Immunological Recovery Research Articles

Immunological and virological response to initial antiretroviral therapy among older people living with HIV in the Canadian Observational Cohort (CANOC).

The aim of this study was to assess the adequacy of immunological recovery and virological suppression in response to antiretroviral therapy (ART) in the growing population of older people living with HIV (PLWH), as treatment regimens become more effective and tolerable. An interprovincial Canadian cohort of treatment-naïve PLWH who initiated ART after 1 January 2000 was used and age assessed in decades. Longitudinal absolute CD4 count response to treatment was modelled using generalized estimating equations. Cumulative incidence functions and proportional hazards models with a competing risk of death were used to estimate time to: (1) CD4≥200 cells/µL, (2) CD4≥500 cells/µL, (3) virological suppression (≤50 copies/mL), and (4) virological failure (>200 copies/mL). In all, 12489 individuals starting ART between 2000 and 2016 with one or more post-treatment CD4 count or viral load were included in the analysis. Age >60 years was associated with lower absolute CD4 recovery (adjusted β=-31 cells/µL) compared with age ≤30 years when pre-treatment CD4 count and other covariates were accounted for. Older age groups were less likely to achieve a CD4≥500 cells/µL, with the greatest effect in the >60 group [adjusted hazard ratio (aHR)=0.69, 95% confidence interval (CI): 0.57-0.84 vs. age ≤30). Older age groups were more likely to achieve viral suppression (age >60, aHR=1.20, 95% CI: 1.05-1.37) and less likely to have virological failure (age >60, aHR=0.46, 95% CI: 0.3-0.71) compared with those aged ≤30 years. Older adults have robust virological responses to ART; however, individuals over the age 60 are more likely to experience blunted CD4 recovery.

Hepatitis B and C infections in HIV-1 patients on combination antiretroviral therapy (cART) in Ghana: implications for immunologic recovery, clinical response to treatment, and hepatotoxicity

BackgroundViral hepatitis could have an impact on the treatment response in HIV patients. In this study, we sought to determine the prevalence of hepatitis B and C infections and examine the effect on the treatment response in HIV-1 patients attending antiretroviral therapy (ART) centers in the Volta and Oti Regions of Ghana. MethodA longitudinal study design was employed. A cohort of 200 newly diagnosed HIV-1 positive adults who met the inclusion criteria (CD4 count ≤350 cells/μl) were enrolled at three ART Centers and initiated on the combination Antiretroviral Therapy (cART) from January 2014 to December 2015. Blood samples obtained from each participant were subsequently screened for the presence of hepatitis B surface antigen (HBsAg) and hepatitis C antibody. Out of the 200 study respondents recruited, 93 HIV mono-infected were randomly selected plus all 17 HIV co-infected were prospectively followed for twelve months. Using standard methods, three consecutive measurements of CD4 cells, haemoglobin, and liver enzymes [(aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] as well as weight measurements were performed at baseline, six months and twelve months, respectively, after treatment initiation. ResultThe overall HIV-viral hepatitis sero-positivity was 8.5%. HBV and HCV co-infections were 7.0% and 1.5% respectively. Among HIV mono-infected CD4 cell count, haemoglobin, and weight significantly increased from baseline to the twelfth month while levels remained statistically comparable in the HIV co-infected patients. The levels of AST, ALT, and ALP were more pronounced (hepatotoxicity) in the HIV co-infected compared to the HIV mono-infected at various time points within the twelve month. ConclusionThe frequency of HIV-hepatitis co-infection was high. This correlates with poor immunological outcome, clinical response to treatment and pronounced hepatotoxicity. The findings, therefore, underscore the need for regular screening of HIV patients for early detection and appropriate management.

Low frequency of cytomegalovirus (CMV) disease despite high prevalence of CMV viraemia in patients with advanced HIV infection: a clinical and immunological 48-week follow-up study.

