Current Opinion in HIV and AIDS最新文献

Purpose of review: The epidemiology of liver disease in people living with HIV has evolved since the arrival of effective hepatitis C virus (HCV) treatment. Nonalcoholic fatty liver disease (NAFLD) in HIV patients is highly prevalent while hepatitis D, hepatitis E, and occult hepatitis B remain underappreciated. We discuss mechanisms of fibrosis in HIV and review clinical outcomes of HIV-associated liver diseases.

Recent findings: HIV-HCV co-infection is receding as a cause of progressive liver disease, but fibrosis biomarkers after HCV treatment remain elevated. Antiretroviral therapy (ART) with anti-hepatitis B virus (HBV) activity promotes stable liver disease, but oversimplifying ART regimens in unrecognized suppressed HBV may lead to activation of HBV. A high prevalence of fibrosis and rapid progression of fibrosis are seen in HIV-associated NAFLD, with visceral fat as a major risk factor. Newer ART such as integrase strand inhibitors may have limited intrinsic hepatoxicity but do increase weight, which may secondarily lead to hepatic steatosis. Promising therapies for HIV-associated NAFLD include tesamorelin and CCR5 blockade agents.

Summary: Our understanding of the natural history and pathogenesis of liver diseases in HIV has advanced and adapted to the changing landscape of liver disease in this population. Future research should evaluate long-term clinical and histological outcomes, prevention strategies, and treatment options to improve morbidity and mortality in HIV-related liver diseases.

Purpose of review: The purpose of this review is to share the excitement of new developments in the field of vaccine vector modalities against infectious diseases. The focus is on HIV-1/AIDS with reference to the most successful as well as currently tested COVID-19 vaccines, and human trials, which best inform iterative vaccine improvements.

Recent findings: Several genetic subunit vaccines against SARS-CoV-2 demonstrated protection against severe disease, obtained Emergency Use Authorization and scaled their production to billions of doses. Many more are in efficacy evaluation. In contrast, development of HIV-1 vaccines has been extremely difficult. Perseverance of scientists is deepening our understanding of what constitutes immunity against HIV-1 infection and how to achieve protective levels of relevant responses by active immunization, passive administration or a combination of both. Novel platforms led by RNA play a pivotal role. However, a difficult virus may require a complex approach. Proof of concept for HIV-1 prevention and cure might be at reach, and when it arrives, it will be a great and needed encouragement to the field.

Summary: Despite the enormous success of drug treatment, vaccines remain the best solution and likely a necessary component of any package that truly ends the AIDS epidemic.

Purpose of review: After over 40 years, the HIV pandemic is amongst the deadliest in history - 100% fatal without treatment, HIV has infected over 84 million people, and has caused over 40 million deaths. Global HIV spending between 2000 and 2015 totaled over a half trillion dollars. Delays in harnessing scientific advances, including 'test and treat' and treatment as prevention of illness, death, and transmission (TasP) provide a cautionary tale applicable to other pandemics. Resource allocation has also been problematic with many highest burden countries spending less than 50% on care and treatment.

Recent findings: Between 2002 and 2021, over $94 billion was budgeted for HIV in 40 sub-Saharan African countries, with 19 countries over $1 billion. In 2021, 8.1 million (32%) People Living with HIV (PLHIV) are still not on treatment; viral suppression data, the most important programme success indicator, is unavailable for 50% of countries. Of 19 countries with at least one billion dollars budgeted, seven have below 80% ART coverage, leaving 3.5 million (29%) of PLHIV off treatment and vulnerable to illness, death, and transmitting the virus to partners and children.

Summary: With additional funding and improved efficiency, achieving the 95-95-95 target to diagnose 95% of all HIV-positive individuals, provide antiretroviral therapy (ART) for 95% of those diagnosed and achieve viral suppression for 95% of those treated by 2030 is feasible and the humane pathway towards ending the HIV pandemic.

Purpose of this review: Broadly neutralising antibodies (bNAbs) are a promising new therapy for the treatment of HIV infection. However, the effective use of bNAbs is impacted by the presence of preexisting virological resistance and the potential to develop new resistance during treatment. With several bNAb clinical trials underway, sensitive and scalable assays are needed to screen for resistance. This review summarises the data on resistance from published clinical trials using the bNAbs 10-1074 and 3BNC117 and evaluates current approaches for detecting bNAb sensitivity as well as their limitations.

Recent findings: Analyses of samples from clinical trials of 10-1074 and 3BNC117 reveal viral mutations that emerge on therapy which may result in bNAb resistance. These mutations are also found in some potential study participants prior to bNAb exposure. These clinical data are further informed by ex-vivo neutralisation assays which offer an alternative measure of resistance and allow more detailed interrogation of specific viral mutations. However, the limited amount of publicly available data and the need for better understanding of other viral features that may affect bNAb binding mean there is no widely accepted approach to measuring bNAb resistance.

