Antiretroviral Drug Treatment Research Articles

First Case of HIV Seroconversion With Integrase Resistance Mutations on Long-Acting Cabotegravir for Prevention in Routine Care.

Long-acting cabotegravir (CAB-LA) is highly effective for HIV prevention, but delayed HIV diagnoses and integrase strand transfer inhibitor (INSTI) resistance were observed in trials. We report the first case in routine clinical care of HIV infection on CAB-LA with INSTI resistance. The SeroPrEP study enrolls individuals in the United States who acquire HIV on pre-exposure prophylaxis modalities to assess diagnostics, antiretroviral (ARV) drug levels, resistance, and treatment outcomes. Resistance mutations in full-length HIV-1 integrase were identified by single-genome sequencing (SGS). Cabotegravir concentrations in plasma and hair segments were measured by liquid chromatography-tandem mass spectrometry. A 23-year-old gender-nonbinary person, male at birth, restarted CAB-LA 6 months after discontinuation due to losing insurance. Prior to restart, HIV-1 RNA was not detected, but 20 days elapsed before CAB-LA injection. After the second CAB-LA injection, HIV antigen/antibody returned reactive (HIV-1 RNA 451 copies/mL). SGS of plasma HIV-1 RNA identified INSTI mutation Q148R in 2/24 sequences 2 days postdiagnosis; commercial genotype failed amplification. Cabotegravir hair concentration was 0.190 ng/mg 2 weeks prediagnosis; plasma cabotegravir was high (3.37 μg/mL; ∼20× PA-IC90) 14 days postdiagnosis. Viral suppression was maintained for 6 months on darunavir/cobicistat/emtricitabine/tenofovir alafenamide, then switched to doravirine + emtricitabine/tenofovir alafenamide due to nausea. In this first case of HIV infection on CAB-LA with INSTI resistance in routine care, cabotegravir resistance was detected only with a sensitive research assay. Accelerated pathways to minimize time between HIV testing and CAB-LA initiation are needed to optimize acute HIV detection and mitigate resistance risk. Sustained product access regardless of insurance is imperative to reduce HIV infections on CAB-LA.

Impact of 1 Year of Large-Scale Antiretroviral Drug Treatment on the Anthropometric Profiles and Treatment Outcomes of HIV-Adult Patients in the Rural District Hospital of Eastern Nigeria

Impact of 1 Year of Large-Scale Antiretroviral Drug Treatment on the Anthropometric Profiles and Treatment Outcomes of HIV-Adult Patients in the Rural District Hospital of Eastern Nigeria

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

A study on quality of life and related factors among HIV-infected men who have sex with men based on latent profile analysis

Objectives: To investigate the potential classification of quality of life in HIV-infected men who have sex with men (HIV-infected MSM) and to analyze possible influencing factors of different categories. Methods: A questionnaire survey was conducted among HIV-infected MSM who received antiretroviral treatment (ART) in an infectious disease hospital in Ji'nan, Shandong Province from October to December 2020. The quality of life scores in six domains were analyzed by latent profile analysis (LPA), and possible related factors of potential classification were explored by ordinal logistic regression analysis. Results: A total of 584 HIV-infected MSM were included in this study. LPA divided their quality of life into three categories, named low score, medium score and high score groups, accounting for 34.4% (201/584), 49.8% (291/584), and 15.8% (92/584), respectively. Multivariate ordinal logistic regression analysis showed that age above 40 years (aOR=1.77, 95%CI:1.11-2.80), monthly average income of 3 000 Yuan and below (aOR=3.15, 95%CI:1.72-5.76), monthly average income of 3 001-5 000 Yuan (aOR=2.26, 95%CI:1.41-3.62), distance to the hospital to receive drugs farer than 40 kms (aOR=1.76, 95%CI:1.07-2.89), and adverse reactions after taking drugs (aOR=2.31, 95%CI:1.65-3.23) were factors associated with low level of quality of life. Conclusions: The qualities of life of HIV-infected MSM showed group heterogeneity and were at high levels. Attention should be focused on HIV-infected MSM who are at older age, with low income, and long distance to access the health facilities. The measures should be taken to reduce the adverse reactions of ART drugs and improve the quality of life.

