FormalPara Key Summary Points

Why carry out this study?

In HIV, therapy has a notable impact on quality of life (QoL), and so regulators recommend the use of patient-reported outcomes (PROs). PROs are increasingly incorporated in clinical trials, but their use in clinical practice is very limited.

The PROMETEO project aimed to reach expert consensus on how to incorporate PROs in the care of people with HIV.

What was learned from the study?

Despite the wealth of information on the benefits of PROs in HIV, the recommendations of an expert panel did not reach consensus at the broad community level.

A deeply rooted aversion to subjectivity and other beliefs may act as barriers.

Much more is needed to convince clinicians to use PROs in their daily practice of people with HIV.

Digital Features

This article is published with digital features, including an infographic, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.20348400.

Introduction

The efficacy and persistence of antiretroviral therapy (ART) for HIV infection have transformed the life expectancy of people living with HIV (PLHIV). Today, after years of progressive improvement, life expectancy is similar to that of the general population. One of the consequences of this evolution is that the diagnostic-therapeutic target published by the World Health Organization (WHO) for the year 2020 was 90%–90%–90% (i.e., 90% of people diagnosed, on treatment, and with viral suppression) [1]. A fourth 90% was added in 2016, relating to health-related quality of life (HRQoL) [2], which will allow that, in addition to sustained viral suppression, PLHIV will also enjoy healthy aging [3].

Patient-reported outcomes (PROs) assess symptoms, health behaviors, and life circumstances associated with HIV and comorbidities resulting from the disease itself and its treatment. PROs focus primarily on specific aspects of health and treatment that can only be elicited through specific questions, such as psychological concepts or non-specific symptoms that are not obvious to the observer (anxiety, fatigue, etc.), and reveal their frequency and severity, as well as their impact on patients’ quality of life [4,5,6,7,8,9]. In addition, PROs also allow the assessment of other important aspects, such as adherence to ART, possible risky sexual behaviors, stigmatization, and depression [10]. Moreover, their use improves doctor–patient communication on more complex issues, such as mental and sexual health [11].

The measurement of PROs is usually performed with PROMs (patient-reported outcomes measures), namely questionnaires, either unidimensional or multidimensional, which can be generic or specifically validated for a particular disease. These questionnaires provide essential data for patient evaluation and follow-up, clinical decision-making, assessment, coping with the disease, and evaluation of therapeutic efficacy and quality of care provided. PROMs allow exploration of the physical, social, mental, and emotional domains of patients, and their application in clinical practice can increase both the commitment to self-care [12] and satisfaction with the healthcare received [13]. Nevertheless, a fundamental premise of the usefulness of these questionnaires is that they must be validated and adapted to the geographical and cultural context as well as to the language in which they are applied [14].

In the case of HIV, it is unquestionable that ART and its toxicity have a notable impact on the HRQoL of PLHIV. Both the EMA (European Medicines Agency) and the FDA (US Food and Drug Administration) have recommended the use of PROMs for the evaluation and optimization of new treatments, given their relationship with therapeutic efficacy and their predictive value on the use of new treatments [15] and health services [16]. PROMs can play a decisive role in the choice of ART regimens since, given equal levels of efficacy and safety, a better assessment of the level of satisfaction, compliance, and comfort with treatment can help determine the most appropriate regimen [17].

On the other hand, PROMs help explain certain discrepancies between the results of clinical trials and those obtained in real life [17]. Although PROMs have been incorporated more frequently in ART efficacy studies in recent years [18,19,20,21,22], their incorporation into clinical practice is proven to be laborious, as a result of, among other reasons, the reluctance of some specialists to use them [23,24,25].

A review of systematic reviews of PROMs for measuring HRQoL in PLHIV showed that the questionnaires with the best properties were the MOS-HIV, the WHOQOL-HIV BREF, and the PROQOL-HIV [26]. There are validations in Spanish of both the MOS-HIV [27] and the WHOQOL-HIV BREF [14].