Summary: Resistance to the bNAbs 10-1074 and 3BNC117 may significantly impact clinical outcome following their therapeutic administration. Predicting bNAb resistance may help to lower the risk of treatment failure and therefore a robust methodology to screen for bNAb sensitivity is needed.

Purpose of the review: To discuss main challenges of therapeutic vaccine clinical trials design, implementation and analyses in the HIV cure field.

Recent findings: Therapeutic vaccines are progressively being postulated as T-cell stimulating agents to use in combination HIV cure strategies, with the addition of immunomodulators, latency reversing agents and/or broadly neutralizing antibodies. Although promising strategies are rapidly evolving in preclinical studies using nonhuman primate models, translation into human testing in randomized controlled clinical trials is more challenging and expensive to conduct. Adaptive designs, access to cohorts of early-treated individuals, consensus on how to safely conduct analytical treatment interruptions, use of alternative statistical methods, development of point-of-care/home-based testing technologies and ensuring early engagement of communities where research is being developed are some of the critical aspects to consider to facilitate clinical trial development in the HIV cure field.

Summary: Design and development of HIV therapeutic vaccine clinical trials poses many challenges, from Phase 0/pilot studies to Phase I/II trials in which efficacy of the intervention is being tested and antiretroviral therapy cessation is needed, complexity of cure trials progressively increases. Understanding fundamental issues and careful planning of therapeutic vaccine clinical trials is crucial to minimize design flaws, reduce loss of follow-ups and missing data while ensuring participant's safety and guarantee valid and accurate analyses and thus, better contribute towards an HIV cure.

Purpose of review: While people with HIV (PWH) are living longer due to advances in antiretroviral therapy, recent data have demonstrated an increased risk of cardiovascular disease (CVD) among this population. This increased risk is thought to be due to both traditional (for example, smoking, diabetes) and HIV-specific (for example, inflammation, persistent immune activation) risk factors. This review focuses on the potential for statin therapy to mitigate this increased risk.

Recent findings: Several randomized clinical trials have demonstrated that statins, a class of lipid-lowering medications, are effective as a primary CVD prevention strategy among people without HIV. Among PWH, statins have been shown to lower cholesterol, exert immunomodulatory effects, stabilize coronary atherosclerotic plaque, and even induce plaque regression.

Summary: Prevention of CVD among the aging population of people with controlled, but chronic, HIV is vital. Data exploring primary prevention in this context are thus far limited. The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is ongoing; this trial will inform the field by investigating the effects of pitavastatin calcium as a primary prevention strategy for major adverse cardiovascular events among PWH on antiretroviral therapy (ART) at low-to-moderate traditional CVD risk.

Purpose of review: The quest for HIV-1 cure could take advantage of the study of rare individuals that control viral replication spontaneously (elite controllers) or after an initial course of antiretroviral therapy (posttreatment controllers, PTCs). In this review, we will compare back-to-back the immunological and virological features underlying viral suppression in elite controllers and PTCs, and explore their possible contributions to the HIV-1 cure research.

Recent findings: HIV-1 control in elite controllers shows hallmarks of an effective antiviral response, favored by genetic background and possibly associated to residual immune activation. The immune pressure in elite controllers might select against actively transcribing intact proviruses, allowing the persistence of a small and poorly inducible reservoir. Evidence on PTCs is less abundant but preliminary data suggest that antiviral immune responses may be less pronounced. Therefore, these patients may rely on distinct mechanisms, not completely elucidated to date, suppressing HIV-1 transcription and replication.

Summary: PTCs and elite controllers may control HIV replication using distinct pathways, the elucidation of which may contribute to design future interventional strategies aiming to achieve a functional cure.

Purpose of review: HIV-1 controller individuals represents a model that can be useful for the development of novel vaccines and therapies. Initial studies pointed to the involvement of improved adaptive immunity, however, new emerging evidence suggests the contribution of innate cells to effective antiviral responses in spontaneous controllers. Therefore, understanding the alterations on innate cell subsets might be crucial to develop new effective therapeutic strategies.

Recent findings: Among different innate immune cells, dendritic cell (DC) and natural killer (NK) cell are essential for effective antiviral responses. DC from controllers display improved innate detection of HIV-1 transcripts, higher induction of interferons, higher antigen presenting capacities and increased metabolism and higher capacities to induce polyfunctional CD8+ T-cell responses. Such properties have been mimicked by Toll-like receptor ligands and applied to DC-based immunotherapies in humans and in animal models. NK cells from controllers display higher expression of activating receptors promoting increased antibody-dependent cellular cytotoxicity (ADCC) and natural cytotoxicity activities. Neutralizing antibodies in combination with interleukin-15 superagonist or interferon-α can increase ADCC and cytotoxicity in NK cells from HIV-1 progressors.

Summary: Mimicking DC and NK cell innate profiles in controllers has become a promising strategy to step forward a novel efficient immunotherapy against the HIV-1 infection.