Journal of Virus Eradication最新文献

Background and aims

Hepatitis B is a leading cause of morbidity and mortality worldwide. In view of the World Health Organization 2030 targets, effective screening of chronic infection is crucial. We have assessed the prevalence and risk factors of hepatitis B surface antigen in adults presenting for screening.

Methods

Free-of-charge and anonymous services for simultaneous hepatitis B, hepatitis C, human immunodeficiency virus and syphilis screening and counseling were provided in four facilities in northern Thailand. Analyses were performed separately in clients born before integration into the 1992 hepatitis B vaccine Thailand's Expanded Program on Immunization and in clients born afterwards.

Results

Between October 2015 and August 2020, hepatitis B surface antigen prevalence was 7.2 % (185/2578) in clients born before 1992 (95 % confidence interval [CI] = 6.2%–8.2 %). In the multivariable analysis, characteristics independently associated with a higher risk of infection were being born male (adjusted odds ratio [aOR] = 1.49, 95 % CI = 1.10–2.01) and being part of a hill tribe (aOR = 1.65, 95 % CI = 1.01–2.70). Forty-two percent were unaware of their infection. In clients born in 1992 or afterwards, prevalence was 1.5 % (43/2933) (95 % CI = 1.1%–2.0 %) and characteristics independently associated with a higher risk were being born between 1992 and 1995 (aOR = 1.90, 95 % CI = 1.00–3.61), being born male (aOR = 2.60, 95 % CI = 1.34–5.07), being part of a hill tribe (aOR = 5.09, 95 % CI = 2.52–10.26) and having ever injected drugs (aOR = 4.33, 95 % CI = 1.23–15.24).

Conclusions

Risk factor-based screening would miss many chronic hepatitis cases. Screening all adults once in their lifetime may be beneficial until the second generation of immunized infants have reached adult age.

Background

To test efficacy, HIV cure-related trials often require a period of intensively monitored interruption of antiretroviral therapy (ART) (analytical treatment interruption or ATI). As individuals who started ART during primary HIV-1 infection (PHI) are often recruited, we have asked people already enrolled into an observational PHI study about their willingness and concerns around participating in cure-related studies involving ATIs.

Methods

People who were diagnosed with PHI and started ART, attending two London HIV clinics, provided informed consent to complete a digital survey in clinic between 21/07/21 to October 31, 2023. Questions comprised sociodemographics, motivations, concerns and practical considerations influencing willingness to participate in studies involving ATIs. Hierarchical clustering of responses was performed using the ‘pheatmap’ R statistical package and ranked from most to least concerned. Responses were cross-referenced with enrolment into an ATI study which recruited from this cohort.

Results

Of 352 eligible participants, 75 completed the survey. The majority were white, cisgender men who have sex with men, 34/75 (45 %) were born outside the UK. 29 (39 %) expressed interest in joining ATI studies. Participants who were interested or unsure in joining ATI studies were primarily motivated (53/65, 82 % very or moderately interested) by an altruistic desire to help scientific research. Across all participants, onward HIV transmission was the predominant concern (67/75, 89 % very or moderately concerned), and similar levels of concerns reported if the HIV-1 viral load threshold to restarting ART was increased from 500 to 50 000 copies/mL. Most participants preferred weekly (23/65, 35 %) or fortnightly (11/65, 17 %) viral load monitoring during an ATI. Before taking part in a study involving an ATI, participants stated they would prefer to discuss this with their HIV doctor (55/65, 85 %).

Conclusion

In this small survey, 39 % of respondents expressed interest in joining studies involving ATIs, primarily for altruistic reasons. Participants were more interested in joining a potential ATI study if a novel intervention was included than simply an ATI alone. The main concern expressed was risk of viral transmission. To inform practical and study design considerations for future ATI studies, unrestricted access for mitigation of transmission risk should be included, and regular, frequent viral load monitoring is preferred.

Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6–4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4–6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity.

