Longitudinal trends and determinants of patient-reported side effects on ART–a Swedish national registry study

Åsa Mellgren; Lars E Eriksson; Maria Reinius; Gaetano Marrone; Veronica Svedhem

doi:10.1371/journal.pone.0242710

. 2020 Dec 23;15(12):e0242710. doi: 10.1371/journal.pone.0242710

Longitudinal trends and determinants of patient-reported side effects on ART–a Swedish national registry study

Åsa Mellgren ^1,², Lars E Eriksson ^3,^4,⁵, Maria Reinius ³, Gaetano Marrone ^6,⁷, Veronica Svedhem ^5,^6,^*

Editor: Giuseppe Vittorio De Socio⁸

PMCID: PMC7757802 PMID: 33362248

Abstract

Introduction

The use of patient-reported outcomes (PROs) to systematically quantify adverse events (AE) will assist in the improvement of medical care and the QoL of patients living with HIV (PLWH). The aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and further evaluate the Health Questionnaire (HQ) as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART.

Materials and methods

The Swedish National Registry InfCareHiv includes an annual self-reported nine-item HQwhich is used in patient-centered HIV care in all Swedish HIV units. In this study, the experience of side effects was addressed. We analyzed 9,476 HQs completed by 4,186 PLWH together with details about their prescribed ART and relevant biomarkers collected during 2011–2017. Data were analyzed using descriptive statistics, Pearson’s correlation coefficient and mixed logistic regression.

Results

The cross-sectional analysis of the HQs showed that the frequency of reported side effects decreased from 32% (2011) to 15% (2017). During the same period, there was a shift in ART prescription from efavirenz (EFV) to dolutegravir (DTG) (positive correlation coefficient r = 0.94, p = 0.0016). Further, PLWH who reported being satisfied with their physical health (OR: 0.47, p = <0.001) or psychological health (OR: 0.70, p = 0.001) were less likely to report side effects than those less satisfied.

Conclusions

Self-reported side effects were found to have a close relationship with the patient’s ratings of their overall health situation and demonstrated a strong correlation with the sharp decline in use of EFV and rise in use of DTG, with reported side effects being halved. This study supports the feasibility of using the HQ as a tool for longitudinal follow up of trends in PROs.

Background

The assessment of patient-reported outcomes (PROs) is emerging as an important tool to ensure the long-term health and improvement in quality of life (QoL) of people living with HIV (PLWH) [1]. The use of PROs to improve the treatment and care of PLWH has been found to be a valuable addition to clinicians’ documentation of laboratory data and biomarkers related to adverse events (AE) [2]. The FDA, and others, recommend that the pharmaceutical industry should include PROs in the clinical outcome assessment (COA) of clinical trials to support the development of new drugs [3] and to let PROs decide treatment choice when studies show non-inferiority. It is well known that the reporting of adverse drug reactions (ADRs) by physicians and patients does not always correspond to clinical trial data and several factors may contribute to this discrepancy [4, 5]. In clinical trials, all unwanted medical events are registered as AEs or serious AEs regardless of whether they are linked to the treatment or not. Causality is difficult to determine since placebo-controlled studies are rare [6]. However, up to a quarter of patients who receive placebo drugs also report ADRs, a phenomenon often referred to as a nocebo effect [7], which is defined as a symptom perceived as negative in response to a sham treatment [8]. Several of the mechanisms known to underlie the nocebo effect, such as the patient-doctor relationship, negative affectivity, and experienced health, can also be detected by PROs [9, 10]. Managing and avoiding AEs and ADRs is important since they result in hospitalization [11, 12] and lead to poorer adherence to antiretroviral treatment (ART) [13, 14]. Observational studies are necessary to be able to unravel real-world data regarding the prevalence of present, slowly evolving and rare ADRs. Qualitative studies can gain a deeper understanding of patients’ experiences of side-effects [15, 16].

There is a call for further research to demonstrate how the use of PROs in the field of HIV can provide a clear link between improvements in PROs and improvements in health and in clinical care [1]. The aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and evaluate the HQ as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART. We also conducted qualitative interviews with PLWH to gain a deeper understanding of what patients receiving HIV care include within the concept of side effects.

Material and methods

The InfCareHIV registry and the Health Questionnaire

InfCareHIV is a web-based, Swedish national quality assurance registry, established in 2008, with 100% coverage of PLWH in Sweden; it currently holds data on 11,064 patients. All HIV care in Sweden is performed within the public health service and microbiological and CD-4 data are transmitted directly from the analyzing laboratory to the InfCare registry. Data on ART is registered manually by an administrator, who is also a healthcare professional, based on information in the medical records. An automated quality check of incoming data takes place annually with the help of the DDM-tool, an instrument created in collaboration with EuroCoord. The Swedish Association of Local Authorities and Regions awarded the InfCareHIV registry the highest rating for data quality of all National Quality Registers in Sweden [17]. PLWH are consecutively enrolled in the registry at time of HIV diagnosis, and ART and laboratory data are monitored at least every six months. The InfCareHIV registry also serves as a database and a clinical support tool [14].

In 2011, a self-reported Health Questionnaire (HQ) assessing PROs was electronically integrated into InfCareHIV to be answered annually by patients either via a website or using a computerized or paper version at the patient’s outpatient clinic. As well as the Swedish version of the HQ, there is also a validated English version available which contributed 8% of all responses in the study. Illiterate patients or patients not fluent in Swedish or English can be offered assistance from an interpreter.

The HQ consists of nine items (S1 Appendix) and has been validated and described in Marrone et al. [14]. The primary aim of the HQ is to assess PROs concerning physical, psychological and sexual health, adherence, side effects and feeling of involvement in care. The results from the HQ form a basis for discussions at the patient’s routine clinical follow-up visit. The use of the HQ provides a more holistic view of the patient’s health and well-being and enhances person-centered HIV care, focusing the consultation on the patient’s current needs. For patients on ART (Item4a) who have experienced side effects (Item 4b), the severity of side effects (Item 4c) is assessed using responses on a five-point Likert scale. In the present study, the term side effects is used to refer to unintended AEs demonstrated by negative or adverse symptoms or physical changes where causality may be possibly, although not necessarily, related to the prescribed ART (e.g. ADRs).

Study population

The data in this study derive from 4,186 individuals ≥18 years who had responded to the HQ at least once during the period 2011 to 2017. Fifteen of these also provided data through individual qualitative interviews. During the data collection period, PLWH received ART according to the Swedish HIV treatment guidelines; these were updated in 2009 [18], 2013 [19] and 2016 [20].

The following variables from the InfCareHIV were used in the analysis: sex, age, route of transmission, country of origin, date of HIV diagnosis, plasma HIV RNA (cop/ml), CD4-cell count (x10⁶/l) and ART. Responses to all the questions on the HQ were analyzed.

