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W2325016498 abstract "Introduction The development of powerful antiretroviral therapies has dramatically altered the outlook for HIV-infected persons. Treatment with combinations of potent antiretroviral drugs (highly active antiretroviral therapy: HAART) can decrease circulating virus levels below assay limits of detection, and prolonged suppression of viral replication results in significant immunologic restoration [1,2]. This, in turn, diminishes the risks of the opportunistic infections that define AIDS. To the extent that AIDS-related morbidity and mortality have fallen recently, newer antiviral therapies have had a measurable impact [3,4] However, the rate of decrease in AIDS-related morbidity and mortality appears to be slowing [5]; consequently, the correct administration of combination therapy is ever more important. Unfortunately, though simpler treatment regimens are now being introduced, many of the present regimens require frequent (thrice daily or more) dosing with many pills on a rigid schedule – often strictly timed in relation to food consumption – in order to ensure that there is always sufficient amounts of drug to block HIV replication. Failure to adhere rigorously to the regimen increases the risk for emergence of resistant viruses. Low plasma drug levels and poor adherence are clear predictors of treatment failure and drug resistance [6,7]. Treatment failure is characterized by increased levels of virus in plasma and an increased risk of immune deterioration, opportunistic infections and death. In the clinic, as many as half of treated patients experience treatment failure after as little as 1 year of therapy [8,9]. Importantly, these regimens are also expensive, with costs for drugs, laboratory monitoring of safety and effectiveness, and physicians’ fees amounting to as much as $15 000 to $20 000 per year or more [10,11]. In short, these complex life-saving treatment regimens are often difficult to adhere to, are very expensive and are associated with a definable risk of treatment failure and the emergence of resistant viruses. Adherence to treatment is a pervasive dilemma in medical care. Adherence to HIV regimens is uniquely problematic because an incomplete course of treatment can be worse than no treatment. It can be harmful and can increase the risk of transmitting resistant virus. We want to examine systematically the idea of withholding treatment under these circumstances. Rationales for withholding antiretroviral therapy Physicians who feel that it is appropriate to withhold combination antiretroviral therapies from non-adherent patients may assert one or more of three arguments. First, it is a waste of scarce resources to prescribe expensive therapies to non-adherent patients. Second, non-adherence, which can lead to drug resistance, threatens public health. Third, the non-adherent patient runs the risk of toxicities and of developing resistant virus. Each of these points is complicated by the difficulty of predicting non-adherence. In our opinion, the first is not supportable; the second rationale is, on its own, not persuasive, and the third rationale is justifiable and should be applied. Cost, efficacy, and the allocation of scarce resources Some have proposed that physicians have not only a right but also a duty to deny antiretroviral therapies to non-adherent patients because treatment would be futile [12]. The problem is in defining futility [13–16]. The concept of futility can sometimes serve to obscure other judgements: that a particular treatment will cost more than the expected benefit, that it will cause unnecessary suffering, or that the patient is so near death that it is time to stop treatment. To be clear, ‘futility’ means ‘of no value’ or ‘of no physiological efficacy.’ Even ‘unsuccessful’ regimens that are incompletely suppressive provide clinical benefit [17]. Therefore, to invoke futility as a justification for withholding HAART is to expose the emptiness of th e futility concept in this case. We propose to consider the problem of the potentially non-adherent patient in terms of rationing a scarce and expensive resource, rather than in terms of futility. Futility and rationing are not the same [18]. Futility implies that an intervention has no efficacy whether it is in short supply or abundance. Rationing means denying scarce therapies to some people who could benefit from them. Because it involves judgements about who deserves treatment, rationing remains a highly contentious issue. One of the least controversial bases for rationing is the relative prospect of success – that is, if there is not enough treatment to go around, it should be given first to those who can benefit the most rather than to those who will benefit only marginally [19]. Failure to take medications properly could put the non-adherent patient with AIDS into the category of only marginally benefiting from treatment. Since the prospect of success involves objective clinical judgements, it is contended that physicians can take the lead in making such determinations. Arguably, society has allowed