The incorporation of PROs and PROMs into routine clinical practice places PLHIV at the epicenter of therapeutic decisions, as it not only allows the identification of patient problems and concerns but also facilitates more efficient and personalized healthcare [3, 17]. Therefore, it is essential to conduct studies to define, validate, and identify which PROs and PROMs should be used by professionals caring for PLHIV.

In this sense, the objective of the PROMETEO project is to reach expert consensus on the use of the most appropriate PROs and PROMs in PLHIV in Spain.

Methods

Study Design

The usual evidence-based consensus methodology was used, including nominal group meetings, systematic literature review, and Delphi survey [28]. It was conducted in full compliance with the principles established in the Declaration of Helsinki, concerning medical research on human subjects, in its latest version, and accordance with the applicable regulations on Good Clinical Practice. After consultation with the Ethics Committee of Comunidad de Madrid, a review and approval was deemed unnecessary given the nature of data collected, namely the absence of health and personal data.

Panel of Experts

To address all the important aspects, a multidisciplinary panel of experts was established, consisting of six infectious disease specialists, a rheumatology specialist with vast experience in the use and validation of PROS, a hospital pharmacist, and a psychosocial researcher with methodological expertise in the design and validation of PROs (also a patient representative). The main functions of this panel consisted of defining the points of greatest debate or controversy; validating the profiles of the most suitable participants/panelists to evaluate the agreement; and drafting the recommendations. In addition, a technical team with experience in systematic reviews and consensus techniques was in charge of editing the first survey, inviting the panel of experts, sending the first round of the Delphi, and analyzing the responses.

Systematic Literature Review

The scientific committee wanted to know what PROMs were used in PLHIV, the domains covered, and the level of validation; where, how often, and by whom the PROMs are collected; at what points in the disease should they be collected, and how to integrate them into clinical practice. The research questions defined by the panel were transformed into the PICOt epidemiological format (Population, Intervention, Comparator, Outcome, and Type of study) to be answered by a systematic review of the literature (Supplementary material).

Search strategy The review was conducted in Medline via PubMed (final search date January 20, 2021). We identified and tested terms from published reviews on “HIV” and “patient-reported outcome measures” to which we applied the necessary modifications to make them sensitive to the control documents (Supplementary material).

Eligibility criteria Three types of studies were included: (a) those describing PROMs (development, psychometric properties, and use in randomized clinical trials (RCTs)); (b) those involving PLHIV and use of PROMs in real-life conditions; and (c) those integrating PROMs into HIV consultations with subsequent measurement of effectiveness (Best practice studies/Health services research). On the other hand, we excluded studies (a) conducted in children or adolescents; (b) those in which HIV was part of a broader set of diseases without specific outcome analysis; and (c) those using PROMs on HIV screening (prevention), identification of barriers and facilitators of treatment or follow-up, patient preferences and determinants of quality of life.

The total number of studies exceeded 22,000, so it was decided to filter the search by systematic reviews only. A single expert reviewer made the selection of studies, first by title, then by abstract, and, in case of doubt or absence of abstract, by detailed reading. The selection was reflected in a flowchart and tables of included and excluded studies. Once the articles had been selected for detailed reading, the systematic reviews that responded to the research questions were screened. In the absence of a systematic review for a specific question, the literature was reviewed with the TripDatabase search engine, a meta-search engine that allows simultaneous access to the information contained in different resources.

For each of the selected studies, the following data were collected: objective, domains explored, and results. In parallel, a table was elaborated with all the PROMs included in the studies, with the following fields: PROMs name, generic or HIV-specific nature, domains and subdomains assessed, original study, number of items, self-administered, free of charge, and a subjective measure of validity based on a quick scan of published validation studies, in BiblioPRO (IMIM, available at https://www.bibliopro.org/) or PubMed, using the name and MeSH term “Validation Studies as Topic”[MeSH].