Preclinical development and pharmacokinetic assessment in macaques of a multipurpose long-acting injectable suspension containing medroxyprogesterone acetate for contraception and rilpivirine for HIV prevention

Depot injections comprising aqueous drug suspensions are widely marketed for long-acting administration of contraceptive progestins and antipsychotics. In recent years, there has been considerable interest in developing similar long-acting injectable products containing antiretroviral drugs for treatment or prevention of HIV infection, culminating in 2020/2021 with the approval of Cabenuva® (which combines the integrase strand transfer inhibitor cabotegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine for treatment of HIV infection) and Apretude (a cabotegravir extended-release injectable suspension for HIV prevention). Here, we describe formulation and preclinical development of a new multipurpose prevention technology product based on a long-acting injectable aqueous suspension formulation combining micronized medroxyprogesterone acetate (the progestin used in the long-acting injectable contraceptive product Depo-Provera®) and a rilpivirine nanosuspension for HIV prevention. Through the application of an extensive range of analytical methods, we have demonstrated that the resulting combination suspension formulation had a bimodal particle distribution, was stable, was sterilised by gamma irradiation, and provided sustained systemic and vaginal exposure of both drugs over at least one month following intramuscular injection in macaques. Further formulation development will be needed to sustain drug concentrations in the systemic/vaginal compartments over longer time periods, and to consider options for use of alternate antiretroviral drugs.

Association of Substance Use with Immunological Response to Antiretroviral Therapy in HIV-Positive Patients from Southwest Ethiopia: A Prospective Observational Study.

Use of psychoactive substances by HIV-positive patients in the course of antiretroviral drug treatment has become a public health problem globally. Substance use (alcohol, nicotine, and khat) during the course of treatment results in interactions with drugs that lead to undesired treatment outcomes. This condition is understudied, and the consequences of substance use among patients on antiretroviral treatment are not well explored. A prospective observational study was conducted among people on antiretroviral therapy (ART) at Jimma University Medical Center in southwest Ethiopia from April 20 to November 27, 2019. Data were collected using the World Health Organization's alcohol, smoking, and substance involvement screening test among adults who have followed antiretroviral therapy for a minimum of 6 months. Logistic regression analysis was done to identify factors associated with immunological response. The inadequate immunological response was defined as patients who were unable to achieve or maintain a CD4 cell count of >350 cells/mm³ after the 6-months of follow-up. Of the 332 patients enrolled, a majority (64.2%) of the respondents were females. The mean (±SD) age of the patients was 38.5 ± 9.5 years. The proportion of participants with a high level of health risk due to alcohol use was 8.4%, while 63.8% of them were non-alcohol users with no health risk. In multivariable logistic regression analysis, moderate and high levels of health risks from alcohol use were significantly associated with increased odds of inadequate immunological response (AOR: 2.9; 95% CI, 1.1-7.4) and (AOR: 4.3; 95% CI, 1.2-14.8), respectively, but the level of health risk from khat and cigarette use showed no association with inadequate immunological response in this study. Moderate and high levels of health risk from alcohol use were independently associated with inadequate immunological response. People living with HIV/AIDS should regularly be screened for and be educated about substance use and its potential negative impact on CD4 cell recovery.

Do ART and Chemsex Drugs Get Along? Potential Drug-Drug Interactions in a Cohort of People Living with HIV Who Engaged in Chemsex: A Retrospective Observational Study.

