Poor Virological Outcome Research Articles

Immunological factors associated with discordant virological response postcombination antiretroviral therapy in pediatric human immunodeficiency virus infection.

Evaluation of immunological factors responsible for discordant virological responses postcombination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-positive children aged <5 years. Immunological profiling of enrolled 30 HIV-positive children was done at enrollment, 6 and 12 months. Flow cytometric analysis was performed for enumeration of counts and percentage of CD4⁺, CD8⁺, and CD19⁺ cells; expression of CD19, CD86, PD-1, CD3, CD8 and CD28 on lymphocytes was evaluated using whole blood staining technique with monoclonal antibodies. HIV-1 viral load was quantified using a real-time polymerase chain reaction. Serum levels of immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin (IgM), and interleukin (IL)-7 were quantitated using quantitative enzyme-linked immunosorbent assay kits. The HIV-infected children were categorized into virological responders (VRs; HIV-1 plasma viral load <47 copies/mL) and virological nonresponders (VNRs; HIV-1 plasma viral load >1000 copies/mL) following 1-year cART. The frequency of CD28⁺ CTLs cells was higher (P < 0.0001), and the frequency of CD28-CTLs cells was lower (P < 0.0001) in VRs than VNRs. CD28⁺ and CD28-CTLs cells correlated with HIV-1 plasma viremia (r = -0.4695, P = 0.01; r = 0.40, P = 0.03, respectively). VRs had higher CD19 percentage (P = 0.04) and count (P = 0.01) than VNRs. CD19⁺ B cells in the VRs had lower expression of CD86 (P = 0.03) and PD-1 (P = 0.002) than VNRs. VR had lower levels of serum IgG (P = 0.03), IgM (P = 0.04), and IL-7 (P = 0.01) than VNRs. High baseline B-cell counts, lower serum IgG, IgM, IL-7 levels, lower activation and exhaustion of B cells, and higher frequency of CD28⁺ CTLs are associated with positive virological response, whereas elevated CD28-CTLs are associated with the poor virological outcomes in HIV-infected children.

Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients.

Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2–14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51–16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80–2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89–0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8–8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7–8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6–13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3–7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.

2249. Insulin Resistance Is Associated with Higher Viral Loads Among HIV-1-Infected Patients Initiated on 12 Months of First-Line Antiretroviral Therapy

BackgroundAs HIV-infected patients are living longer due to ART and decreasing mortality, the burden of noncommunicable diseases (NCDs) is expected to rise. With the implication of Insulin resistance (IR) and inflammation in the pathogenesis of Diabetes Mellitus (DM), DM is likely to be increasing in the HIV-infected patients in the Sub-Saharan Africa (SSA). HIV is characterized with systemic inflammation and markers which quickly decrease with ART initiation regardless of type of ARV regimen though they do not normalize. We thus assessed the relationship between IR and Virologic treatment failure among HIV-1-infected individuals at 12 months of first-line ART in the Zambian ART program.MethodsWe conducted a cross-sectional survey among HIV-1-infected individuals at 12 months (±3 months) of first-line ART. Systematic sampling was performed and 20 clinics were selected based on the random starting-point, sampling interval and cumulative population size giving a sample size of 460. Eligible patients had their fasting blood specimens collected for VL, insulin, blood glucose, high sensitive c-reactive protein (hsCRP), tumour necrosis factor alfa (TNFa) and Lipogram. Anthropometric indices were also measured including visceral fat. Insulin resistance (IR) was determined using Homeostatic model assessment (HOMA). Proportions for each outcome at linearized standard error 95% confidence interval and summary estimates were determined. Viral Load suppression (VLS) was defined according to the detection threshold which was <20 copies/mL and treatment failure was defined as VL > 1,000 copies/mL.ResultsOf the 473 patients enrolled, 142 (30%): 95% CI (26%, 34%) had IR. 19% of Individuals with IR had treatment failure compared with 5.7% with treatment failure and without IR (P-value < 0.0001). Treatment success was associated with less likelihood of IR (OR 0.26 (0.14, 0.48), P-value < 0.0001. Among individuals with VLS, 82, out of 142 (58%) 95% CI (0.54%, 0.70%) had IR compared with 232 out of 331, (70%) 95% CI (65%, 75%) who did not have IR (P-value = 0.042)ConclusionPatients with poor virological outcomes at 12 months of first-line ART had increased likelihood of insulin resistance compared with those with treatment success. There was good evidence to suggest that the proportion of those with VLS and IR was less than those with VLS and no IR.Disclosures All authors: No reported disclosures.