The quality of the included systematic reviews, with or without meta-analysis, was assessed using the AMSTAR-2 scale, available online at https://amstar.ca/Amstar-2.php, which assesses the overall confidence in the results of a systematic review (high, moderate, low, or critically low) [29]. The lowest quality is associated with reviews of observational studies. Finally, studies developing or analyzing a particular PROM were assessed using the COSMIN consensus checklist [30, 31].

Consensus Meeting for the Formulation of Recommendations

Once the literature review had been completed, and based on the aspects indicated in the first meeting, the results were presented and discussed in a virtual meeting. The scientific committee agreed on four overarching or guiding principles and 10 recommendations. These were discussed and edited in front of the members of the committee until a consensus was reached.

Delphi Survey

The guiding principles and recommendations were transported into the items of a Delphi survey to seek the consensus of a larger group. The survey was conducted anonymously online and was sent to a group of 80 health professionals attending to PLHIV and another group of representatives of PLHIV. Before sending out the Delphi, the items were reviewed by patient research partners, who required some modifications of the language to make it more accessible to all audiences. Each item had to be scored with a 0 to 10 scale with 0 meaning no agreement and 10 meaning full agreement, and there were open text boxes for comments. Disagreement was defined as values below 40 and agreement above 70. The idea was to reach a consensus in two to three Delphi rounds, maintaining only the items with the largest agreement (aggregated scores 8–10 over 80%).

Results

Systematic Review

The search produced a total of 729 articles (only systematic reviews). After reading the title and abstract, we excluded 676 and selected 52 for detailed reading, plus one extracted by secondary search from the bibliographic references of the selected articles. Finally, 35 studies were included (Fig. 1).

Fig. 1
figure 1

Flowchart of the recovered, screened, and included studies

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Fifteen of the included studies are systematic reviews of PROMs, six of randomized clinical trials (RCTs) in which PROMs were used as endpoints, and eight of observational studies with PROMs (Supplementary material).

The included studies mention up to a total of 140 PROMs, of which 52 are specific to PLHIV, and that covered five major domains: quality of life, self-management, social factors, spirituality, and satisfaction (Table 1).

Table 1 Questionnaires on PROs specific to PLHIV
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The development of some of these HIV-specific PROMs, such as the MOS-HIV, the FAHI, or the WHOQOL-HIV BREF, was based on generic instruments, with the participation of both HIV-positive individuals and health professionals. Each of these PROMs has demonstrated excellent psychometric properties in the HIV population [32]. Among the most widely used HIV-specific questionnaires are the MOS-HIV, the FAHI, and the HIV-SI/SDM [17, 32].

The MOS-HIV questionnaire is one of the PROMs with the best psychometric properties and is also the most widely accepted among healthcare professionals [26, 33]. It consists of 35 items covering 10 domains (including physical function, pain, social role/function, emotional well-being, etc.), is self-administered, and takes approximately 10 min to complete [34]. Among its limitations are the limited contribution of PLHIV during its development [26]. The MQOL-HIV, whose usefulness derives from the important consideration of the specific problems of PLHIV, is not as useful as the PROQOL-HIV or the WHOQOL-HIV BREF [26]. By adapting generic questionnaires, other instruments specific to PLHIV have been obtained, such as the FAHI (“Functional Assessment of HIV Infection”), developed from a scale used in patients with cancer (FACT-G) and containing 44 items related to the domains of physical, emotional, family, social well-being, and relationship with the physician [34]. It is self-administered, with an implementation time of less than 15 min, and assesses HRQoL based on patients’ experiences in the previous 7 days [26, 35]. Another specific HRQoL questionnaire in PLHIV is the PozQoL, which has demonstrated excellent conceptual validity, with good reliability, consistency, and temporal stability, and of which there is a Spanish version [35]. The PozQoL and FAHI questionnaires show good correlation and a high degree of concordance in the concepts evaluated [35]. In clinical research, the reference questionnaire on HIV-related symptoms is the HIV-SI/SDM [32].

