Use Of Zidovudine Research Articles

Incidence and risk factors of anaemia among people on antiretroviral therapy in Harare.

Anaemia is associated with reduced quality of life and increased mortality risk among people living with HIV (PLHIV). Although antiretroviral therapy (ART) reduces the prevalence of anaemia, some patients remain at risk after commencing ART. We estimated the incidence of anaemia after ART commencement and identified associated risk factors. We analysed outpatient records at Newlands Clinic, Harare, Zimbabwe. Patients (≥ 5 years old) who were commenced on ART between January 2016 and December 2020 were included and were followed up for up to 2 years. Patients with anaemia at ART commencement and women who were pregnant at any time during follow-up were excluded. Cox proportional hazards regression was used to assess independent risk factors for anaemia. During the study, 1110 patients ≥ 5 years old were commenced on ART with a prevalence of anaemia of 40.0%. Five hundred and twenty-nine patients met the inclusion criteria and were followed up for 823.7 person-years. The median age was 36.1 years and 290 (58.4%) were female. The incidence rate of anaemia after ART commencement was 176.1 per 1000 person-years (95% confidence interval [CI]: 149.6-207.2). Females (aHR: 2.09; 95% CI: 1.46-3.00, P < 0.001), zidovudine use (aHR: 3.50 96% CI: 2.14-5.71, P < 0.001), age 5-12 years or > 50 years, and the presence of World Health Organization stage III/IV disease (aHR: 2.19; 95% CI: 1.14-5.71, P = 0.019) had higher odds of developing anaemia. The incidence of anaemia after ART commencement was high. Female sex, zidovudine use, age and the presence of stage III/IV disease were independent risk factors for anaemia. Clinicians should screen PLHIV on ART regularly for anaemia.

Targeting EBV Encoded Viral Kinases with GCV, AZT, Rituximab and Dexamethasone (GARD) Results in Durable Responses in Patients with CNS Lymphoproliferative Disease

Introduction: Epstein-Barr virus positive (EBV+) central nervous system lymphoproliferative diseases (CNS-LPD) are aggressive clinical conditions with poor prognosis. EBV+ CNS-LPD often occurs in the setting of immune suppression and comorbidities (solid organ transplant, autoimmunity). Treatment with high-dose methotrexate has increased survival but is not a viable option for all patients, highlighting the need for alternative treatments. Previous research has reported EBV+ CNS-LPD exhibits unique genetic and immunobiological signatures, however, few studies have reported on the epigenetic landscape. We have previously reported use of ganciclovir (GCV), zidovudine (AZT), rituximab and dexamethasone (GARD) regimen induced complete and durable responses in a cohort of 13 patients with primary CNS post-transplant lymphoproliferative disease (PCNS-PTLD). Here we present 24 patients (10 from prior cohort and 14 new) with EBV+ CNS-LPD treated with GARD. We extend follow-up time for the previous cohort and add molecular context to clinical observations. We performed DNA methylation and expression analysis of EBV viral kinases in available tumor samples and revealed unique viral epigenetic states leading to expression of antiviral drug targets in an array of EBV+ CNS-LPD. Methods: We conducted an IRB-approved, retrospective review of patients with EBV+ CNS-LPD treated with GARD at The Ohio State University Wexner Medical Center between 1998-2022. Patient information was extracted from the electronic medical record. Treatment consisted of two-week induction of twice daily IV GCV/AZT (5mg/kg and 1,500 mg) IV dexamethasone (10-40mg), and weekly rituximab (375mg/m 2). After induction, dexamethasone was tapered, and GCV/AZT was switched to maintenance oral dosing of 450mg valganciclovir twice daily and 300mg of AZT twice daily. Rituximab was administered on days 1, 8, 15, and 22. Two-year overall survival (OS), five-year OS, and overall response rate were assessed. Available CNS-LPD biopsy samples were obtained, and expression of EBV lytic genes BZLF1, BXLF1 (thymidine kinase), and BGLF4 (protein kinase) were measured via qRT-PCR. Mass spectrometry based EpiTYPER assay was used to report the percentage of DNA CpG methylation in the gene promoters for viral BZLF1, BXLF1, BGLF4 and LMP1 genes . Biopsies from 17 patients with systemic PTLD with no CNS involvement were used for comparison. Results: 24 patients with EBV+ CNS-LPD were identified. 21 (87.5%) patients were diagnosed with a primary CNS-LPD (PCNS-LPD). Of the PCNS-LPD, 14 patients were PCNS-PTLD, 4 were receiving immunosuppression for autoimmune conditions, 1 patient had type 2 diabetes and two had no known history of immunosuppression. The remaining three patients had systemic PTLD with secondary CNS involvement. Diffuse large B-cell lymphoma was the most common histology (11; 45.8%) followed by grade 3 lymphomatoid granulomatosis (5; 20.8%), B-cell LPD (5;20.8%), polymorphic PTLD (2;8.3%) and one large cell lymphoma of ambiguous lineage. All patients were HIV negative. EBER was positive in all biopsies and EBV PCR of cerebrospinal fluid was positive in patients without biopsy. Sixteen patients (66.7%) achieved a completed response, with an overall response rate of 83%. Two-year OS was 62.5% (95% CI, 45.8-85.2%) and five-year OS was 52.8% (95% CI, 35.7%-77.9%). Five CNS-LPD brain biopsies were available for analysis. qRT-PCR of biopsy specimens showed expression of LMP1, BXLF1, and BGLF4, but not BZLF1. Expression of BGLF4 was significantly higher (p=1.35e-5) in CNS-LPD when compared to systemic EBV+ PTLD. EpiTYPER data showed significantly decreased promoter methylation for viral kinases BXLF1 and BGLF4 (p=0.0281 p=0.0089). Conclusions: We have shown that GARD regimen shows efficacy in the treatment of EBV+ CNS-LPD, with 62.5% two-year OS and 52.8% five-year OS. Our results provide the molecular basis for expression of lytic viral kinases BXLF1 and BGLF4 in CNS-LPD by showing that both genes exhibit decreased promotor methylation. This expression of viral kinases in CNS-LPD supports the mechanistic rationale of this antiviral approach and could be further investigated as a predictive biomarker. Overall, this research highlights unique epigenetic features of EBV in CNS-LPD that support the use of antiviral, specifically the GARD regimen, in EBV+ CNS-LPD.