The aim of the study was to investigate the dynamics of cytomegalovirus (CMV) replication and CMV-specific immune response recovery after antiretroviral treatment (ART) initiation in patients with advanced HIV infection. A prospective observational study of patients with HIV infection and CD4 counts of <100 cells/µL was carried out (September 2015 to July 2018). HIV viral load (VL), CD4 count and CMV VL were determined by quantitative polymerase chain reaction (PCR) at baseline and at 4, 12, 24 and 48weeks, and CMV-specific immune response was determined by QuantiFERON-CMV assay at baseline and 48weeks. All patients were started on ART but only those with CMV end-organ disease (EOD) received anti-CMV treatment. Fifty-three patients with a median age of 43.6 [interquartile range (IQR) 36.7-52.4] years were included in the study. At baseline, the median CD4 count was 30 cells/µL (IQR 20-60 cells/µL) and the median HIV VL was 462000 HIV-1 RNA copies/mL (IQR 186000-1300000 copies/mL). At baseline, 32% patients had detectable CMV viraemia but none had detectable CMV viraemia at 48weeks. Only one of 53 (1.9%) patients developed EOD during follow-up. Seven (13.2%) patients were lost to follow-up and six (11.3%) died; none of the deaths was related to CMV. Similar percentages of patients had a CMV-specific immune response at baseline (71.7%) and at 48 weeks (70.0%). The magnitude of this response tended to increase over time [median 1.63 (IQR 0.15-5.77) IU/mL at baseline vs. median 2.5 (IQR 0.1-8.325) IU/mL at 48weeks; P=0.11]. We did not find any risk factors associated with 48-week mortality. Although the prevalence of CMV viraemia in patients with advanced HIV infection remains high, achieving a good immunological recovery through ART is enough to suppress CMV viraemia, without an increased risk of CMV EOD. The prevalence of a CMV-specific immune response was high and endured over time.

Expansion of GARP-Expressing CD4+CD25-FoxP3+ T Cells and SATB1 Association with Activation and Coagulation in Immune Compromised HIV-1-Infected Individuals in South Africa.

Although antiretroviral treatment lowers the burden of human immunodeficiency virus (HIV)-related disease, it does not always result in immunological recovery. This manifests as persistent chronic inflammation, immune activation or exhaustion that can promote the onset of co-morbidities. As the exact function of regulatory T (Treg) cells in HIV remains unclear, this cross-sectional study investigated three expression markers (Forkhead box protein P3 [FOXP3], glycoprotein A repetitions predominant [GARP], special AT-rich sequence binding protein 1 [SATB1]) and compared their expansion between CD4+CD25- and CD4+CD25++ T cells. Age-matched study subjects were recruited (Western Cape, South Africa) and sub-divided: HIV-negative subjects (n = 12), HIV-positive naïve treated (n = 22), HIV-positive treated based on CD4 count cells/µL (CD4 > 500 and CD4 < 500) (n = 34) and HIV-treated based on viral load (VL) copies/mL (VL < 1000 and VL > 1000) (n = 34). Markers of immune activation (CD38) and coagulation (CD142) on T cells (CD8) were assessed by flow cytometry together with FOXP3, GARP and SATB1 expression on CD4+CD25- and CD4+CD25++ T cells. Plasma levels of interleukin-10 (IL-10; anti-inflammatory marker), IL-6 (inflammatory marker) and D-dimer (coagulation marker) were assessed. This study revealed three major findings in immuno-compromised patients with virological failure (CD4 < 500; VL > 1000): (1) the expansion of the unconventional Treg cell subset (CD4+CD25-FOXP3+) is linked with disease progression markers; (2) increased GARP expression in the CD4+CD25- and CD4+CD25++ subsets; and (3) the identification of a strong link between CD4+CD25-SATB1+ cells and markers of immune activation (CD8+CD38+) and coagulation (CD8+CD142+ and D-dimer).

Successful Allogeneic Peripheral Blood Stem Cell Transplantation in 4 Wiskott-Aldrich Syndrome Patients.

Allogeneic hematopoietic stem cell transplantation is a potential curative treatment in Wiskott-Aldrich syndrome (WAS). Here, we analyzed the outcomes in 4 WAS patients who underwent this procedure with peripheral blood stem cell (PBSC) in our center. Four patients with severe WAS phenotype have received allogeneic hematopoietic stem cell transplantation between January 2014 and December 2019 from matched sibling donors with PBSC. Two different preparative conditioning regimens were provided: the first associated busulfan-cyclophosphamide (2 patients) and the second with busulfan-fludarabine administered to the others. Cyclosporine gave as preferred graft-versus-host disease prophylaxis with a short course of methotrexate. All patients achieved engraftment after PBSC with a median CD34+ cell count: 13.6×106/kg (8 to 24.9×106/kg). Chronic graft-versus-host disease developed in 2 patients treated by cyclosporine-steroids with complete resolution. Chimerism for all the patients was fully donor (>95% donor). After a median follow-up of 41 months (8 to 74 mo), all patients (100%) are alive, healthy, with complete clinical, immunologic, and hematologic recovery, without signs of WAS. This limited study with high-dose PBSC transplantation approach for WAS, demonstrated a safe and effective treatment option, with rapid engraftment, without complications, excellent long-term outcomes, independent of conditioning regimen.

