-
Cancer Treatment Reviews Nov 2021Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains... (Review)
Review
Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
Topics: Humans; Multiple Myeloma
PubMed: 34597912
DOI: 10.1016/j.ctrv.2021.102284 -
Frontiers in Immunology 2022Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4 T cells can induce HBV... (Review)
Review
Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4 T cells can induce HBV specific B cells and CD8 T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8 T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may "wake up" immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the "dominant population" for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.
Topics: Humans; Hepatitis B Surface Antigens; CD8-Positive T-Lymphocytes; Hepatitis B; Hepatitis B virus; Adaptive Immunity; Antigens, Viral
PubMed: 36466821
DOI: 10.3389/fimmu.2022.1075916 -
Cellular and Molecular Life Sciences :... Jul 2022Although combination antiretroviral therapy (ART) has reduced mortality and improved lifespan for people living with HIV, it does not provide a cure. Patients must be on... (Review)
Review
Although combination antiretroviral therapy (ART) has reduced mortality and improved lifespan for people living with HIV, it does not provide a cure. Patients must be on ART for the rest of their lives and contend with side effects, unsustainable costs, and the development of drug resistance. A cure for HIV is, therefore, warranted to avoid the limitations of the current therapy and restore full health. However, this cure is difficult to find due to the persistence of latently infected HIV cellular reservoirs during suppressive ART. Approaches to HIV cure being investigated include boosting the host immune system, genetic approaches to disable co-receptors and the viral genome, purging cells harboring latent HIV with latency-reversing latency agents (LRAs) (shock and kill), intensifying ART as a cure, preventing replication of latent proviruses (block and lock) and boosting T cell turnover to reduce HIV-1 reservoirs (rinse and replace). Since most people living with HIV are in Africa, methods being developed for a cure must be amenable to clinical trials and deployment on the continent. This review discusses the current approaches to HIV cure and comments on their appropriateness for Africa.
Topics: Antiretroviral Therapy, Highly Active; HIV Infections; HIV-1; Humans; Virus Activation; Virus Latency
PubMed: 35794316
DOI: 10.1007/s00018-022-04421-z -
Cornea Apr 2023The purpose of this study was to evaluate the safety and efficacy of lotilaner ophthalmic solution, 0.25%, compared with vehicle for the treatment of Demodex blepharitis. (Randomized Controlled Trial)
Randomized Controlled Trial
Lotilaner Ophthalmic Solution, 0.25%, for the Treatment of Demodex Blepharitis: Results of a Prospective, Randomized, Vehicle-Controlled, Double-Masked, Pivotal Trial (Saturn-1).
PURPOSE
The purpose of this study was to evaluate the safety and efficacy of lotilaner ophthalmic solution, 0.25%, compared with vehicle for the treatment of Demodex blepharitis.
METHODS
In this prospective, randomized, controlled, double-masked, phase 2b/3 clinical trial, 421 patients with Demodex blepharitis were randomly assigned in a 1:1 ratio to receive either lotilaner ophthalmic solution, 0.25% (study group), or vehicle without lotilaner (control group) bilaterally, twice daily for 43 days. Patients were evaluated at days 8, 15, 22, and 43. Outcome measures were complete collarette cure (collarette grade 0), clinically meaningful collarette cure (grade 0 or 1), mite eradication (0 mites/lash), erythema cure (grade 0), composite cure (grade 0 for collarettes/erythema), and drop comfort. Adverse events were also evaluated.
RESULTS
At day 43, the study group achieved a statistically significantly higher proportion of patients with clinically meaningful collarette cure (81.3% vs. 23.0%; P < 0.0001), complete collarette cure (44.0% vs. 7.4%; P < 0.0001), mite eradication (67.9% vs. 17.6%; P < 0.0001), erythema cure (19.1% vs. 6.9%; P = 0.0001), and composite cure (13.9% vs. 1.0%; P < 0.0001) than the control group. Nearly 92.0% of patients rated the study drop as neutral to very comfortable. All ocular adverse events in the study group were mild, with the most common being instillation site pain.
CONCLUSIONS
Twice-daily treatment with a novel lotilaner ophthalmic solution, 0.25% for 43 days, is safe and effective for the treatment of Demodex blepharitis compared with the vehicle control.