Short-term toxicity assessment of combined use of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in vitro and in vivo.

A combination of zidovudine (AZT), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother-to-child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity. An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus, and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28-day feeding test was conducted to assess the potential subacute toxicity. In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose-dependent manner in mice (P<0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high-dose group was lower than that in the control group (P<0.05); the relative weights of the liver, kidney, spleen, and brain increased (P<0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high-dose group. The hemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high-dose group increased (P<0.05). The total protein, albumin, cholesterol, and blood glucose levels of male and female rats in the high-dose group were significantly decreased (P<0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium- and high-dose groups increased significantly (P<0.05). The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.

Distinct patterns of fasting plasma glucose and lipid profile levels over time in adults tested positive for HIV on HAART in Shanghai, China, revealed using growth mixture models.

This study sought to identify potential change patterns and predictors of fasting plasma glucose (FPG) and lipid levels after initiating highly active antiretroviral therapy (HAART). A retrospective cohort study was conducted on 1,572 patients tested positive for HIV who initiated HAART between January 2010 and October 2020 in Shanghai, China. The growth mixture models (GMM) were used for capturing subgroups of FPG trajectories as well as triglyceride (TG) and total cholesterol (TC) dual-trajectories. Multinomial logistic regression models identified correlates of given trajectories. The median follow-up time was 2.0 years (IQR 1.0-4.7). Three FPG trajectory subgroups were identified as FPG low-stable (62.3%), medium-stable (30.5%), and high-increasing (7.2%). Furthermore, three subgroups of TG and TC dual-trajectories were identified as TG and TC high-slight increasing (13.7%), low-rapid increasing (27.6%), and a subgroup of medium-stable TC and slight-decreasing TG (58.7%). Older age, high TG, FPG, BMI, CD4 count of <200 at baseline, and initial use of zidovudine (AZT) and protease inhibitors (PIs) helped to identify the class with increasing glucose or lipid metabolism trajectories. The change patterns of plasma glucose and lipid in patients tested positive for HIV were heterogeneous and tailored interventions should be considered in specific subgroups.

Progression of non-anemic macrocytosis to anemia in HIV-positive persons receiving zidovudine-containing regimens in a resource-limited setting.

Non-anemic macrocytosis is frequently observed among HIV-positive persons treated with zidovudine in resource-limited settings. Although zidovudine-associated anemia is well recognized, the probability and predictors of progression from non-anemic macrocytosis to anemia are still unknown. A retrospective cohort study was conducted among HIV-positive persons receiving zidovudine-containing antiretroviral therapy (ART) with non-anemic macrocytosis. Kaplan-Meier and Cox regression analyses were used to determine the probability and predictive factors of progression from non-anemic macrocytosis to anemia, respectively. Of 318 HIV-positive persons, 59.4% were male; mean age was 44.3years. The median follow-up duration was 5.8years. The probabilities of progression to anemia at 1, 3 and 4years were estimated at 9.4, 17.3 and 21.3%, respectively. Almost all anemia was mild asymptomatic. Duration of zidovudine use [hazard ratio (HR) = 1.141; 95% confidence interval (CI),1.036-1.256; p = .007], CD4 count prior to start zidovudine [HR = 0.991; 95%CI,0.982-0.999; p = .038], and hematocrit level at development of macrocytosis [HR = 0.683; 95%CI,0.541-0.861; p = .001] were significant factors to predict progression to anemia. Non-anemic macrocytosis in HIV-positive persons receiving zidovudine-containing ART can progress to anemia. Longer duration of zidovudine use, lower CD4 cell counts at ART initiation, and lower hematocrit level at development of macrocytosis are predictive factors for progression to anemia.

Intrapartum use of zidovudine in a large cohort of pregnant women living with HIV in Italy

BackgroundIntravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is <50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy. MethodsObservational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT. ResultsA total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and <50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA < 50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI <0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group. ConclusionsIn ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use.

