Long-term Highly Active Antiretroviral Therapy Research Articles

Safety and Efficacy of Immune Checkpoint Inhibitors in the Treatment of Hodgkin Lymphoma in People Living with Human Immunodeficiency Virus: A Case Series

Introduction: Immune checkpoint inhibitors (ICI) have changed the landscape of cancer treatment. They work by disrupting the binding of immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4, which function to prevent over-activation of the immune system. By interrupting this binding, the body's natural immune response against cancer cells is enhanced. Nivolumab and pembrolizumab, two ICIs that target PD-1, are approved for use in relapsed/refractory Hodgkin lymphoma (HL). HIV is associated with higher rates of cancer, including HL. Several studies have demonstrated the safety of ICI in people with HIV (PWH) in many types of cancer. Unfortunately, many cancer clinical trials continue to exclude PWH without consideration of long-term adherence to highly active antiretroviral therapy (HAART), normal CD4+ counts, or undetectable viral loads because of fear regarding increased adverse events (AEs) and poor outcomes. In addition, studies have shown that PWH diagnosed with cancer are less likely to receive any cancer treatment. Here, we present three cases of PWH diagnosed with HL and treated with an ICI and examine their outcomes and ICI-related AEs. In addition, we discuss five matched cases of people without HIV infection diagnosed with HL and treated with an ICI. Methods: A retrospective study was performed for HL patients at an NCI-designated comprehensive cancer center from 2015 to 2022, diagnosed with HIV (confirmed with antibody testing) and treated with an ICI. Three patients met these criteria. HIV-negative matches for the above patients were identified based on diagnosis, treatment, stage, sex, and age. Five patients with HL without HIV infection were identified as appropriate matches based on these criteria. Demographic data and clinical outcomes data were collected from the electronic medical record. The common terminology criteria for adverse events (CTCAE) were used to classify and grade AEs. Due to a small sample size, statistical analyses and comparisons were not performed between PWH and PWOH Results: Demographic data (Table 1) and clinical response/outcome data (Table 2) are shown for all patients. Patients 1, 2, and 3 were HIV positive, while patients 4, 5, 6, 7, and 8 were HIV negative. ICI-related AEs were documented in three patients, one with and two without HIV. Patient 1, who was not compliant with HAART (CD4+ 70, viral load 1.39x10 6), experienced grade 4 myocarditis (confirmed on cardiac MRI) after cycle 2 with nivolumab, with pulseless electrical activity requiring pressor support and mechanical ventilation for four days, along with high-dose steroid taper, IV diuresis, and initiation of guideline-directed medical therapy (GDMT). Nivolumab was discontinued, and the patient was lost to follow-up with reported death three months later, attributed to HL. Patient 7 developed symptomatic grade 2 hypothyroidism on nivolumab after two cycles, requiring levothyroxine, to which the patient responded appropriately. Nivolumab was continued. Patient 8 experienced grade 3 myocarditis (confirmed on cardiac MRI) after cycle 7 of pembrolizumab, with hospitalization for IV diuretics and GDMT initiation. Pembrolizumab was discontinued. Discussion: In conclusion, ICIs are a therapeutic option for the treatment of HL in PWH. This limited case series suggests that PWH on long-term HAART tolerate ICIs well. The patient in our study who was not compliant with HAART experienced grade 4 myocarditis, with death attributed to lymphoma three months later. This may suggest an increased risk of ICI-related AEs and poorer outcomes in patients not on HAART and/or with poorly controlled HIV. However, further studies are required to investigate this risk, as our sample size was too small to draw statistically meaningful conclusions. Interestingly, one patient without HIV infection also experienced ICI-related myocarditis, but of less severe grade (grade 3 versus grade 4) than the patient with HIV. Most patients from both groups had an overall survival (OS) of more than two years, which may suggest that ICIs are not associated with decreased OS in patients with HIV infection. Unfortunately, our study was limited by the sample size, and statistical comparison of patients with and without HIV infection could not be performed. Further research is needed to investigate the tolerance and efficacy of ICIs as therapeutic options in PWH with Hodgkin lymphoma.