Topics: Humans; Ophthalmic Solutions; Prospective Studies; Double-Blind Method; Blepharitis
PubMed: 35965392
DOI: 10.1097/ICO.0000000000003097 -
Current Opinion in HIV and AIDS Jan 2023Recent years have seen major investments into HIV cure research, seeking a permanent cure or remission. The purpose of this review is to consider how this important... (Review)
Review
PURPOSE OF REVIEW
Recent years have seen major investments into HIV cure research, seeking a permanent cure or remission. The purpose of this review is to consider how this important research agenda could be broadened to include issues of acceptability and appropriateness for different populations.
RECENT FINDINGS
We discuss how the definitions of cure such as functional cure (remission) or complete cure (viral elimination) could be interpreted differently by various populations. We also discuss the different methods of cure and the importance of including Africa in cure research to ensure that emerging remedies could be trialled and utilized on the continent that bears the brunt of the AIDS pandemic.
SUMMARY
We propose that the social science research of HIV cure acceptability should be done concurrently with the basic and clinical sciences, to ensure that cure methods consider stakeholder preferences.
Topics: Humans; HIV Infections; Africa; Investments; Pandemics; Social Sciences
PubMed: 36503877
DOI: 10.1097/COH.0000000000000771 -
Viruses Mar 2019There is broad scientific and societal consensus that finding a cure for HIV infection must be pursued. The major barrier to achieving a cure for HIV/AIDS is the... (Review)
Review
There is broad scientific and societal consensus that finding a cure for HIV infection must be pursued. The major barrier to achieving a cure for HIV/AIDS is the capacity of the HIV virus to avoid both immune surveillance and current antiretroviral therapy (ART) by rapidly establishing latently infected cell populations, termed latent reservoirs. Here, we provide an overview of the rapidly evolving field of HIV cure/remission research, highlighting recent progress and ongoing challenges in the understanding of HIV reservoirs, the role of HIV transcription in latency and immune evasion. We review the major approaches towards a cure that are currently being explored and further argue that small molecules that inhibit HIV transcription, and therefore uncouple HIV gene expression from signals sent by the host immune response, might be a particularly promising approach to attain a cure or remission. We emphasize that a better understanding of the game of "cat and mouse" between the host immune system and the HIV virus is a crucial knowledge gap to be filled in both cure and vaccine research.
Topics: Animals; Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Disease Models, Animal; Disease Reservoirs; HIV Infections; HIV-1; Humans; Immune Evasion; Immunotherapy; Transcription, Genetic; Virus Latency
PubMed: 30889861
DOI: 10.3390/v11030269 -
Indian Journal of Sexually Transmitted... 2019HIV is a chronic well manageable disease. Highly active antiretroviral therapy improves the quality of life of people living with HIV, but the treatment has to be... (Review)
Review
HIV is a chronic well manageable disease. Highly active antiretroviral therapy improves the quality of life of people living with HIV, but the treatment has to be continued lifelong, as the total cure has not been established. Cost of treatment, drug toxicities, interaction with other drugs and persistence of inflammation and acceleration of the aging process, all put together, warrant an urgent need for a total cure. Even though one case had been proved to be cured, still a practical cure is far beyond the reach. Numerous approaches and strategies had been put forth to achieve a cure; still they are to be proved with human studies. This article reviews the major approaches, recent advances in the venture of HIV cure, and the safety concerns involved.
PubMed: 31143852
DOI: 10.4103/ijstd.IJSTD_112_15 -
BMC Medical Research Methodology Mar 2020The mortality risk among cancer patients measured from the time of diagnosis is often elevated in comparison to the general population. However, for some cancer types,... (Review)
Review
BACKGROUND
The mortality risk among cancer patients measured from the time of diagnosis is often elevated in comparison to the general population. However, for some cancer types, the patient mortality risk will over time reach the same level as the general population mortality risk. The time point at which the mortality risk reaches the same level as the general population is called the cure point and is of great interest to patients, clinicians, and health care planners. In previous studies, estimation of the cure point has been handled in an ad hoc fashion, often without considerations about margins of clinical relevance.