Frequency of anemia in HIV perinatally exposed newborns at Hospital Teófilo Dávila, El Oro-Ecuador, 2018

BACKGROUND: HIV / AIDS is one of the most significant epidemics in the world; infection in children is the result of mother- to- child transmission in most of the cases. One of the proposed prophylaxis protocols recommends the administration of antiretroviral drugs, such as zidovudine, a drug that, among its side effects, causes anemia in a large percentage of patients who receive it. The aim of this study was to determine the frequency of anemia in newborns, perinatal exposed to HIV, who received zidovudine, at Hospital “Teófilo Dávila,” El Oro- Ecuador, in 2018. METHODS: Observational, descriptive and cross-sectional study, carried out with 50 full-term neonates, delivered by C-section, exposed to HIV, with antiretroviral treatment that includes the use of zidovudine, hospitalized in the neonatology service of Hospital Teófilo Dávila, located in the city of Machala, in 2018. RESULTS: Of the entire population, 56% (n = 28) of the sample were males. The presence of anemia (hemoglobin ˂10g/dl) was demonstrated in 28 (56%) of the 50 patients in the sample, among patients with anemia 75% (n = 21) had normocytic anemia, 64% of the anemias (n = 18) were normochromic. CONCLUSION: 56% of the neonates exposed to HIV during pregnancy who received zidovudine, developed anemia; most of these anemias were normocytic and normochromic.

Antiretroviral therapy use in selected countries in Latin America during 2013–2017: results from the Latin American Workshop in HIV Study Group

To document antiretroviral use in Latin America during the last decade. We collected indicators from 79 HIV health care centres in 14 Latin American Spanish-speaking countries for 2013-2017. Indicators were analysed by age, sex and other characteristics and weighted by the estimated people under care (PUC) population in each country. We gathered information on 116 299 PUC. One-third belonged to centres reporting a shortage of at least one antiretroviral therapy (ART) drug for >30 days during 2017. At end 2017, 95.1% of PUC were receiving ART. During 2013-2017, 45 329 people living with HIV were admitted to 39 centres. ART initiated during the first year after admission increased from 76.7% in 2013 to 83.8% in 2017. In 35 centres across the study period, 71.7% of PUC started ART with tenofovir disoproxil fumarate and lamivudine, and zidovudine use decreased. The third most common ART drug, EFV, reached 64.8%. Raltegravir and other alternatives increased annually to almost 10% of total use in 2017. Initial ART in Latin America is not based on the most recent scientific evidence and recommendations; use of drugs with higher efficacy and safety profiles and guarantee of ART availability continues to be a public health challenge.

Adult T-Cell Leukemia/Lymphoma: Clinical Characteristics and Outcome of Aggressive Subtypes Treated at a Tertiary Cancer Center

Introduction:Adult T-cell leukemia/lymphoma (ATLL) is a disease that develops in a small proportion of individuals who are chronically infected with human T-cell lymphotropic virus type 1 (HTLV-1). Infection is endemic in some parts of the world, Brazil included1.According to the Shimoyama classification, there are four ATLL subtypes: (1) acute, (2) lymphomatous, (3) chronic, and (4) smoldering2. The acute and lymphomatous subtypes are grouped together as aggressive subtypes and often appear with hypercalcemia, cutaneous lesions and visceral dysfunctions.To define a first line treatment for aggressive ATLL is challenging, as the disease is often refractory even to intensive chemotherapy. According to a meta-analysis, patients with the acute subtype should receive antiviral therapy with zidovudine (AZT) and interferon-alfa (INF) and patients with the lymphomatous subtype should receive chemotherapy, both followed by allogeneic stem cell transplantation (ASCT) when feasible3.The aim of this study is to describe the clinical and laboratory characteristics, as well as outcomes of patients with aggressive ATLL treated at a single center in Rio de Janeiro, Brazil.Methods: This is a retrospective study. All patients diagnosed with acute or lymphomatous ATLL (according to the Shymoiama classification) between January 2011 and January 2017 have been evaluated. Diagnosis criteria included positive serology for HTLV-1 and histologically or cytologically proven T-cell malignancy. All patients were treated and followed-up in the Hematology Department of Instituto Nacional de Cancer in Rio de Janeiro, Brazil.Statistical analyses were performed using SPSS software, version 21 (SPPS Inc., Chicago, IL, USA).Results: A total of 28 patients with aggressive ATLL were analyzed: patient characteristics are summarized in Table 1.Most patients (57%) were treated initially with chemotherapy (CT), usually CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with 21-days intervals between cycles. Remaining patients were treated with antiviral therapy (AZT/INF). Treatment was considered adequate for the clinical subtype in 23 patients (82%). All patients received monthly intratechal chemotherapy.Complete response was achieved in 5 patients (18%) and partial response in 3 additional patients (11%), with an overall response rate of only 29%. Median survival time was 16.7 months (8 and 17 months for acute and lymphoma types, respectively, not statistically significant). The only factor associated with better survival was at least partial response to first line treatment (Fig 1). The main cause of death was progression of the primary disease.Only three patients (10%) were submitted to ASCT (two related and one unrelated). Two are alive one year after transplantation without evidence of the disease. The other patient died a few months after the transplantation of progressive disease.Discussion: Treatment of aggressive ATLL is challenging, as patients often appear with a heavy tumor burden and a disease refractory to primary treatment or quickly relapse after remission. A large recent Japanese study including 344 patients with aggressive ATLL showed survival times of 8.3 and 10.6 months for the acute and lymphomatous subtypes, respectivelly4. Despite the limitations of our study, including its retrospective nature and the small sample, our resultsprovide relevant information from cases of an endemic area with limited number of studies. At least a partial response to first line treatment is necessary for long term survival.Conclusion:Treatment of aggressive ATLL are ineffective and limited. The challenge is to develop therapeutic approaches with higher response rates and to increase the number of patients undergoing ASCT.References1 - Proietti FA, Carneiro-Proietti ABF, Catalan-Soares BC, et al. Global epidemiology of HTLV-1 infection and associated diseases. Oncogene 2005;24:6058-682 - Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. Br J Haematol 1991;79:428-373 - Bazerbachi A, Plumelle Y, Ramos JC, et al. Meta-analysis on the use of zidovudine and interferon-alpha in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010;28:4177-834 - Katsuya H, Ishitsuka K, Utsunomiya A, et al. Treatment and survival among 1594 patients with ATL. Blood 2015;126:2570-2577. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Influence of maternal use of tenofovir disoproxil fumarate or zidovudine in Vietnamese pregnant women with HIV on infant growth, renal function, and bone health.