The anti-HIV potential of imidazole, oxazole and thiazole hybrids: A mini-review

Human immunodeficiency virus (HIV) especially HIV-1 infection and its progression to acquired immune deficiency syndrome (AIDS) remains a significant global health challenge. The advent of the highly active antiretroviral therapy (HAART) has greatly extended the life expectancy of patients living with HIV, but it has become evident that long-term HAART will not eliminate the HIV reservoir and cure the infection. Moreover, the drug resistance and undesirable side effects hamper efficacious therapy, creating an urgent need to develop novel, more effective and less toxic anti-HIV therapeutics. Imidazole, oxazole and thiazole with two heteroatoms at meta-position of five-membered rings are fascinating structures and constitute an important class of heterocycles in drug discovery. Their derivatives could exert the anti-HIV activity through diverse mechanisms and possess promising antiviral activity against both drug-sensitive and drug-resistant HIV strains. This review summarizes the research progress made regarding the anti-HIV potential of imidazole, oxazole and thiazole hybrids, and the structure–activity relationships (SARs) are also discussed to facilitate further rational design of more effective candidates, covering articles published from 2012 to 2022.

The Potential of Moringa oleifera to Ameliorate HAART-Induced Pathophysiological Complications.

Highly active antiretroviral therapy (HAART) comprises a combination of two or three antiretroviral (ARV) drugs that are administered together in a single tablet. These drugs target different steps within the human immunodeficiency virus (HIV) life cycle, providing either a synergistic or additive antiviral effect; this enhances the efficiency in which viral replication is suppressed. HIV cannot be completely eliminated, making HAART a lifetime treatment. With long-term HAART usage, an increasing number of patients experience a broadening array of complications, and this significantly affects their quality of life, despite cautious use. The mechanism through which ARV drugs induce toxicity is associated with metabolic complications such as mitochondrial dysfunction, oxidative stress, and inflammation. To address this, it is necessary to improve ARV drug formulation without compromising its efficacy; alternatively, safe supplementary medicine may be a suitable solution. The medicinal plant Moringa oleifera (MO) is considered one of the most important sources of novel nutritionally and pharmacologically active compounds that have been shown to prevent and treat various diseases. MO leaves are rich in polyphenols, vitamins, minerals, and tannins; studies have confirmed the therapeutic properties of MO. MO leaves provide powerful antioxidants, scavenge free radicals, promote carbohydrate metabolism, and repair DNA. MO also induces anti-inflammatory, hepatoprotective, anti-proliferative, and anti-mutagenic effects. Therefore, MO can be a source of affordable and safe supplement therapy for HAART-induced toxicity. This review highlights the potential of MO leaves to protect against HAART-induced toxicity in HIV patients.

Outcomes of cardiovascular magnetic resonance imaging in people living with HIV

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction People living with human immunodeficiency virus (HIV, PLWH) are at increased risk of cardiovascular disease (CVD). HIV infection and accelerated traditional risk factors due to highly-active antiretroviral therapy (HAART) are proposed mechanisms for increased rate of heart failure (HF). The pathophysiological drivers of myocardial dysfunction and worse cardiovascular outcome in HIV remain poorly understood. Purpose To examine prognostic relationships of cardiac imaging measures with cardiovascular outcome in PLWH on HAART. Methods This is a prospective observational longitudinal study using cardiac magnetic resonance (CMR) imaging in consecutive PLHWH on long-term HAART who were screened for underlying CVD and followed up clinically for adjudicated adverse cardiovascular events (cardiovascular mortality, non-fatal acute coronary syndrome, an appropriate device discharge, or a documented HF hospitalization). Imaging protocol included routine assessment of cardiac volumes and function, scar by late gadolinium enhancement, myocardial perfusion and native T1 /T2 mapping. Time-to-event analysis was performed from the index CMR exam to the first single event per patient Systematic risk scores for CVD (Framingham risk score (FRS), Data Collection on Adverse effects of anti-HIV Drugs score, D:A:D and MAGGIC integer score) were calculated using original online calculators. Results 156 participants (males 62%, 50 [42-57] years of age) were included. 24 events were observed (4 HF deaths, 1 sudden cardiac death, 2 non-fatal acute myocardial infarction, 1 appropriate device discharge and 16 HF hospitalizations) during a median follow-up of 13 [9-19] months. Patients with events had higher native T1 (ms, 1149 [1115-1163] ms vs. 1110 [1075-1138] ms), native T2 (ms, 40 [38-41] vs. 37 [36-39]), LV mass index (g/m², 65 [49-77] vs. 57 [49-64]) p < 0.05 for all). In multivariable analyses, native T1 was independently predictive of adverse events (ChiSq 15.9, p < 0.001, native T1 (10 ms) hazard ratio (95% confidence interval) 1.20 (1.08-1.33), p = 0.001), followed by a model that also included LV mass (ChiSq 17.1, p < 0.001). Traditional cardiovascular risk scores were not predictive of the adverse events. Conclusions Native myocardial T1 and LV mass by CMR, as opposed to traditional cardiovascular risk scores, predict cardiovascular outcome in PLWH, together reflecting the pathological myocardial remodeling of myocardial fibrosis and inflammation that potentially explain higher rates of HF in PLWH as compared to the non-infected population. These findings may inform personalized approaches to screening and early intervention to reduce the burden of HF.