The impact of food insecurity on HIV outcomes in Senegal, West Africa: a prospective longitudinal study

BackgroundUnderstanding the impact of food insecurity on HIV outcomes is critical for the development and implementation of effective, evidence-based interventions to address food insecurity and improve the HIV care cascade. We conducted a prospective, longitudinal study to determine the impact of food insecurity on HIV outcomes in Senegal, West Africa.MethodsHIV-infected individuals presenting for care and initiation of ART through the Senegalese National AIDS program in Dakar and Ziguinchor were eligible for enrollment. Data were collected using interviews, clinical evaluations, laboratory analyses, and chart review at enrollment, month 6, and month 12. Logistic regression was used to determine the association between food insecurity and HIV outcomes.ResultsAmong the 207 participants in this study, 70% were female and the median age was 37 years. The majority (69%) were food insecure at enrollment, 29% were severely food insecure, and 38% were undernourished. Nearly a third (32%) had no formal education, 23% practiced agriculture, and 40% owned livestock. The median daily food expenditure per person was $0.58. The median round trip transportation time to clinic was 90 min (IQR 30–240). The median cost of transportation to clinic was $1.74. At month 12, 69% were food insecure, 23% were severely food insecure, and 14% were undernourished. At month 12, 43% had not disclosed their HIV status; food insecurity was associated with non-disclosure of HIV-status due to fear of stigmatization and feelings of shame. Severe food insecurity was a strong predictor of loss to follow-up (OR 3.13 [1.08–9.06]) and persistent severe food insecurity was associated with virologic failure (OR 5.14 [1.01–26.29]) and poor adherence to ART 8.00 [1.11–57.57]. Poor nutritional status was associated with poor immunologic recovery (OR 4.24 [1.56–11.47]), virologic failure (OR 3.39 [1.13–10.21]), and death (OR 3.35 [1.40–8.03]).ConclusionSeverity and duration of food insecurity are important factors in understanding the relationship between food insecurity and HIV outcomes. Our findings highlight the importance of nutritional status, socioeconomic opportunity, and self-stigmatization in the complex pathway between food insecurity and HIV outcomes. Interdisciplinary, multisectoral efforts are needed to develop and implement effective interventions to address food insecurity among people living with HIV.

An Immune Recovery-Based Revaccination Protocol for Pediatric Hematopoietic Stem Cell Transplant Recipients: Revaccination Outcomes Following Pediatric HSCT

Following hematopoietic stem cell transplant (HSCT), patients are at increased risk of vaccine-preventable diseases (VPDs) and experience worse outcomes of VPDs compared to immunocompetent patients. Therefore, patients are routinely vaccinated post-HSCT to restore VPD immunity. Published guidelines recommend revaccination based on time post-HSCT, although optimal revaccination timing and the value of using other clinical and laboratory variables to guide revaccination remain unclear. An institutional immune recovery-based protocol to guide timing of revaccination is used at Children's Hospital Colorado. This protocol incorporates time from transplant, time off immunosuppressive therapy and intravenous immunoglobulin replacement, absence of active graft-versus-host disease (GVHD), and minimum absolute CD4 count, absolute lymphocyte count (ALC), and immunoglobulin G (IgG) levels. The objective of this study is to evaluate the performance of this immune recovery-based revaccination protocol by determining rates of seroprotective vaccine responses achieved and describing demographic, clinical, and laboratory markers associated with protective antibody titers post-revaccination. Rates of seroprotection following revaccination were retrospectively determined for patients who received autologous or allogeneic HSCTs at Children's Hospital Colorado from 2007 to 2017. Percent seropositivity after revaccination was determined for ten VPDs: measles, mumps, rubella, varicella, tetanus, diphtheria, Haemophilus influenzae type B (Hib), poliovirus, hepatitis B virus (HBV), and Streptococcus pneumoniae. The impact of covariates, including post-HSCT vaccine timing, patient demographics, clinical features (diagnosis, donor and conditioning regimen data, GVHD, cytomegalovirus disease), and laboratory parameters (CD4 count, ALC, IgG level), on rates of seroprotection post-revaccination was determined using Wilcoxon rank sum, Fisher's exact, or chi-square tests, as appropriate. One hundred-twelve unique patients among 427 HSCT recipients had available data for both revaccination timing and vaccine titers. Among these, high rates of seroprotection were achieved after revaccination for rubella (100%), diphtheria (100%), tetanus (100%), and Hib (98%). More modest rates of seroprotection were achieved after revaccination with HBV (87%) and pneumococcal conjugate (85%) vaccines. Seroprotection was lower after revaccination with measles (76%), pneumococcal polysaccharide (72%), mumps (67%), and varicella (25%) vaccines. Greater rates of seroprotection were associated with younger age (hepatitis B vaccine, P = .04), lack of prior rituximab treatment (pneumococcal conjugate vaccine, P = .005), lack of total body irradiation (pneumococcal conjugate vaccine, P = .03), and receipt of a non-cord blood transplant (pneumococcal polysaccharide vaccine, P = .04). These results suggest that a revaccination protocol that incorporates both time post-HSCT and patient-specific indicators of immunologic recovery can achieve high rates of seroprotection against most VPDs. Seroprotection rates for HBV and PCV were notably among the highest reported in children post-HSCT, suggesting that an immune recovery-based protocol may improve seroprotection for some VPDs that frequently are associated with lower vaccine responses post-HSCT. Seroprotection rates for other VPDs remained suboptimal after revaccination. Therefore, evaluation of additional strategies, such as the use of novel markers of immune competence and new vaccines, to further optimize protection against VPDs in this population is warranted.