Statistical methods

Mean and standard deviation or median and interquartile range, t-test or the Wilcoxon rank-sum (Mann-Whitney) test were used to summarize numerical variables and compare their values between two groups, frequencies and percentages. A chi-square test was used to summarize and compare categorical variables. Pearson’s correlation coefficient was used to test the correlation between numerical variables. Svyset Stata prefix was used to take into account the effect of data being clustered within patients. The answers to the questions concerning physical, psychological and sexual satisfaction were dichotomized into not satisfied (corresponding to Likert-scale answers: very unsatisfied, unsatisfied, rather unsatisfied and rather satisfied) and satisfied (corresponding to Likert-scale answers: satisfied and very satisfied) in accordance with other Swedish studies using the Li-Sat scale [21]). The answers concerning feeling involved in care (Item 5) were dichotomized into yes (corresponding to Likert-scale answers: sometimes, always) or no (corresponding to: never, seldom) and the answers concerning satisfied with care (Item 6) were dichotomized into satisfied (corresponding to Likert Scale answers: satisfied or very satisfied) and not satisfied (corresponding to: very unsatisfied, unsatisfied, rather unsatisfied and rather satisfied).

A mixed logistic regression model with side effects (yes/no) as outcome was used to assess the determinants of self-reported side effects among patients by testing the following variables: gender, mode of transmission, born in Sweden or not, CD4 nadir, (were fixed variables), years since start of treatment, age, years since diagnosis, CD4 at time of questionnaire, viral load<50 cop/mL at time of questionnaire, reported number of missed doses of HIV medication, and ratings for satisfaction with physical health, psychological health and sexual life, satisfaction with HIV healthcare, and feeling involved in their own care. A backward stepwise regression model was used with the significance level for removal from the model set at p<0.20. Complete case analysis was used for the mixed regression model. Odds Ratios (OR) and their 95% confidence interval (CI) were estimated. P-values <0.05 were considered statistically significant. STATA version 15 (StataCorp, College Station, Texas, USA) was used for the analysis.

Qualitative interviews

Fifteen participants were interviewed by the third author (MR) using a semi-structured interview guide to gain a deeper understanding of the participants’ experiences of side effects. Participants were asked if they had experienced side effects, if side effects had interfered with their everyday life and how they would explain the concept of “side effects” (for the complete interview guide, see S1 Interview guide). The participants were recruited by research nurses in a process of purposeful sampling; the participants had been living with HIV for over a year, were durably virally suppressed, and could speak Swedish and/or English.

Interpretive description [22], an approach suitable for exploring actual real-world questions, was used as the analytic framework. Transcripts from the audio-recorded interviews were read through several times by MR and all text concerning side effects was selected and imported into Nvivo 11. All lines of text were first labeled in a process of open coding with the aim of identifying patterns in the transcripts, and a broad-based coding scheme was set up with descriptions of reoccurring codes. This coding scheme was then altered in the coding process, enabling the same line of text to be labeled with several codes. The members of the author group discussed the coding and, in a process of grouping codes together, identified two overall themes that corresponded to the aim of investigating patients’ experiences of side-effects: 1) Participants’ interpretations and explanations of the meaning of the concept side effects of antiretroviral therapy and 2) Participants descriptions of experienced AEs that negatively affected their life and well-being.

Ethics

The study was approved by the regional Ethics Committee in Gothenburg (Dnr 293–16 and Dnr 579–18). The procedures for the qualitative interviews were approved by the Regional Ethics Committee in Stockholm (#2013/335–32). Informed written consent was collected prior to all interviews.

Results

Between 2011 and 2017 the National InfCareHIV registry included 7,489 PLWH who were receiving care; 4,186 of these were included in this study. The participants had responded to a total of 9,137 questionnaires during the time period for the study. The study population and reasons for exclusion are described in a flow chart (Fig 1).

Each individual patient included had, on average, responded to the HQ twice (median, range 1–8), 398 patients responded to the HQ twice during a calendar year. Data concerning sociodemographics, epidemiology, CD4 cell count nadir, CD4 cell count and proportion of patients with an HIV viral load <50 cop/mL are presented in Tables 1 and 2 together with the results from the HQs including the patient-reported prevalence of side effects. Side effects were reported on 20.3% of the HQs (1,854 of 9,137). Of the patients who had experienced side effects, 1,808 (97.5%) specified the extent to which they were troubled by the side effects: 448 (24.8%) reported that they were affected to some or a large extent while 1,360 (75.2%) reported that they were affected to a minor or no extent. Fifteen PLWH, eight women and seven men, aged 30–64 years, participated in the qualitative interviews. All were Swedish citizens, although their country of origin varied, and they had been living with HIV for between 2 and 33 years.

Table 1. Patients’ characteristics at their first visit (n = 4,186).

Characteristics	Total (Col %)
	4,186 (100)
Gender
Female	1,493 (35.7)
Male	2,693 (64.3)
Age in years (Mean, SD^@)	46.4 (11.5)
HIV route of transmission
Heterosexual	2,173 (52.2)
Men who have sex with men (MSM)	1,480 (35.5)
Drug use	247 (5.9)
Blood products	58 (1.4)
Unknown/Other	150 (3.6)
Missing	19 (0.4)
Country of origin
Abroad	2,328 (55.6)
Sweden	1,858 (44.4)
CD4 cell count nadir in cells/mm3 (Median, Interquartile range)	214 (150.1)
Years since HIV diagnosis (Mean, SD)	10.8 (7.8)
Missing	18 (0.4)

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Table 2. Frequency of side effects reported by PLWH on ART in relation to gender, age, route of transmission, origin, CD4-cell count, missed doses of ART, PROs, time on ART and time since HIV diagnosis (9,137 HQs).

Characteristics	Side effects No (Row %)	Side effects Yes (Row %)	P-value
HIV-related characteristics
Total	7,283 (79.7)	1,854 (20.3)
Gender			0.108^*
Female	2,553 (78.8)	687 (21.2)
Male	4,730 (80.2)	1,167 (19.8)
Age in years (Mean, SD^@)	48.2 (11.4)	47.7 (11.0)	0.060^**
HIV route of transmission			<0.001^*
Heterosexual	3,836 (80.2)	945 (19.8)
Men who have sex with men (MSM)	2,477 (77.5)	719 (22.5)
Drug use	563 (88.0)	77 (12.0)
Blood products	91 (79.1)	24 (20.9)
Unknown/Other	209 (76.6)	64 (23.4)
Country of origin			0.827^*
Abroad	3,833 (79.6)	981 (20.4)
Sweden	3,450 (79.8)	873 (20.2)
CD4 cell count nadir in cells/mm3 (Median, Interquartile range)	209.1 (142.7)	202 (138.7)	0.053^***
CD4 cell count in cells/mm3 at HQ^& (Median, Interquartile range)	600.4 (283.1)	590.7 (259.7)	0.18^***
HIV Viral Load <50 cop/mL at HQ^&			0.08^**
No	454 (76.4)	140 (23.6)
Yes	6,613 (80.1)	1,644 (19.9)
Years since start of ART^# (Mean, SD)	9.5 (6.5)	9.9 (6.8)	0.007^**
Years since HIV diagnosis (Mean, SD)	12.2 (7.8)	12.8 (8.2)	0.002^**
Health Questionnaire results
Missed ART^# doses during the previous week			<0.001^*
0	6,343 (80.8)	1,511 (19.2)
1–2	752 (73.2)	276 (26.8)
3+	101 (73.2)	37 (26.8)
Satisfied with physical health			<0.001^*
No	2,449 (71.6)	973 (28.4)
Yes	4,798 (84.6)	871 (15.4)
Satisfied with psychological health			<0.001^*
No	2,540 (72.9)	946 (27.1)
Yes	4,688 (84.1)	889 (15.9)
Satisfied with sexual life			<0.001^*
No	3,459 (75.8)	1,104 (24.2)
Yes	3,403 (83.4)	605 (16.6)
Satisfied with care			<0.001^*
No	313 (69.3)	139 (30.7)
Yes	6,906 (80.3)	1,693 (19.7)
Feel involved in care			<0.001^*
No	927 (71.3)	373 (28.7)
Yes	6,156 (81.2)	1,422 (18.8)

