cost-Utility of Bictegravir/Tenofovir Alafenamide/Emtricitabine in Naive Patients over 18 Years of Age Living with Human Immunodeficiency Virus Type 1 Infection, from the Colombian’s Health System Perspective

To estimate the cost-utility of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) versus other triple combination antiretroviral therapies for naive patients over 18 years of age living with Human Immunodeficiency Virus type 1 (HIV-1) infection, without current or previous resistance to integrase strand transfer inhibitors, TAF or FTC, from the Colombian’s health system perspective.

Progressive Characteristics of HIV Infection in the Elderly in the Cohort of the Internal Medicine Department of the Points G University Hospital, Bamako. Mali

Few data are available on HIV infection in the elderly and they are an important population in our different cohorts in view of the improvement in the quality of care over the last ten years. Objective: to determine the clinical and immunovirological characteristics as well as the acceptance of antiretroviral drugs in this patient population. This is a cohort study of the files of PLHIV (People living with HIV) aged 50 years or more, followed in the Internal Medicine Department of the Point G University Hospital between January 2007 and December 2012. Results: Out of 161 HIV-infected patients in the cohort, 38 were aged 50 years or older, of whom 11 met the criteria and were included. The median age was 55 years, 90.9% of whom were in the [50 - 59 years] age group, with 63.6% being women (sex ratio = 0.57). At admission, 3 patients (27.3%) had prurigo and 2 (18.2%) had oral-pharyngeal candidiasis. At inclusion, 45.5% of patients were classified as WHO stage 2 and one as WHO stage 4. All were on ARVs, including 10 on 1st line HIV-1 and 1 on HIV-2. On triple therapy, the average weight gain was 5.1 kg at D15 and 6.84 kg at M6. However, at M12 there was a weight loss of 1.04 kg. The mean CD4 T cell gain was +102/mm3 at M6 and +188/mm3 at 12 months. At D0, mean viral load = 565024.75 copies/mm3 [99 - 1100000] in 4/11. At M12, two patients had undetectable viral loads. Conclusion: The prevalence of HIV in elderly subjects is certainly underestimated. Thanks to triple antiretroviral therapy, PLHIV are aging with HIV but screening is not systematically proposed during consultations in elderly subjects. It is necessary to reinforce communication about HIV at all ages.

Reversible Gynecomastia in HIV-Infected Man Treated With Triple Antiretroviral Therapy Containing Efavirenz: A Case Report

Gynecomastia is benign hypertrophy of male breast glandular tissue, either unilateral or bilateral, secondary to increased estrogen/testosterone ratio (elevated estrogen level, decreased testosterone levels, or both). The condition can be related to a medical disease or caused by some drugs.Since the introduction of triple antiretroviral therapy (TAT), we have seen an improvement in the prognosis of human immunodeficiency virus (HIV) infection.Here we report the case of a 53-year-old man receiving follow-up care in Internal Medicine for HIV infection receiving TAT (tenofovir/efavirenz/emtricitabine). After one year, the patient presented in the Department of Endocrinology, Diabetology, Metabolic Diseases, and Nutrition of Hassan II University Hospital Center, Fez, with bilateral gynecomastia. Hormonal exploration did not reveal any abnormality, so the gynecomastia was attributed to efavirenz use. The regimen was replaced by tenofovir, lamivudine, and dolutegravir. The gynecomastia was resolved within two months of discontinuing efavirenz.In summary, we think that secondary gynecomastia should be suspected and screened in HIV patients receiving efavirenz-containing regimens.

Similar CD4/CD8 Ratio Recovery After Initiation of Dolutegravir Plus Lamivudine Versus Dolutegravir or Bictegravir-Based Three-Drug Regimens in Naive Adults With HIV

