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Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. We look at new approaches to unravelling the complex virus–host interactions that lead to persistent infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV.

Background In 2016, the World Health Organization (WHO) adopted a new Global Health Sector Strategy on HIV for 2016–2021. It establishes 15 ambitious targets, including the ‘90-90-90’ target calling on health systems to reduce under-diagnosis of HIV, treat a greater number of those diagnosed, and ensure that those being treated achieve viral suppression. Discussion The WHO strategy calls for person-centered chronic care for people living with HIV (PLHIV), implicitly acknowledging that viral suppression is not the ultimate goal of treatment. However, it stops short of providing an explicit target for health-related quality of life. It thus fails to take into account the needs of PLHIV who have achieved viral suppression but still must contend with other intense challenges such as serious non-communicable diseases, depression, anxiety, financial stress, and experiences of or apprehension about HIV-related discrimination. We propose adding a ‘fourth 90’ to the testing and treatment target: ensure that 90 % of people with viral load suppression have good health-related quality of life. The new target would expand the continuum-of-services paradigm beyond the existing endpoint of viral suppression. Good health-related quality of life for PLHIV entails attention to two domains: comorbidities and self-perceived quality of life. Conclusions Health systems everywhere need to become more integrated and more people-centered to successfully meet the needs of virally suppressed PLHIV. By doing so, these systems can better meet the needs of all of their constituents – regardless of HIV status – in an era when many populations worldwide are living much longer with multiple comorbidities.

Background A dolutegravir (DTG)-based antiretroviral regimen has been rolled out for pregnant women in low- and middle-income countries since 2020. However, available safety data are limited to a few clinical trials and observational studies. Hence, we present real-world pregnancy and birth outcome safety data from a large sample multicenter cohort study in Ethiopia. Methods A retrospective cohort study was conducted in fourteen hospitals across Ethiopia from 2017 to 2022. HIV-infected pregnant women were followed from the date of prevention of mother-to-child transmission (PMTCT) care enrolment until the infant was 6–8 weeks old. The primary safety outcome was a composite of adverse pregnancy events comprising spontaneous abortion, intrauterine fetal death (IUFD) before onset of labor, preterm birth, and maternal death. Additionally, a composite adverse birth outcome was assessed, comprising intrapartum fetal demise, low birth weight, and neonatal death. Finally, a composite of adverse pregnancy or birth outcome was also investigated. The exposure of interest was the antiretroviral treatment (ART) regimen used during pregnancy for PMTCT of HIV. Results During the study period, 2643 women were enrolled in routine PMTCT care. However, 2490 (92.2%) participants were eligible for the study. A total of 136/1724 (7.9%, 95% CI: 6.7–9.3%) women experienced adverse pregnancy outcomes. Fewer women in the DTG-based group (5.4%, 95% CI: 3.7–7.5%) had adverse pregnancy outcomes than in the Efavirenz (EFV)-based group (8.3%, 95% CI: 6.6–10.3%), P  = 0.004. After controlling for baseline differences, the DTG group had a 43% lower risk of adverse pregnancy outcomes (adjusted odd ratio (AOR), 0.57; 95% CI, 0.32–0.96%) and a 53% lower risk of preterm birth (AOR, 0.47; 95% CI, 0.22–0.98%) compared to the EFV group. A total of 103/1616 (6.4%, 95% CI: 5.2–7.7%) women had adverse birth outcomes. Although the difference was not statistically significant, fewer women in the DTG group (30/548; 5.5%, 95% CI: 3.7–7.7%) than in the EFV group (57/830; 6.9%, 95% CI: 5.2–8.8%) had adverse birth outcomes. Conclusions In this study, we observed that DTG-based regimens were associated with better pregnancy and birth outcome safety profiles, reaffirming the WHO recommendation. However, a prospective study is recommended to assess uncaptured maternal and perinatal adverse outcomes, such as congenital abnormalities, and infant growth and neurocognitive development.