Effects of Artesunate Tablet on Immune Activation and Reconstitution Among Highly Active Antiretroviral Therapy-Treated Patients with Incomplete Immune Responses

The level of T cell activation is a better predictor of CD4+ T cell depletion in highly active antiretroviral therapy (HAART) patients than viral load. Artesunate is an artemisinin derivative that has an immunomodulatory effect. This study investigated whether artesunate tablet reduces T cell activation and improves immune reconstitution among patients with suboptimal immune recovery despite receiving long-term effective HAART. This was a randomized prospective parallel open-label trial consisting of 45 participants whose plasma HIV load was effectively suppressed by HAART for >18 months and who had CD4+ T cell counts of <300 cells/μL or an increase of <20% from baseline. The patients were randomized 2:1 into the artesunate group or the control group and received artesunate tablets (orally, 50 mg two times daily) combined with HAART or HAART alone, respectively. T cell subsets, activation markers, clinical symptoms, viral load, and side effects were assessed. By 48 weeks, artesunate tablet did not improve CD4+ T cell recovery or reduce the activation of T cell subsets but induced in a smaller decline in the expression of T cell activation markers among HAART patients with incomplete immune responses. However, artesunate tablet did appear to reduce the level of T cell apoptosis. One subject developed moderate anemia. Long-term use of artesunate tablet is unlikely to produce substantial clinical benefits in patients receiving HAART who exhibit an incomplete immune response.

Myocardial Fibrosis and Inflammation by CMR Predict Cardiovascular Outcome in People Living With HIV

ObjectivesThe goal of this study was to examine prognostic relationships between cardiac imaging measures and cardiovascular outcome in people living with human immunodeficiency virus (HIV) (PLWH) on highly active antiretroviral therapy (HAART). BackgroundPLWH have a higher prevalence of cardiovascular disease and heart failure (HF) compared with the noninfected population. The pathophysiological drivers of myocardial dysfunction and worse cardiovascular outcome in HIV remain poorly understood. MethodsThis prospective observational longitudinal study included consecutive PLWH on long-term HAART undergoing cardiac magnetic resonance (CMR) examination for assessment of myocardial volumes and function, T1 and T2 mapping, perfusion, and scar. Time-to-event analysis was performed from the index CMR examination to the first single event per patient. The primary endpoint was an adjudicated adverse cardiovascular event (cardiovascular mortality, nonfatal acute coronary syndrome, an appropriate device discharge, or a documented HF hospitalization). ResultsA total of 156 participants (62% male; age [median, interquartile range]: 50 years [42 to 57 years]) were included. During a median follow-up of 13 months (9 to 19 months), 24 events were observed (4 HF deaths, 1 sudden cardiac death, 2 nonfatal acute myocardial infarction, 1 appropriate device discharge, and 16 HF hospitalizations). Patients with events had higher native T1 (median [interquartile range]: 1,149 ms [1,115 to 1,163 ms] vs. 1,110 ms [1,075 to 1,138 ms]); native T2 (40 ms [38 to 41 ms] vs. 37 ms [36 to 39 ms]); left ventricular (LV) mass index (65 g/m2 [49 to 77 g/m2] vs. 57 g/m2 [49 to 64 g/m2]), and N-terminal pro–B-type natriuretic peptide (109 pg/l [25 to 337 pg/l] vs. 48 pg/l [23 to 82 pg/l]) (all p < 0.05). In multivariable analyses, native T1 was independently predictive of adverse events (chi-square test, 15.9; p < 0.001; native T1 [10 ms] hazard ratio [95% confidence interval]: 1.20 [1.08 to 1.33]; p = 0.001), followed by a model that also included LV mass (chi-square test, 17.1; p < 0.001). Traditional cardiovascular risk scores were not predictive of the adverse events. ConclusionsOur findings reveal important prognostic associations of diffuse myocardial fibrosis and LV remodeling in PLWH. These results may support development of personalized approaches to screening and early intervention to reduce the burden of HF in PLWH (International T1 Multicenter Outcome Study; NCT03749343).