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

Virological and Immunologic Outcome of HIV Infected Drug Experienced Adults in North Central Nigeria

Background: Antiretroviral therapy (ART) has decreased the mortality and morbidity among people living with HIV and AIDS (PLWH). Viral load (VL) has been used by clinicians as primary tool recommended by WHO to monitor patients progress on High Antiretroviral active therapy (HAART). There is a paucity of information on Virological and immunological outcomes of HIV infected drug experience adults’ patients in north central Nigeria. We conducted a tertiary hospital based cross-sectional study at federal medical centre in Nasarawa state between December 2019 to march 2020. Method: A total of 474 HIV positive adult were enrolled using a Systematic random technique. Blood specimen for CD+4 T cells count and viral load determination were obtained and PCR-Real time and Flow-cytometry were used to estimate plasma viral load and CD4+ T cell count respectively. Frequency was used to determine percentage and logistic regression was used to determine the associated factors with Virological suppression and immunology outcome in patients on HAART 95% CI and odd ratio (OR) was used to measure strength of association. Results: From the 474 cohort that were enrolled 34.6% were on WHO baseline clinical stage IIV and 57.8% of cohort were on HAART, started treatment regimen in less than a year with 42.2% diagnosed and confirmed with HIV infection between 1-5years. 57.8% were transferred into the centre as a major reason for enrolment. 57.8% has history of TB treatment in the past while 42.2% of the study participants who were eligible for treatment initiation were determine by CD4+ counts with a median interquartile range of 180 (92-300) cells/mm3. virological suppression (VL level < 1000 copies/ml) was found in 85% (95% CI 77.7, 86.1) of study participants, and it has been associated with CD4 cell count between 250 and 400 cells/mm3 (adjusted odds ratio (AOR) = 2.56; 95% CI 1.14, 5.75) and > 499 cells/mm3 (AOR = 7.71; 95% CI 3.48, 17.09) at VL testing and current age > 40 years old (AOR = 5.40; 95% CI 2.3, 10.01). Similarly, favourable immunological status (≥250 cells/mm3 for male and ≥ 600 cells/mm3 for female) was observed in 52.9% (95% CI 47.4, 58.8) of the study participants. Baseline CD4 cell count of > 200 cells/mm3, age at enrolment of 26 through 40 years old, and urban residency were significantly associated with favourable immunological outcome. Conclusion: Low Immunological recovery among study cohort was observed although viral suppression was shown in majority of the HIV infected adult who are on HAART. Early initiation on HAART should be encouraged in other to achieve immunological recovery and viral suppression in order to achieve the USAIDS- 90-90-90 to end HIV pandemic by 2030.