Tenofovir disoproxil fumarate (TDF) is still widely prescribed for human immunodeficiency virus (HIV)-infected pregnant women, despite its renal and bone toxicity. Although TDF-exposed infants often show transient growth impairment, it is not clear whether maternal TDF causes infantile rickets via maternal/fetal renal dysfunction in Asian populations. This prospective observational study was conducted in Vietnam and involved pregnant HIV-infected women treated with TDF-based regimen (TDF group) or zidovudine-based regimen (AZT-group). At birth, 3, 12, and 18 months of age, and included body length, weight, head circumference, serum alkaline phosphatase (ALP), creatinine, calcium, phosphorus, urine-β2-microglobulin (U-BMG), percentage of tubular reabsorption of phosphate (%TRP), and radiographic wrist score for rickets. Age-adjusted multivariate linear regression analysis evaluated the association of TDF/AZT use during pregnancy with fetal renal function and bone health. The study included 63 mother-infant pairs (TDF group = 53, AZT group = 10). In the mothers, detectable U-BMG (>252 μg/L) was observed more frequently in the TDF- than AZT group (89 vs 50%, p<0.001), but other renal/bone parameters were similar. In infants, maternal TDF use was not associated with growth impairment, renal dysfunction, or abnormal bone findings, but with a slightly higher ALP levels (p = 0.019). However, shorter length was associated with maternal AZT (p = 0.021), and worse radiographic scores were associated with LPV/r (p = 0.024). In Vietnamese population, TDF usage during pregnancy was not associated with infant transient rickets, growth impairment, or renal dysfunction, despite mild maternal tubular impairment. Maternal AZT and LPV/r influenced infant growth and bone health, though further studies are needed to confirm this finding.

The 1G/1G+1G/2G Genotypes of MMP1 rs1799750 Are Associated with Higher Levels of MMP-1 and Are Both Associated with Lipodystrophy in People Living with HIV on Antiretroviral Therapy.

In HIV-infected patients, antiretroviral therapy (ART) is associated to adipose tissue redistribution known as lipodystrophy (LD). This study aimed at verifying the association between the polymorphism of the MMP1 gene (rs1799750) (1G/2G) and the serum levels of matrix metalloproteinase 1 (MMP-1) with LD and its subtypes in people living with HIV on ART. This is a cross-secional study. LD was self-reported. The determination of the MMP1 rs1799750 gene polymorphism was performed by real-time PCR, and the serum concentrations of MMP-1 were quantified by the enzyme-linked immunosorbent assay (ELISA) method. Of 404 participants, 204 (51%) were diagnosed with LD, of whom 89 (43%) had mixed lipodystrophy (ML), 72 (35%) had lipohypertrophy (LH), and 43 (22%) had lipoatrophy (LA). There was an association between the genotypes 1G/1G+1G/2G and higher serum levels of MMP-1 (p = .025). There was no association of MMP1 (1G/2G) with LD. Other factors associated with LD were current CD4 ≤ 350 [odds ratio (OR) = 4.85, confidence interval (CI) = 1.78-47.99, p = .0033] and serum MMP-1 levels >6.81 (OR = 2.67, CI = 1.21-6.08, p = .0165). Factors associated with ML: current CD4 ≤ 350 (OR = 5.59, CI = 1.69-20.39, p = .006); with LH: number of antiretroviral regimens used: 2 (OR = 2.06, CI = 1.01-4.20, p = .0460) and 3+ (OR = 2.09, CI = 1.00-4.35, p = .0477), and current CD4 ≤ 350 (OR = 2.08, CI = 1.00-4.24, p = .0461); and with LA: current viral load >40 (OR = 2.52, CI = 1.03-5.91, p = .0372) and current use of zidovudine (OR = 2.97, CI = 1.32-6.54, p = .0074). Higher levels of MMP-1 were associated with genotypes 1G/2G+1G/1G and with LD. Other individual risk factors were independently associated with LD, and its subtypes, suggesting that the pathogenesis itself is differently manifested for each type of LD.