The CEAT-HIV is a useful, valid, and reliable instrument for measuring treatment adherence. It is used in many countries, including Spain, and in addition to the English and Spanish versions it is also available in other languages such as Portuguese and Romanian [36].

One limitation of questionnaires developed specifically for PLHIV is their length (e.g., HIV-HOPES, FAHI, PROQOL-HIV), which prolongs completion time and makes them difficult to use as a method of evaluation [35]. The HIV-HOPES (“HIV Overview of Problem/Evaluation System”) questionnaire, for instance, consists of 168 items and 35 subscales. An additional limitation of this PROM is the negative formulation of the questions, which makes it difficult to interpret the answers and can lead to errors [34].

The most commonly used generic questionnaires in HIV research are the EQ-5D, the SF-36, and the WHOQOL-BREF. An important advantage of the use of these generic instruments is the possibility of comparing the HRQoL of PLHIV with that of patients with other chronic diseases or even in PLHIV with other concomitant diseases. On the other hand, one of their limitations is their lower sensitivity to changes in the evolution of the disease or its treatment [26].

Delphi

In the first Delphi-round, 120 people participated, of whom 80 were health professionals and 40 PLHIV. The response rate was high, with percentages of 79% among health professionals (n = 63) and 100% of PLHIV (n = 40). Four percent of respondents were less than 30 years old, 36% between 30 and 49, and 60% between 50 and 70 years old. The distribution by age group (30–49 and 50–70) was somewhat different, with a higher proportion of health professionals in the 50–70 age group. Sixty-three percent were male, 35% female, and 2% other. The PLHIV belonged to different NGOs (ACCAVIH, ADHARA, AGAVIH, etc.), 33% had been living with the virus for 2–10 years and 67% for more than 10 years. Regarding sexual orientation, 36% were heterosexual, 56% homosexual, and 8% were included in other categories. Very importantly, 17.5% of the PLHIV who participated in the first round were at risk of social exclusion.

Guiding Principles

There are four guiding principles of these recommendations: (1) the patient should be the center of attention; (2) when identifying needs, it is essential to take into account the patient’s perception as assessed by the PROs; (3) questionnaires are useful, whether used individually or collectively; and (4) questionnaires provide valuable information for decision-making.

Table 2 shows the results of the first round of the Delphi, both globally and by type of respondent. There was unanimity between PLHIVs and health professionals that the focus is on the patient, but this was not the case for the other three principles, where high standard deviations and much lower scores were obtained for health professionals than for PLHIVs.

Table 2 Delphi agreement with principles proposed by healthcare providers people living with HIV
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These results indicate that PLHIV support the use of PROMs, even if not validated, and believe that they allow for individualized treatment. PLHIV point out the importance of concise questions, with clear response options, and easy-to-understand vocabulary. Some comments included in the free text by some health professionals may help understand this polarization: “the questionnaires do not allow decision-making”, “their only usefulness is to obtain information”, “there is an excessive number of PROMs”, “their completion is improvised and not very reflexive”, “they can be manipulated (by an institution or organization) to obtain the desired response”, “they require time that physicians do not have”, and “the perception of the PLHIV is not always real”. This reflects either a misconception of PROMs or a bad experience.

Recommendations

Ten recommendations were issued (Table 3) and the results of the Delphi are shown in Table 4.

Table 3 Recommendations for the use of patient-reported outcomes in people living with HIV
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Table 4 Results of the agreement with the recommendations obtained in the Delphi round
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The responses obtained in all the recommendations, except the first and last, again showed a very significant polarization between PLHIV and health professionals. These results led the scientific committee to conclude that it would not be possible to achieve a rapprochement of positions in a second Delphi round, and so it was decided to suspend the second round and show the results obtained in the first round, with all its controversy.