IMPACT OF TREATMENT WITH DIRECT ACTING ANTIVIRAL AGENTS (DAAS) ON MIXED CRYOGLOBULINEMIA OF HCV EGYPTIAN PATIENTS

Background: Up to 74% of patients affected by HCV have HCV-related extrahepatic manifestation (EHMs) including autoimmune diseases, mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas (NHL).Objective: To study the impact of treatment with direct acting antiviral agents (DAAS) on mixed cryoglobulinemia of HCV Egyptian patients. Patients and methods: This study was carried out in cooperation between the Hepato-gastroenterology and Infectious Diseases Department, Al-Azhar University, Cairo, and Shebin Elkom Fever Hospital from March 2018 to December 2019. The study included 80 patients with HCV-related EHMs including cutaneous (30 patients), musculoskeletal (30 patients) and renal manifestation (20 patients). All patients were naive to treatment with DAAs (Sofosbuvir/Daclatasvir ± Ribavirin regimen). Results: Purpuric papules of the lower extremities were the most frequent cutaneous lesion (80%), and arthralgia was the most frequent in musculoskeletal manifestations (90%). Diffuse membranoproliferative glomerulonephritis was the most frequent lesion in patients, with renal manifestations (90%). Significant increase occurred in the serum cryoglobulin levels and RF, with significant decreasein C3 and C4 serum levels in all groups. There were significant decrease in the mean cryoglobulin levels from positive to negative, with significant decline in RF concentrations, and rise in C3 and C4 serum levels approaching the normal values. There were improvements in the presenting HCV-MC clinical manifestations in variable degrees, rangingfrom 71.42% in patients with glomerulonephritis to 98.4% in patients with purpura. Eighty-seven percent of the included patients showed complete response (clinical, virologicaland immunological recovery), and 13% showed partial response (virological and immunological recovery without clinical improvement of cryoglobulinemia associated manifestations). Conclusion: DAAs, in the form of Sofosbuvir/Daclatasvir ± Ribavirin regimen, were treatment of choice for HCV infection, and considered in cases of HCV-MC as they were associated with clinical improvement in most patients.

The biobehavioral impacts of sexual violence: Findings from an acute repeat survivor of vaginal rape.

Background:Individuals who have experienced repeat sexual violence victimization face adverse mental and physical health outcomes, including immune and stress response functioning. We aim to further understand repeat sexual violence victimization to develop responsive and appropriate treatment for survivors of sexual violence.Methods:We present the immunological and contextual findings of a participant (N = 1) who experienced repeat sexual violence victimization during her enrollment in The THRIVE Study, a prospective case–control study of women aged 14–45 years, who have experienced recent consensual vaginal penetration (“controls”) or forced vaginal penetration (“cases”). Participants complete a survey, HIV/sexually transmitted infection, and pregnancy testing, blood sampling for C-reactive protein and adrenocorticotrophic hormone, collection of cervicovaginal fluid for immunological biomarkers, and self-collection of saliva samples for cortisol measurements, across study visits (Baseline, 1, and 3 months).Results:The case study participant, aged 18 years upon enrollment, experienced sexual trauma before four of five study visits. Trends in the mental health indicators demonstrate reciprocal fluctuations in adverse mental health and resilience in accordance with revictimization and circumstantial changes. Suppressed immune biomarkers appear to correlate with increased adverse mental health, while mental health recovery trends with immunological recovery. The participant presents with dysregulated hypothalamic–pituitary–adrenal axis diurnal profile.Conclusions:This profile illustrates the intra-individual biobehavioral impact of experience with revictimization over the course of 6 months, capturing experiences that are rarely studied either longitudinally or with the depth of the current research. The findings underscore the value of monitoring cervicovaginal immune functioning and hypothalamic–pituitary–adrenal axis dysregulation in coordination with changes in mental health over the course of repeated sexual trauma.

Potential Dietary Interventions for COVID-19 Infection Based on the Gut-Immune Axis: An Update Review on Bioactive Component of Macronutrients.

Recently emerged coronavirus, known as SARS-CoV-2 or Covid-19 is considered as a serious threat for human health. Due to unavailable specific drugs for this virus, there is an urgent need for supportive cares. Epigenetic immune boosting approaches and developing anti-inflammatory agents by gut-associated bioactive macronutrients can be plausible protective cares for COVID-19. Suitable intake of bioactive macronutrients including prebiotics, fatty acids, proteins and branched-chain amino acids may result in anti-viral responses through modulating macrophages and dendritic cells via Toll-like receptors, decreasing viral load, inactivating the enveloped viruses, increasing the anti-inflammatory metabolites and inhibiting the proliferation of microbial organisms. Bioactive macronutrients may help in promotion of immunological responses and recovery acceleration against Covid-19. This review focuses on the mechanisms of bioactive macronutrients and related clinical trials on enveloped viruses with emphasis on gut-microbiome-immune axis. Macronutrients and this axis may be conducive strategies to protect host against the viral infection.

Integrase Inhibitors Use and Cytomegalovirus Infection Predict Immune Recovery in People Living With HIV Starting First-Line Therapy.