Does antiretroviral therapy cause congenital malformations? A systematic review and meta-analysis.

OBJECTIVESThis meta-analysis investigated the risk of congenital anomalies among infants of human immunodeficiency virus-infected pregnant women who were exposed to antiretroviral therapy (ART).METHODSCohort studies, case-control studies, randomized controlled trials, and controlled clinical trials were reviewed by searching MEDLINE/PubMed, Embase, Web of Science, Scopus, AIDSLINE, CINAHL, Cochrane Library, and Google/Google Scholar. Methodological quality was assessed using the GRADE evaluation. A DerSimonian and Laird random-effects model was used. Subgroup analyses and meta-regression were used to investigate heterogeneity.RESULTSThe electronic searches yielded 765 items. After quality assessment and grading, 30 studies were suitable for metaanalysis. In total, 1,461 congenital anomalies were found among 53,186 births. Children born to women receiving combined antiretroviral therapy (cART) had an approximately 10% higher risk of developing congenital anomalies (relative risk [RR], 1.09; 95% confidence interval [CI], 1.04 to 1.14). A subgroup analysis found no significant difference in the risk of congenital anomalies between cART and efavirenz users. However, zidovudine and protease inhibitor (RR, 1.09; 95% CI, 1.00 to 1.19) users were found to have a 10% increased risk of congenital anomalies, and integrase inhibitor users had a 60% increase in risk (RR, 1.61; 95% CI, 1.60 to 2.43). The subgroup results should be interpreted cautiously because of the moderate heterogeneity (I2 =58%).CONCLUSIONSThe use of protease inhibitors, integrase inhibitors, zidovudine, and newer drugs should be carefully considered in pregnant women. Further studies are needed to address environmental, nutrition, and adherence factors related to ART. Establishing a congenital anomalies surveillance system is recommended.

Aspectos bioéticos na prevenção da transmissão vertical e manejo do tratamento com antirretrovirais em gestantes portadoras de HIV/AIDS no Brasil

In 2012, the United Nations Organization together with the World Health Organization reported that by the end of 2011 there would be about 34 million infected with the human immunodeficiency virus worldwide. Among other forms, the vertical transmission has been a focus of attention in the sense that there has been an increase in cases of infection in women. In this context, this study aims to present antiretroviral treatment in pregnant women with HIV/AIDS, as well as to discuss the bioethical aspects related to the prevention of vertical transmission. In 1994, protocol 076 showed that the use of zidovudine in pregnant women who had the virus during prenatal and childbirth and in the baby during the first six weeks of life, reduced the transmission of the virus by 2/3 for children. Subsequently, the Ministry of Health adopted measures to reduce the incidence of vertical transmission. Nowadays the doctor can make use of guidelines and must use the treatments available for the good of the patients, according to their capacity and judgment, according to the hippocratic tradition, provided that are adequately measured the risks that such medicines can promote to the pregnant woman and to the baby.

Impact of Cutaneous Involvement on the Clinical Outcome of Adult T-Cell Leukemia/Lymphoma: A Study from the Latin American Group of Lymphoproliferative Disorders (GELL)