People living with HIV (PLWH) who engaged in chemsex are at risk of potential drug-drug interactions (pDDIs) with recreational drugs. This study aimed to characterize pDDIs between antiretroviral treatment (ART) and chemsex drugs and evaluate their association with unscheduled relevant hospital consultations. We conducted a single-center, retrospective, observational study in a series of gay, bisexual, and other men who have sex with men (gbMSM) living with HIV who engaged in chemsex and who attended a tertiary hospital in Barcelona, Spain, from February 2018 through August 2019. Associations between all recorded pDDIs and relevant unscheduled consultations were estimated using the incidence rate (IR) per 100 person-years of those events compared between patients with no pDDI (green flag) or moderate severity pDDI (orange flag) with patients with high severity pDDI (red flag) using the incidence rate ratio (IRR). Among 172 PLWH engaged in chemsex, 249 ART regimens were prescribed: 44% based on integrase inhibitors, 30% on boosted ART, and 26% based on non-nucleoside reverse transcriptase inhibitors. The substances and recreational drugs most frequently used were erectile dysfunction agents (83%), methamphetamine (79%), GHB (77%), and alkyl nitrites (71%). Polydrug use was reported in 52%. We observed 2048 pDDIs. Of these, 23% were orange flag pDDIs; 88% related to boosted ARTs. The IR of the 285 unscheduled relevant episodes in patients with orange flag pDDIs was 64.67 (95%CI 40.07-89.28). The IRR of green flag pDDIs was 1.05 (95%CI 0.60-1.8; p = 0.876). One in four pDDIs were of moderate severity but no significant increase in the incidence of unscheduled relevant consultations was observed. A high number of unscheduled consultations, predominantly for psychiatric events and intoxication, were observed. Beyond using non-boosted ART to minimize pDDIs, other factors related to the practice of chemsex must be addressed, in order to offer a better approach.

HIV-AN INFECTIOUS DISEASE THAT IMPOSES THREAT TO LIFE

HIV/AIDS is one of the fatal diseases within the world and is caused by human immunodeficiency virus. Aids initially cause immune system failure resulting in infection and risk of cancers. HIV infection caused by blood transfusion and by using contaminated syringes, HIV is present in body in 2 forms – Free virus & within infected immune cells. CD4 T- cells are infected by HIV and reduce its numbers by breaking down T-cells. Most of the symptoms of HIV are opportunistically caused by bacteria, virus, fungi etc. The infection is smaller than 1% per annum in couples who used condoms. Female condoms may provide equal level of protection. The treatment of antiretroviral drugs has changed AIDS from a life-threatening disease to a feasible disease. Research has known how the virus replicates, manipulates, and hides in infected persons. Although our understanding is increased about the virus yet, a cure and vaccine remain tough.

Dolutegravir hypersensitivity reaction: the need for strengthening pharmacovigilance systems with optimization of antiretroviral therapy in HIV programs in resource-limited settings: case report

The incidence of antiretroviral therapy-related adverse drug reaction among people living with HIV in Liberia is unknown. For PLWH, unexplained new symptoms or deaths are often attributed to advanced HIV disease itself or opportunistic infections like tuberculosis. Surveillance systems for monitoring newly introduced combination antiretroviral drug treatments within HIV programs are either suboptimal or non-existent. Furthermore, when adverse drug reactions occur or are suspected by clinicians, the laboratory capacity for monitoring, diagnosis and medical treatment may be lacking. A 44-year woman diagnosed with HIV infection 5 years previously and on a regimen of lamivudine/zidovudine (3TC/AZT) and nevirapine (NVP) with viral suppression developed fever, rash and facial swelling 2 days after being transitioned to dolutegravir (DTG) based combination antiretroviral therapy and a backbone of lamivudine/tenofovir (3TC/TDF) as part of the Liberia National strategy for antiretroviral therapy treatment optimization. She was found to be acutely ill looking with fever, hives and angioedema but no features of anaphylaxis. Investigation was limited because of absence of routine laboratory monitoring, but her blood work showed eosinophilia. Following evaluation, a diagnosis of dolutegravir induced hypersensitivity reaction with angioedema was made. She was managed as outpatients on antihistamines and steroids. Dolutegravir (DTG) was also discontinued and substituted with ritonavir-boosted lopinavir (LPV/r) while retaining the 3TC/TDF backbone and relevant health education was provided. Symptoms resolved completely, and she was doing well at follow up 4 weeks later. We present a first case of hypersensitivity reaction leading to drug discontinuity following roll-out of dolutegravir as a first line cART in Liberia to call to attention the challenges of detecting and managing ART adverse drug reactions in a resource-limited setting and review the relevant literature to highlight the need for strengthening pharmacovigilance and laboratory monitoring systems in HIV programs in developing countries through planning, health systems strengthening and collaboration.