BackgroundThe initiation of antiretroviral treatment based on a 2-drug regimen (2DR) with dolutegravir plus lamivudine has demonstrated non-inferior efficacy than dolutegravir-based three-drug regimens (3DR). We aimed to assess whether the treatment initiation with this 2DR has a different impact on the CD4/CD8 ratio recovery than INSTI-based 3DR.MethodsWe emulated a target trial using observational data from the Spanish HIV Research Network cohort (CoRIS). The outcomes of interest were the normalization of the CD4/CD8 ratio at 48 weeks using three different cutoffs: 0.5, 1.0, and 1.5. We matched each participant who started 2DR with up to four participants who received 3DR. Subsequently, we fitted generalized estimating equation (GEE) models and used the Kaplan–Meier method for survival curves.ResultsWe included 485, 805, and 924 participants for cutoffs of 0.5, 1.0, and 1.5, respectively. At 48 weeks, 45% of participants achieved a CD4/CD8 ratio >0.5, 15% achieved a ratio >1.0, and 6% achieved a ratio >1.5. GEE models yielded a similar risk of reaching a CD4/CD8 ratio >0.5 (OR 1.00, 95% CI 0.67 - 1.50), CD4/CD8 >1.0 (OR 1.03, 95% CI 0.68 - 1.58), and CD4/CD8 >1.5 (OR 0.86, 95% CI 0.48 - 1.54) between both treatment strategies. There were no differences between 2DR and 3DR in the incidence ratio of CD4/CD8 ratio normalization at 0.5, 1.0 and 1.5 cut-offs.ConclusionsIn this large cohort study in people with HIV, ART initiation with dolutegravir plus lamivudine vs. dolutegravir or bictegravir-based triple antiretroviral therapy showed no difference in the rates of CD4/CD8 normalization at 48 weeks.

Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants.

ABSTRACTThe “shock and kill” strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD4+ T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-κB genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful “shock and kill” strategies.IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4+ T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.

Raltegravir 1200\xa0mg once daily as maintenance therapy in virologically suppressed HIV-1 infected adults: QDISS open-label trial

BackgroundRaltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy.MethodsThe QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm.ResultsOf 100 participants 91% maintained viral suppression (95% CI: 83.6–95.8) at week 24 and 89% (81.2–94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3–4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007).ConclusionRAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes.Trial registration: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.

Early structural brain development in infants exposed to HIV and antiretroviral therapy in utero in a South African birth cohort.

IntroductionThere is a growing population of children who are HIV‐exposed and uninfected (HEU) with the successful expansion of antiretroviral therapy (ART) use in pregnancy. Children who are HEU are at risk of delayed neurodevelopment; however, there is limited research on early brain growth and maturation. We aimed to investigate the effects of in utero exposure to HIV/ART on brain structure of infants who are HEU compared to HIV‐unexposed (HU).MethodsMagnetic resonance imaging using a T2‐weighted sequence was undertaken in a subgroup of infants aged 2–6 weeks enrolled in the Drakenstein Child Health Study birth cohort, South Africa, between 2012 and 2015. Mother–child pairs received antenatal and postnatal HIV testing and ART per local guidelines. We compared subcortical and total grey matter volumes between HEU and HU groups using multivariable linear regression adjusting for infant age, sex, intracranial volume and socio‐economic variables. We further assessed associations between brain volumes with maternal CD4 cell count and ART exposure.ResultsOne hundred forty‐six infants (40 HEU; 106 HU) with high‐resolution images were included in this analysis (mean age 3 weeks; 50.7% male). All infants who were HEU were exposed to ART (88% maternal triple ART). Infants who were HEU had smaller caudate volumes bilaterally (5.4% reduction, p < 0.05) compared to HU infants. There were no group differences in other subcortical volumes (all p > 0.2). Total grey matter volume was also reduced in infants who were HEU (2.1% reduction, p < 0.05). Exploratory analyses showed that low maternal CD4 cell count (<350 cells/mm3) was associated with decreased infant grey matter volumes. There was no relationship between timing of ART exposure and grey matter volumes.ConclusionsLower caudate and total grey matter volumes were found in infants who were HEU compared to HU in the first weeks of life, and maternal immunosuppression was associated with reduced volumes. These findings suggest that antenatal HIV exposure may impact early structural brain development and improved antenatal HIV management may have the potential to optimize neurodevelopmental outcomes of children who are HEU.

Particularities of radiological lesions in smear-positive and HIV-positive tuberculosis patients in the era of triple antiretroviral therapy at Jamot Yaoundé hospital

Introduction: The aim of this work was to compare the radiological lesions during bacilliferous tuberculosis between HIV positive patients under ARV treatment and HIV negative patients. Methodology: This was a, descriptive and comparative study conducted from December 1, 2018 to May 31, 2019 (6 months) at Jamot Yaoundé Hospital. Smearpositive tuberculosis patients meeting our inclusion criteria were enrolled in the study. We split them into two groups, HIV + and HIV -. The comparison of the data was made by the Chi² test, that of the quantitative data with the Student's T test. A p-value less than 0.05 was considered significant. Results: In total, we recruited 145 patients divided into 2 groups of 63 HIV + patients and 82 HIV-patients. The radiological peculiarities found in HIV were as follows: Normal radiography was more frequent, P = 0.004. Interstitial syndrome was less common. Bilateral involvement was predominant. Right localization and upper lobe lesions were less frequent, P &lt;0.05. Micronodular lesions were more frequent, P &lt;0.05. During the alveolar syndrome, the left side was less affected and the upper lobe was the most; p &lt;0.05. Cavitary, pleural, mediastinal and bronchial syndromes did not show statistically significant differences. Conclusion: Although a normal x-ray does not exclude pulmonary tuberculosis, the x-ray lesions are multiple but are dominated by the interstitial syndrome. In patients immunocompromised to HIV, bilateral involvement predominates. The right localization and lesions of the upper lobe are less frequent. Micronodular lesions are frequent.