them to do so, for example in allocating organs for transplantation, where physicians may withhold organ transplants from individuals with severe drug or alcohol addiction because of concerns about future risk behavior [20–23]. Even so, denial of a treatment based on marginal benefit as a result of demonstrated non-adherence, as in the case of renal dialysis, have met with inconsistent rulings in the courts [24]. The issue is even more complicated when adherence and hence ‘benefit’ cannot be predicted. If eligibility to receive potentially life-saving therapies is dependent upon unreliable predictors of adherence (see below), it is difficult to justify rationing based upon application of these predictors. Rationing necessarily entails making judgements not only about who is more likely to benefit but also, since the magnitude and nature of the benefit may differ from one to another, about who is more deserving. When judgements about futility must be made, physicians can claim some special expertise about the physiological efficacy of treatment. By contrast, judgements about who is more deserving of treatment are fundamentally moral or public policy judgements and, as such, should not be made by individual physicians or even the profession of medicine [25,26]. We are not persuaded that scarcity or cost concerns justify individual physicians making decisions to withhold antiretroviral therapies. Public health risks Poor adherence to antiretroviral therapy results in incomplete suppression of viral replication, which facilitates emergence of resistant viruses [27]. Resistant viruses may be passed on to sex partners [28], to others who share needles for injection or perhaps even to health-care workers who are accidentally exposed while providing care. In every society, the protection of public health may, at times, clash with individual rights. As the danger to the public grows, society's willingness to defer to individual choice diminishes. If the danger is extreme, the state is prepared to be coercive. The state has frequently limited individual freedom to protect the public from spread of infectious disease. As examples, the state inspects and regulates the sale and preparation of food, requires immunization of children (with religious exemptions) as a condition of school attendance and requires directly observed therapy and limits freedom of travel (including involuntary commitment) [29] for some persons with multidrug-resistant Mycobacterium tuberculosis infection. Quarantine for communicable disease is a drastic but accepted limitation on individual freedom. Although transmission of multidrug-resistant HIV has been documented, the magnitude and the frequency of this risk is uncertain. At least one study has demonstrated that even in a highly vulnerable group (injecting drug users) no cases of drug-resistant HIV were found [30]. Likewise, two other studies in persons recently infected with HIV found very low frequencies of high-level drug resistance [31–33]. However, a recent Canadian study found that nearly 10% of recently infected persons harbored multidrug-resistant viruses [34]. While traditional medical ethics dictate that the physician's first duty is to the patient, public policy recognizes that physicians also have a duty to the public and to identifiable third parties at risk in particular to protect them from harm, including the harm from transmissible diseases. Is the risk to the public health of sufficient magnitude to justify withholding effective therapies from persons predicted to be non-adherent to treatment for HIV? Although there is precedent for restricting individual choice when public health is at risk, the issues raised in the examples above can be distinguished from the risks of transmission of multidrug-resistant HIV. Keeping the food supply safe from transmissible diseases is of broad benefit to all who consume food. Widespread immunization protects not only the immunized but also society as a whole through induction of ‘herd immunity'. Persons infected with multidrug-resistant M. tuberculosis can place at risk for untreatable infection persons who knowingly or unknowingly share housing or shelter with them. Other epidemic infectious diseases, such as cholera, typhoid fever and plague, for which patients have been quarantined, have placed members of society unknowingly at risk through water-borne, food-borne, air-borne or vector-borne transmission. In contrast, HIV is spread only through intimate sexual contact or through blood exposure. Therefore, it can be argued that individuals can limit their risk for infection through cautious behavior. Nevertheless, the fact that members of the public can take measures to protect themselves does not necessarily relieve physicians of their duty to protect the public from harm. In our view, there are too many uncertainties to support withholding therapies to protect the public health. First, as outlined below, our ability to predict non-adherence is suspect. Consequently, although application of this policy might protect the non-HIV-positive public by limiting transmission of multidrug-resistant virus, the