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^@ SD = Standard Deviation

^# ART = Antiretroviral Therapy

^& HQ = Health Questionnaire

* Chi-squared test

** T-test

*** Wilcoxon rank-sum (Mann-Whitney) test.

Frequency of patient-reported side effects by calendar year

During the study period, 1,301 (31.1%) PLWH reported experiencing side effects at least once. The cross-sectional analysis of the annual HQ data showed that the frequency of reported side effects decreased from 32% (196/620) in 2011 to 15% (197/1,330) in 2017 (Fig 2).

Fig 3 shows the percentage per year of PLWH prescribed efavirenz (EFV) or dolutegravir (DTG), respectively, and percentage of PLWH reporting side effects. There was a statistically significant positive correlation coefficient between yearly percentage of patients prescribed EFV and percentage of patients reporting side effects (r = 0.94, p = 0.0016), and a statistically significant negative correlation between percentage of patients prescribed DTG and percentage of patients reporting side effects (r = -0.83, p = 0.02). The use of early generations of protease inhibitors (PI) decreased over the corresponding period; the use of lopinavir decreased from 7.5% to 1.2% and atazanavir (ATV) from 13.9% to 4.1%.

Multivariable analyses

The multivariable analyses, run on 7,835 observations (complete case analysis), showed that the reporting of side effects was statistically significantly associated with other PROs; however, the analysis does not determine causality. PLWH who reported being satisfied with their physical health (OR: 0.47, 95% CI 0.39–0.37), psychological health (OR: 0.70, 95% CI 0.57–0.84) or sexual life (OR: 0.74, 95% CI 0.62–0.89) were less likely to report side effects than those who were less satisfied. In addition, PLWH who felt involved in their care were less likely to experience side effects than those who did not feel involved in their care (OR 0.66, 95% CI 0.53–0.82). PLWH who reported having missed one or two doses of ART during the previous week were more likely to report side effects (OR: 1.50, 95% CI 1.17–1.91) compared to patients who reported no missed doses. There was a negative correlation between age and reporting of side effects and a borderline positive correlation between years since HIV diagnosis and CD4-cell count and reporting of side effects (Table 3).

Table 3. Logistic regression: Determinants for reporting having experienced side effects in 4,186 PLWH based on 9,137 Health Questionnaires from between 2011 and 2017.

	Odds Ratio	95% CI interval	P-value
Age	0.98	0.97–0.99	0.001
Years since HIV diagnosis	1.01	1.00–1.03	0.051
CD4 cell count in cells/mm3 at HQ	1.00	1.00–1.00	0.020
Missed ART doses during the previous week
0	ref	ref	Ref
1–2	1.50	1.17–1.91	0.001
3+	1.03	0.54–1.95	0.937
Satisfied with physical health
No	ref	ref	Ref
Yes	0.47	0.39–0.57	<0.001
Satisfied with psychological health
No	ref	ref	ref
Yes	0.70	0.57–0.84	<0.001
Satisfied with sexual life
No	ref	ref	ref
Yes	0.74	0.62–0.89	0.002
Feel involved in care
No	ref	ref	Ref
Yes	0.66	0.53–0.82	<0.001

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Associations between side effects and ART

The study cohort had received 9,331 prescriptions for a third agent in their ART (Table 4). Side effects were reported on 1,854 HQs, of which 1,831 patients were on ART including a third agent and 23 on ART without a third agent. Of those who reported side effects, the most common third agent was EFV followed by darunavir (DRV) and atazanavir (ATV) (Table 4). These three substances were also the most prescribed third agents (Table 4).

Table 4. Prevalence of prescribed third agent in PLWH experiencing side effects and of prescribed third agent in ART of PLWH who completed the Health Questionnaire during 2011–2017.

Third agent in ART of PLWH experiencing side effects	Number	Percentage
Efavirenz	493	27.0
Darunavir	343	18.7
Atazanavir	317	17.3
Dolutegravir	202	11.0
Raltegravir	147	8.0
Rilpivirine	113	6.2
Lopinavir	108	5.9
Nevirapin	93	5.1
Other	15	0.8
Total	1831	100
Third agent in ART of PLWH when completing the HQ	Number	Percentage
Efavirenz	2,586	27.7
Atazanavir	1,529	16.4
Darunavir	1,478	15.8
Dolutegravir	1,270	13.6
Rilpivirine	772	8.3
Raltegravir	621	6.7
Nevirapine	517	5.5
Lopinavir	436	4.7
Other	122	1.3
Total	9,331	100

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Two themes were identified in the analysis of the qualitative interviews

The first theme was “Participants’ interpretations and explanations of the meaning of the concept side effects of antiretroviral therapy”. Most participants described side effects as being when the medication affected the body in a harmful way. One said that they occurred when the body resisted the medication and others that they only first considered a bodily reaction to be a side effect when their doctor had confirmed it. Others suggested that all events, both physical and social, that occurred while taking medication were side effects, since for example having to leave social activities early to go home to take your medication could be considered a side effect.

The second theme was “Participants’ descriptions of bodily sensations or experienced AEs that negatively affected their life and well-being”. There was great variation in the type of bodily sensations and/or side effects described by the participants. These are summarized in Table 5 under the categories Visible changes, Measurable changes, Non-measurable changes, Concerns about future side effects (SE) and Effects of taking ART. Most participants said that they did not currently have side effects from their HIV medication. However, many participants reported having previously experienced side effects and some described bodily sensations or events, although they were not sure if they were connected to their medication. Participants repeatedly reported that it could be difficult to know if something they experienced was caused by their medication. Some also described concerns about the medicine possibly doing something to them that they were unaware of and which might only show signs when they were older. Several participants referred to the medicine as poison and expressed concerns that the medicine might cause internal damage, accelerate aging or have unknown long-term effects. Participants who had other chronic diseases as well as HIV described difficulty in knowing if experienced events, e.g. erectile dysfunction, were caused by one or other of the diseases or by the medication.

Table 5. Possible adverse events and experiences that participants described as side effects.