We explored predictors of CD4/CD8 ratio improvement and optimal immunological recovery (OIR) after initiation of antiretroviral therapy (ART) in naive people living with HIV (PLWH). Retrospective multicenter study including naive PLWH starting ART with 2 nucleos(t)ide reverse transcriptase inhibitors + 1 integrase strand transfer inhibitor (InSTI) or non-NRTI or protease inhibitor (PI). PLWH were followed from the time of ART initiation (baseline) to the discontinuation of first-line regimen, virological failure, death, or loss to follow-up. Estimated incidence and predictors of time to CD4/CD8 ratio normalization (defined as ≥1) and OIR (defined as CD4/CD8 ratio ≥ 1 plus CD4 ≥ 500 cells/µL plus CD4% ≥ 30%) were explored by Kaplan-Meier curves and Cox regression analysis. Overall, 1428 PLWH (77.8% males, median age 39 years, 55.1% with positive cytomegalovirus (CMV) antibodies, median HIV-RNA 4.80 log copies/mL, median CD4 323 cells/µL, median CD4/CD8 ratio 0.32) were included, of which 21.5% (n = 307), 44.5% (n = 636), and 34% (n = 485) treated with InSTI-, PI-, and NNRTI-based regimens, respectively. The estimated proportion of CD4/CD8 normalization and OIR at 36 months was 38.6% and 32.9%, respectively. Multivariate analysis showed that InSTI-based regimens had a higher probability of CD4/CD8 ratio normalization and OIR both in the total population (P < 0.001 versus PI) and in advanced naive PLWH (P ≤ 0.001 versus PI and NNRTI). Moreover, subjects with positive CMV serology showed a lower probability of CD4/CD8 ratio normalization and OIR (P < 0.001). InSTI-based regimens showed a better immune recovery, suggesting that the type of first-line ART can influence immune reconstitution. PLWH with positive CMV serology showed an increased risk of suboptimal immune recovery.

The influence of haemodialysis on CD4+ T-cell counts in people living with human immunodeficiency virus with end-stage kidney disease.

BackgroundIn South Africa it is estimated that 7.9 million people are living with human immunodeficiency virus (HIV). HIV is associated with an increased risk of kidney disease. For people living with HIV (PLWH) who develop end-stage kidney disease (ESKD), access to renal replacement therapy can be difficult. Kidney transplantation is a cost-effective option, with improved overall survival and better quality of life. In Johannesburg, the eligibility criteria for kidney transplantation include a sustained CD4+ T-cell count of > 200 cells/μL and suppressed HIV replication.ObjectiveTo investigate the influence of haemodialysis on the lymphocyte subsets in PLWH with ESKD. In addition, all available %CD4+ T-cell counts, absolute CD4+ T-cell counts and viral load measurements were collected to assess the longitudinal trends of these measurements in PLWH with ESKD.MethodsThis was a cross-sectional study comparing two groups. The HIV-infected study participants (n = 17) and HIV-uninfected controls (n = 17) were recruited from renal dialysis centres in Johannesburg from 2017 to 2018. Demographic data and social data were collected from all the study participants (n = 17). Blood samples were collected from all the study participants (before and after a haemodialysis session), and the lymphocyte subsets were then measured. The available longitudinal data for the serial CD4+ T-cell counts and HIV viral loads were collected (n = 14).ResultsOur cohort showed a statistically significant increase in the post-dialysis percentage of CD4+ T cells (5%, p < 0.001) and the absolute CD4+ T-cell counts (21 cells/µL, p < 0.03). The longitudinal trend analysis for the percentage of CD4+ T cells revealed a significant increase in five participants (36%), and a single patient (7%) had a significant decrease in the longitudinal trend analysis for the absolute CD4+ T-cell counts. The longitudinal trend analysis for HIV viral load revealed the majority of our participants were not virologically suppressed.ConclusionThis study showed that haemodialysis does not have an immediate negative impact on CD4+ T-cell count, suggesting that immunologic recovery is not impeded by treatment of the underlying ESKD.