Safety and Experience With Combined Antiretroviral Prophylaxis in Newborn at High-risk of Perinatal HIV Infection, in a Cohort of Mother Living With HIV-infant Pairs.

Perinatal transmission of HIV has dramatically decreased in high-income countries in the last few years with current rates below 1%, but it still occurs in high-risk situations, mainly pregnant women with late diagnosis of infection, poor antiretroviral adherence and a high viral load (VL). In these high-risk situations, many providers recommend combined neonatal prophylaxis (CNP). Our aim was to evaluate the safety and toxicity of CNP in infants deemed at high-risk of HIV infection among mother-infant pairs in the Madrid Cohort. Prospective, multicenter, observational cohort study between years 2000 and 2019. The subgroup of newborns on CNP and their mothers were retrospectively selected (cohort A) and compared with those who received monotherapy with zidovudine (cohort B). Infants with monotherapy were classified according to treatment regimes in long (6 weeks) and short (4 weeks) course. We identified 227 newborns (33.3% preterm and 7 sets of twins) with CNP. A maternal diagnosis of HIV-1 infection was established during the current pregnancy in 72 cases (36.4%) and intrapartum or postpartum in 31 cases (15.7%). Most infants received triple combination antiretroviral therapy (65.6%; n = 149). The perinatal transmission rate in cohort A was 3.5% (95% confidence interval: 1.13%-5.92%). Infants from cohort A developed anemia (26.1% vs. 19.4%, P = 0.14) and neutropenia more frequently at 50-120 days (21.4% vs. 10.9%, P < 0.01), without significant differences in grade 3 and 4 anemia or neutropenia between the two cohorts. There were no differences in increased alanine aminotransferase. Neutropenia was more common in the long zidovudine regimes. Our findings provide further evidence of the safety of CNP in infants with high-risk of HIV-1 perinatal transmission.

Trends in hospitalizations and deaths in HIV-infected patients in Spain over two decades.

The prognosis of HIV infection dramatically improved after the introduction of triple antiretroviral therapy 25 years ago. Herein, we report the impact of further improvements in HIV management since then, looking at all hospitalizations in persons with HIV (PWH) in Spain. A retrospective study using the Spanish National Registry of Hospital Discharges. Information was retrieved since 1997-2018. From 79 647 783 nationwide hospital admissions recorded during the study period, 532 668 (0.67%) included HIV as diagnosis. The mean age of PWH hospitalized increased from 33 to 51 years (P < 0.001). The rate of HIV hospitalizations significantly declined after 2008. Comparing hospitalizations during the first (1997-2007) and last (2008-2018) decades, the rate of non-AIDS illnesses increased, mostly due to liver disease (from 35.9 to 38.3%), cardiovascular diseases (from 12.4 to 28.2%), non-AIDS cancers (from 6.4 to 15.5%), and kidney insufficiency (from 5.4 to 13%). In-hospital deaths occurred in 5.5% of PWH, declining significantly over time. Although most deaths were the result from AIDS conditions (34.8%), the most frequent non-AIDS deaths were liver disease (47.1%), cardiovascular events (29.2%), non-AIDS cancers (24.2%), and kidney insufficiency (20.7%). Hospital admissions in PWH significantly declined after 2008, following improvements in HIV management and antiretroviral therapy. Non-AIDS cancers, cardiovascular events and liver disease represent a growing proportion of hospital admissions and deaths in PWH.

Clinical and radiological epidemiological features of smear-positive tuberculosis patients in the era of triple antiretroviral therapy