Visible changes	Measurable changes	Non-measurable changes	Concerns about future SE	Effect of taking ART
Redistribution of body fat	Elevated liver enzymes	Altered sensation in the mouth	Accelerated aging	Difficulty swallowing tablets
Blood in urine	Elevated creatinine	Dizziness	Worrying about what is happening in their body	Nausea from thinking about the tablets
Brown urine	Neuropathy	Tiredness		Limited social life
Thin legs		Feeling awkward
Yellow eyes		Joint pain
Yellow skin		Nausea
Erectile dysfunction		Pain
Having trouble walking		Bloated stomach
Vomiting		Feeling drunk

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Discussion

This observational study of 4,186 PLWH demonstrates that self-reported side effects are common and diverse, but that the reported prevalence had halved during the study period from 32% of the answered HQs in 2011 to 15% in 2017. The introduction of new antiretroviral agents probably contributed to this decrease since we found a correlation between the drop in reported side effects and alterations in the prescribed third agent in ART during the time period. The changes in ART prescription, recommended by the Swedish HIV treatment guidelines [18–20] and also presented in a previous study [23], were characterized by the decline in prescription of EFV and PI and the increased prescription of integrase inhibitors as third agents.

EFV has a well-known adverse reaction profile with neuropsychiatric side effects and the prescription of EFV has decreased from 25% in 2011 to 15.8% in 2017 [24]. DTG is well tolerated, has less organ impact and fewer interactions with other drugs, and a lower risk of discontinuation due to AEs compared to EFV [25]. Thus, we found a decrease in patient-reported side effects, a corresponding decrease in the prescription of drugs with well-known AEs and an increase in the prescription of DTG. In the future, when choosing between two ART with equivalent virologic outcome, PROs can be of major importance when making decisions concerning treatment strategy, as is already the case in other medical fields such as oncology [26]. The HQ has proved to be a valid instrument for monitoring ART adherence [14] and it has now also been shown to be a useful tool for following trends in PROs that address side effects over time.

In the present study, PLWH who missed 1–2 doses of ART during the previous week were 1.5 times more likely to report experiencing side effects. The relationship between reported side effects and poorer adherence has been confirmed both in the Swedish population of PLWH [14] and internationally [27, 28] and interventions that support skills for managing side effects have demonstrated positive effects on ART adherence [29].

The analysis of the PROs on the HQs showed that reports of side effects were least prevalent among those who reported being satisfied or very satisfied with their physical health. In these patients the reports of side effects were lower by more than half compared to those who rated their physical health as less satisfactory. There was also an association with the individual’s reported satisfaction with their psychological health, where the reports of side effects were about one-third lower among those reporting being satisfied with their psychological health compared to those who were less satisfied. This association between PROs, where high self-rated health was a determinant for fewer experienced side-effects, highlights the side-effect issue as a central topic that should be raised in the patient’s interactions with healthcare professionals. Assessing the patient’s experience of their overall global health gives the opportunity to take measures to support PLWH in the improvement of their quality of life.

The qualitative interviews with PLWH showed that, although virally suppressed, they described a variety of negative bodily sensations that they related to their treatment. The experiences of side effects included AEs that were visible and measurable as well as mental processes and experiences in the form of negatively charged thoughts where it was unclear if causality was related to the prescribed drugs. Some even suggested that a side effect could be any kind of negative effect associated with the ART, including impacts such as difficulty swallowing tablets or having to adjust their life to enable them to take their medication in private. These thoughts and experiences, including concerns about ongoing and expected future symptoms, some probably due to a lack of knowledge about the medical effects of the ART, are generally not counted as AEs in clinical trials and this could be built upon to further understand the nocebo concept.

When working with patients experiencing side effects, it could be worth acknowledging that it may be difficult for patients to understand whether or not a negative bodily sensation they are experiencing is linked to their ART or to a particular drug. Other aspects worth acknowledging are that patients may fear that their treatment will be harmful from a long-term perspective and that effects related to parallel diagnoses and treatments as well as residual side effects from previous ART can be difficult to distinguish from the effects originating from their current ART.

Side effects may be a reason for changing ART and studies have shown that this can improve the quality of life of PLWH [30]. Nevertheless, when a patient is experiencing side effects it is important to understand the underlying cause in order to be able to improve their QoL, which may not necessarily involve a change in ART.

In this study, PLWH who reported that they felt involved in their care were less likely to report side effects. Involvement in care may reduce the prevalence of side effects both as a result of the patient’s own expectations being addressed and also through well-functioning patient-caregiver communication [31–33]. Additionally, since the PROs were assessed over time in the study, part of the decline in prevalence could be a result of an increase in patient-centered HIV care where the experience of side-effects was addressed.

Study constraints consist mainly of the fact that parameters that may be of importance for people’s experiences of side effects, such as co-morbidity, level of education, work life situation, family situation, alcohol and drug use, are not available in InfCareHIV. We have not assessed the decline of side effects according to prescribed third agent at individual level but instead at an ecological level; the relationship between side effects and prescribed third agent at individual level could not be assessed since the HQ is performed annually without relation to ART changes. The HQ also does not capture the exact symptoms that the patients are experiencing; the HQ is designed to be brief and to facilitate the clinical consultation. We therefore performed the qualitative part of this study to investigate the aspects that patients include in the concept of side-effects, which was found to be a considerably diverse range of experienced side effects.

Conclusion

In this study, reported side effects were found to have a close relationship with the patient’s overall global health and a strong correlation with the sharp decline in the use of EFV and rise in the use of DTG, with reported side effects being halved. This study supports the feasibility of using the HQ as a tool for longitudinal follow up of trends in PROs.

Supporting information

S1 Appendix

(DOCX)

Click here for additional data file.^{(20.7KB, docx)}

S1 Interview guide

(DOCX)

Click here for additional data file.^{(12.3KB, docx)}

Acknowledgments

We thank Pernilla Albinsson, Department of Infectious Diseases, Karolinska University Hospital, for help with the Health Questionnaire.

Data Availability

All data files are available from the National assurance registry InfCareHIVdatabase from the day of accepted for publication.(https://qrcstockholm.se/register/anslutna-register/infcarehiv-och-infcarehepatit/).

Funding Statement

VS has received funding from the Gilead Sciences Nordic Fellowship Programme and the Department of Communicable Disease Control Health Protection Public Health Agency of Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0242710.r001

Decision Letter 0

Giuseppe Vittorio De Socio

12 Aug 2020

PONE-D-20-19335

Longitudinal trends in patient-reported outcomes addressing side effects and prescribed third agent in ART – a Swedish national registry study

PLOS ONE

Dear Dr. Svedhem,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: Dear Authors,

your article is well written and cover the interesting topic of the use of PROs in clinical practice in PLWH. However, I suggest to revise the manuscript and the abstract for some grammar and punctuation errors before re-submission.

Reviewer #2: PLoS One

Longitudinal trends in patient-reported outcomes addressing side effects and prescribed third agent in ART - a Swedish national registry study - Mellgren Å. et al.

This longitudinal study aimed at investigating the associations between self-reported side effects in relation to other patient-reported outcomes (PROs), demographic and laboratory data, and prescribed third agent in ART (9,476 Health Questionnaires analyzed, from 4,186 people living with HIV).

PROs are a key tool for the implementation of patient-centered HIV care, and observational studies measuring PROs in a “real life” setting are needed to complement data from clinical trials. The study by Mellgren et al. offers a valuable contribution to the field.