Immunogenicity of pneumococcal vaccination in HIV infected individuals: A systematic review and meta-analysis

BackgroundThe objective of this systematic review and meta-analysis was to summarise the literature regarding the immunogenicity of pneumococcal conjugate vaccines (PCV) and pneumococcal polysaccharide vaccines (PPSV) in adult people living with HIV (PLWH) in the era of advanced combination antiretroviral therapy (cART).MethodsThe systematic review protocol was published online (PROSPERO ID: CRD 42020153137). We searched Medline (Ovid), EMBASE (Ovid), and the Global Health Library for publications from 2000 to June 11, 2020. We included all studies in adult PLWH that reported vaccine immunogenicity outcomes. The primary outcome was seroconversion rate (SCR) after PCV, PPSV and PCV/PPSV combined. For random-effects meta-analysis, we included studies defining SCR as a ≥ 2-fold increase in IgG from baseline, and reporting SCR for serotypes 6B, 14, or overall SCR, 1–3 months after vaccination.FindingsOur search identified 1597 unique studies, of which 115 were eligible for full-text assessment. Of these, 39 met the inclusion criteria (11 RCTs; 28 cohort studies). A high degree of heterogeneity was observed. Nineteen studies were included in the meta-analysis. Pooled overall SCRs were 42% (95% CI 30–56%), 44% (95% CI 33–55%) and 57% (95% CI 50–63%) for PLWH who received PPSV, PCV or a combination of PCV/PPSV, respectively. Compared to PPSV alone, a combination of PCV/PPSV yielded higher SCRs (OR 2.24 95% CI 1.41- 3.58), whereas we did not observe a significant difference in SCR between PCV and PPSV23 alone. There were no statistically significant differences in geometric mean post-vaccination antibody concentrations between vaccination schedules. Vaccination at higher CD4 cell counts improved immunogenicity in 8/21 studies, especially when PCV was administered. No studies assessed the long-term immunogenicity of PCV followed by PPSV23. Quality of evidence ranged from poor (n = 19) to good quality (n = 7). A limited number of pneumococcal serotypes was assessed in the majority of studies.InterpretationWe show that the recommended immunisation schedule consisting of a combination of PCV13/PPSV23, is immunogenic in PLWH in the era of advanced cART. However, the durability of this vaccination schedule remains unknown and must be addressed in future research. Vaccination with PCV should be delayed until immunological recovery (CD4>200) in recently diagnosed PLWH for optimal immunogenicity. The evidence gathered here supports wide implementation of the combination of PCV/PPSV23 for all PLWH. We recommend reassessment of this strategy once higher-valent PCVs become available.FundingHMGG is funded by a public research grant of ZonMw (project number 522004005).

IFNL4 Genotype Does Not Associate with CD4 T-Cell Recovery in People Living with Human Immunodeficiency Virus.

Immune non-responders (INRs) are people with HIV infection who fail to restore their CD4 T-cell counts in spite of prolonged virologic suppression, a condition associated with higher rates of all-cause mortality. The mechanisms of immune non-response are not entirely clear. We used existing clinical and genetic data from AIDS Clinical Trials Group clinical trials to ask whether an IFNL4 single-nucleotide polymorphism, shown to be associated with outcomes for other infectious diseases, correlated with immune non-response for HIV. Analysis of data from 426 participants with clearly defined CD4 T-cell recovery phenotypes, including 88 INRs with CD4 < 200 cells/mm3 after 2 years of suppressive antiretroviral therapy, did not identify an association of IFNL4 genotype with immune non-response. Thus, the IFNL4 genotype is unlikely to influence immunologic recovery.

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

AbstractCombination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Plasmablastic lymphoma in Johannesburg, South Africa, in the era of widescale antiretroviral therapy use.

Plasmablastic lymphoma (PBL) is a clinically aggressive lymphoma which has a predilection for extranodal sites and is frequently HIV-associated. The incidence of non-Hodgkin lymphoma is thought to be reduced by widescale antiretroviral therapy (ART) coverage, but the literature is sparse as regards the impact of ART on the incidence of PBL and its outcomes in South Africa (SA). This study aimed to compare factors of interest in cases of PBL diagnosed before and after the widespread availability of ART in Johannesburg, SA. All cases of PBL diagnosed in the state sector hospitals of Johannesburg in 2007 and 2017 (before and after the widespread availability of ART, respectively) were extracted from the laboratory information system, and factors of interest compared. The majority (>95%) of cases of PBL were seen among people with HIV infection (PWH) at both time-points, and the proportion of patients on ART and with virological suppression (VS) increased significantly in 2017. However, the number of cases of PBL did not differ significantly between the twoyears assessed, comprising 46/397 (11.6%) and 53/582 (9.6%) of all lymphomas in 2007 and 2017, respectively (P=0.23). Ongoing risk for PBL among PWH with virological control and immunological recovery was evident in 2017, as 18.9% of the patients had both VS and CD4 counts >200 cells/μL at diagnosis. Inferior survival times were associated with elevated lactate dehydrogenase (LDH) levels and Epstein Barr virus (EBV) negativity, but were not influenced by the presence of AIDS, ART or VS. EBV negativity was significantly associated with VS, and appeared to flag a particularly aggressive form of the disease. Widescale ART coverage has not reduced the incidence of PBL in Johannesburg, and an ongoing risk for this disease among PWH with adequate virological control and immunological recovery persists.

