Antiretroviral Therapy Era Research Articles

7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB–Akt–NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.

Cardiac adiposity as a modulator of cardiovascular disease in HIV.

With the number of people living with human immunodeficiency virus (HIV) steadily increasing, cardiovascular disease has emerged as a leading cause of non-HIV related mortality. People living with HIV (PLWH) appear to be at increased risk of coronary artery disease and heart failure (HF), while the underlying mechanism appears to be multifactorial. In the general population, ectopic cardiac adiposity has been highlighted as an important modulator of accelerated coronary artery atherosclerosis, arrhythmogenesis and HF with preserved ejection fraction (HFpEF). Cardiac adiposity is also strongly linked with obesity, especially with visceral adipose tissue accumulation. This review aims to summarize the possible role of cardiac fat depositions, assessed by imaging modalities,as potential contributors to the increased cardiac morbidity and mortality seen in PLWH, as well as therapeutic targets in the current ART era. Review of contemporary literature on this topic. Despite antiretroviral therapy (ART), PLWH have evidence of persistent, HIV-related systemic inflammation and body fat alterations. Cardiac adiposity can play an additional role in the pathogenesis of cardiovascular disease in the HIV setting. Imaging modalities such as echocardiography, cardiac multidetector computed tomography and cardiac magnetic resonance have demonstrated increased adipose tissue. Studies show that high cardiac fat depots play an additive role in promoting coronary artery atherosclerosis and HFpEF in PLWH. Systemic inflammation due to HIV infection, metabolic adverse effects of ART, adipose alterations in the ageing HIV population, inflammation and immune activation are likely important mechanisms for adipose dysfunction and disproportionately occurrence of ectopic fat depots in the heart among PLWH. High cardiac adiposity seems to plays an additive role in promoting coronary artery atherosclerosis and HFpEF in PLWH. The underlying mechanisms are multiple and warrant further investigation. Improved understanding of the regulating mechanisms that increase cardiovascular risk in HIV infection may give rise to more tailored therapeutic strategies targeting cardiac fat depots.

Clinical and morphological characteristic of kidney damage in HIV/HCV co-infected patients who did not receive antiretroviral therapy

In the era of antiretroviral therapy (ART), the development of chronic kidney disease in HIV-infected patients is a significant complication not directly related to acquired immunodeficiency syndrome (AIDS), the risk of which is increased with co-infection with hepatitis C virus (HCV). The pathogenetic pathways of the development of kidney tissue damage and the formation of a morphological substrate for each of the viruses are different, but the immune-mediated mechanisms are a common link for the development of immune complex diseases. We studied renal necropsy samples in 20 patients with HIV/HCV co-infection who did not receive ART, and the dependence of the identified morphological substrate on the level of CD4+ in the blood, to assess and predict their morphogenesis. We observed predominantly segmental mesangial proliferation with an expansion of the mesangial matrix and glomerular involvement ≥50 % in 15 (75 %) cases and glomerular involvement <50 % in 3 (15 %) cases. Endocapillary proliferation (E), infiltration of glomeruli with monocytes, neutrophil leukocytes, segmental macrophages were found in 2 (10 %) cases with the involvement of ≥ 50 % of glomeruli, which was regarded as an exudative component of the inflammatory response. In all cases, sclerosis of capillary loops was verified, which was mainly accompanied by their collapse, thickening of the capillary walls, namely the basement membranes of capillaries and segmental sclerosis of capillary loops of the glo­meruli of varying severity. Initial interstitial stromal fibrosis was found in 5 (25 %) cases, degenerative changes in the convoluted tubules — in 9 (45 %), mainly with the T0–T1 level. Positive expression of IgA, IgM, IgG, and C3 complement fractions in the form of linear and granular deposits along the capillary endothelium was detected with an intensity of “+” to “++”. We compared the verified morphological pattern and the level of CD4+ in the blood and found that patients with deeper immunosuppression show fewer changes, mainly characterized as sclerotic. Moreover, with an increase in the level of CD4+, the morphological substrate is enriched with a proliferative component. Expression of immunoglobulins and components of the complement system in immonohistochemical assay, in particular in areas of sclerotic changes, verifies the presence of prolonged immune complex associated lesions. To determine the detailed morphogenesis, it is advisable to perform a further correlation analysis of the data obtained with the control.

Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

The intersection of drug interactions and adverse reactions in contemporary antiretroviral therapy.

Advances in antiretroviral therapy (ART) have transformed HIV infection into a chronic and manageable condition. The introduction of potent and more tolerable antiretrovirals (ARVs) with favorable pharmacokinetic profiles has changed the prevalence and nature of drug-drug interactions (DDIs). Here, we review the relevance of DDIs in the era of contemporary ART. Management of DDIs remains an important challenge with modern ART, primarily due to increased polypharmacy in older persons living with HIV. Significant DDIs exist between boosted ARVs or older nonnucleoside reverse transcriptase inhibitors and comedications for chronic comorbidities (e.g., anticoagulants, antiplatelets, statins) or complex conditions (e.g., anticancer agents, immunosuppressants). Newer ARVs such as unboosted integrase inhibitors, doravirine, and fostemsavir have reduced DDI potential, but there are clinically relevant DDIs that warrant consideration. Potential consequences of DDIs include increased toxicity and/or reduced efficacy of ARVs and/or comedications. Management approaches include switching to an ARV with less DDI potential, changing comedications, or altering medication dosage or dosing frequency. Deprescribing strategies can reduce DDIs and polypharmacy, improve adherence, minimize unnecessary adverse effects, and prevent medication-related errors. Management of DDIs requires close interdisciplinary collaboration from multiple healthcare disciplines (medicine, nursing, pharmacy) across a spectrum of care (community, outpatient, inpatient).

A Prospective Study Evaluating Changes in Histology, Clinical and Virologic Outcomes in HBV-HIV Co-infected Adults in North America.

Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined. Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n=139). Demographic, clinical, serological, and virological data were collected at entry and every 24weeks for ≤ 192weeks. Paired liver biopsies were obtained at study entry and at ≥ 3years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n=114), median age was 49years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm3 and 93% had HIV<400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20IU/mL) in 61% and < 1,000IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n=1), alanine aminotransferase flare (n=2), and HBeAg loss (n=13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n=62; median 3.6years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P=0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P=0.58). In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.

Altered White Matter Tracts in the Somatosensory, Salience, Motor, and Default Mode Networks in 7-Year-Old Children Living with Human Immunodeficiency Virus: A Tractographic Analysis.

Introduction: Even with the increased access and early initiation of combination antiretroviral therapy, children with perinatally acquired human immunodeficiency virus (CPHIV) continue to demonstrate white matter alterations. Children perinatally HIV-exposed, but uninfected (CHEU) alike show differences in white matter integrity compared with children who are HIV-unexposed and uninfected (CHUU). Objectives: Mapping white matter connections that link gray matter regions that form resting-state (RS) functional networks may demonstrate whether structural and functional connectivity alterations in HIV infection and exposure may be related. We hypothesized reduced structural connectivity in CPHIV within the default mode network (DMN), visual, ventral DMN (vDMN), somatosensory, salience, auditory, motor, executive, basal ganglia, and posterior DMN (pDMN). We also hypothesized that CHEU will have increased structural connectivity compared with CHUU in the vDMN, somatosensory, pDMN, dorsal attention, salience, auditory, motor and basal ganglia. Methods: Study participants were 61 seven-year-old CPHIV and 46 age-matched children who are HIV uninfected (CHU) (19 CHEU). We used diffusion tensor imaging-based tractography to investigate white matter connections that link gray matter regions within RS functional networks. Results: We found altered white matter integrity in the somatosensory, salience, default mode, and motor networks of CPHIV compared with CHU. The superior temporal cortex, superior frontal cortex, and putamen were affected in all four networks and have also been reported to demonstrate morphological alterations in the same cohort. In CHEU, white matter integrity was higher in the visual network, pDMN, and motor network compared with CHUU. Conclusion: Our results suggest that altered white matter integrity may influence gray matter morphology and functional network alterations. Impact statement The long-term effects of human immunodeficiency virus (HIV) and exposure on the developing brain in the combination antiretroviral therapy era are still not well known. We use diffusion tensor imaging-based tractography to explore these effects on white matter connections that link gray matter regions within functional networks. Our findings provide a context for HIV-associated white matter and connectivity abnormalities.

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.