Its major strengths are its longitudinal design with a large sample size and the use of mixed methods (quantitative survey + qualitative interviews) for data collection.

The manuscript is well written and pleasant to read.

However, several points need clarification or complementary analyses. I have also a series of minor comments for the authors to improve the presentation of their study.

Points which need clarification/complementary analyses:

MATERIAL AND METHODS

Study population:

There is a mismatch between the presentation of patients’ selection in the Study population section (“The data in this study derive from 4,186 individuals ≥ 18 years who had responded to the HQ at least once during 2011-2017”) and its presentation in the Results section (“the question regarding experience of side effects was unanswered in 3.6% of the HQs; these HQs were therefore excluded from the analyses”).

Was the selection made on patients or on visits?

But I also understood that all patients analyzed were receiving ART (i.e. a selection was first made on visits, excluding visits without treatment).

This should be better explained (perhaps with a flow chart?).

Comparison tests:

- It’s unusual to present comparisons of patients’ characteristics (Table 1) using tests based on repeated measures (even if cluster effect is taken into account using a Stata command). “Visits” are compared, and not individuals. This makes difficult the understanding of the study population’s characteristics. I suggest the authors present characteristics of patients at the time first HQ was completed.

- The authors used t-test to compare continuous characteristics between patients who reported side effects and those who did not. This test better suits to normally distributed variables, such as (probably) age and other “duration” variables (time since HIV diagnosis and time since ART initiation) but not to CD4 counts. I suggest using the Wilcoxon rank-sum (Mann-Whitney) test to compare nadir and CD4 counts between groups, and to present median [interquartile range] instead of mean (SD) in Table 1 for these two variables.

Graphical representation of change in the percentage of patients reporting side effects:

Figure 1 presents, for each year of the study period (2011-2017), the percentage of patients who reported side effects.

- I suggest not to connect points, as the sample of patients is not the same for each year (“each included individual had responded on average three times”).

- A 95% confidence interval should be added for each percentage in the figure.

Figure 2 is interesting and raises the following question: why not testing a time-dependent variable “Prescribed third agent: EFV, DTG, other” directly in the models? (I’m not convinced by the explanation given line 319 to 323).

Mixed-effects logistic regression models:

The authors analyzed factors associated with report of side effects. Previous studies in the literature showed that self-reported symptoms could impact both quality of life (QoL) and adherence to treatment. I think that testing QoL-related variables (i.e. satisfaction with physical health, psychological health, sexual life) and missed ART doses as potential correlates of side effects may pose a problem of reverse causality. The authors should remove these four variables from the models (maybe just show their correlations with side effects at first time HQ was completed – Table 1).

It’s unclear which variables were fixed and which were time-dependent in the models. I think gender, HIV route of transmission, country of origin, and CD4 count nadir were fixed, and the other variables were time-dependent – is this the case?

Administration mode of the HQ:

Is information about the administration mode of the HQ (paper, web, computerized…) available? Can it be tested in the model?

Literacy/foreign language:

Can the authors document the percentage of patients who needed assistance to fill in the HQ? (this could also be tested in the model).

Minor comments:

ABSTRACT

- Line 45: “efavirence” must be corrected into “efavirenz”.

- The conclusion of the abstract should contain a short sentence about the feasibility of using the HQ (as in the conclusion of the manuscript).

MATERIAL AND METHODS

Statistical methods:

- Please cite the complete reference of the statistical software used for the analysis of quantitative data.

RESULTS

Table 1:

- Measurement units should be added in the variable label (age in years, CD4 in cells/mm3).

- Please add information on missing values (for instance, adding the % of missing values between parentheses for each variable).

- Reformulations: “Route of transmission” should be replaced with “HIV route of transmission”, “CD4 nadir” with “CD4 cell count nadir”, “Missed doses previous week” with “Missed ART doses during the previous week”, “Viral load<50” with “HIV viral load<50”, “Years since diagnosis” with “Years since HIV diagnosis”.

- Please add the spell-out form of all abbreviations (ART, SD, HQ) as a footnote.

- “Socio-demographic characteristics of respondents” include gender, age, and country of origin. HIV route of transmission, CD4 nadir, HIV viral load, years since start of ART, years since diagnosis and CD4 cell count at HQ should be presented under a different subtitle (perhaps “HIV-related characteristics”).

- Please add information on the type of statistical tests used as a footnote.

DISCUSSION

The lack of information in the HQ about the type of symptoms perceived should be acknowledged as a limitation for the study.

Reviewer #3: General comment:

This is a study that aims to summarize patient-reported aniretroviral drug side effects in a large number of HIV infected persons from a Swedish national registry from 2011 to 2017. The data analysis is based on the 9-item Health Questionnaire (HQ) submitted to the registry annually. The main study finding (a correlation between side effects and usage of 3rd antiretroviral agent) is not based on an individual level analysis and represents the main limitation of the study.

The major difficulty encountered in the review is the reporting of results. Sometimes the number of patients is reported and at other times number of HQ responses. However, when a number is reported it is often not clear whether it refers to the number of individuals or number of HQ. Since the main study aim is to look at a 7-year trend I would also expect that the study population of each individual year would be described. The time trend is presently presented only in percentages (no absolute numbers) of a limited number of features (side effects, efavirenz and dolutegravir usage). If space is a concern this data could be presented as s supplement. There is also little data (except on 15 interviewed persons) on the type of side effects patients experienced.

Specific comments:

Abstract

Please omit the subheading “Discussion” as this is usually not part of an abstract. The conclusion may include implications of the study, but they should reflect the main findings. Please consider revising the concluding sentence. Since no counselling intervention has been done, I am not sure the conclusion is based on the findings of the study.

Efavirenz is also misspelled (“efavirence”).

Background

Line 61: Please check the wording “biometric”. Are those “biometrics” biomarkers or CD4 cell counts and HIV1-RNA tests or something else?

Line 82: The aim of the study includes only the third ART agent (see discussion).

Material and Methods

Would suggest providing more information on the InfCareHIV registry. For example, how is the laboratory and ART data collected? Is it thru labs and pharmacies or they depend on entry by health care professionals or something else?

Please also report how the questions that have a Likert scale are reported? For example, in the Result section Table 1 reports on items from the HQ as yes/no whereas in the questionnaire many items (How satisfied are you with your physical health, How satisfied are you with your psychological wellbeing, How satisfied are you with your sexual life, Do you feel involved in the planning and realization of your HIV care and treatment? How satisfied are you with the quality of care provided at your HIV clinic) have a 4, 5 or 6 point scale. So, please indicate which answers were considered “yes” and which “no”.

Study population

Please also explain why only the “third agent” of an ART regiment was analyzed. Side effect can also occur from the NUCs backbone. What about patients on dual therapy or those who used more than 3 drugs? Were they excluded? This should be reported in the Method section.

Statistical methods:

Line 116. The chi-square test is used for categorical variables, so please consider rephrasing the sentence.

