Journal of Virus Eradication最新文献

Antiretroviral therapy (ART) aims to inhibit HIV replication, decrease CD4 T cell loss, and immune function recovery in order to reduce the morbidity and mortality associated with the infection. Treatment should also, improve quality of life and control HIV spread. However, incomplete viral suppression still occurs during ART. Viral suppression and virological failure (VF) thresholds vary between studies in terms of virological rebound (VR) states using different detection thresholds. Further understanding of influencing factors and adverse outcomes in various VR states should provide important guidance for HIV treatment.

High profile international goals have been set for the elimination of hepatitis B virus (HBV) infection as a public health threat by the year 2030. Developing and expanding equitable, accessible translational HBV research programmes that represent real-world populations are therefore an urgent priority for clinical and academic communities. We present experiences and insights by an expert interdisciplinary group focusing on barriers that impede adults living with HBV infection from participating in clinical studies. Our viewpoint describes barriers we have identified through working in a variety of settings across South Africa, including lack of education and awareness, experiences of stigma and discrimination, challenges for governance and data management, and a burden of complex morbidity. Through identifying these challenges, we propose solutions and interventions, highlight new approaches, and provide a framework for future research.

Introduction

Hepatitis C (HCV) is associated with extra-hepatic involvment, morbidity as well as metabolic changes. Whether these might be reversible if sustained virologic response (SVR) is achieved by direct-acting antiviral (DAA) therapy remains unknown.

Methods

Chronic hepatitis C (CHC) individuals receiving DAA treatment with SVR were compared to those who underwent spontaneous clearance (SC) of HCV infection at the 2-year follow-up. Plasma oxidative stress markers (oxidized low-density lipoprotein (oxLDL), 8-hydroxy-2′-deoxyguanosine (8-OHdG), malondialdehyde (MDA) and ischemia-modified albumin (IMA)) as well as progression of liver fibrosis were evaluated.

Results

Compared to SC individuals, those in the CHC group exhibited at baseline higher levels of oxLDL, 8-OHdG and IMA but not of MDA. In the SC group, 8-OHdG levels were elevated at 2-year post-SVR (p = 0.0409), while the DAA-treated CHC group showed decrease in oxLDL (p < 0.0001) and 8-OHdG (p = 0.0255) levels, approaching those of the SC group, but increased MDA (p = 0.0055) levels. Additionally, oxLDL levels were positively correlated with liver stiffness measurements at SVR (p = 0.017) and at 1 year post- SVR (p = 0.002).

Conclusions

Plasma oxLDL showed post-SVR normalization after clearance of HCV viremia with DAAs and was associated with levels of hepatic fibrosis.

The ability of immunoglobulin-based HIV biologics (Ig-HIV), including broadly neutralizing antibodies, to suppress viral replication in pre-clinical and clinical studies illustrates how these molecules can serve as alternatives or adjuncts to antiretroviral therapy for treating HIV infection. However, the current paradigm for delivering Ig-HIVs requires repeated passive infusions, which faces both logistical and economic challenges to broad-scale implementation. One promising way to overcome these obstacles and achieve sustained expression of Ig-HIVs in vivo involves the transfer of Ig-HIV genes to host cells utilizing adeno-associated virus (AAV) vectors. Because AAV vectors are non-pathogenic and their genomes persist in the cell nucleus as episomes, transgene expression can last for as long as the AAV-transduced cell lives. Given the long lifespan of myocytes, skeletal muscle is a preferred tissue for AAV-based immunotherapies aimed at achieving persistent delivery of Ig-HIVs. Consistent with this idea, recent studies suggest that lifelong immunity against HIV can be achieved from a one-time intramuscular dose of AAV/Ig-HIV vectors. However, realizing the promise of this approach faces significant hurdles, including the potential of AAV-delivered Ig-HIVs to induce anti-drug antibodies and the high AAV seroprevalence in the human population. Here we describe how these host immune responses can hinder AAV/Ig-HIV therapies and review current strategies for overcoming these barriers. Given the potential of AAV/Ig-HIV therapy to maintain ART-free virologic suppression and prevent HIV reinfection in people living with HIV, optimizing this strategy should become a greater priority in HIV/AIDS research.

Background & aims

Despite effective direct-acting antivirals (DAAs), hepatitis C virus (HCV) prevalence is high among people who inject drugs (PWIDs) and non-adherence to therapy remains a major obstacle towards HCV elimination in this subpopulation. To overcome this issue, we have combined ongoing opioid agonist therapy (OAT) with DAAs in a directly-observed therapy (DOT) setting.

Method

From September 2014 until January 2021 PWIDs at high risk of non-adherence to DAA therapy, who were also on OAT, were included into this microelimination project. Individuals received their OAT and DAAs under supervision of healthcare workers as DOT in a pharmacy or low-threshold facility.

Results

In total, 504 HCV RNA-positive PWIDs on OAT (387 men, 76.8%; median age: 38 years [IQR 33–45], HIV: 4.6%; hepatitis B: 1.4%) were included into this study. Two thirds reported ongoing intravenous drug use (IDU) and half of them had no permanent housing. Only 41 (8.1%) were lost to follow-up and two (0.4%) died of reasons unrelated to DAA toxicity. Overall, 90.7% of PWIDs achieved sustained virological response 12 weeks after treatment (SVR12) (95% CI: 88.1–93.2%). By excluding those lost to follow-up and hose who had died of causes unrelated to DAAs, the SVR12 rate was 99.1% (95% CI: 98.3–100.0%; modified intention-to-treat analysis). Four PWIDs (0.9%) experienced treatment failure. Over a median follow-up of 24 weeks (IQR 12–39), 27 reinfections (5.9%) were observed in individuals with the highest IDU rates (81.2%). Importantly, even though some were lost to follow-up, all completed their DAA treatment. By using DOT, adherence to DAAs was excellent with only a total of 86 missed doses (0.3% of 25,224 doses).

Conclusions

In this difficult-to-treat population of PWIDs with high rates of IDU , coupling DAA treatment to OAT in a DOT setting resulted in high SVR12 rates equivalent to conventional treatment settings in non-PWID populations.

The HIV reservoir is a population of 1–10 million anatomically dispersed, latently infected memory CD4⁺ T cells in which HIV DNA is quiescently integrated into human chromosomal DNA. When antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The detection of many populations of identical HIV sequences at unique integration sites implicates CD4⁺ T cell proliferation as the critical driver of reservoir sustainment after a prolonged period of effective ART. Initial reservoir formation occurs during the first week of primary infection usually before ART is started. While empirical data indicates that both de novo infection and cellular proliferation generate latently infected cells during early untreated infection, it is not known which of these mechanisms is predominant. We developed a mathematical model that recapitulates the profound depletion and brisk recovery of CD4⁺ T cells, reservoir creation, and viral load trajectory during primary HIV infection. We extended the model to stochastically simulate individual HIV reservoir clones. This model predicts the first detection of HIV infected clones approximately 5 weeks after infection as has recently been shown in vivo and suggests that substantial, uneven proliferation among clones during the recovery from CD4⁺ lymphopenia is the most plausible explanation for the observed clonal reservoir distribution during the first year of infection.