Feasibility of Rapid Case Ascertainment for Cancer in East Africa: An Investigation of Community-Representative Kaposi Sarcoma in the Era of Antiretroviral Therapy

BackgroundRapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa. MethodsTo determine the feasibility of RCA for KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements. ResultsWe identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%). ConclusionsWe found that RCA ― an important tool for cancer research in resource-rich settings ― is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa.

Mucocutaneous diseases in the combined antiretroviral therapy era: prevalence and spectrum in HIV seropositive children and adolescents in Durban, South Africa.

Mucocutaneous diseases (MCD) have been commonly described among human immunodeficiency virus (HIV) infected patients before the combined antiretroviral therapy (cART) era. There is limited data on the frequency and type of MCD in the cART era in African children and adolescents. This study aimed to describe the prevalence and spectrum of MCD in South African children and adolescents seropositive for HIV on cART. A cross-sectional study of 310 participants aged 0-19 years attending a public sector ART clinic at King Edward VIII Hospital, Durban, South Africa, was conducted. Demographic, clinical, and laboratory information was obtained from the participants and hospital records. Participants were examined. Data were collated and analyzed with SPSS version 23. MCD were observed in 77.4% of HIV-infected children. The prevalence was higher among males and adolescents above 16 years old (83.9%). Infectious skin disorders (44.7%) were less common than noninfectious dermatoses (55.3%). More common disorders encountered included generalized pruritus (32.6%), fungal infections (20.9%), and inflammatory (20.4%) and pigmentary (20.4%) skin disorders. Tinea capitis and pedis were the most prevalent fungal infections, while oral candidiasis (0.2%) was the least. Inflammatory skin disorders and dyschromia appeared to be more common than in the pre-cART era. While MCD are still common in HIV-infected children and adolescents in the cART era, the pattern and types of disorders have changed to a predominance of non-infectious dermatoses.

Treatment of AIDS-related Kaposi's Sarcoma With Low-dose Radiotherapy - Follow-up on 2,305 Tumours.

We aimed to report our experience obtained by treating AIDS-related Kaposi's sarcoma (KS) with radiotherapy before the era of antiretroviral therapy. This investigation was performed as a quality control of KS patients treated with low-dose radiotherapy at our department. KS patients referred to our section from 1983 up until 1990, were treated three times with radiotherapy (29-50 kV, 2-4 Gy), once every second week. Initially, 74 skin KSs were treated three times with 2 Gy, of which 70% were treated successfully. Hereafter, other 2,066 KSs on the skin were treated three times with 4 Gy with a very high success rate of 93%. Additional 165 mucous KSs were treated three times with 4 Gy, of which 91% were treated successfully. Low-dose radiotherapy is effective for the treatment of many AIDS-related KS patients.

Stage-Dependent Within-Individual Comparison Reveals SIV-Specific Activation/Exhaustion Shift in Rhesus Macaques.

It is challenging to trace the complicated individual-based variations of HIV-specific immunocompetence shift during the successful antiretroviral therapy (ART) era. Using eight rhesus monkeys simulating a longitudinal stage-dependent cohort (baseline-SIV acute infection-SIV suppression by ART-ART withdrawal), baseline immunocompetence monitoring for 28 days (SIV-negative stage, SN) was compared with host immunocompetence undergoing 90-day ART treatment (SIV-suppressed stage, SS) to reveal the SIV-specific immunity shift aroused by undetectable individual viral replication. During acute SIV infection for 98 days (SIV-emerged stage, SE), immune activation was compared with re-immune activation post ART for 49-day follow-up (SIV-rebounded stage, SR) to reveal the SIV-specific immune activation variation aroused by detectable individual viral replication. Individual immunocompetence was measured by co-expression of CD4, CD8, CD38, HLA-DR, CCR7, CD45RA, and PD-1 on T cells and a cytokine panel. Compared with SN, mild immune activation/exhaustion was characterized by increased CD38+ HLA-DR– CD4+/CD8+ T-cell subsets and PD-1+ memory CD4+/CD8+ T-cell subsets with three elevated cytokines (MIP-1β, IL-8, and IL-10) significantly emerged in SS. Compared with SE, SR produced more exhaustion characterized by increased PD-1+ CD4+ TCM cells and decreased PD-1+ CD4+ TEM cells with four elevated pro-inflammatory cytokines (IFN-γ, IL-1β, IL-6, and TNF-α). By such individualized stage-dependent comparison, the sustainable immune activation was found from activation/exhaustion shifted into exhaustion during the longitudinal viral persistence. Further, validated SIV accelerates host immunosenescence continuously independent of viral replication.