Study of association of urine albumin to creatinine ratio with endothelial dysfunction in HIV patients on HAART

Background: In HIV (Human immunodeficiency virus) positive patients several factors have been proposed to explain the cardiovascular (CV) risk, which include pro-athero-thrombotic viral effect, infection-mediated immune dysfunction and possible effects of HAART(Highly active antiretroviral therapy). Presence of endothelial dysfunction, an early CV risk marker, in HIV-infected patients on long-term HAART. Endothelial dysfunction can be measured by bFMD (Brachial artery flow mediated vasodilatation). Urine albumin to creatinine ratio (UACR) is frequent in HIV patients and is predictor of cardiovascular risk. UACR and endothelial dysfunction are positively associated in HIV affected patients thereby increased UACR might help to identify endothelial dysfunction in HIV patients on HAART.&#x0D; Aims and Objectives: • To measure urine albumin to creatinine ratio in HIV patients on HAART. • To find out correlation between UACR and bFMD.&#x0D; Materials and Methods: Study was conducted on HIV Patients admitted to hospital, considering the inclusion and exclusion criteria. Detailed clinical history, examination and Blood investigations were done. Endothelial function was assessed by brachial artery flow mediated vasodilatation(bFMD).&#x0D; Results: Among 100 HIV patients, 14% had UACR &lt;30 and 86% had UACR &gt;30 and mean UACR is 90 ±06. Mean BFMD was 8.44 ± 7.65. We identified a significant Negative correlations were found between bFMD and UACR(r=- 0.832, P=&lt;0.001).&#x0D; Conclusion: Use of urine albumin to creatinine ratio (UACR) as a routine screening tests in those who are HIV positive on HAART can be used to find out those cases of HIV who are progressing towards cardiovascular impairment so that newer approaches can be used in them to prevent further cardiovascular involvement.

Orofacial lesions associated with long-term highly active antiretroviral therapy among HIV-seropositive adults in Ibadan, Nigeria.

Introductionhighly active antiretroviral therapy (HAART) has contributed to a reduction in HIV- related oral lesions and improved quality of life among HIV seropositive patients. However, the therapy is not without its side effects. This study was aimed at assessing the self- reported orofacial manifestations due to long term use of HAART, as well as the pattern of oral lesions on examination.Methodsthis was a cross-sectional study conducted among HIV seropositive adult patients in Ibadan, who had been on HAART for at least two years. Data were collected using an interviewer-administered questionnaire. Clinical diagnosis of HIV-related oral lesions was made according to the EC-Clearinghouse criteria. Data analysis was done using SPSS version 25.Resultsthe study participants comprised of 227 HIV seropositive patients who were HAART experienced, with 54 (24%) males and 173 (76%) females. Their mean age (±SD) was 44.7 (±9.4) years. The participants CD4 count ranged from 13-1338cells/mm3, with a median count of 341 cells/mm3. About half (45%) of the participants noted one or more orofacial changes since they commenced HAART. These oral changes included dryness of mouth, burning sensation, abnormal taste, melanotic hyperpigmentation, oral thrush, ulcers, and parotid swelling. Most of those who reported oral changes had been on HAART over 10 years (p=0.03), and the changes were more reported among those on the first-line regimen.Conclusionmelanotic hyperpigmentation was the most common oral lesion found and burning mouth syndrome was the most commonly reported complain among HIV-seropositive adults who are on long-term HAART.

Anti-Retroviral Protease Inhibitors Regulate Human Papillomavirus 16 Infection of Primary Oral and Cervical Epithelium.