Introduction: The aim of this work was to compare the epidemiological, clinical and radiological aspects during bacilliferous tuberculosis between HIV positive patients under ARV treatment and HIV negative. Methodology: This was a prospective, descriptive and comparative study conducted from December 1, 2018 to May 31, 2019 (6 months) at Jamot Yaoundé Hospital. Smear-positive tuberculosis patients meeting our inclusion criteria were enrolled in the study. We split them into two groups, HIV + and HIV - Data were analyzed using SPSS 23.0 software. The comparison of the data was made by the Chi² test, that of the quantitative data with the Student's T test. A p-value less than 0.05 was considered significant. Results: For HIV positive, the mean age was 41.1 ± 14.4 years versus 39.8 ± 14.8 years in the HIV negative group. HIV + patients aged 35 to 44 were more represented [49.5 versus 17.1% (P &lt;0.0001)]. The sex radio was 1.03 for the HIV positive versus 3.31 for the HIV negative group. The HIV + group had fewer single people, had more history of tuberculosis (22.2 versus 9.8%). HIV + patients were more likely to have a WHO performans status score 4, and were more febrile [96.8 versus 85.4% (p = 0.021)]. The normal chest x-ray was more common. Interstitial and alveolar syndromes were less common. Conclusion: The proportions of both sexes were almost identical. Almost half were 35 to 44 years old They had more history of tuberculosis. A WHO score of 4 and were generally febrile. Chest x-ray was often normal.Interstitial and alveolar syndromes were less common.

Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy

The latent viral reservoir formed by HIV-1, mainly in CD4 + T cells, is responsible for the failure of antiretroviral therapy (ART) to achieve a complete elimination of the virus in infected individuals. We previously determined that CD4 + T cells from individuals with chronic myeloid leukemia (CML) on treatment with dasatinib are resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral effect is the preservation of SAMHD1 activity. In this study, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIV-infected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML (1:65,000), three male individuals were recruited in Spain and Germany. These individuals had been on treatment with standard ART and dasatinib for median 1.3 years (IQR 1.3–5.3 years). Reservoir size and composition in PBMCs from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells was reduced more than 5-fold in these individuals. The reactivation of proviruses from these cells was reduced more than 4-fold and, upon activation, SAMHD1 phosphorylation was reduced 40-fold. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. Therefore, treatment of HIV-infected individuals with dasatinib as adjuvant of ART could disturb the reservoir reactivation and reseeding, which might have a beneficial impact to reduce its size.

The effects of orally administered lactoferrin in the prevention and management of viral infections: A systematic review.

SummaryIt has been demonstrated that lactoferrin (LF) plays a role in host defence, but evidence on its potential antiviral property from clinical studies is fragmented. Our systematic review aimed at identifying the effects of orally administered LF against virus infections. The systematic search was conducted on PubMed, Scopus, Web of Science, BioRxiv.org and ClinicalTrials.gov from database inception to 7th January 2021. Eligible articles investigated any virus family and provided data on the effects of orally administered LF of any origin in the prevention and/or management of confirmed viral infections in people of any age. A narrative synthesis of the results was performed. Quality was assessed with the Cochrane Risk‐Of‐Bias and ROBINS‐1 tools. A total of 27 records were included, nine of which were registered protocols. We found data on Flaviviridae (n = 10), Retroviridae (n = 3), Coronaviridae (n = 2), Reoviridae (n = 2) and Caliciviridae (n = 1). Most published trials were at high risk of bias. The findings were heterogeneous across and within viral families regarding virological, immunological and biological response, with no clear conclusion. Some weak but positive results were reported about decrease of symptom severity and duration, or reduction in viral loads. Despite high tolerability, the effects of LF as oral supplement are still inconsistent, both in preventing and managing viral infections. Small sample sizes, variety in recruitment and treatment protocols, and low study quality may have contributed to such heterogeneity. Better‐designed studies are needed to further investigate its potential benefits against viral infections, including SARS‐CoV‐2.

Weight changes after antiretroviral therapy initiation in CoRIS (Spain): a prospective multicentre cohort study.

IntroductionWeight gain after starting antiretroviral therapy (ART) is a major problem that can increase morbidity. Our main objective was to evaluate the effects of initial ART on weight change in a large prospective cohort of HIV‐positive individuals.MethodsThis was a prospective cohort study of 13,198 subjects included in the Spanish HIV Research Network (CoRIS) between January 2004 and November 2018. We included subjects who started triple ART and achieved HIV RNA suppression within 48 weeks. We fitted linear mixed models adjusted for potential confounders to compare longitudinal changes in weight. We used Cox proportional‐hazard models to compare treatment groups’ times to transition to a higher body mass index (BMI) category.ResultsWe analysed data from a total of 1631 individuals resulting in 14,965 persons/years and 14,085 observations. Individuals retained in the final multivariable model were representative of the overall cohort. NNRTI‐based first‐line ART was associated with a lower average weight gain compared to PI‐ (+0.7 kg per year, 95% CI 0.5 to 1.0, p < 0.001) and INSTI‐based (+0.9 kg per year, 95% CI 0.7 to 1.1, p < 0.001) regimens. Individuals starting ART with TAF+FTC had greater weight gain than those receiving TDF+FTC (+0.8 kg per year, 95% CI 0.3 to 1.4, p = 0.004). Women and black persons presented a greater weight gain than men and non‐black individuals. Differences in weight trajectories were driven mainly by changes during the first year of ART. The NNRTI group was less likely to transition from normal weight to overweight than the PI (aHR 1.48, 95% CI 1.18 to 1.85) and INSTI groups (aHR 1.30, 95% CI 1.03 to 1.64). PIs but not INSTIs were associated with a higher rate of overweight‐to‐obesity shift (aHR 2.17, 95% CI 1.27 to 3.72). No differences were found among INSTIs in the transition to a higher BMI category.ConclusionsINSTI‐ and PI‐based first‐line ARTs are associated with greater weight gain compared to NNRTI‐based ART. Within the NRTIs, TAF+FTC was most strongly associated with weight gain. This heterogeneous effect of ART on body weight could affect the long‐term risk of some non‐communicable diseases.

