Abstract:The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multi-disciplinary approach, critical social, behavioral, ethical, and economic issues permeatin… Show more
“…It should be noted that the lymphatic system has been an area of interest for the delivery of anticancer nanomedicines in recent years [126, 130, 131] and may be worthy of further specific development in the area of antiretroviral therapy, especially considering the role of the lymphatics in HIV pathogenesis [132], the presence of viral reservoirs within lymph nodes [133], and their identification as a key target for eradication strategies [134, 135]. Importantly, subcutaneous delivery (rather than intramuscular delivery) has been at the forefront of gaining access to the lymphatics in cancer and was recently extensively reviewed [136].…”
Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning
Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.
“…It should be noted that the lymphatic system has been an area of interest for the delivery of anticancer nanomedicines in recent years [126, 130, 131] and may be worthy of further specific development in the area of antiretroviral therapy, especially considering the role of the lymphatics in HIV pathogenesis [132], the presence of viral reservoirs within lymph nodes [133], and their identification as a key target for eradication strategies [134, 135]. Importantly, subcutaneous delivery (rather than intramuscular delivery) has been at the forefront of gaining access to the lymphatics in cancer and was recently extensively reviewed [136].…”
Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning
Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.
“…This is consistent with previous literature When asked to explain their sense of willingness to take risk in HIV cure research, few respondents mentioned personal benefit. The reasons they gave strongly tended toward altruistic motivations and feelings of community and identity. showing that people's HIV‐positive identities influence their willingness to take risk for participating in HIV cure trials 20 . In fact, when asked to explain their sense of willingness to take risk, few of the respondents in our study mentioned personal benefit, as many felt their lives were currently good.…”
Despite doing well on antiretroviral therapy, many people living with HIV have expressed a willingness to accept substantial risks for an HIV cure. To date, few studies have assessed the specific quantitative maximal risk that future participants might take; probed whether, according to future participants, the risk can be offset by the benefits; and examined whether taking substantial risk is a reasonable decision. In this qualitative study, we interviewed 22 people living with HIV and used standard gamble methodology to assess the maximum chance of death a person would risk for an HIV cure. We probed participants’ reasoning behind their risk‐taking responses. Conventional inductive content analysis was used to categorize key themes regarding decision‐making. We found that some people would be willing to risk even death for an HIV cure, and some of their reasons were plausible and went far beyond the health‐related utility of an HIV cure. We contend that people's expressed willingness to take substantial risk for an HIV cure should not be dismissed out of hand.
“…An important role of social science is to inform real‐world decision making . The cross‐sectional ANRS‐APSEC study, nested inside the IAS “Towards an HIV cure,” enabled us to explore, for the first time, the following three questions: (1) What trial design attributes most influence PLWH and physician trial acceptability?…”
Introduction
Despite the advent of HIV cure‐related clinical trials (HCRCT) for people living with HIV (PLWH), the risks and uncertainty involved raise ethical issues. Although research has provided insights into the levers and barriers to PLWH and physicians' participation in these trials, no information exists about stakeholders' preferences for HCRCT attributes, about the different ways PLWH and physicians value future HCRCT, or about how personal characteristics affect these preferences. The results from the present study will inform researchers' decisions about the most suitable HCRCT strategies to implement, and help them ensure ethical recruitment and well‐designed informed consent.
Methods
Between October 2016 and March 2017, a discrete choice experiment was conducted among 195 virally controlled PLWH and 160 physicians from 24 French HIV centres. Profiles within each group, based on individual characteristics, were obtained using hierarchical clustering. Trade‐offs between five HCRCT attributes (trial duration, consultation frequency, moderate (digestive disorders, flu‐type syndrome, fatigue) and severe (allergy, infections, risk of cancer) side effects (SE), outcomes) and utilities associated with four HCRCT candidates (latency reactivation, immunotherapy, gene therapy and a combination of latency reactivation and immunotherapy), were estimated using a mixed logit model.
Results
Apart from severe SE – the most decisive attribute in both groups – PLWH and physicians made different trade‐offs between HCRCT attributes, the latter being more concerned about outcomes, the former about the burden of participation (consultation frequency and moderate SE). These different trades‐offs resulted in differences in preferences regarding the four candidate HCRCT. PLWH significantly preferred immunotherapy, whereas physicians preferred immunotherapy and combined therapy. Despite the heterogeneity of characteristics within the PLWH and physician profiles, results show some homogeneity in trade‐offs and utilities regarding HCRCT.
Conclusions
Severe SE, not outcomes, was the most decisive attribute determining future HCRCT participation. Particular attention should be paid to providing clear information, in particular on severe SE, to potential participants. Immunotherapy would appear to be the best HCRCT candidate for both PLWH and physicians. However, if the risk of cancer could be avoided, gene therapy would become the preferred strategy for the latter and the second choice for the former.
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