health of those who are already HIV positive would be jeopardized since some who would adhere to treatment but are identified as potentially non-adherent will not receive life-saving therapies. Second, even in the non-adherent patient, it is not certain that drug resistance will develop. As many as 25% of persons who have ‘failed’ HAART may harbor virus that is fully sensitive to the treatment regimen [35]. Third, even partial adherence to treatment may, for a time, decrease levels of HIV and may, for a time, decrease the risk of HIV transmission. In order for there to be a recognizable threat to the public health, four contingencies would have to occur: the patient would have to be non-adherent; the non-adherence would have to cause drug resistance; the patient and partner would have to engage in high-risk behavior; and the resistant virus would have to be transmitted. Estimation of the cumulative probability that each of these events will occur in any individual instance is so uncertain that the risk to the public health, in our opinion, is too unpredictable to justify withholding treatment from any individual for public health considerations. As the frequency with which drug-resistant viruses are transmitted may change with time, an increasing risk to the public health may require a reanalysis of this position. Risks to the patient Non-adherent patients place themselves at risk. Non-adherence limits the likelihood of treatment benefit; it also places persons at risk of the twin dangers of toxicity and resistance to future treatment. Toxicity HIV therapies have toxicities that necessitate periodic monitoring. Yet patients who do not adhere to the medication regimen are apt not to adhere to toxicity-screening schedules. While most treatment toxicities are not immediately life threatening, some, such as liver toxicities (for which periodic monitoring is recommended) or hypersensitivity reactions (wherein intermittent treatment poses greatest risk), may prove fatal [36–38]. Among patients with advanced HIV infection, treatment regimens that include as many as ten different medications or more are not unusual. As the number of prescribed medications increases, the risk of drug toxicities increases. Importantly, currently available protease inhibitors and non-nucleoside reverse transcriptase inhibitors have the potential for life-threatening adverse interactions with other medications. Resistance Effective antiretroviral treatment requires strict commitment to the regimen. Incomplete adherence introduces selection pressure, which favors the emergence of resistant viruses, rendering these treatments ineffective for the remainder of the patient's life. The most active and durable therapies available at present are regimens that contain at least one protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Unfortunately, viruses that emerge resistant to one of these classes are in almost all instances relatively or completely resistant to other currently available antivirals drugs of that same class. Therefore, early treatment failures may have profound and possibly lifelong implications. Clinical experience Experience in the clinic, where treatment failure is frequent, vividly demonstrates the difficulties of adherence and its consequences in clinical practice. Cross-sectional retrospective studies have found that as many as half of patients who have been treated with combination therapies including protease inhibitors have ‘failed’[8,9]. Although incomplete adherence is only one factor contributing to failure, the outcome for these patients is of concern. Though many who ‘fail’ remain well in the short term, viruses obtained from these patients often demonstrate high levels of resistance to all currently available antiretroviral therapies; the significance of this resistance is confirmed by the frequent inability of revised therapies to decrease viral replication when applied in salvage regimens [39–41]. Preventing emergence of multidrug-resistant virus therefore is clearly in the patient's interest, and prescribing these drugs to patients who will predictably fail to take them properly is not appropriate. In our view, this rationale justifies withholding antiretroviral therapies from patients who will be non-adherent. It may seem inconsistent to regard the danger of resistance as a rationale for withholding therapy for the patient's own good but not for the good of the public health, but we think not. A physician can predict that a non-adherent patient will experience treatment failure, including the likely development of resistance. Making a prediction about the consequences to the public of a single patient's non-adherence is much more speculative and is greatly diluted by the chain of possibilities discussed above. The decision to withhold or defer therapy from an individual in his/her own interest must take into account the stage of HIV disease and the confidence with which one can predict poor adherence. Therefore in the patient with advanced disease at imminent risk of life-threatening complications, antiretroviral therapies should be offered. With less-advanced