Background

Understanding factors affecting the size and the evolution of the HIV reservoir is essential for the development of curative strategies. This study aimed to assess the impact of antiretroviral therapy (ART) initiated during primary infection (PHI) vs chronic infection (CHI) on the levels and dynamics of integrated HIV-1 DNA, a biomarker of viral persistence.

Methods

Integrated and total HIV-1-DNA were measured in the blood of 92 patients treated during PHI (early group) and 41 during CHI (deferred group), at diagnosis, ART initiation, and 12–24 months on treatment.

Results

On ART, detectable (>1.78 log₁₀ copies/10⁶ PBMCs) integrated HIV-1 DNA levels were significantly lower in the early vs deferred group (2.99 log₁₀ vs 3.29 log_10, p = 0.005). The proportion of undetectable integrated HIV-1 DNA tended to be higher in the early group vs deferred group (61 % vs 46 %; p = 0.133).

Conclusion

Treatment initiated at PHI limits the levels of integrated HIV-1 DNA in blood. However, initiating treatment at CHI does not allow reaching such low levels in most patients, probably because the stable proviruses at that stage are present in the less prone to elimination long-lived cells. Thus, early ART could provide an opportunity to preparing for functional cure and eradication strategies.

The measles virus (MeV) and canine distemper virus (CDV) belong to the genus Morbillivirus of the Paramyxoviridae family. They are enveloped viruses harboring a non-segmented negative-sense RNA. Morbilliviruses are extremely contagious and transmitted through infectious aerosol droplets. Both MeV and CDV may cause respiratory infections and fatal encephalitis, although a high incidence of brain infections is unique to CDV. Despite the availability of a safe and effective vaccine against these viruses, in recent years we are witnessing a strong resurgence of Morbillivirus infection. Measles still kills more than 100,000 people each year, and CDV causes widespread outbreaks, especially among wild animals, including non-human primates.

No drugs are currently approved for MeV and CDV. Therefore, the identification of effective antiviral agents represents an unmet medical need. Here, we have investigated the potential antiviral properties of nitazoxanide (NTZ) against MeV and CDV. Antiviral activity was explored with live virus and cell-based assays. NTZ is a thiazolide that is approved by the FDA as an antiprotozoal agent for the treatment of Giardia intestinalis and Cryptosporidium parvum. Further, nitazoxanide and its metabolite tizoxanide have recently emerged as broad-spectrum antiviral agents. We found that NTZ blocks the MeV and CDV replication, acting at the post-entry level. Moreover, we showed that NTZ affects the function of the viral fusion protein (F), impairing viral spread. Our results indicate that NTZ should be further explored as a therapeutic option in measles and canine distemper virus treatment.

Objective

This work sought to estimate population measles seroprevalence and heterogeneity in the antibody concentration distribution that could be explained by the birth-year cohort according to the opportunity of viral and vaccine exposure, applied to data from Medellín, Colombia.

Methods

Prevalence of IgG antibodies was analyzed for measles based on a population study with a random sample of 2098 individuals from 6 to 64 years of age. Finite mixture models were used to estimate global seroprevalence and that of three birth-year cohorts (I: born up to 1982; II: 1983–1994; III: born since 1995). Multiple linear regression permitted adjusting the concentration of antibodies by cohort, zone, and sex.

Results

Globally, seronegativity was 6.5% (95% CI 4.9– 8.6), seropositivity of 78.4% (95% CI 75.1–81.4), and equivocal of 15.1% (95% CI 12.5–18.1). Two components were found with skewed normal distribution, which reclassified those equivocal as seropositive. Differences were observed by cohort in the geometric mean of antibodies [Cohort I: 1704.6; II: 562.2; III: 802.1 milli-international units per milliliter (mIU/mL] and seronegativity (Cohort I: 4%; II:13.3%; III: 8.9%). Antibody concentration increased by 1.26 mIU/mL in residents in the rural area, while diminishing in individuals from cohort II (by 3.02 mIU/mL) and cohort III (by 2.14 mIU/mL).

Conclusion

The younger cohorts (II and III) had a lower antibody concentration (higher seronegativity), indicating the need to monitor periodically seroprevalence and an eventual reestablishment of the transmission in these groups with higher risk of infection.