About the implementation of questionnaires, a significant percentage of healthcare professionals indicated that it should be the nursing staff, educators, patient associations, or other health center personnel with specific training who should help in the completion of the PROMs. In addition, they insisted on the lack of time in the consultation rooms to incorporate the evaluation of the questionnaires, which, if used at all, should be self-administered, offering patients training on their completion by other professionals, such as auxiliary personnel. Some of the professionals’ responses were a total rejection of the PROMs.

On the other hand, the PLHIV supported the recommendations and pointed out that the PROMs should be brief, clear, and concise, and that they should include some open-ended questions because sometimes they do not feel identified with some of the answers. In addition, they again commented that PROMs allow for more individualized treatment by the physician and that training for completion is important because of the complexity of some questions.

Discussion

The purpose of using PROMs is to assess the perceptions and opinions of PLHIV on different aspects related to their health. These tools are useful for the initial evaluation and follow-up of patients [37], clinical decision-making [13, 37, 38], treatment planning [39,40,41], and evaluation of the efficacy [17, 26, 37, 42,43,44]. In addition, PROMs enhance correct self-management and coping with the disease [45, 46], help evaluate the quality of care provided, and improve the patient–physician relationship [13, 36, 38, 47]. Therefore, it is necessary to have valid, reliable PROMs that are easy to complete, score, and interpret, so that the resulting information is representative and complete [26, 44].

Our approach to reach recommendations is not without limitations. First, it was done in a single country, Spain. Secondly, the samples of experts and patient representatives might be considered small or biased. Doing the study in a single country facilitates discussion and comprehension, as everything happens in a language and a culture with which all participants are comfortable. It also facilitates implementation, as the problems that arise will be very typically the problems that would have occurred in a larger sample in the same country. As to the number, for Delphi studies, representativeness is a more relevant issue than quantity, and the demographic statistics of both samples reflect very well the underlying populations, and it is without doubt that the results reflect very clearly the expected controversy and diversity of opinions. Also, the sample of professionals is very representative and covers a large proportion of the population of interest.

We tried to establish a set of guiding principles and recommendations on the use of PROMs in PLHIV supported by the literature. The guiding principle is that the focus of care should be on the patient, a principle that dates back to 1987 and is used internationally to advocate for quality healthcare [42] and as such should be sensitive to patients and their families [12]. A fundamental characteristic of patient-centered care is transparency, based on information obtained through measurement instruments. In this context, PROMs complement the traditional method of obtaining information, based on the medical history and physical examination [13]. In addition, in chronic diseases, such as HIV, it is very important to expand the information [42] and questionnaires with free-text responses make it possible to collect a type of information that is difficult to obtain by other means [48].

The second principle (inquiring about the views and listening to the perceptions of PLHIV about their state of health and the evolution of their disease) refers to “humanizing care”, a fact to be taken into account in the context of today’s increasing dependence on technology [49].

Concerning the individual and collective usefulness of the questionnaires (third principle), it should be emphasized that their overall usefulness depends, among other reasons, on the participation of the PLHIV in their selection. In this way, and thanks to their cascade effect, multiple individual benefits are achieved derived from a greater perception of the symptoms and better physician–patient interaction [45, 50]. At the collective level, the use of PROMs makes it possible to audit the quality, appropriateness, and performance of the care services provided, and to improve the allocation and efficiency of the services provided and resources [13, 47].

Finally, about the fourth principle, several studies point out that greater knowledge of the factors that are important for PLHIV facilitates therapeutic planning in the consultation room [39,40,41] and allows physicians to have a more holistic perspective [51, 52]. There is evidence that the regular use of PROMs not only improves medical decision-making [38], as this principle indicates, but also symptom recognition, doctor–patient communication [53], and the identification of related problems [11], which facilitates coping with the disease [46].