disease, the rationale for deferring therapy for the non-adherent patient becomes more compelling. The question, however, is whether it is possible to predict non-adherence. The problem of predicting adherence Studies of adherence have failed to demonstrate a relationship between physicians’ estimates of adherence and actual adherence to treatment. Moreover, there seem to be no patient characteristics that predict non-adherence. Generally, adherence to medical treatment is poor, with only two thirds of patients taking enough medicines to provide therapeutic effect [42]. Adherence is particularly poor in patients who are asymptomatic, who have chronic illness or for whom the therapy is toxic, complicated or has no immediate discernible effect [43,44]. Combination antiretroviral therapies are therefore likely to present adherence problems and this has been demonstrated [45,46]. In one report, 79% of patients missed one or more of doses of their protease inhibitor medication: 16% missed a dose in the last day, 26% missed one or more doses in the last 3 days and 22% took a ‘drug holiday’ for one or more full days [47]. Among patients on protease inhibitor therapy who changed their regimens, 38% were revised for non-adherence [48]. Doctors are unable to predict adherence to therapy in general, usually overestimating it [49,50], and are even less able to predict non-adherence, with accuracies as low as 10%[51]. There is little reason to suppose that doctors’ predictions are better with respect to antiretroviral therapies. Indeed, clinicians’ estimates of adherence to combination therapy were nearly 20% too high. In studies of HIV therapy, demographic characteristics do not dependably predict adherence [45,47,52]. Race and ethnicity have predicted adherence in several studies [53,54] but were found irrelevant elsewhere [45]. Even if the association were consistent, it would be difficult, if not unconscionable, to devise a strategy to withhold therapy using race or ethnicity as a predictor of adherence. Even the homeless, whose lives tend to be disorganized and who are less likely to be offered antiretroviral therapy [55], can demonstrate acceptable levels of adherence [56,57]. Not any of the factors — perceived quality of life, stage of disease [58,59] and knowledge about the importance of adherence [47] — determines actual adherence by patients. In a recent study of non-adherent HIV-positive patients receiving combination therapy, more than half had a history of substance abuse [60]. Similarly, poor viral suppression was associated with intravenous drug use [61]. Patients with these dependencies should receive individualized evaluation and intervention before antiretroviral therapy is initiated to improve the chances for adherence even though the effectiveness of these approaches remain unproven. The best predictor of adherence is the initial level of adherence [62]. Recently, Valdez et al. found that the number of missed clinic visits prior to prescription of combination antiretrovirals independently predicted treatment failure [8]. The percentage of appointments kept is also a good indicator of adherence [63] and virologic success [61]. Until the development of simpler treatment regimens, adherence remains the weak link in effective treatment for HIV infection. At best, even a non-judgemental physician cannot predict adherence. At worst, concerns about adherence may unjustly stigmatize patients who are considered to be part of a group with undesirable social or behavioral characteristics. Finally, at least one more serious problem with adherence remains. We do not know exactly how incomplete adherence must be to result in the development of resistance; the ability of any individual to ‘tolerate’ incomplete adherence without loss of viral suppression may vary substantially according to individual differences in drug absorption distribution, and metabolism; it is also likely to vary according to the treatment regimen. Therefore, non-adherence in itself is not an all or nothing proposition. Policy implications Faced with the difficulties of predicting non-adherence, various policy recommendations have emerged. None is categorical but there is a continuum of positions ranging from bias towards prescribing to the recognition that there may be instances where it is justifiable, even obligatory, to withhold HIV treatment. Bangsberg and colleagues note a preliminary duty to stabilize patients with respect to housing, provision of health care and difficulties with chemical dependency and mental illness. After this, if patients remain unstable yet competent and there are indications for treatment, there is an obligation to prescribe [64]. Lerner et al. propose a model of dialogue and negotiation and suggest that, if in doubt, the bias should be to prescribe, with the clinician retaining ‘veto power’ if the patient will not create a plan or treatment that is medically appropriate [65]. A recent US National Institutes of Health (NIH) panel concluded that, although the likelihood of adherence to the regimen is a principal factor to be considered in deciding to begin therapy, ‘. . . no