Please state which was the outcome variable in mixed logistic regression. The phrase “ratings of side effects” might suggest that the answer 4c of the HQ was used, although I would assume that the answer to 4b was used. How many patients were included into the multivariable model? From Table 1 it seems that there were some missing data (individual responses do not add to total responses) so this needs to be mentioned. It seems that the multivariable model did not include the type of ART given to the patients despite the fact that the relationship of 3rd agent and self-reported side effects was the main study aim. Inclusion of ART type might give a direct association of ART type and side effects. Was there a specific reason why ART was not included into the multivariable model? If so, this should be explained. Was calendar year of assessment included into the model? Was to model checked for multicollinearity? Was the model checked for significant interactions?

Results:

Please clarify the numbers presented in the first paragraph. If 4186 PLWH filled out a total of 9476 questionnaires then, on average, one person filled out 2.3 HQ. Yet, the last sentence of the paragraph suggests that the average was 3. Also, when referring to percentages from a sample please include the numbers from which these percentages are derived from. For example, if 562 is 5.6% then 100% should be 10036. But this figure is not mentioned previously. Also, it is not clear what is the absolute number of those who did not answer the question regarding experience of side effect (3.6% of what number?). I would suggest making a flow chart clearly outlining the study population and the number of HQs analyzed. The HQ was filled out once a year over a period of 7 years (see Method section), yet the range of individual responses was from 1 to 8 (line 159). This means that at least one patient had filled 2 HQ in a calendar year. Please clarify.

Line 160: What does the “biomarker data” refer to? If it is the CD4 cell count and viral load this could be mentioned instead of naming them biomarkers. What was the total number of patients that had self-reported side effects? The Results sections reports mainly on the number of HQ and not on number of patients.

Table 1. needs to be revised. It is presently a mix of frequencies based on the number of patients and frequencies based on the number of questionnaires filled out. This is confusing and very difficult to follow. Tables should be self-explanatory (without reading the text). All numbers should be reevaluated or explained. For example, it is not clear how many females had side effects. The total number of females is 1493, yet Table 1 reports 2553 with no side effects (probably number of HQ, not no. females) and 687 did have side effects (number of HQ?). Vertical sums in columns 2 and 3 also do not add to the totals on top of table (missing data?). The same is true for many other numbers (but not for all). It is also difficult to understand the meaning of means for some variables (age, CD4 cell count). For example, the “total” mean for age is lower than the mean in those with and without side effects. This should also be explained. It seems that one patient contributed to the mean age several times. To avoid misunderstandings, would suggest separate tables on number of patients and number of responses or some other clear presentation of data. Also, some characteristics on the bottom of Table 1 (viral load, years since ART and diagnosis and CD4 cell count at HQ) are under the subheading “Health questionnaires results” could be moved to another or a new subheading.

The annual HQ data is reported only in percentages, please add the absolute annual number. Please consider moving the sentence starting on line 174 (During the same period….) elsewhere (is not a result of the study).

In text, there are two figures referred to Fig.2. One in line 180 states that “Fig. 2 shows the percentage….“. The other at line 188 states „Fig2“. Logistic regression:……“. Please clarify.

For Fig 3.tiff referred in text as Fig.2. could you also report the absolute numbers (not only percentages). The vertical (y) and horizontal (x) axis have no titles. Any data on the nucleoside backbone usage? Please add the letter for the correlation coefficient before 0.94 and -0.83). This figure actually repeats the line for fig1.tiff. So, there is no need to have both Fig1.tiff and Fig3.tiff.

As some variables were omitted from multivariable logistic regression analysis, please provide results of the bivariable analysis in a supplemental table. Fig 2.tiff is incomplete. Figures should also be self-explanatory. No reference categories are included for categorical variables (yes vs no or something else). No units of measurements for age (per 1 year?, per 10-year?), CD4-cell count (per 1 cell? Per 10 cells?), year since HIV-diagnosis (per 1-year?) are mentioned. “Psyche” is jargon. It is difficult to see from Fig. 2.tiff the “negative correlation” between age and side effects, and “positive” for years of diagnosis and CD4 cell count (see lines 199-201). This might be because a small unit of measurement has been used for those continuous variables. Consider increasing the unit. However, I do assume that “(Fig 3)” mentioned on line 201 is the figure 2.tiff. If so, please correct the reference to figure. It would be useful to readers to have a footnote explaining what an OR < 1 or an OR > 1 means. I suspect that the line range are 95% CI, but this should be mentioned in a footnote.

Fig 3. Lines 202 to 204 is also mentioned as fig 2 on line 180. In the section on “Associations between side effects and ART” it is not clear how many individuals received prescriptions. The total number of prescriptions is presented (n=9311), but are those also the number of patients? I would assume that 9331 prescriptions have been recorded at the time of HQ reporting, but this needs to be clear in text (can be done in the Method section). Tables 2 and 3 can be combined. There is no need to report the cumulative percentage, and the decimal place can be set to 1. There is no mention of results obtained from question 4c (To what extent are you troubled by medical side effects?). Since the focus of the paper is on side effects it would be useful to have this data.

Consider rephrasing the title of Table 4. into “Possible adverse drug events and…….”

Discussion:

Consider expanding the limitations of the study (not able to make a cause-effect conclusion, no type of side effects recorded….).

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Reviewer #1: No

Reviewer #2: Yes: Fabienne MARCELLIN

Reviewer #3: No

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PLoS One. 2020 Dec 23;15(12):e0242710. doi: 10.1371/journal.pone.0242710.r002

Author response to Decision Letter 0

6 Nov 2020

Reviewer # 1:

Dear Authors, your article is well written and cover the interesting topic of the use of PROs in clinical practice in PLWH. However, I suggest to revise the manuscript and the abstract for some grammar and punctuation errors before re-submission

Author reply: We thank reviewer 1 for these highly supportive comments. We have made a thorough review of the text and revised it to improve the language.

Reviewer # 2

2.1.1. There is a mismatch between the presentation of patients’ selection in the Study population section (“The data in this study derive from 4,186 individuals ≥ 18 years who had responded to the HQ at least once during 2011-2017”) and its presentation in the Results section (“the question regarding experience of side effects was unanswered in 3.6% of the HQs; these HQs were therefore excluded from the analyses”).

The first sentence suggests that patients who responded at least once to the HQ (any item or items specifically related to side effects? This should be explained) were selected – so, a selection on patients. But I also understood that all patients analyzed were receiving ART (i.e. a selection was first made on visits, excluding visits without treatment). This should be better explained (perhaps with a flow chart?).

Author reply: Thank you for this suggestion. We have now made a flow chart (new figure 1) to clarify the study population and corrected the text in line 196-200.

2:2:1 It’s unusual to present comparisons of patients’ characteristics (Table 1) using tests based on repeated measures (even if cluster effect is taken into account using a Stata command). “Visits” are compared, and not individuals. This makes difficult the understanding of the study population’s characteristics. I suggest the authors present characteristics of patients at the time first HQ was completed.

Author reply: Following the reviewer´s comments, we have now divided Table 1 into Table 1a and Table 1b: in Table 1a we present the Patients’ characteristics at their first visit (n=4,186) while in Table 1b we present the data from the Health Questionnaires.