Association Between ART Adherence and Mental Health: Results from a National HIV Sero-Behavioural Survey in South Africa.

This paper assesses the levels of antiretroviral treatment (ART) adherence and mental health distress among study participants in a national behavioural HIV-sero prevalence study South Africa. The study was a cross-sectional population-based multi-stage stratified cluster random survey, (SABSSM V, 2017). Structured questionnaires were used to collect information on socio-demographics, HIV knowledge, perceptions, HIV testing and HIV treatment history. Study participants were tested for HIV infection, antiretroviral use, viral suppression, and ART drug resistance. A total of 2155 PLHIV aged 15years or older who were on ART were included in the study. Incidence of either moderate or severe mental health distress was 19.7%. Self-reported ART adherence among study participants with no, mild, moderate, or severe mental distress was 82%, 83%, 86% and 78%, respectively. The adjusted odds ratio for ART non-adherence was 0.58 (95% CI 0.24; 1.40) for mild mental distress, 0.82 (95% CI 0.35; 1.91) for moderate mental distress and 2.19 (95% CI 1.14; 4.19) for severe mental distress groups compared to the no mental health distress group. The other factors that were associated with ART non-adherence in adjusted models included education level, alcohol use and province/region of residence. The study revealed that mental health remains a challenge to ART adherence in South Africa. To improve ART adherence, HIV continuum of care programs should include screening for mental health among people living with HIV.

Point-of-Care Detection of Nonadherence to Antiretroviral Treatment for HIV-1 in Resource-Limited Settings Using Drug Level Testing for Efavirenz, Lopinavir, and Dolutegravir: A Validation and Pharmacokinetic Simulation Study.

Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.

Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain.

Although antiretroviral therapy (ART) during pregnancy is effective in limiting vertical HIV transmission, adverse outcomes persist amongst uninfected children exposed to antiretroviral drugs in utero. Membrane-associated drug transporters, metabolic enzymes, and tight junction proteins play important roles in adult antiretroviral drug disposition and toxicity; however, the fetal expression of these proteins in the context of ART, and their impact on in-utero antiretroviral drug distribution remain poorly understood. This study aimed to characterize the role of these proteins in modulating in-utero antiretroviral drug exposure. Pregnant mice were exposed to an ART regimen consisting of lamivudine, abacavir, atazanavir, and ritonavir, at clinically relevant doses. Fetal brain, liver, placenta amniotic fluid, and maternal plasma were collected on gestational day 18.5 and concentration of antiretroviral drugs in fetal tissues was measured by LC/MS/MS, whereas transporter expression was assessed by qPCR. Abacavir and lamivudine were detected in fetal brain and amniotic fluid, whereas atazanavir and ritonavir were detected in amniotic fluid only. Robust mRNA expression of key transporters was observed in adult and fetal tissues, and sex differences were identified in the expression of Abcc1 and Slc29a1 in the placenta. Antiretroviral drug exposure was associated with a reduction in relative placental Abcg2, Abcc1, and Slc29a1 expression. These findings identify a novel effect of fetal sex and antiretroviral drug treatment on the expression of placental transporters in a mouse model, and characterize the penetration of lamivudine and abacavir into fetal brain, uncovering a potential role of transporters in modulating fetal exposure to antiretroviral drugs.

Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale?