METHODS
We review existing methods for estimating the cure point and discuss new clinically relevant measures for quantifying the mortality difference between cancer patients and the general population, which can be used for cure point estimation. The performance of the methods is assessed in a simulation study and the methods are illustrated on survival data from Danish colon cancer patients.
RESULTS
The simulations revealed that the bias of the estimated cure point depends on the measure chosen for quantifying the excess mortality, the chosen margin of clinical relevance, and the applied estimation procedure. These choices are interdependent as the choice of mortality measure depends both on the ability to define a margin of clinical relevance and the ability to accurately compute the mortality measure. The analysis of cancer survival data demonstrates the importance of considering the confidence interval of the estimated cure point, as these may be wide in some scenarios limiting the applicability of the estimated cure point.
CONCLUSIONS
Although cure points are appealing in a clinical context and has widespread applicability, estimation remains a difficult task. The estimation relies on a number of choices, each associated with pitfalls that the practitioner should be aware of.
Topics: Colonic Neoplasms; Computer Simulation; Humans; Risk Factors
PubMed: 32216765
DOI: 10.1186/s12874-020-00946-8 -
Seminars in Immunology Jan 2021Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful - for those who can access and afford it... (Review)
Review
Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful - for those who can access and afford it - yet HIV infection persists indefinitely in a reservoir of cells, despite effective ART and despite host antiviral immune responses. An HIV cure is therefore the next aspirational goal and challenge, though approaches differ in their objectives - with 'functional cures' aiming for durable viral control in the absence of ART, and 'sterilizing cures' aiming for the more difficult to realize objective of complete viral eradication. Mechanisms of HIV persistence, including viral latency, anatomical sequestration, suboptimal immune functioning, reservoir replenishment, target cell-intrinsic immune resistance, and, potentially, target cell distraction of immune effectors, likely need to be overcome in order to achieve a cure. A small fraction of people living with HIV (PLWH) naturally control infection via immune-mediated mechanisms, however, providing both sound rationale and optimism that an immunological approach to cure is possible. Herein we review up to date knowledge and emerging evidence on: the mechanisms contributing to HIV persistence, as well as potential strategies to overcome these barriers; promising immunological approaches to achieve viral control and elimination of reservoir-harboring cells, including harnessing adaptive immune responses to HIV and engineered therapies, as well as enhancers of their functions and of complementary innate immune functioning; and combination strategies that are most likely to succeed. Ultimately, a cure must be safe, effective, durable, and, eventually, scalable in order to be widely acceptable and available.
Topics: Antiviral Agents; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Virus Latency
PubMed: 32981836
DOI: 10.1016/j.smim.2020.101412 -
Computer Methods and Programs in... Nov 2022Within medical research, cure models are useful for analyzing time-to-event data in the scenario where a proportion of the analyzed individuals are expected to never...
BACKGROUND AND OBJECTIVE
Within medical research, cure models are useful for analyzing time-to-event data in the scenario where a proportion of the analyzed individuals are expected to never experience the event of interest. Cure models are also useful for modelling the relative survival in scenarios where a proportion of the individuals are expected to eventually experience a mortality rate similar to that of the general population. Here we present two R packages, cuRe and rstpm2, that provide researchers with several tools for performing statistical inference using parametric cure models.
METHODS
Cure models are commonly used to estimate 1) the proportion of individuals that are cured and 2) the event-time distribution of individuals who are not cured. This can be done using simple parametric distributions for the event-time distribution of the uncured, but our implementations also enable fitting of more flexible spline-based cure models. The parametric framework of both packages ensures that cure models for the relative survival can easily be used.
RESULTS
The cuRe package contains two main functions for estimating parametric mixture cure models; one based on simple parametric distributions (e.g. Weibull or exponential) and one utilizing a spline-based formulation of the cure model. The rstpm2 package enables estimation of spline-based latent cure models, i.e., cure models with no explicit parameters modelling the proportion of cured individuals.
CONCLUSIONS
Through the R-packages cuRe and rstpm2, a wide range of different parametric cure models can be fitted. The cuRe package also contains a number of useful post-estimation procedures for computing the time to statistical cure and conditional probability of cure, which may spread the use of cure models in medical research.
Topics: Humans; Survival Analysis; Models, Statistical
PubMed: 36126436
DOI: 10.1016/j.cmpb.2022.107125