Background Ethiopia aims to eliminate mother-to-child transmission (MTCT) of HIV by 2030. In 2020, Dolutegravir-based antiretroviral treatment (ART) regimen optimization was done for the Prevention of Mother-to-Child Transmission (PMTCT). However, data tracking progress, particularly post-rollout of the Dolutegravir (DTG)-based regimen, and the real-world effectiveness of the new regimen are unavailable. Methods A multicenter retrospective cohort study was conducted among HIV-infected mothers and their HIV-exposed infants visiting the selected hospitals for routine care. Eligible participants were HIV-exposed infants enrolled in the PMTCT care from 2017 to 2022. However, only the 2021 and 2022 birth cohorts were considered post-DTG optimization considering 2020 a year of optimization. The cumulative incidence of perinatal MTCT tested at 6–8 weeks of infant age, and end of care MTCT tested at 18 months of age was assessed. The exposures of the study were the infant birth cohort years and the different ART regimens used for PMTCT of HIV. Results Among a total of 2,643 routine care enrolled participants, 2521 (95.4%) HIV-exposed infants were included in the analysis. Of these, 210 were on follow-up and excluded from the breastfeeding MTCT analysis. A total of 30/2521(1.2%) [95% confidence interval (CI): 0.8-1.7%] were positive for HIV at 6–8 weeks. Additionally, 11 /2281 (0.50%) (95% CI: 0.3-0.9%) were positive during breastfeeding. At the end of the care, 41/2311 (1.8%) (95% CI: 1.3-2.4%) infants were HIV-positive. The highest end-of-care MTCT was reported in 2019 and 2022 birth cohorts while the lowest was in 2018 (P-value > 0.3). However, after adjusting for baseline characteristics, the trend showed a decrease in transmission rates following the rollout of DTG-based regimen, although statistical significance was not reached. The adjusted odds ratios (AORs) for perinatal, breastfeeding, and end-of-care transmission rates were 0.34 (95%CI: 0.08–1.39), 0.29(95%CI: 0.03–3.05), and 0.38(95%CI: 0.11–1.26) respectively. Compared with the Efavirenz (EFV)-based regimen, the DTG-based regimen was associated with a lower risk of MTCT in both the perinatal (AOR 0.23, 95% CI: 0.06–0.85) and at the end of care (AOR 0.27, 95% CI: 0.09–0.82). Pregnant women who started ART at late gestation had the highest transmission rate regardless of ART regimens (P-value < 0.001). Conclusions In the studied cohort population, we observed less than 3% MTCT rate at the end of PMTCT care. The findings might suggest the achievement of MTCT elimination at the hospital level. Although the DTG-based regimen demonstrated a lower risk of transmission, other contributing factors, such as late ART initiation, should be urgently addressed. Future research should focus on prospective designs, interventions targeting late ART initiation, and understanding regional disparities to further advance efforts to eliminate MTCT by 2030.

Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen. Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir–emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962. Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112–133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI −0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively). Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL. European Union Sixth Framework Programme, Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories.

Today there are many licensed antiviral drugs, but the emergence of drug resistant strains sometimes invalidates the effects of the current therapies used in the treatment of infectious diseases. Compared to conventional antiviral drugs, monoclonal antibodies (mAbs) used as pharmacological molecules have particular physical characteristics and modes of action, and, therefore, they should be considered as a distinct therapeutic class. Despite being historically validated, antibodies may represent a novel tool for combatting infectious diseases. The current high cost of mAbs' production, storage and administration (by injection only) and the consequent obstacles to development are outweighed by mAbs' clinical advantages. These are related to a low toxicity combined with high specificity and versatility, which allows a specific antibody to mediate various biological effects, ranging from the virus neutralization mechanisms to the modulation of immune responses. This review briefly summarizes the recent technological advances in the field of immunoglobulin research, and the current status of mAb-based drugs in clinical trials for HIV and HCV diseases. For each clinical trial the available data are reported and the emerging conceptual problems of the employed mAbs are highlighted. This overview helps to give a clear picture of the efficacy and challenges of the mAbs in the field of these two infectious diseases which have such a global impact.