With growing interest and efforts to achieve a hepatitis B (HBV) cure, HBV therapeutics have increasingly entered the clinical testing phase. In designing an early phase clinical trial aimed at HBV cure, the heterogeneity in participants and the choice of a biomarker endpoint that signals a cure requires careful consideration. We describe the key elements to consider during the development of HBV clinical trials aimed at a functional cure, and how we have addressed them in the design of a phase II AIDS Clinical Trials Group (ACTG) study, A5394 (NCT05551273). The trial we present is for persons with both HIV and HBV, a unique population that has much to gain from an HBV cure. Our decisions on the design elements are specific to the study agent and the targeted population, but our deliberations may be informative in the emerging field of early phase HBV trials aimed at cure.

Despite more than 20 years of combination antiretroviral therapy (cART), complete eradication of HIV remains a daunting task. While cART has been very effective in limiting new cycles of infection and keeping viral load below detectable levels with partial restoration of immune functions, it cannot provide a cure. Evidently, the interruption of cART leads to a quick rebound of the viral load within a few weeks. These consistent observations have revealed HIV ability to persist as an undetectable latent reservoir in a variety of tissues that remain insensitive to antiretroviral therapies. The ‘Block-and-Lock’ approach to drive latent cells into deep latency has emerged as a viable strategy to achieve a functional cure. It entails the development of latency-promoting agents with anti-HIV functions. Recent reports have suggested sulforaphane (SFN), an inducer of NRF-2 (nuclear erythroid 2-related factor 2)-mediated antioxidative signaling, to possess anti-HIV properties by restricting HIV replication at the early stages. However, the effect of SFN on the expression of integrated provirus remains unexplored. We have hypothesized that SFN may promote latency and prevent reactivation. Our results indicate that SFN can render latently infected monocytes and CD4⁺ T cells resistant to reactivation. SFN treatments antagonized the effects of known latency reactivating agents, tumor necrosis pactor (TNF-α), and phorbol 12-myristate 13-acetate (PMA), and caused a significant reduction in HIV transcription, viral RNA copies, and p24 levels. Furthermore, this block of reactivation was found to be mediated by SFN-induced NRF-2 signaling that specifically decreased the activation of NFκB signaling and thus restricted the HIV-1 promoter (5′LTR) activity. Overall, our study provides compelling evidence to highlight the latency-promoting potential of SFN which could be used in the ‘Block-and-Lock’ approach to achieve an HIV cure.

Background

The significance of hepatitis B virus (HBV) in cerebrospinal fluid (CSF) is unclear.

Methods

Synchronous serum and CSF samples were collected from 13 patients. HBV DNA, full-length genome, quasispecies, phylogenetic tree, compartmentalization and mutation of the reverse transcriptase (RT) region were performed based on PCR and sequencing methods.

Results

HBV DNA was detected in the CSF of 3 antiviral-naïve individuals and 1 individual after successful antiviral therapy. Complete full-length HBV genomes were isolated from the CSF of 5 individuals, including 2 with undetectable serum HBV DNA. Ten individuals exhibited distinct CSF-serum quasispecies, 8 harbored independent CSF-serum genetic compartmentalization and phylogenetic trees, and 5 lamivudine/entecavir-associated resistance mutations only in the CSF. The frequencies of rtL180M and rtM204I/V mutations in both serum and CSF were higher in HIV-HBV-coinfected individuals than in the HBV-monoinfected ones (serum: rtL180M: 3.9% vs. 0, P = 0.004; rtM204I/V: 21.3% vs. 0, P < 0.001; CSF: rtL180M: 7.6% vs. 0, P = 0.026; rtM204I/V 7.6% vs. 1.6%, P = 0.097).

Conclusion

CSF is a potential HBV reservoir, and HBV in CSF harbors distinct evolution and mutation characteristics from those in serum. HIV infection increases the possibility of HBV rtL180M and rtM204I/V mutations in both serum and CSF.