2:2:2 The authors used t-test to compare continuous characteristics between patients who reported side effects and those who did not. This test better suits to normally distributed variables, such as (probably) age and other “duration” variables (time since HIV diagnosis and time since ART initiation) but not to CD4 counts. I suggest using the Wilcoxon rank-sum (Mann-Whitney) test to compare nadir and CD4 counts between groups, and to present median [interquartile range] instead of mean (SD) in Table 1 for these two variables.

Author reply: We have followed the reviewer´s advice and have modified the hypothesis tests accordingly in Table 1b.

2:3:1 Figure 1 presents, for each year of the study period (2011-2017), the percentage of patients who reported side effects.

2:3:1a- I suggest not to connect points, as the sample of patients is not the same for each year (“each included individual had responded on average three times”).

-2:3:1b A 95% confidence interval should be added for each percentage in the figure.

Author reply: Thank you for your advice. We have made a new figure (Figure 2)

2:3:2 Figure 2 is interesting and raises the following question: why not testing a time-dependent variable “Prescribed third agent: EFV, DTG, other” directly in the models? (I’m not convinced by the explanation given line 319 to 323,

Author reply: The Health Questionnaire (HQ) data are captured annually without specification of treatment change. We don’t have systematically collected data with the aim of evaluating PROs with respect to each ART. The interesting analysis you suggest requests a completely different design with data collection to follow a protocol for monitoring substance change, treatment outcome and patient evaluation of adverse event (AE) after changing 1-3 substances, preferably with a prospective design, similar to a clinical trial. Therefore, the analyses presented in the manuscript represent those made at an ecological correlation, not individual level data. In the present study we wanted to focus on our initial aim: to evaluate the HQ as a tool for following trends in patient-reported side effects over time in relation to the trends in prescribed third agent. To clarify this, we have changed the text in study limitations, row 433-434. 

2:4:1 The authors analyzed factors associated with report of side effects. Previous studies in the literature showed that self-reported symptoms could impact both quality of life (QoL) and adherence to treatment. I think that testing QoL-related variables (i.e. satisfaction with physical health, psychological health, sexual life) and missed ART doses as potential correlates of side effects may pose a problem of reverse causality. The authors should remove these four variables from the models (maybe just show their correlations with side effects at first time HQ was completed – Table 1).

Author reply: In earlier work, as well as in the present study, we have chosen to analyze and present associations and relationships between PROs rather than causality (since QoL is dependent on several factors). We have clarified this in row 296-297. Table 1b now provides the requested correlations.

2:4:2 It’s unclear which variables were fixed and which were time-dependent in the models. I think gender, HIV route of transmission, country of origin, and CD4 count nadir were fixed, and the other variables were time-dependent – is this the case?

Author reply: Yes, the reviewer is correct, we have clarified this in line 153.

2:5 Administration mode of the HQ:

2:5:1 Is information about the administration mode of the HQ (paper, web, computerized…) available? Literacy/foreign language. Can it be tested in the model? Can the authors document the percentage of patients who needed assistance to fill in the HQ? (this could also be tested in the model).

Author reply: The Health Questionnaire cohort includes patients from 220 nations and language issues are a common source of difficulties in communication in daily care, even if translators are frequently used. However, information about whether the HQ is completed by the patient on their own or with assistance from a healthcare professional or interpreter is not documented. Apart from the Swedish version, a validated English version exists and the English version was used by 8% of the cohort. Since the model includes country of birth, this variable would have a collinearity problem and therefore not be included in the model. The possibility for patients to answer a web version of the HQ was started in 2017 and during the first year only 75 (< 1%) patients chose this mode of response, we therefore judge that there are too few to have a potential effect if included in the present analysis, but we will include this as a possible covariate in analyses of future cohorts. We have added information about this in lines 105-110.

2:6 ABSTRACT

-2:6:1 Line 45: “efavirence” must be corrected into “efavirenz”.- The conclusion of the abstract should contain a short sentence about the feasibility of using the HQ (as in the conclusion of the manuscript).

Author reply: We thank the reviewer for noting this and have corrected the text accordingly and added a sentence regarding feasibility in the abstract conclusions.

2:7.1 Statistical methods:

- Please cite the complete reference of the statistical software used for the analysis of quantitative data.

Author reply: We thank the reviewer for reminding us about it. We have now added the full reference at the end of the “Statistical Methods” paragraph (lines 162-163).

2:8:1 Measurement units should be added in the variable label (age in years, CD4 in cells/mm3). Please add information on missing values (for instance, adding the % of missing values between parentheses for each variable). Reformulations: “Route of transmission” should be replaced with “HIV route of transmission”, “CD4 nadir” with “CD4 cell count nadir”, “Missed doses previous week” with “Missed ART doses during the previous week”, “Viral load<50” with “HIV viral load<50”, “Years since diagnosis” with “Years since HIV diagnosis”. Please add the spell-out form of all abbreviations (ART, SD, HQ) as a footnote. Socio-demographic characteristics of respondents” include gender, age, and country of origin. HIV route of transmission, CD4 nadir, HIV viral load, years since start of ART, years since diagnosis and CD4 cell count at HQ should be presented under a different subtitle (perhaps “HIV-related characteristics”). Please add information on the type of statistical tests used as a footnote.

Author reply: We thank the reviewer for this advice, which we have fully followed and have modified the text in Tables 1a and 1b.

2:9:1 The lack of information in the HQ about the type of symptoms perceived should be acknowledged as a limitation for the study.

Author reply: Thank you for this comment. We have added a sentence in line 435 in the limitations section. However, we find the qualitative interviews to be a strength in being able to obtain background facts on which to build further data collection concerning symptoms.

Reviewer 3;1 The main study finding (a correlation between side effects and usage of 3rd antiretroviral agent) is not based on an individual level analysis and represents the main limitation of the study.

Author reply: We thank the reviewer for this very relevant comment. We agree that the complete picture of patients’ side effects would involve assessing the third agent used at an individual level. Since the HQ data are captured annually without specification to treatment change we don’t have systematically collected data with the aim of evaluating PROs with respect to each ART and correlations have therefore been made at an ecological level. For the present study, however, we wanted to focus on our initial aim: to evaluate the HQ as a tool for following trends in patient-reported side effects over time in relation to the trends in prescribed third agents. To clarify this, we have made a small change in the title and the aim in lines 34-37 and 84-87.

3:2 The major difficulty encountered in the review is the reporting of results. Sometimes the number of patients is reported and at other times number of HQ responses. However, when a number is reported it is often not clear whether it refers to the number of individuals or number of HQ. Since the main study aim is to look at a 7-year trend I would also expect that the study population of each individual year would be described. The time trend is presently presented only in percentages (no absolute numbers) of a limited number of features (side effects, efavirenz and dolutegravir usage). There is also little data (except on 15 interviewed persons) on the type of side effects patients experienced

Author reply: Thank you for these comments. We have revised the manuscript accordingly: the study population and number of HQ are presented in a flow chart in Figure 1, annual HQ in Figure 2, and we have added the study population in absolute numbers at the beginning and end of the study period in line 275. We have added to what extent the patients were troubled by the side effects in lines 208-211. We have also added the limitation regarding the type of side effects that the patients experience in lines 434-439.