Immunological and virological efficacy of different antiretroviral regimens initiated during acute/recent HIV infection.

Antiretroviral treatment (ART) during acute/recent HIV infection decreases transmission and optimizes immune recovery but the optimal ART-regimen in this setting is unknown. The objectives were to analyze the virological efficacy, immunological reconstitution and tolerability of different ART-regimens at 3 years after starting ART during acute/recent HIV infection. Retrospective cohort study of consecutive acutely/recently infected patients who started ART within 6 months postinfection. We compared regimens based on protease-inhibitors (N = 28), integrase-strand-transfer-inhibitors (InSTI, N = 87) and nonnucleoside-reverse-transcriptase-inhibitors (N = 22). Virological suppression (viral load <50 copies/ml), immune reconstitution (CD4 T-cell count >900 cells/μl and CD4/CD8 ratio >1) and adverse events leading to ART discontinuation at 1 and 3 years were compared. Baseline characteristics were comparable among groups. Overall viral suppression at 1 (96%) and 3 years (99%) was comparable in all ART regimens and, InSTI group, comparable for dolutegravir and elvitegravir within InSTIs. CD4 T-cell counts at 1 year were comparable in all ART regimens. Overall proportion of patients reaching CD4 cell count more than 900 cells/μl and CD4/CD8 ratio more than 1 was 36% and 40% and 46% and 63% at 1 and 3 years, respectively with no differences among ART regimens. Starting ART during the earliest Fiebig stages (I-V vs. VI) was associated with higher rates of CD4 cell count more than 900 cells/μl at 3 years (P = 0.027). Discontinuation due to adverse events was more frequent with nonnucleoside-reverse-transcriptase-inhibitors compared with other ART classes. Viral suppression and immunological recovery were excellent, with no differences between ART regimens. Earlier ART initiation was associated with a higher proportion of long-term immunological recovery.

Immunovirological treatment outcomes after 2 years of antiretroviral therapy in children living with the human immune deficiency virus in Lagos Nigeria

Background/objective: The World Health Organization (WHO) recommends routine assessment of antiretroviral treatment outcomes to detect treatment failure early and prevent the development of drug resistance. The aim of this study was to describe treatment outcomes of antiretroviral therapy (ART) over 2 years in children living with the human immune deficiency virus enrolled in the paediatric HIV clinic at the Lagos UniversityTeaching Hospital (LUTH).Materials and methods: This was a retrospective study of antiretroviral treatment outcomes in 278 children receiving antiretroviral therapy at the paediatric HIV clinic of LUTH. Demographic, clinical and laboratory data were retrospectively collected from clinical records of pediatric patientswho received antiretroviral therapy for 2 years ( from November 2015 to December 2017) . Virological failure was defined as viral load &gt; 400 copies/ml and immunological failure was defined as a CD4 count &lt;100 cells/mm3 or CD4 % &lt;15% after receiving antiretroviral agents for 12 months. Data was analysed using graph pad prism version 5.0.Results: After 12 months on antiretroviral therapy (ART), 101 (36%) had virological failure while 14 (5%) and 36 (13%) failed immunologically [CD4 count &lt;100 cells/mn3 and CD4 &lt;15% respectively]. Virological blips were observed at 24 months in 6.1% of patients while immunovirological discordance occurred in 30% of patients (poor virological clearance despite good immunological recovery) . High baseline viral load (&gt;5000 copies/ml), poor adherence (&lt;95%) and low baseline CD4 counts (101-249 cells/mn3) were significantly associated with virological failure, while low baseline CD4 counts (&lt;350 cells/mn3) and poor adherence (&lt;95%) were significantly associated with immunologic failure.Conclusion: The treatment outcomes observed in this study are similar to those reported in earlier studies. At 1 and 2 years of antiretroviral therapy , there was immune restoration however 101 (36%) and 87 (31%) respectively had virological failure despite good adherence to therapy and good Immunological restoration. This calls for early initiation and switch to second and third line drugs .&#x0D; Key words: Human immunodeficiency virus (HIV), zidovudine, lamivudine, nevirapine, virological blips, immunovirological discordance , children, Nigeria.