individual patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristics judged by some to lend itself to noncompliance’[66]. The International AIDS Society US Panel says ‘commitment to therapy and willingness to adhere to a complex regimen’ determines ‘the strength of a recommendation for initiating therapy’[67]. Finally, Bayer has been quoted to say that not only is it not unethical to refuse to prescribe in the short run because of the long-term inability of the patient to comply, but ‘in fact, the reverse may be the unethical thing to do. To say otherwise, is to say that patients have the right to harm themselves with new medication’[68]. Elsewhere, Bayer and Stryker propose that a situation could arise where ‘clear and compelling’ evidence demonstrates that a patient could not or would not be adherent. In such a case, failing to withhold therapy would be an abrogation of professional responsibility [12]. In our view, giving all infected persons access to antiretroviral therapies in the hope that most will prove to be adherent, or that newer non-cross-resistant therapies will be developed in time to provide salvage for persons who fail current regimens, may under-rate the dangers of resistance both to the patient and possibly to others. By the same token, we do not believe that an expectation of non-adherence justifies withholding HAART. As noted above, physicians’ ability to predict non-adherence is poor. Moreover, with time, with better understanding and with other life changes, a patient's chances for better adherence may improve. We therefore advocate a policy of withholding antiretrovirals from potentially non-adherent patients while taking concurrent measures to help the patient to achieve sufficient understanding and social support to maximize the likelihood of successful antiviral treatment. We recognize that, in some instances, delaying therapy may carry significant risks [69]. Persons with very advanced disease may be at substantial risk for life-threatening infections. Even partially effective therapies may provide some benefit to these persons and these should be offered. Nonetheless, antiviral treatment of HIV infection is not a medical emergency. We support delaying therapy for weeks or even months for nearly all HIV-infected patients. Rather than immediately beginning therapy, we believe physicians should commence what one author has called ‘an informed negotiation’[70], devoting several visits to discussion and education about the need for adherence and to addressing modifiable barriers to adherence. In this model, the decision to start therapy is rolling and incremental. Such decisions are best made in the context of a consistent longitudinal relationship with a single provider. At some point, all efforts to maximize adherence may appear to have been exhausted and the patient may still seem to be a poor risk. In this setting, the imminent risk of opportunistic complications must be balanced against the risks and consequences of treatment failure, and this calculus applied to the decision to recommend treatment. As has been suggested earlier [71], persons with advanced disease at short-term risk for opportunistic infections should be offered therapy in virtually all instances. Now the task is to improve the prediction of adherence and to enhance adherence both in patients accepted for therapy and in those initially deferred. In the meantime, physicians must work with patients until both agree that it is time to begin antiretroviral therapy. Responsible decisions will still involve judgement calls. In the context of stable physician/patient relationships, mutual trust and a willingness to work together toward maximizing the chance for adherence, such judgement calls are acceptable, particularly if decisions and the reasons for them are openly shared. We base our conclusions and recommendations on the observation that, historically, the relationship between medical care providers and HIV-infected patients has been largely collaborative. The AIDS community has been exceptionally well educated, active, organized and involved. Under these circumstances, the limited paternalism we advocate is a minimal risk. The epidemic now reaches populations who struggle with poverty, social dislocation, and drug use and who lack political power [72]. As these traditionally disenfranchised groups come to require a larger proportional share of HIV care, the chance for misunderstanding, misinterpretation and attenuation of the heretofore-strong patient–physician alliance is real. We must take care that concerns about adherence do not become excuses for abandonment. Acknowledgements The authors would like to thank Drs Robert Schooley, David Cooper, Hernan Valdez and Renslow Sherer for critical comments and suggestions, and Janet Morrison for assistance preparing the manuscript." @default.
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W2325016498 title "Should physicians withhold highly active antiretroviral therapies from HIV-AIDS patients who are thought to be poorly adherent to treatment?" @default.
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