Late presentation for HIV impairs immunological but not virological response to antiretroviral treatment.

The aim of this study was to examine the impact of late presentation (CD4+ cell count <350 cells/μl or an AIDS-defining event) on effectiveness and safety of initial antiretroviral therapy (ART) and to evaluate whether treatment response depends on first-line ART regimen in late presenters. ART-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) starting triple ART between 2010 and 2018. We used multivariable models to assess differences in viral suppression (viral load <50 copies/ml), immunological response (change in CD4+ cell count, CD4% (>29%) and CD4/CD8 normalization (>0.4 and >1) multiple T-cell marker recovery (MTMR): CD4+ cell count more than 500 cells/μl and CD4% >29% and CD4/CD8 >1), and treatment discontinuation due to adverse events (TDAE) at 48 weeks from ART initiation. Out of 8002 participants, 48.7% were late presenters. Of them, 45.8% initiated ART with a NNRTI- (mostly TDF/FTC/EFV), 33.9% with a protease inhibitor (mostly TDF/FTC+boosted DRV) and 20.3% with an INI-based regimen (mostly ABC/3TC/DTG). At 48 weeks, late presenters had similar viral suppression, but worse immunological response, than non-late presenters with no difference on TDAE. Late presenters initiating with NNRTI-based regimens were more likely to achieve viral suppression than those starting with INI-based, due to the higher chance of achieving viral suppression observed with TDF/FTC/RPV compared to ABC/3TC/DTG. Initial treatment with NNRTI or protease inhibitor based showed similar immunological response than the INI-based regimens, which showed lower rates of TDAE than NNRTI- and protease inhibitor based regimens. Despite safety and effectiveness of initial ART in terms of viral suppression, late presenters may not experience complete immunological response. In late presenters, effectiveness and safety depends on both the class and the specific first-line ART regimen.

Overdose mortality is reducing the gains in life expectancy of antiretroviral-treated people living with HIV in British Columbia, Canada.

A remarkable reduction in AIDS-related mortality has been achieved through the widespread use of triple combination antiretroviral therapy, considerably increasing the life expectancy of people living with HIV (PLWH). However, these survival gains are now at risk in North America due to an unprecedented public health emergency: the deadly drug overdose epidemic. Drug overdoses are now the leading cause of unintentional death in British Columbia (BC), Canada and the United States due to synthetic opioids (e.g., fentanyl) in illegal markets. This manuscript aimed to estimate the effect of overdose mortality on life expectancy and identify covariates associated with the hazard for overdose mortality in the presence of competing risk among PLWH in BC. Those eligible were aged ≥20 years, initiated antiretroviral therapy from 1-Apr-1996 to 30-Dec-2017, and were followed until 31-Dec-2017, last contact or death date. We estimated the potential gains in life expectancy from abridged life tables. We modelled the association between covariates and the cause-specific hazard for overdose mortality, accounting for mortality of other causes as a competing risk. Among the 10,362 PLWH, 3% experienced overdose mortality. The life expectancy at age 20 increased by 8.7 years from 2002-2007 to 2008-2013 compared to only 3.0 years from 2008-2013 to 2014-2017. The potential gain in life expectancy was 3.3 years at age 20 during the ongoing overdose epidemic (2014-2017). There were gender differences in life expectancies throughout the study period. People who have ever injected drugs, women and viral load monitoring non-compliance were key covariates associated with an increased hazard of overdose mortality. Survival gains among PLWH have been considerably reduced due to the ongoing overdose epidemic.

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation.

Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1-infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-γ spot forming cells (SFC) per 106 PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8+ and CD4+ T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4+ T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.