Lymphoma in HIV-2-infected patients in combination antiretroviral therapy era.

To describe lymphoma in HIV-2-infected patients and compare their characteristics with lymphoma in HIV-1-infected patients. Ancillary analysis from a single center prospective cohort of HIV-lymphoma. We report on 16 patients with HIV-2-lymphoma diagnosed after 1996 and included in a prospective cohort of HIV lymphoma. Five additional HIV-2-infected patients coinfected with HIV-1 or/and HTLV-I (6 lymphomas) are separately reported. The incidence of lymphoma in HIV-2-infected patients was evaluated in the French multicentric HIV-2 cohort. Incidence of lymphoma in the French HIV-2 cohort was estimated as 0.6/1000 patient-years. In our series, the median CD4+ cell count was 166 × 106/l at the time of lymphoma diagnosis and 50% of patients had undetectable plasma HIV-2-RNA. Lymphomas were non-Hodgkin lymphoma (n = 12) and classical Hodgkin lymphoma (n = 4). Similarly to HIV-1-lymphoma, clinical presentation was aggressive in most cases. All but one patient received intensive chemotherapy. Complete remission was achieved in 13 cases and 1 patient relapsed. The overall survival was not statistically different from that observed in patients with HIV-1 lymphoma. The six additional lymphomas observed in five HIV-2-infected patients coinfected with HIV-1 or/and HTLV-I presented with similar clinical presentation but worse prognosis. Despite the lower pathogenicity of HIV-2, the risk of developing lymphoma seems to be close to that observed in HIV-1 population with similar lymphoma characteristics. Compared with HIV-1, HIV-2-infected patients developed lymphoma later in their life but at a similar CD4+ cell count level.

FDG PET/computed tomography can detect region-specific neuronal changes following antiretroviral therapy in HIV-infected patients.

FDG PET/computed tomography can detect region-specific neuronal changes following antiretroviral therapy in HIV-infected patients.

Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology.

HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviours, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available.In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model, and determined effects of PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) on Tat-induced behavioural impairments and neuropathologies.We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using α7 nAChR knockout mice, we showed that α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Last, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, α7 nAChR activation and the p38 MAPK signalling pathway.Taken together, these findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggested that α7 nAChR modulator PNU-125096 holds significant promise for development of therapeutics for HAND.

Confound, Cause, or Cure: The Effect of Cannabinoids on HIV-Associated Neurological Sequelae.

The persistence of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) in the era of effective antiretroviral therapy suggests that modern HIV neuropathogenesis is driven, at least in part, by mechanisms distinct from the viral life cycle. Identifying more subtle mechanisms is complicated by frequent comorbidities in HIV+ populations. One of the common confounds is substance abuse, with cannabis being the most frequently used psychoactive substance among people living with HIV. The psychoactive effects of cannabis use can themselves mimic, and perhaps magnify, the cognitive deficits observed in HAND; however, the neuromodulatory and anti-inflammatory properties of cannabinoids may counter HIV-induced excitotoxicity and neuroinflammation. Here, we review our understanding of the cross talk between HIV and cannabinoids in the central nervous system by exploring both clinical observations and evidence from preclinical in vivo and in vitro models. Additionally, we comment on recent advances in human, multi-cell in vitro systems that allow for more translatable, mechanistic studies of the relationship between cannabinoid pharmacology and this uniquely human virus.

Coinfection with HCV or HBV Increases the Risk of Lymphoma in HIV-Positive Patients: A Combined Analysis of the Lymphovir-ANRS-CO16 and Fhdh-ANRS-CO4 Cohorts