Effectiveness and Risk Factors for Virological Outcome of Raltegravir-Based Therapy for Treatment-Experienced HIV-Infected Patients.

ObjectiveWe evaluated the effectiveness of a raltegravir (RAL)-containing regimen plus an optimized background regimen in HIV-1 highly treatment-experienced patients.DesignA retrospective cohort, multicentre study was conducted.MethodsAdult (>16 years old) HIV treatment-experience patients starting therapy with a RAL-containing regimen were included. Effectiveness was evaluated as the percentage of patients with an undetectable HIV-1 RNA viral load (<50 and <200 copies/mL) after 48 weeks, and changes in CD4+ cell counts. We evaluated the risk factors associated with treatment failure.ResultsOf the 107 patients in the cohort, 86% were men, the median age was 45 years [interquartile range (IQR) 40–52] and the median number of previous regimens was six (IQR 4–7). After 48 weeks of treatment, 73% (IQR 63–80%) of patients (n = 78) had a viral load of <50 copies/mL and 85% (IQR 77–90%) (n = 91) had <200 copies/mL. In a logistic regression model, risk factors associated with a virological outcome of HIV-1 RNA of <200 copies/mL were age >40 years [odds ratio (OR) 5.61; 95% confidence interval (CI) 1.61–18.84; P = 0.006] and use of tenofovir in the regimen (OR 0.16; 95% CI 0.03–0.80; P = 0.026).ConclusionsIn this Mexican cohort, RAL achieved high rates of virological suppression and an increase in CD4+ cell count in highly treatment-experienced patients infected with HIV-1. Age >40 years was associated with a good virological outcome, contrary to tenofovir use, which was associated with a poor virological outcome.

CD38+CD8+ and CD38+CD4+ T Cells and IFN Gamma (+874) Polymorphism Are Associated with a Poor Virological Outcome

ABSTRACTThe main objective of the work was to evaluate the use of CD38 on T lymphocytes, IFNγ (+874 A/T), and IL-10 (−1082 A/G) polymorphisms in HIV-infected patients under antiretroviral (ARV) therapy. Sixty-one patients were selected at the outpatient clinic for HIV infection at the Hospital São José de Doenças Infecciosas, Fortaleza, Ceará, Brazil. The patients were classified into two groups, according to viral load after one year of ARV therapy. In the aviremic group (group I), a reduction of 35.5% of CD38+CD4+ T cells was observed (p = 0.02) and 49.3% of CD38+CD8+ T cells (p = 0.001). In the viremic group (group II), a reduction of 37.2% of CD38+CD4+ T cells (p = 0.067), and 21.4% of CD38+CD8+ T cells (p = 0.60) occurred. No association was found between IL-10 (−1082) polymorphism and the type of response to ARV therapy. Regarding the gene polymorphism on IFNγ (+874 T/A), 73.34% of group I and 33.3% of group II presented the AA genotype. The relative risk of the individuals carrying AA genotype or the A allele and not being able to suppress the viral load level after one year of ARV therapy was 3.44 (1.25–9.45; p = 0.014) or 2.35 (1.05–5.26; p = 0.027), respectively. Our data suggested that an augmented frequency of activated CD38+CD8+ T cells as well as the presence of the A allele of IFNγ polymorphism could contribute to a reduced virological suppression in patients under antiretroviral therapy.

Factors associated with poor CD4 and viral load outcomes in patients with HIV/AIDS.

Suboptimal viral suppression and CD4 response to antiretroviral treatment (HAART) is known to cause poor outcomes with the increase cost of treatment. We aimed to assess factors associated with such control among HIV/AIDS patients in Malaysia. Four hundred and six HIV/AIDS patients, using Antiretroviral Therapy (ART) for at least the past three months, treated as outpatients at medication therapy adherence clinics (MTAC) were recruited. CD4 cell counts, viral load readings along with co-variants such as socio-demographic factors, adverse drug reactions, comorbidities, and medication record were obtained. Statistical Package for Social Sciences (SPSS(®)) version 18 and STATA IC(®) version 12 were used for data analysis. CD4 counts were found highest among those within the age category 41-50 years (390.43 ± 272.28), female (402.64 ± 276.14), other ethnicities (400.20 ± 278.04), and participants with no formal education (414.87 ± 290.90). Patients experiencing adverse effects had a 2.28 (95%CI:1.25-4.18) fold greater risk of poor CD4 control, while patients with comorbidities had 2.46 (95%CI:1.02-5.91) fold greater risk of mild viral suppression. Adverse drug reactions, co-morbidities were found to be significantly associated with poor immunological and virological outcomes in HIV/AIDS patients. However, a comprehensive evaluation is needed to better understand other confounders.