Simple SummaryIn 2016, globally, 36.7 million people were living with Human Immunodeficiency Virus (HIV), of which 53% had access to anti-retroviral therapy (ART) (UNAIDS 2017 Global HIV Statistics). The risk of Human Papillomavirus (HPV) associated oropharyngeal, cervical and anal cancers are higher among patients infected with HIV in the era of ART. Generally, HPV infections are self-limiting, however, persistent HPV infection is a major risk to carcinogenic progression. Long intervals between initial infection and cancer development imply cofactors are involved. Co-factors that increase infectivity, viral load, and persistence increase risk of cancer. We propose that the ART Protease Inhibitors (PI) class of drugs are novel co-factors that regulate HPV infection in HIV-infected patients. We developed a model system of organotypic epithelium to study impact of PI treatment on HPV16 infection. Our model could be used to study mechanisms of HPV infection in context of ART, and for developing drugs that minimize HPV infections.Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk for HPV-associated cancers. In this manuscript, we report that Protease Inhibitors (PI) treatment of three-dimensional tissues derived from primary human gingiva and cervical epithelial cells compromised cell-cell junctions within stratified epithelium and enhanced paracellular permeability of HPV16 to the basal layer for infection, culminating in de novo biosynthesis of progeny HPV16 as determined using 5-Bromo-2′-deoxyuridine (BrdU) labeling of newly synthesized genomes. We propose that HAART/PI represent a novel class of co-factors that modulate HPV infection of the target epithelium. Our in vitro tissue culture model is an important tool to study the mechanistic role of anti-retroviral drugs in promoting HPV infections in HAART-naïve primary epithelium. Changes in subsequent viral load could promote new infections, create HPV reservoirs that increase virus persistence, and increase the risk of oral and cervical cancer development in HIV-positive patients undergoing long-term HAART treatment.

Fundus manifestations and HIV viral loads of AIDS patients before and after HAART.

To investigate the fundus manifestations and human immunodeficiency virus (HIV) viral loads of acquired immune deficiency syndrome (AIDS) patients before and after highly active antiretroviral therapy (HAART). This retrospective study included 21 AIDS patients (42 eyes) who presented to the Department of Ophthalmology, Peking Union Medical College Hospital, from 2007 to 2011. Among the patients, 16 showed a good response to HAART, 3 presented drug resistance and 2 were pre-HAART. All patients underwent comprehensive ophthalmic examinations. The HIV viral loads and the CD4+ T-cell counts were also determined. The best-corrected visual acuity (BCVA) of 38 eyes (19 patients) was improved, and cytomegalovirus retinitis (CMVR) in 5 eyes (3 patients) regressed after HAART. Furthermore, 16 patients treated with effective HAART had decreased plasma HIV viral loads (<78 copies/mL) and increased CD4+ T-cell counts (343±161 cells/µL, P<0.005), but the HIV viral load in tears was still detected at 2404 copies/mL. The CD4+ T-cell count was lower in the CMVR group than in the non-CMVR group (P=0.022), but the HIV viral load in the tears was not significantly different between the two groups (P=0.439). Most patients with AIDS show a good viral response with a decreased HIV viral load and an increased CD4+ T-cell count in plasma after HAART. However, the HIV viral load remain quite high in the tear samples. Based on our results, we suggest that AIDS patients undergo long-term HAART that should not be interrupted.

Two types of poor immunological responder showing distinct responses to long-term HAART

ObjectivesMost previous studies on poor immunological responders (PIRs) have been performed on one cohort at one time-point following highly active antiretroviral therapy (HAART). The aim of this study was to investigate whether there are different subtypes of PIR and whether a certain population might achieve better immune reconstitution following longer HAART. MethodsThis study was designed as an ambispective cohort study, including a 4–5-year retrospective study and a 2-year prospective follow-up investigation. Thymic output, activated T cell and regulatory T cell (Treg) subset frequencies, expression levels of interferon-stimulated genes, and plasma concentrations of neopterin were determined at 4–5 years and 6–7 years following HAART initiation. ResultsPIRs were subdivided into two populations after 4–5 years of HAART, according to the kinetics of T cell recovery. Type II PIRs exhibited a significantly lower percentage of naïve CD4+ T cells and CD31+ naïve CD4+ T cells compared with type I PIRs. After an additional 2 years of HAART treatment, type I PIRs showed a better outcome than type II PIRs. Furthermore, it was found that 2 years of additional HAART could persistently improve thymic output. ConclusionsThe two PIR subgroups are different in terms of immune characteristics and the response to prolonged HAART.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice.

Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15.5months). We found that systemic administration of individual NRTIs, including ddC (2'-3'-dideoxycytidine), ddI (didanosine), AZT (3'-azido-3'-deoxythymidine) and d4T (2', 3'-didehydro-2', 3'-dideoxythymidine), induced allodynia in similar magnitudes and temporal profiles. We used ddC as a representative to investigate cellular and molecular processes induced by NRTIs in the spinal cord that probably underlie the development of allodynia. The results showed that ddC caused evident neuroinflammation in the spinal cord, suggested by the up-regulation of proinflammatory cytokines TNF-α and IL-1β and the reactions of microglia and astrocytes. In addition, we found that Wnt5a, a critical regulator of neuroinflammation, was also up-regulated. Pharmacological inhibition of Wnt5a blocked ddC-induced up-regulation of TNF-α and astrocyte reaction, while activation of Wnt5a signaling potentiated these processes. Furthermore, our data showed that inhibition of Wnt5a significantly reversed ddC-induced mechanical allodynia in aging mice. The results collectively suggest that NRTIs may contribute to the development of chronic pain in aging patients by inducing Wnt5a-regulated neuroinflammation.

Antiretroviral Treatment-Associated Labia Majora Lipohypertrophy: A Rare Case and Plastic Surgical Treatment Options

The emergence of highly active antiretroviral therapy (HAART) has revolutionized the prognosis of HIV-infected patients. However, the extended use of HAART is associated with a disfiguring complication termed lipodystrophy, a disorder of body fat maldistribution causing peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). Lipoatrophy commonly affects the face, legs, buttocks and arm, whilst lipohypertrophy frequently favours the abdomen, breast and dorsocervical region. To our knowledge, we present only the second documented case in the literature of a labia majora lipohypertrophy in a HIV-positive patient receiving long-term HAART. The severity of labial abnormality caused significant physical and functional morbidities. Labiaplasty with dermolipectomy of the labia majora and excisional lipectomy of the mons pubis was successfully performed. At a 6-month follow-up, patient had no recurrence with resolution of symptoms and resumption of normal activities of daily living (ADL).

CD127 Expression in Naive and Memory T Cells in HIV Patients Who Have Undergone Long-Term HAART.

To evaluate cluster of differentiation (CD)127 expression in T cells of patients with HIV-1 and the relationship of CD127 expression with disease progression. We divided 139 patients infected with human immunodeficiency virus type 1 (HIV-1) who had undergone highly active antiretroviral therapy (HAART) into 3 groups: patients with poor recovery (CD4+T < 350/μ;L, patients with general recovery (CD4+T = 350 - ∼600/μL) and patients with good recovery (CD4+T > 600/μL). Counts and percentages of naïve (CD45RA+) and memory (CD45RO+) T cells and CD127 expression were determined using flow cytometry. CD4+CD45RO+, CD4+CD45RA+, CD4+ CD45RO+ CD127+, and CD4+CD45RA+CD127+T-cell counts in patients with good recovery were higher than in patients with poor recovery and those with general recovery patients (P <.05). Percentages of CD45RO+ were increased, and percentages of CD45RA+ and CD127 in T cells were decreased in patients with poor and general recovery (P <.05). CD127 values were positively correlated with CD4+T-cell counts and percentages of CD45RA+ subsets (P <.05). CD127 expression in T cells is decreased in patients with HIV-1 and is related to recovery of CD4+T-cell counts and to naïve subsets.

A relationship between CD4 count and oral manifestations of human immunodeficiency virus-infected patients on highly active antiretroviral therapy in urban population.

Introduction:Human immunodeficiency virus (HIV) infection gradually destroys the body's immune system, which makes it harder for the body to fight infections. HIV infection causes a quantitative and qualitative depletion of CD4 lymphocyte count, which increases the risk of opportunistic infections. Thus, CD4 count is one of the key factors in determining both the urgency of highly active antiretroviral therapy (HAART) initiation and the need of prophylaxis for opportunistic infections.Aim:This study aims to evaluate the prevalence and variations in the oral manifestations of HIV/acquired immune deficiency syndrome patients on HAART therapy in urban population and their association with CD4 count.Materials and Methods:A study was conducted by screening eighty patients who were HIV positive in an urban location. Both adult and pediatric patients were screened for oral manifestations and simultaneously CD4 count was also evaluated. Patients with HIV infection for variable time period who are under HAART were considered.Statistical Analysis:Measures of central tendency were used to analyse the data.Results:HIV infection destroys the immune system of an individual, making the patient susceptible to various infections and malignancies. With the advent of antiretroviral therapy, the scenario has changed drastically. We have observed that patients with CD4 counts between 164 and 1286 show relatively few oral manifestations. Long-term HAART therapy causes pigmentation, xerostomia and angular cheilitis but is taken up quite well by the patients.Conclusion:In this study, eighty patients with HAART from urban population showed very minimal oral findings because of good accessibility for treatment and awareness about HIV infections. The patients who were on long-standing HAART treatment also showed minimal oral manifestation such as pigmentation and xerostomia. Hence, we conclude that recognition, significance and treatment of these lesions in patients with HIV infection do not require elaborate setup and can be treated with basic primary health care.