BACKGROUNDHuman immunodeficiency virus (HIV) infection has been linked to an increased risk of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). In the HIV-uninfected population, hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are both associated with an increased risk of NHL. Scarce data suggest an increased risk of HL in patients chronically infected with HBV. HCV and HBV coinfections are frequent among persons living with HIV (PLWHIV). The impact of HCV and HBV infections on HIV-associated lymphoma in the era of combined antiretroviral therapy (cART) deserves evaluation. METHODSWe compared the prevalence of HBV and HCV coinfections between PLWHIV with lymphoma who were enrolled in the Lymphovir French National Agency for Research on AIDS and Viral Hepatitis (ANRS)-CO16 cohort and PLWHIV enrolled in the French Hospital Database on HIV (FHDH-ANRS-CO4) with at least one follow-up visit in 2011 (n = 48 186). This cohort has been shown to be representative of PLWHIV under care in France.Lymphovir-ANRS-CO16 cohort enrolled consecutive HIV-infected individuals with lymphoma (NHL or HL) in 32 centers. The histological diagnosis was established using the 2008 WHO classification and was confirmed within the French hematopathology network (LYMPHOPATH). Finally, we analyzed the characteristics and outcomes of lymphomas in coinfected patients. RESULTSBetween 2008 and 2015, 179 patients with HIV-related lymphomas were enrolled, of whom 110 had NHL (61%) and 69 had HL (39%), The HCV serology, available for all the patients, was positive in 38 cases (29 with NHL and 9 with HL). Among 26 HCV+ patients with available data, 15 had detectable HCV RNA load at lymphoma diagnosis, five had Child-Pugh A cirrhosis, two had liver fibrosis, and one had an extrahepatic manifestation (type III cryoglobulinemia). Overall, the HCV seroprevalence was 26% among patients with NHL, a proportion significantly higher than that in the FHDH-ANRS-CO4 cohort (14%) (odds ratio (OR): 2.15, 95% confidence interval [1.35-3.32])(Table). There was no association between HCV and HL (prevalence 13%, OR: 0.90 [0.39-1.82]).The distribution of NHL subtypes among the 29 patients with HCV infection was as follows: DLBCL (n=17), MZL (n=3), plasmablastic lymphomas (n=3), primary effusion lymphoma (PEL) (n=3), BL (n=2), and T-cell lymphoma (n=1). HCV was significantly associated with DLBCL (prevalence 33%, OR: 2.91 [1.53-5.34]). Among the patients with DLBCL, 13/17 HCV+ patients had at least one site of extranodal involvement, compared to 16/34 HCV- patients (p=0.05). Four DLBCL patients received anti-HCV therapy after treatment of their lymphoma, consisting of IFN/ribavirin, either alone (n=1) or direct antiviral agents (n=3). A sustained virological reponse and a durable remission of their lymphoma were obtained in each case. Remarkably, a man with splenic MZL received anti-HCV therapy with interferon and ribavirin with no other lymphoma treatment, leading to long-lasting both virological and hematological complete responses. During follow-up, 10 deaths occurred among HCV+ patients with NHL due to progression of lymphoma (n=8) or solid tumours (n=2). With a median follow-up of 43 months, the 2-year OS among NHL patients tended to be lower in HCV+ patients (Figure).HBV status was available for 177 of the 179 lymphoma patients, of whom 15 had chronic HBV infection based on HBs Ag positivity (n=13) or HBV DNA positivity (n=2). Five patients had NHL (DLBCL (n=2) and BL (n=3)) and 10 had HL. Overall, chronic HBV infection was present in 5% of patients with NHL, which did not differ from the value of the FHDH-ANRS-CO4 cohort (7%) (OR: 0.60 [0.19-1.45]). In contrast, the prevalence of chronic HBV infection was higher among patients with HL than in the FHDH-ANRS-CO4 (14%; OR: 2.16 [0.98-4.27]). CONCLUSIONAs compared with the general cohort of HIV-infected patients, HCV coinfection was associated with an increased risk of NHL, especially DLBCL, and tended to be associated with poorer outcome. While no increase in the risk of NHL was observed among HBV coinfected patients, chronic HBV infection was associated with an increased risk of HL. Our findings suggest that chronic antigenic stimulation induced by HCV or HBV contribute to lymphomagenesis in HIV-infected patients. It paves the way for evaluation of novel therapeutic strategies based on the newest direct antiviral agents for HCV coinfected patients. [Display omitted] DisclosuresCoiffier:Celltrion, Inc: Consultancy, Honoraria. Coppo:Alexion: Consultancy, Research Funding; Ablynx: Consultancy, Research Funding; Octapharma: Consultancy.