Despite the wealth of information on the benefits of PROMs, it has not been possible to reach a consensus on the recommendations established, as a result of significant discrepancies between health professionals and PLHIV, and within the groups, which prevented a second round of the Delphi from being carried out. This discrepancy may be reflecting a deeply rooted aversion to subjectivity and other beliefs that act as a barrier. Although a high percentage of physicians believe that data collection through PROMs does not produce objective benefits in the therapeutic relationship or the involvement of patients in their treatment, most of these beliefs are based on studies not performed in PLHIV and published more than 30 years ago [54]. Since then, there has been a spectacular growth in the development and validation of PROMs [55].

The reality is that the penetration of PROMs in clinical practice in HIV is limited because of, among other reasons, physicians' perception of their competencies, the lack of information on their importance, feasibility, and support or resources to incorporate them into the daily dynamics of care [24, 56]. These data underline the importance of professional training and the need to introduce PROMs in the context of other clinical priorities [24, 37]. In fact, in our survey, healthcare professionals manifested their concern about new requirements derived from the implementation of PROMs.

The use of PROMS is incorporated into the clinical practice of other medical fields, such as rheumatic diseases or inflammatory bowel disease. One way to promote their use in PLHIV is to reduce the burden associated with their compliance and to achieve a balance between the frequency of administration and their complexity [13, 37].

As in other chronic diseases, treatment adherence is a fundamental aspect of living with HIV. Adherence is a complex phenomenon involving multiple factors [57]. PROMs provide insight into motivations for adherence and facilitate a relationship with the physician [58] in which the patient freely expresses his or her preferences and becomes involved in the treatment, resulting in improved adherence [38, 59, 60]. There is no single PROM for assessing adherence to ART in PLHIV, and there are many influences from various factors, such as quality of life and depression, which show significant variability between different cultures, sexes, ages and socioeconomic strata [61,62,63].

Another aspect addressed in the recommendations is the use of electronic questionnaires that allow PLHIV to record and track changes in health status in their own home, encouraging engagement and self-care between visits [45]. Despite the advantages of electronic systems for completing questionnaires through cell phone applications, web pages, e-mails, etc., their use in clinical practice is not yet well established [64, 65]. One of the reasons may be the lack of electronic devices among some PLHIV, especially the elderly who are at risk of social exclusion, although it seems unlikely that this is a real barrier given the rapid growth of these devices in all age and socioeconomic strata, as recently demonstrated by a study carried out in the UK [66]. Electronic collection of PROMs is becoming increasingly popular as it reduces completion time and the likelihood of errors, allowing the results to be used on an individual basis [42] or in series [67, 68]. However, the possibility of completing PROMs on electronic devices does not imply the abandonment of the paper format, as there are still PLHIV with a clear preference for the latter.

The PROMETEO project has revealed a significant perception gap regarding the use of PROMs in the consultation room between PLHIV and their physicians and polarized perceptions within both collectives. Among the reasons given by health professionals for not implementing PROMs, the lack of time in the consultation room and the lack of other professionals, such as nurses, to be in charge of their completion, stand out. In addition, it has been observed that health professionals overlook information on the usefulness and benefits of PROMs specific to PLHIV in multiple health domains, such as quality of life, adherence, social factors, or satisfaction with care. On the other hand, PLHIV value them positively and demand the use of simple tools written in a language appropriate to their situation. The barriers mentioned are solvable and a rapprochement between the attitudes of professionals and PLHIV should be encouraged to achieve a consensus that can improve the quality of life of these people. The benefits of the implementation of PROMs will also result in a better allocation and efficiency of healthcare resources, which is essential in today’s healthcare system.

Conclusion

Despite the lack of consensus, the scientific committee of PROMETEO suggests a differentiated use of PROMs between newly diagnosed and follow-up PLHIV. In newly diagnosed cases, the use of general PROMs (multidimensional) is recommended, preferably in paper format to facilitate a more personalized conversation, while in PLWHA attending follow-up visits, PROMs for assessment of specific areas are preferable and electronic format is favored to study the evolution. PROMs can play a fundamental role in the adoption of an individual-centered care approach.