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm caused by the Human T-cell Leukemia Virus Type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwide and is most endemic in Southwestern Japan, Western Africa, the Caribbean basin and South America. Cutaneous signs of ATLL are varied and may consist of macules (M), plaques (P), multiple papules (MP), tumoral nodules (TN), erythroderma (E) or mixed-lesions (≥2 predominant lesions, ML). M and P forms are believed to carry a better prognosis. However, data on cutaneous presentation of ATLL remains scarce. Herein, we report cases of ATLL with cutaneous involvement diagnosed in 4 Latin American countries over the last 3 decades. METHODS: We retrospectively analyzed patients (pts) diagnosed with ATLL between January 1995 and December 2019. ATLL subtypes were classified according to the Shimoyama criteria into acute, lymphomatous, chronic and smoldering. Primary cutaneous tumoral (PCT) variant was classified according to the 2019 International Revised ATLL Consensus. We designed 2 cohorts: the first, ATLL pts with cutaneous involvement, and the second, matched cases without cutaneous involvement. We determined the type of skin lesion as well as the survival associated with the various types of skin lesions. We compared the frequency of clinical features using Fisher's exact test. Treatment response was assessed according to Tsukasaki et al. (JCO 2009) criteria. To be classified as complete response (CR), partial response, and stable disease, these had to persist for a period of at least 4 weeks. We analyzed survival data according to ATLL subtype, cutaneous involvement status, and type of skin lesion using the Kaplan-Meier method and Log rank test. RESULTS: A total of 169 pts with ATLL were identified; 63 had cutaneous involvement and 106 did not. Clinical features are shown in Table 1. In both groups the median age was 57 years with a female predominance. Cutaneous involvement was most frequently found in acute (41%) and lymphomatous (37%) ATLL pts. The E (24%) and P (22 %) types were the most frequent skin lesions. Disease stage, presence of B symptoms, hypercalcemia, ECOG ≥2, elevated LDH, and IPI/ PIT score were not different among groups. Table 2 and Table 3 summarize the first-line therapy used and response rates. The use of first-line zidovudine plus interferon alpha (AZT-IFN), regardless of the type of skin lesion, resulted in relatively high response rates [overall response (OR) 100%, n=8; CR 62.5%] as compared to multi agent-chemotherapy (OR 33.3%, n=12). Overall, the presence of cutaneous involvement was associated with better overall survival (OS) compared to non-cutaneous involvement (aHR 0.55 [95% CI: 0.37-0.82], p&amp;lt;0.01; 1-year OS 53% vs. 27%, respectively, p=0.012) (Figure 1). PCT pts had better outcome compared to acute and lymphomatous ATLL forms (1-year OS 75% vs. 39% vs. 25%, respectively, p=0.002). The presence of P and MP skin lesions was associated with better OS compared to other subtypes (1-year OS: P/MP 65% vs. others 41%, respectively, p=0.027) (Figure 2, supplemental figure 1). In a multivariate analysis, hypercalcemia was an independent poor prognostic factor for survival among ATLL pts with cutaneous involvement (aHR 3.99 [95% CI: 139-11.45], p=0.01) (supplemental figure 2). One patient with lymphomatous ATLL and plaque lesions underwent allogeneic stem cell transplant with high-dose chemotherapy after achieving CR with AZT-IFN; patient remains alive and progression-free for 17 months. Illustrative cases of cutaneous ATLL are shown in Figure 3. CONCLUSION: In Latin American pts with aggressive ATLL, cutaneous involvement appears to be associated with better survival compared to non-cutaneous involvement. PCT subtype, an ATLL variant characterized by isolated skin lesions with no organ involvement and poor outcome, appeared to have a better prognosis compared to acute and lymphomatous ATLL forms. P and MP skin lesions were both associated with better survival. Hypercalcemia was found as an independent prognostic factor for survival in pts with cutaneous involvement. Finally, AZT-IFN appears to be reasonable first-line option for aggressive ATLL subtypes with cutaneous involvement regardless of the type of skin lesion at diagnosis, based on the relatively high response rates observed in this subset; further investigation in randomized clinical trials is needed. Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Takeda: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Altamirano:Hospital Nacional Guillermo Almenara Irigoyen: Other: Servicio de Hematologia. Perini:Abbvie: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Research Funding; Kymera: Consultancy; TG Therapeutics: Research Funding; Janssen: Consultancy, Research Funding. Ramos:NIH: Research Funding. Villela:amgen: Speakers Bureau; Roche: Other: advisory board, Speakers Bureau.

Anemia and Associated Factors Among Adults with Human Immune Deficiency Virus on Antiretroviral Therapy in Public Health Facilities of Kembata Tembaro Zone, Southern Ethiopia: A Cross-Sectional Study.

BackgroundAnemia is an independent prognostic marker of HIV/AIDS disease progression. It causes impaired physical functioning, psychological distress, poor quality-of-life, and reduces life expectancy in HIV patients. However, there is limited information in Ethiopia. Therefore, the aim of this study was to assess the magnitude of anemia and associated factors among adult HIV patients on antiretroviral therapy in public health facilities of Kembata Tembaro Zone, southern Ethiopia.MethodsWe conducted a facility-based cross-sectional study. A total of 401 HIV patients attending antiretroviral therapy nested in five health facilities were included in the analysis. Simple random sampling was employed using medical record number to select study units. Data were collected using pretested and structured questionnaire, anthropometric measurements were taken, and a drop of capillary blood was collected to determine hemoglobin level by HemoCue 301 analyzer. Clinical related data were collected from patient medical records by using a structured checklist. The collected data were coded and entered into EpiData version 3.1 and exported to SPSS version 20 for analysis. Logistic regression analysis was carried out to identify factors associated with anemia and statistical tests were declared significant at a P-value<0.05.ResultsThe magnitude of anemia among adults HIV patients attending ART was 26.2%, 95% CI=21.7–30.4. Being female (AOR=2.06, 95% CI=1.02–4.16), body mass index <18.5 Kg/m2 (AOR=2.28, 95% CI=1.09–4.78), Zidovudine use (AOR=3.71, 95% CI=1.9–7.26), having had an opportunistic infection (AOR=5.46, 95% CI=1.67–17.7), and WHO stage III or IV (AOR=5.71, 95% C=2.68–12.14) were significantly associated with the occurrence of anemia.ConclusionAnemia was found to be a moderate public health problem among ART attendants in the current study area. Thus, early detection and intervention targeting Zidovudine users, females, patients having body mass index <18.5 Kg/m2, patients having opportunistic infections, and patients having clinical WHO stage III or IV disease is vital to reduce the magnitude of anemia and its consequences.