After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major causes of morbidity and mortality have switched from opportunistic infections and AIDS-related neoplasms to cardiovascular and liver diseases. HIV itself may lead to liver damage and subsequent liver fibrosis (LF) through multiple pathways. Apart from HIV, viral hepatitis, alcoholic and especially non-alcoholic liver diseases have been implicated in liver involvement among PLWH. Another well known cause of hepatotoxicity is ART, raising clinically significant concerns about LF in long-term treatment. In this review we present the existing data and analyze the association of LF with all ART drug classes. Published data derived from many studies are to some extent controversial and therefore remain inconclusive. Among all the antiretroviral drugs, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, seem to carry the greatest risk for LF, with integrase strand transfer inhibitors and entry inhibitors having minimal risk. Surprisingly, even though protease inhibitors often lead to insulin resistance, they do not seem to be associated with a significant risk of LF. In conclusion, most ART drugs are safe in long-term treatment and seldom lead to severe LF when no liver-related co-morbidities exist.

Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation.

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.

Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075

ObjectivesHPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period. MethodsAssessments included 64 participants with HIV (39 MSM, 24 TGW, and one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays. ResultsOver 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up. ConclusionsOver 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly threefold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.

Fabrication And Evaluation Of Self-Emulsifying Drug Delivery System (SEDDS) Of Antiretroviral Drug For Treatment Of HIV

Fabrication And Evaluation Of Self-Emulsifying Drug Delivery System (SEDDS) Of Antiretroviral Drug For Treatment Of HIV

THE RELATIONSHIP OF BASIC CLINICAL STATUS WITH THE QUALITY OF LIFE OF HIV AND AIDS PATIENTS

Background: The success of individual antiretroviral drug (ARV) treatment in patients with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) was determined by conducting a routine evaluation of the patients’ Cluster of Differentiation 4 (CD4) count. The indicators used to measure the success of the HIV and AIDS treatment were mortality, mobility, and quality of life (QoL). Purpose: The purpose of this research was to analyze the relationship between clinical status (smoking status, duration of ARV therapy, the CD4 count, and body mass index [BMI]) and the QoL of patients with HIV and AIDS who were stable during treatment. Methods: This type of research was quantitative analytical research with a cross-sectional design. This research was conducted at Dr. Soetomo Hospital, Surabaya, from September to November 2017. The study population was patients with HIV and AIDS in Dr. Soetomo Hospital, Surabaya. The research sample was taken by purposive sampling with the inclusion criteria being patients with HIV and AIDS who had been treated for ≥6 months with adherence ≥95% and who came directly to the hospital. Results: The majority of respondents were female (53.36%), junior/senior high school graduates (66.67%), married (62.22%), non-smoking (75.56%), had undergone ARV therapy for ±10 years (77.78%), and had a QoL in the adequate category (62.22%). The basic clinical status with a significant relationship with the respondents’ QoL were the CD4 count (p = 0.00) and BMI (p = 0.00). Conclusion: There was a relationship of the CD4 count and BMI with the QoL of the patients with HIV and AIDS.

Modeling within-host viral dynamics: The role of CTL immune responses in the evolution of drug resistance

To study the emergence and evolution of drug resistance during treatment of HIV infection, we study a mathematical model with two strains, one drug-sensitive and the other drug-resistant, by incorporating cytotoxic T lymphocyte (CTL) immune response. The reproductive numbers for each strain with and without the CTL immune response are obtained and shown to determine the stability of the steady states. By sensitivity analysis, we evaluate how the changes of parameters influence the reproductive numbers. The model shows that CTL immune response can suppress the development of drug resistance. There is a dynamic relationship between antiretroviral drug administration, the prevalence of drug resistance, the total level of viral production, and the strength of immune responses. We further investigate the scenario under which the drug-resistant strain can outcompete the wild-type strain. If drug efficacy is at an intermediate level, the drug-resistant virus is likely to arise. The slower the immune response wanes, the slower the drug-resistant strain grows. The results suggest that immunotherapy that aims to enhance immune responses, combined with antiretroviral drug treatment, may result in a functional control of HIV infection.