Secreted Wnt Antagonists During Eradication of Cytomegalovirus Infection in Solid Organ Transplant Recipients

We evaluated secreted wingless (Wnt) modulators during cytomegalovirus (CMV) infection in solid organ transplant recipients (SOTr). The major findings were: (i) Plasma levels of Dickkopf-1 (DKK-1) were significantly lower in patients with CMV DNAemia above lower level of quantification at baseline. (ii) Receiver operating characteristic analysis indicated that low DKK-1 and increased secreted frizzled related protein-3 levels were predictors of poor virological outcomes during follow-up. Our findings demonstrate an imbalanced pattern of circulating secreted Wnt modulators in SOTr with poor virological outcomes following treatment for CMV disease, and may suggest a role for dysregulated Wnt signaling on viral pathogenesis during CMV infection.

Temporal Association Between Incident Tuberculosis and Poor Virological Outcomes in a South African Antiretroviral Treatment Service

Introduction:The temporal relationship between incident tuberculosis (TB) and virological outcomes during antiretroviral therapy (ART) is poorly defined. This was studied in a cohort in Cape Town, South Africa.Methods:Data regarding TB diagnoses, ART regimens, and 4-monthly updated viral load (VL) and CD4 count measurements were extracted from a prospectively maintained database. Rates of virological breakthrough (VL > 1000 copies/mL) and failure (VL > 1000 copies/mL on serial measurements) following initial VL suppression were calculated. Poisson models were used to calculate incidence rate ratios (IRRs) and identify risk factors for these virological outcomes.Results:Incident TB was diagnosed in 391 (28.5%) of 1370 patients during a median of 5.2 years follow-up. Five hundred seventy-eight episodes of virological breakthrough and 231 episodes of virological failure occurred, giving rates of 10.0 episodes per 100 person-years and 4.0 episodes per 100 person-years, respectively. In multivariate analyses adjusted for baseline and time-updated risk factors, TB was an independent risk factor for adverse virological outcomes. These associations were strongly time dependent; the 6-month period following diagnosis of incident TB was associated with a substantially increased risk of virological breakthrough (IRR: 2.3, 95% confidence interval: 1.7 to 3.2) and failure (IRR: 2.6, 95% confidence interval: 1.6 to 4.3) compared with time without a TB diagnosis. Person-time preceding TB diagnosis or more than 6 months after a TB diagnosis was not associated with poor virological outcomes.Conclusions:Incident TB during ART was strongly associated with poor virological outcomes during the 6-month period following TB diagnosis. Although underlying mechanisms remain to be defined, patients with incident TB may benefit from virological monitoring and treatment adherence support.

Personal barriers to antiretroviral therapy adherence: Case studies from a rural Uganda prospective clinical cohort

Although good adherence to antiretroviral therapy (ART) is essential for successful treatment outcomes, some patients may have specific personal barriers to ART adherence. To study specific personal barriers to ART adherence. Quantitative data on patients' health status, ART adherence, CD4 cell counts and viral loads were collected, and qualitative data on life experiences of five patients with poor ART outcomes and adherence were also collected. Out of 35 patients with poor immunological and virological ART outcomes, 17 (49%) also had poor ART adherence. Patient 1 had no living child and did not disclose her HIV serostatus to her spouse because she wanted to have a child. Patient 2 was an orphan with neither social nor family support. Patient 3 stopped ART when she conceived, returned to the study clinic when pregnant again and was sickly. She was switched to second-line ART with satisfactory outcomes. Patient 4, a 14 year old orphan had missed ART for 2 months when his treatment supporter was away. Patient 5 aged 66 years stopped ART which he blamed for his erectile dysfunction. ART adherence counselling should target specific personal barriers to ART adherence like: lack of family support, health and sexual life concerns, desire to have children and family instability.