The challenging of HIV care 1 year after of coronavirus disease 2019 pandemic: results from a Brazilian cohort.

The challenging of HIV care 1 year after of coronavirus disease 2019 pandemic: results from a Brazilian cohort.

Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe

SummaryBackgroundFaltered linear growth and pubertal delay, which are both common in children with HIV in sub-Saharan Africa, might affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with bone density adjusted for skeletal size in peripubertal children in Zimbabwe.MethodsWe did a cross-sectional study of baseline data from the IMVASK cohort, which enrolled children aged 8–16 years with HIV who had been taking antiretroviral therapy (ART) for at least 2 years, and children of the same age without HIV. Children with HIV were recruited from public sector HIV clinics at Parirenyatwa General Hospital and Harare Central Hospital (Harare, Zimbabwe), and children without HIV were recruited from six schools in the same suburbs that the hospitals serve. Sociodemographic, clinical, and anthropometric data were collected. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone outcomes of total-body less-head bone mineral content for lean mass adjusted for height (TBLH-BMCLBM), and lumbar spine bone mineral apparent density (LS-BMAD), and we assessed the prevalence of low TBLH-BMCLBM and low LS-BMAD (defined by Z-scores of less than −2·0). Size adjustment techniques were used to overcome the size dependence of DXA measurement. We used linear regression models, with multiple imputation for missing data, to assess relationships between risk factors and TBLH-BMCLBM and LS-BMAD Z-scores in children with and without HIV.FindingsWe recruited 303 children with HIV (mean age 12·4 years [SD 2·5]; 151 [50%] girls) and 306 children without HIV (mean age 12·5 years [SD 2·5]; 155 [51%] girls). In children with HIV, median age of HIV diagnosis was 3·0 years (IQR 1·2–5·8), and median ART duration was 8·1 years (6·2–9·5); for 102 (34%) children, ART included tenofovir disoproxil fumarate (TDF). Children with HIV had a higher prevalence of low TBLH-BMCLBM Z-score than children without HIV (29 [10%] of 279 children with available data vs 18 [6%] of 292 with available data; p=0·066) and a higher prevalence of low LS-BMAD Z-score (40 [14%] of 279 vs 17 [6%] of 293 with available data; p=0·0007). HIV and male sex were associated with earlier pubertal (Tanner) stage. The negative associations between HIV and Z-scores for TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in girls. Among children with HIV, TDF exposure and orphanhood were associated with lower TBLH-BMCLBM Z-score in confounder-adjusted analysis. Current TDF use (vs non-TDF-based ART) was associated with a reduction in TBLH-BMCLBM Z-score of 0·41 (95% CI 0·08–0·74; p=0·015) and in LS-BMAD Z-score of 0·31 (0·08–0·69; p=0·12).InterpretationDespite ART, HIV is associated with substantial skeletal deficits towards the end of puberty. The extent of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa are a concern for future adult fracture risk.FundingWellcome Trust.

Human umbilical cord mesenchymal stem cell transfusion in immune non-responders with AIDS: a multicenter randomized controlled trial

We examined the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) infusion for immune non-responder (INR) patients with chronic HIV-1 infection, who represent an unmet medical need even in the era of efficient antiretroviral therapy (ART). Seventy-two INR patients with HIV were enrolled in this phase II randomized, double-blinded, multicenter, placebo-controlled, dose-determination trial (NCT01213186) from May 2013 to March 2016. They were assigned to receive high-dose (1.5 × 106/kg body weight) or low-dose (0.5 × 106/kg body weight) hUC-MSC, or placebo. Their clinical and immunological parameters were monitored during the 96-week follow-up study. We found that hUC-MSC treatment was safe and well-tolerated. Compared with baseline, there was a statistical increase in CD4+ T counts in the high-dose (P < 0.001) and low-dose (P < 0.001) groups after 48-week treatment, but no change was observed in the control group. Kaplan–Meier analysis revealed a higher cumulative probability of achieving an immunological response in the low-dose group compared with the control group (95.8% vs. 70.8%, P = 0.004). However, no significant changes in CD4/CD8+ T counts and CD4/CD8 ratios were observed among the three groups. In summary, hUC-MSC treatment is safe. However, the therapeutic efficacy of hUC-MSC treatment to improve the immune reconstitution in INR patients still needs to be further investigated in a large cohort study.