Long-term effect of highly active antiretroviral therapy on immunologic features in children.

Highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus infection (HIV) into a chronic condition. The effects of long-term HAART on the immune system activity of early infected children are not fully understood. Hence, the aim of this review is to investigate immune system recovery and residual alteration in HIV-infected children receiving HAART in high-income countries. A systematic review was performed by searches of PubMed and references of the relevant articles. Studies published between January 1, 2000 and April 1, 2014 and conducted in high-income countries reporting data on immunological features in HIV-infected children receiving HAART were included in this review. Fifty-three articles were included in this review. Present knowledge on B-cell and T-cell function, immunoglobulin production, response to vaccine and innate immune system activity in HIV-infected children receiving HAART is discussed. Starting therapy as soon as diagnosis is ascertained and monitoring vaccine response in children under HAART are the most important tools to safeguard immunological function in HIV-infected children.

The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals.

The incidence of HIV-associated dementia has been greatly reduced in the era of highly active antiretroviral therapy (HAART); however milder forms of cognitive impairment persist. It remains uncertain whether HAART regimens with a high degree of central nervous system penetration effectiveness (CPE) exert beneficial neurological outcomes in HIV-infected (HIV+) individuals on stable treatment. Sixty-four HIV-infected adults on HAART were assigned a CPE score using a published ranking system and divided into high (≥7; n = 35) and low (<7; n = 29) CPE groups. All participants completed neuropsychological testing in addition to structural neuroimaging. Neuropsychological tests included measures known to be sensitive to HIV with values converted into standardized scores (NPZ-4) based on published normative scores. A semi-automated methodology was utilized to assess brain volumetrics within cortical (grey and white matter) and subcortical (thalamus, caudate, putamen) regions of interest. Analyses assessed NPZ-4 and brain volumetric differences between HIV+ individuals with high and low CPE scores. No significant differences in brain integrity were observed between the two groups. Long-term HAART regimens with a high degree of CPE were not associated with significantly improved neuropsychological or neuroimaging outcomes in HIV+ adults. Results suggest that alternate mechanisms may potentially contribute to better neurological outcomes in the era of HAART.

Relationship of long-term highly active antiretroviral therapy on salivary flow rate and CD4 Count among HIV-infected patients.

Objectives:To determine if long-term highly active antiretroviral therapy (HAART) therapy alters salivary flow rate and also to compare its relation of CD4 count with unstimulated and stimulated whole saliva.Materials and Methods:A cross-sectional study was performed on 150 individuals divided into three groups. Group I (50 human immunodeficiency virus (HIV) seropositive patients, but not on HAART therapy), Group II (50 HIV-infected subjects and on HAART for less than 3 years called short-term HAART), Group III (50 HIV-infected subjects and on HAART for more than or equal to 3 years called long-term HAART). Spitting method proposed by Navazesh and Kumar was used for the measurement of unstimulated and stimulated salivary flow rate. Chi-square test and analysis of variance (ANOVA) were used for statistical analysis.Results:The mean CD4 count was 424.78 ± 187.03, 497.82 ± 206.11 and 537.6 ± 264.00 in the respective groups. Majority of the patients in all the groups had a CD4 count between 401 and 600. Both unstimulated and stimulated whole salivary (UWS and SWS) flow rates in Group I was found to be significantly higher than in Group II (P < 0.05). Unstimulated salivary flow rate between Group II and III subjects were also found to be statistically significant (P < 0.05). ANOVA performed between CD4 count and unstimulated and stimulated whole saliva in each group demonstrated a statistically significant relationship in Group II (P < 0.05). There were no significant results found between CD4 count and stimulated whole saliva in each groups.Conclusion:The reduction in CD4 cell counts were significantly associated with salivary flow rates of HIV-infected individuals who are on long-term HAART.