Osteoprotegerin: A Biomarker With Many Faces

Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is a soluble decoy receptor for the osteoclast differentiation factor receptor-activator of nuclear factor κB ligand (RANKL) that inhibits interaction between RANKL and its membrane-bound receptor RANK (Figure).1 The RANKL/OPG/RANK axis has been shown to regulate bone remodeling2,3 and was more recently found to be involved in carcinogenesis as well as central thermoregulation.4,5 This system has also been linked to the development of atherosclerosis and plaque destabilization.6,7 RANKL exhibits several properties with relevance to atherogenesis, such as promotion of inflammatory responses in T cells and dendritic cells, induction of chemotactic properties in monocytes, induction of matrix metalloproteinase (MMP) activity in vascular smooth muscle cells (SMC), and RANKL has also been found to have prothrombotic properties.2,8 In observational studies, elevated circulating OPG levels have been associated with prevalence and severity of coronary artery disease, cerebrovascular disease, and peripheral vascular disease.2,8 Circulating OPG levels are increased in patients with acute coronary syndrome,9 and enhanced expression has been found within symptomatic carotid plaques.10 Elevated OPG levels have also been associated with the degree of coronary calcification in the general population as a marker of coronary atherosclerosis.11 OPG has been reported to predict survival in patients with heart failure after acute myocardial infarction,12 to predict heart failure hospitalization and mortality in patients with acute coronary syndrome,9 and to be associated with long-term mortality in patients with ischemic stroke.13 There are also a few …

IL1A alleles associate with a virological response to antiretroviral therapy in HIV patients beginning therapy with advanced disease

Among Australians treated for advanced HIV disease, a suboptimal virological response was associated with allele 2 at interleukin 1 alpha (IL1A)-889 and IL1A+4845. This is confirmed and investigated using patients from AIDS Clinical Trials Group study 384 (n=532). Among non-African-American patients with CD4 T-cell count of< or = 100 cells/microl at baseline, IL1A+4845(*)TT was associated with poor virological outcome (P=0.03). Differences were smaller with higher baseline CD4 T-cell counts. IL1A-889 and IL1A+4845 were not in linkage disequilibrium in African-American patients, and IL1A+4845(*)T did not affect outcome.

Risk factors for poor virological outcome at 12 months in a workplace-based antiretroviral therapy programme in South Africa: A cohort study

BackgroundReasons for the variation in reported treatment outcomes from antiretroviral therapy (ART) programmes in developing countries are not clearly defined.MethodsAmong ART-naïve individuals in a workplace ART programme in South Africa we determined virological outcomes at 12 months, and risk factors for suboptimal virological outcome, defined as plasma HIV-1 viral load >= 400 copies/ml.ResultsAmong 1760 individuals starting ART before July 2004, 1172 were in follow-up at 12 months of whom 953 (81%) had a viral load measurement (median age 41 yrs, 96% male, median baseline CD4 count 156 × 106/l). 71% (681/953) had viral load < 400 copies/ml at 12 months. In a multivariable analysis, independent predictors of suboptimal virological outcome at 12 months were <1 log decrease in viral load at six weeks (odds ratio [OR] 4.71, 95% confidence interval [CI] 2.56–8.68), viral load at baseline (OR 3.63 [95% CI 1.88–7.00] and OR 3.54 [95% CI 1.79–7.00] for 10,001–100,000 and >100,000 compared to <= 10,000 copies/ml, respectively), adherence at six weeks (OR 3.50 [95% CI 1.92–6.35]), WHO stage (OR 2.08 [95% CI 1.28–3.34] and OR 2.03 [95% CI 1.14–3.62] for stage 3 and 4 compared to stage 1–2, respectively) and site of ART delivery. Site of delivery remained an independent risk factor even after adjustment for individual level factors. At 6 weeks, of 719 patients with self-reported adherence and viral load, 72 (10%) reported 100% adherence but had <1 log decrease in viral load; conversely, 60 (8%) reported <100% adherence but had >= 1 log decrease in viral load.ConclusionVirological response at six weeks after ART start was the strongest predictor of suboptimal virological outcome at 12 months, and may identify individuals who need interventions such as additional adherence support. Self reported adherence was less strongly associated but identified different patients compared with viral load at 6 weeks. Site of delivery had an important influence on virological outcomes; factors at the health system level which influence outcome need further investigation to guide development of effective ART programmes.