Increased risk of dizziness in human immunodeficiency virus-infected patients taking zidovudine and efavirenz combination: a Brazilian cohort study.

Neuropsychiatric adverse effects (NPAE) related to efavirenz, mainly dizziness, is detrimental to human immunodeficiency virus (HIV) treatment. Our study aims at evaluating if zidovudine use potentiates the risk of dizziness related to efavirenz when used together and whether there are significant differences in over time distribution of this NPAE and others relatively frequents regarding efavirenz regimen without zidovudine. Human immunodeficiency virus-infected patients under efavirenz-containing different therapy were enrolled. A retrospective analysis of official medical records was accomplished to collect clinical data regarding NPAE occurrence and severity. Univariate statistic and statistical model based on survival analyses were performed. One hundred sixty-two patients were included, of these seventy-seven (47.5%) had NPAE reported, such as dizziness (more frequent), depression and insomnia. Univariate statistical analysis demonstrated that the combined use of efavirenz with zidovudine increased the NPAE risk (OR: 2.5; P-value: 0.008), mainly dizziness risk (OR: 3.5; P-value: 0.009) and survival analysis showed that such combination is associated with dizziness occurrence faster (HR: 2.9; P-value: 0.02). The results may contribute to clarify the dizziness occurrence dynamics in therapy with efavirenz and zidovudine by identifying susceptibilities and assisting in the choice of combined antiretroviral therapy.

Inactivation of thymidine kinase as a cause of resistance to zidovudine in clinical isolates of Escherichia coli: a phenotypic and genomic study.

The antiviral zidovudine has been recently identified as an active drug against resistant Enterobacteriaceae, but prevalence of resistance to this compound remains unknown. The aim was to estimate the prevalence of clinical Escherichia coli isolates resistant to zidovudine and to decipher the mechanism of zidovudine resistance. We screened 537 isolates on zidovudine-containing agar plates and studied their thymidine kinase (tdk) gene sequences, the putative target involved in zidovudine resistance. Moreover, sequence analysis of 633 complete genomes of E. coli was performed to investigate mutation in the tdk gene. A comparative genomic analysis was done on an in vitro zidovudine-resistant mutant. After screening on our medium containing 2.7 mg/L (10 μM) zidovudine, nine strains had a zidovudine MIC >26.7 mg/L. The gene was absent in three isolates, inactivated by an IS (IS1X2 and ISApl1) in two isolates and mutated in four isolates. A genomic analysis of 633 E. coli genomes showed heterogeneity of the tdk gene sequence, with 27 different sequences. Among them, three genomes showed an inactivation of the gene (IS, stop codon and no tdk gene sequence). The in vitro mutant E. coli had 27 SNPs in eight genes of the core genome compared with the initial strain. Our study reports zidovudine-resistant clinical isolates of E. coli, presumably related to tdk inactivation. Diversity of Tdk in bacterial genomes can be large. Other mechanisms need to be considered in zidovudine resistance. The use of zidovudine in antibiotic-resistant infections needs to be in combination and should be tested before clinical administration.

Safety of 6-week Neonatal Triple-combination Antiretroviral Postexposure Prophylaxis in High-risk HIV-exposed Infants.

Combination antiretroviral drug regimens are increasingly preferred for neonatal postexposure prophylaxis (PEP) among HIV-exposed infants with high-risk of transmission. We evaluated the adverse events associated with the use of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP) for neonatal PEP during the first 6 weeks of life. A prospective cohort of non-breast-fed HIV-exposed infants was conducted at 5 clinical sites in Thailand. Study population included 100 high-risk HIV-exposed infants (maternal HIV RNA > 50 copies/mL prior to delivery or received antiretroviral therapy less than 12 weeks) and 100 low-risk HIV-exposed neonates. High-risk infants received ZDV/3TC/NVP for 6 weeks whereas low-risk HIV-exposed neonates received a 4-week regimen of ZDV. Complete blood count, aspartate transaminase and alanine transaminase were assessed at birth, 1, 2 and 4 months of life. From October 2015 to November 2017, 200 infants were enrolled, of which 18.5% had low birth weight < 2500 g. The proportion of infants with anemia grade 2 or higher at 1 and 2 months of life between ZDV/3TC/NVP and ZDV prophylaxis was 48.5% vs 32.3% (P=0.02); nevertheless, severe anemia (grade 3) was not significantly different; 9.2% vs 10.2% (P=0.81), respectively. At 1 month old, infants on ZDV/3TC/NVP prophylaxis had significantly higher grade 2 anemia versus infants on ZDV alone (33.0% vs 13.4%; P=0.001); however, no difference was observed at 2 months old. No differences in neutropenia or hepatotoxicity between infant prophylactic regimens were observed. Triple antiretroviral neonatal PEP with ZDV/3TC/NVP for 6 weeks in high-risk HIV-exposed infants did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy prophylaxis.