Long-term effect of Haart on biochemical profiles of HIV/AIDS patients in a tertiary health facility in Benin city, Nigeria

Purpose: To assess the long-term effect of highly active antiretroviral therapy (HAART) on biochemical parameters of HIV-infected patients in University of Benin Teaching Hospital (UBTH), Benin City, Nigeria.Methods: HIV/AIDS patients on HAART for 2 - 8 years (297), those who were not on HAART (112, positive control), and healthy subjects (103, negative control) were recruited in the Infectious Diseases Clinic (IDC) of UBTH. Their sera were assayed for biochemical parameters. WHOQoL bref instrument was used to assess patients’ Quality of life (QoL).Results: Patients who have been on HAART had significantly elevated ALT and AST levels (p &lt; 0.001) but mild liver toxicity. QoL of these patients was not significantly different from that of the healthy controls. The levels of Na+ (133.4 ± 5.2 mmol/l), K+ (3.6 ± 0.4 mmol/l) and Cl- (101.3 ± 4.0 mmol/l) were significantly lower in patients on HAART than those of the positive (137.5 ± 5.1, 3.9 ± 0.5, 104.3 ± 5.7 mmol/l respectively, p &lt; 0.001). Also, levels of creatinine (0.8 ± 0.2 mg/dl), TBil (0.5 ± 0.2 mg/dl), and CB (0.3 ± 0.5 mg/dl) were significantly higher in patients on HAART than those of either the positive (0.7 ± 0.3, 0.4 ± 0.2, 0.2 ± 0.1 mg/dl) or negative (0.7 ± 0.3, 0.3 ± 0.1, 0.2 ± 0.1 mg/dl) controls respectively (p &lt; 0.001).Conclusion: Treatment with HAART for 2 - 8 years may not produce severe hepatotoxicity in HIV/AIDS patient though mild liver toxicity should be expected. The patients’ QoL was not negatively affected by the use of HAART for 2 - 8 years.Keywords: Biochemical parameters, HIV/AIDS, Long-term HAART, Quality of life (QoL).

Relationship between discordant response to HAART, Tregs, immune activation and low-level viraemia.

IntroductionThe incomplete immune recovery upon effective long-term highly active antiretroviral therapy (HAART) has been associated with increased morbidity and mortality in HIV infected patients [1]. Immune cellular activation, Tregs or very low-level viraemia has been alternatively suspected, but never investigated simultaneously [2].Materials and MethodsWe performed a cross-sectional study in 87 aviraemic patients (men=62, mean CD4+T cells=570/mm3, mean duration of HAART=12 years). Patients with at least 500 CD4+ T cells /mm3 were classified as complete immunological responders (cIR), whereas remaining patients were classified as inadequate immunological responder (iIR). Tregs were characterized based on CD4+CD25highFoxP3+phenotype using a one-step intracellular staining. Effector Tregs and terminal effectors Tregs were respectively defined as CD4+CD25+FoxP3+CD45RA-, and CD4+CD25+FoxP3+CD45RA-HLADR+phenotypes as recently described [3]. Activated T cells were identified using (i) elevated HLA-DR expression for CD4+T cells, and (ii) increased expressions of HLA-DR, or CD38, or both (HLADR+CD38+cells) for CD8+T cells. Very low-level viraemia was defined as detectable viraemia between 1 and 39 cp/mL. Univariate and multivariate analyses were performed to identify determinants of iIR.ResultsThirty-nine patients were classified as iIR, and 48 as cIR. Patients from the iIR group were significantly older (55 vs 50 years, p=0.027), and had percentages of activated CD4+ T cells, Tregs, effector Tregs and terminal effector Tregs significantly higher (5.3 vs 4%, p=0.014; 9 vs 7.5%, p=0,022; 8 vs 6.3%, p=0.01 and 1.8 vs 1.3%, p=0,033 among CD4+T cells, respectively). Neither the percentage of activated CD8+T cell nor very low-level viraemia were found to be associated with iIR. In the multivariate analysis, nadir of CD4+T cell count and percentage of Tregs were the only two parameters independently associated with iIR (OR=2.339, p=0.001, and OR=0.803, p=0.041, respectively).ConclusionsWe present here the largest study investigating simultaneously immune response to long-term HAART, immune activation of CD4+ and CD8+ T cells, Tregs percentages and very low-level viraemia. Our results highlight the importance of Tregs in CD4 homeostasis. This aspect should now be prospectively explored in a large cohort of patients.