Abstract 375: Insights Into Molecular Mechanism of Cardiovascular Disorder in HIV+ Patients

Background: Antiretroviral therapy (ART) improves the survival of people living with HIV (PLHIV); however, the rate of cardiovascular disorder and heart failure is significantly increased among the PLHIV. Molecular basis of heart failure in the PLHIV undergoing antiretroviral drug treatment is not clear. The aim of this study is to explore the role of antiretroviral drugs in post translational modification of histones and its epigenetic regulation of gene expression in cardiomyocytes. Methods and Results: Primary rat ventricular cardiomyocytes were treated with a combination of antiretroviral drugs (5 μM of Atazanavir, Abacavir, Ritonavir and Lamivudine) for 4, 12 and 24 hours, and expression of major histone marks playing a role in gene activation (H3K9ac and H3K27ac) and repression (H3K27me3, H3K9me3) were evaluated by western blotting. Our data suggest that treatment with antiretroviral drugs leads to de-acetylation at H3K9ac and H3K27ac, and promotes methylation at H3K27me3 and H3k9me3. Additionally, the expression of epigenetic modifying enzymes was examined by PCR array in cardiomyocytes treated with antiretroviral drugs. PCR array data show that histone deacetylase enzyme Sirt1/2, and methyltransferase enzyme Suv39h1 and Ezh12 were upregulated in drug treated cardiomyocytes. Further, western blot data show that Sirt1, Suv39h1 and Ezh2 protein expression was significantly upregulated in drugs treated cardiomyocytes. Moreover, expression analysis of human cardiac tissue further shows that expression of Sirt1, Suv39h1 and Ezh2 was significantly upregulated in HIV+ patients heart compares to healthy donor. Mechanistically, our data show that expression of epigenetic modifying enzymes was differentially regulated in drug treated cardiomyocytes which may lead to epigenetic modifications of histone proteins. Conclusion: Antiretroviral drug treatment promotes epigenetic alteration in the chromatin which may lead to a change in gene expression of cardiomyocytes. This study may lead to novel therapeutic strategies for the treatment of heart failure in PLWHA.

COVID-19 and Prophylactic Measures for HIV Children of Ratodero, Larkana

Ratodero is Taluka of population 224,000 in the district Larkana of Sindh, Pakistan. In the HIV outbreak (2019), 1132 HIV patients were reported in the Ratodero, amongst them, 901 (80%) were children and the majority (735) below the age of 5 years.1 Larkana district is included among the cities where eight (8) COVID-19 carrier pilgrims from Iran were first confirmed as virus positive.2 Followed by community transmission in the area with the confirmation of the virus in the two individuals.3There was reported shortage of the personnel protection equipment (PPEs) for the Medical Professional engaged in the tests of the COVID-19 as well as the shortage of Kits, so less number of Covid-19 tests were conducted, therefore the actual number of Covid-19 positive can abruptly raise with the availability of Kits and PPEs.4 There is a complete lockdown in the area since last week of March 2020. There is one medical University with an affiliated hospital. Collaborative efforts of the University teaching hospital and the district administration have constituted a team of experts for necessary actions to combat with expected Corona-19 outbreak. In such circumstances of the existence of HIV in Ratodero as an alarm of threats for another health risk for the poor HIV children of Ratodero Larkana.&#x0D; Dated 09 April 2020. there was a random selection of 20 such HIV children of Ratodero below the age 5, to have look on their physical health and to confirm the quantity/availability of ART (antiretroviral treatment) at their home. It was found that 30% of children were found physically weak. The confirmed average availability of remaining ART drugs was found available for use in the next 14 days. Generally, the children are the population of developing immunity (vulnerable age group) hence there can be increased risk if Co-Infection of Covid-19 if hits the Ratodero Taluika. Therefore the District of Larkana in general but the Taluka Ratodero, in particular, need special attention from the health administration.&#x0D; Following preventive measures can be useful to prevent the spread of Covid-19 among the HIV children of Ratodero, Larkana.