PS1097 ADULT T‐CELL LEUKEMIA/LYMPHOMA: EPIDEMIOLOGY, CLINICAL FEATURES AND OUTCOME OF A CARIBBEAN COHORT FROM GUADELOUPE

Background:Adult T‐cell leukemia/lymphoma (ATLL) is a rare mature T‐cell malignancy first described in Japan in 1977. The causative agent of ATLL has been identified as the human T cell lymphotropic virus type 1 (HTLV‐1) which is endemic in Japan, Caribbean area, Central and South America and parts of sub‐Saharan Africa. Whereas Japanese cohorts of ATLL are commonly described, the studies gathering ATLL in the Caribbean islands are less frequently provided. ATLL is an unfrequent and subsequently unknown in Europa in opposite to the French overseas departments of the caribbean area.Aims:To report and describe ATLL in the lesser Antilles at the modern area of zidovudine and interferon treatment.Methods:We identified ATLL patients diagnosed in our institution between 2014 and 2018. Charts were reviewed to report clinicopathologic features, treatment patterns and outcomes of this Caribbean cohort exclusively diagnosed in Guadeloupe (French West Indies). ATLL diagnosis is based for all patients on the presence of a clonal T cells proliferation along with positivity for HTLV‐1 serology.Results:Among 309 patients positive for HTLV‐1 in this period, 24 developed an ATLL (7.76%). The median age at presentation is of 59 years (27–92). The sex ratio M/F was 11/13 (0.84). Based on the Shimoyama classification, 14 patients (58,9%) had acute subtype, 9 (37,5%) had lymphomatous and 1 (4,1%) chronic/smoldering disease. 22/24 had lymphadenopathy or deep tumoral syndrom at diagnosis whereas 2 patients presented splenomegaly. LDH was elevated in 23 patients (mean rate is 4.36N (0.94 – 28.03)). Hypercalcemia was present in half of the cases (mean value of 2,69 mg/dL (1.46 – 4.22)). Lymphocytosis was present in 7 patients (29%) and typical flower cells in 14 cases. Circulating lymphocyte phenotyping, performed for 19 patients, showed clonal T‐cells in 15 cases. Two third of the available karyotype were complex with abnormalities of the chromosome 14 in 50% of the cases.Most of the patients (n = 22, 91.6%) received first‐line treatment, whereas 8.3% (n = 2) quickly passed away before initiating any specific medication. As first line, 11 patients were treated by zidovudine and pegylated interferon +/‐ corticosteroid, 10 patients received a polychimiotherapy only or associated with zidovudine and peg‐interferon and one received corticosteroid only. Among the 15 patients with relapse or refractory diseases, 6 were able to receive a second line treatment. One patient benefits from haploidentical bone marrow transplantation. Five patients are still alive at last follow‐up : 3 patients in complete response (including the transplanted patient), 2 in partial response. Among them, 4 are still treated with interferon and zidovudine. Mean overall survival is 10.1 months (0.2–58.4). Among the 18 death with available data: 10 were related to ATLL progression, 6 related to infections and 2 patients died with acute respiratory distress syndrome.Summary/Conclusion:We report the first description of ATLL in Guadeloupe island. Compared to Japanese cohorts, we have younger patients and dominance of acute and lymphomatous ATLL subtypes. Cytologic detection of flower cells needs trained biologists and Shimoyama classification requires a very low blood cell count (&lt;1%) for lymphomatous category. Nevertheless, this detection can be improved by immunophenotyping which might be worthly introduced in this classification. Despite large and early use of zidovudine and interferon, with or without chemotherapy, ATLL remains a very poor prognostic disease confirming that innovative therapies are still needed.

Antiretroviral-induced adverse drug reactions in HIV-infected patients in Mali: a resource-limited setting experience.

Background:There are few reports in the literature from sub-Saharan Africa (SSA) regarding antiretroviral-induced adverse drug reactions (ADRs). Antiretroviral therapy (ART) is now widely available in SSA, and ADRs during HIV infection are also frequent. In this study, we reported the frequency and risk factors of ART-induced ADRs in a Malian population.Methods:This prospective cohort study was performed in the HIV Care and Counseling Centre (CESAC) of Mali from 2011 to 2012. Adult patients infected with HIV and who had recently started ART were included and followed-up clinically Were included in this study, adult patients living with HIV and had recently started ART who were followed up for at least 6 months to determine the incidence of ADRs using Naranjo’s classification scale.Results:During this study, 357 (42.3%) patients presented ADRs (40.1% of our patients (n=338) experienced at least one ADR, and 2.2% (n=19) experienced at least two ADRs). The prevalence of ADRs by organ system was: 45.9% neurological (n=164); 29.4% metabolic (blood chemistry) (n=105); 15.4% hematological (n=55). High probable rate of ADR was observed as indicated by the Naranjo score in 83.7% of the cases. Zidovudine (AZT) and stavudine (d4T) use was identified as a risk factor for either anaemia or peripheral neuropathy whereas nevirapine (NVP) and female gender were risk factors for skin reactions. Patients with advance disease had the highest rate of ADRs compared to the others.Conclusions:Based on the Naranjo probability scale, our data show that ADRs such as peripheral neuropathy and anemia are very frequent. These ADR was linked to AZT and D4T. Our findings highlight the need for active monitoring, continuous pharmacovigilance of ART and change of some ART drug in this population.