Background Lymphocyte-activation gene (LAG)3 is a 498 aa transmembrane type I protein acting as an immune inhibitory receptor. It is expressed on activated lymphocytes, natural killer cells and plasmacytoid dendritic cells. In activated lymphocytes, LAG3 expression is involved in negative control of cell activation/proliferation to ensure modulation and control of immune responses. In view of its deregulated expression in tumor-infiltrating lymphocytes, LAG3, together with the additional immune checkpoint inhibitors CTLA4 and PD1, is considered a major target in order to reverse the immunosuppression typically mounting in oncologic diseases. Since many patients still fail to respond to current immune checkpoints-based therapies, the identification of new effective immune inhibitors is a priority in the ongoing fight against cancer. Results We identified a novel human single-chain variable fragment (scFv) Ab against a conformational epitope of LAG3 by in vitro phage display technology using the recombinant antigen as a bait. This scFv (referred to as F7) was characterized in terms of binding specificity to both recombinant antigen and human LAG3-expressing cells. It was then rebuilt into an IgG format pre-optimized for clinical usage, and the resulting bivalent construct was shown to preserve its ability to bind LAG3 on human cells. Next, we analyzed the activity of the anti-LAG3 scFvF7 using two different antigen-specific CD8 + T lymphocyte clones as target cells. We proved that the reconstituted anti-LAG3 F7 Ab efficiently binds the cell membrane of both cell clones after peptide-activation. Still more significantly, we observed a striking increase in the peptide-dependent cell activation upon Ab treatment as measured in terms of IFN-γ release by both ELISA and ELISPOT assays. Conclusions Overall, the biotechnological strategy described herein represents a guiding development model for the search of novel useful immune checkpoint inhibitors. In addition, our functional data propose a novel candidate reagent for consideration as a cancer treatment.

There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from \"dose adjustment/closer monitoring\", in mild to moderate liver disease, to \"the use is contraindicated\" in severe liver disease.

Background Ebola hemorrhagic fever is caused by the Ebola filovirus (EBOV), which is one of the most aggressive infectious agents known worldwide. The EBOV pathogenesis starts with uncontrolled viral replication and subversion of both the innate and adaptive host immune response. The multifunctional viral VP35 protein is involved in this process by exerting an antagonistic action against the early antiviral alpha/beta interferon (IFN-α/β) response, and represents a suitable target for the development of strategies to control EBOV infection. Phage display technology permits to select antibodies as single chain Fragment variable (scFv) from an artificial immune system, due to their ability to specifically recognize the antigen of interest. ScFv is ideal for genetic manipulation and to obtain antibody constructs useful for targeting either antigens expressed on cell surface or intracellular antigens if the scFv is expressed as intracellular antibody (intrabody) or delivered into the cells. Results Monoclonal antibodies (mAb) in scFv format specific for the EBOV VP35 were isolated from the ETH-2 library of human recombinant antibodies by phage display technology. Five different clones were identified by sequencing, produced in E.coli and expressed in CHO mammalian cells to be characterized in vitro. All the selected scFvs were able to react with recombinant VP35 protein in ELISA, one of the scFvs being also able to react in Western Blot assay (WB). In addition, all scFvs were expressed in cell cytoplasm as intrabodies; a luciferase reporter gene inhibition assay performed in A549 cells showed that two of the scFvs can significantly hamper the inhibition of the IFN-β-induced RIG-I signaling cascade mediated by EBOV VP35. Conclusion Five antibodies in scFv format recognize an active form of EBOV VP35 in ELISA, while one antibody also recognizes VP35 in WB. Two of these scFvs were also able to interfere with the intracellular activity of VP35 in a cell system in vitro. These findings suggest that such antibodies in scFv format might be employed to develop therapeutic molecules able to hamper EBOV infections.