3:3 Abstract

Author reply: We have revised the abstract and corrected the spelling. However, since some of the experiences were fears or other non-medical symptoms, we interpret the results as being that the counselling has contributed to the decline in side effects. All the HQs are followed up in routine clinical follow up visits. This has been clarified in line 113-116.

3:4 Background

3,4a: Line 61: Please check the wording “biometric”. Are those “biometrics” biomarkers or CD4 cell counts and HIV1-RNA tests or something else?

Author reply: We thank the reviewer for this observation, we have corrected the sentence using the word biomarkers in line 64.

3.4b Line 82: The aim of the study includes only the third ART agent (see discussion).

Author reply: Yes, the aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and further evaluate the Health Questionnaire (HQ) as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART.

3:5 Material and Methods

Author reply: The InfCareHIV registry has earned the highest rating for data quality of all National Quality Registers in Sweden (for reference please see http://kvalitetsregister.se/englishpages.2040.html. We have included additional information on the InfCareHIV registry in the Method in lines 94-102 to clarify this further.

3:5:3 Please also report how the questions that have a Likert scale are reported? For example, in the Result section Table 1 reports on items from the HQ as yes/no whereas in the questionnaire many items (How satisfied are you with your physical health, how satisfied are you with your psychological wellbeing, How satisfied are you with your sexual life, Do you feel involved in the planning and realization of your HIV care and treatment? How satisfied are you with the quality of care provided at your HIV clinic) have a 4, 5 or 6 point scale. So, please indicate which answers were considered “yes” and which “no”.

Author reply: We have added information about the dichotomization in the methods section in lines 141-150.

3:6 Study population

Please also explain why only the “third agent” of an ART regiment was analyzed. Side effect can also occur from the NUCs backbone.

Author reply: We thank the reviewer for this comment, the answer is closely related to your comment 3:7:6-7. During the study time most of the changes made in the Swedish National HIV treatment Guidelines concerned the third agent, new substances were developed in NNRTIs and INIs, while we used the same Nucleosides. During recent years, more interest has been paid to the backbone and it is certainly true that NUCs also cause AE. However, the Health Questionnaire (HQ) data are captured annually without specification to treatment change. Thus, the data may be captured before or after treatment change, so relationships between side effects and prescribed third agent or backbone could not be assessed at an individual level. For this study we wanted to focus on our initial aim, to evaluate the HQ as a tool for following trends in patient-reported side effects over time in relation to the trends in prescribed third agents. This study shows that patients put into the concept of side effects more aspects than are usually considered as being AE in clinical trials and patients’ reports of side effects correlate with the decrease in prescription of efavirenz and increase in prescription of dolutegravir. A clinical trial with a protocol relating PROs to treatment change for each of the included components would be far beyond the aim of this study. The HQ would not be sufficient in that situation. We have expanded on this in the limitations section in line 434.

3:6 b

What about patients on dual therapy or those who used more than 3 drugs?

Were they excluded? This should be reported in the Method section

Author reply: We included all patients with a prescribed third agent and did not exclude those who used more than 3 drugs. The use of a third agent is presented in Table 3.

3:7:1 Line 116. The chi-square test is used for categorical variables, so please consider rephrasing the sentence.

3:7:2 Please state which was the outcome variable in mixed logistic regression.

3:7:3 The phrase “ratings of side effects” might suggest that the answer 4c of the HQ was used, although I would assume that the answer to 4b was used.

3:7.4 How many patients were included into the multivariable model?

3:7:5 From Table 1 it seems that there were some missing data (individual responses do not add to total responses) so this needs to be mentioned.

Author reply: We thank the reviewer for this advice. We have made changes accordingly on lines 135-138, 151, 297 and Table 1b. Ratings of side effects is Item 4c.

3:7:6-7 It seems that the multivariable model did not include the type of ART given to the patients despite the fact that the relationship of 3rd agent and self-reported side effects was the main study aim. Inclusion of ART type might give a direct association of ART type and side effects. Was there a specific reason why ART was not included into the multivariable model?

Author reply: We thank the reviewer for this very relevant comment that relates to comments 3:1 and 3:6 a. The Health Questionnaire (HQ) data are captured annually without specification of treatment change and therefore the data could not be assessed at an individual level. We have modified the title, the aim (34-37 and 84-87) and clarified that ART was not in the statistical model.

3:7:8 Was calendar year of assessment included into the model?

3:7:9 Was to model checked for multicollinearity?

3:7:10 Was the model checked for significant interactions?

Author reply: We are grateful for the energy and time that the reviewer has given to our manuscript. The calendar year was not included in the model. The model was checked for collinearity using variance inflation factor (VIF) but none was found. The model was not checked for significant interactions for two reasons: firstly, the authors did not believe there was any particular interaction to be tested according to current knowledge about this topic, secondly, the model with interactions would have added unnecessary complexity to the interpretation of the parameters.

Reviewer 3:8 Results:

3:8:1 Please clarify the numbers presented in the first paragraph. If 4186 PLWH filled out a total of 9476 questionnaires then, on average, one person filled out 2.3 HQ. Yet, the last sentence of the paragraph suggests that the average was 3. Also, when referring to percentages from a sample please include the numbers from which these percentages are derived from. For example, if 562 is 5.6% then 100% should be 10036. But this figure is not mentioned previously. Also, it is not clear what is the absolute number of those who did not answer the question regarding experience of side effect (3.6% of what number?). I would suggest making a flow chart clearly outlining the study population and the number of HQs analyzed.

Author reply: We understand that the presentation of the patient´s selection was unclear and we have now made a flow chart to clarify the study population (Figure 1).

3:8:1c The HQ was filled out once a year over a period of 7 years (see Method section), yet the range of individual responses was from 1 to 8 (line 159). This means that at least one patient had filled 2 HQ in a calendar year. Please clarify.

Author reply: The patients were invited to respond to the web-based HQ two months prior to their annual follow-up appointment. Also, the patients’ regular visits sometimes occur within 12 months due to factors such as re-scheduled visits or holidays. This has resulted in several patients (n=398) responding to the HQ twice during a calendar year, we have inserted a comment about this in line 203.

3:8:2 Line 160: What does the “biomarker data” refer to? If it is the CD4 cell count and viral load this could be mentioned instead of naming them biomarkers.

Author reply: We thank the reviewer for her/his patient consideration with the intention of increasing the readability of the text. We have now corrected the wording (now line 205).

3:8:2b What was the total number of patients that had self-reported side effects? The Results sections reports mainly on the number of HQ and not on number of patients.

Author reply: 1,301 patients (31.1%) experienced side effects at least once. This has been added to the manuscript (line 208).

3:8:3 Table 1. needs to be revised. It is presently a mix of frequencies based on the number of patients and frequencies based on the number of questionnaires filled out. This is confusing and very difficult to follow. Tables should be self-explanatory (without reading the text). All numbers should be reevaluated or explained. For example, it is not clear how many females had side effects. The total number of females is 1493, yet Table 1 reports 2553 with no side effects (probably number of HQ, not no. females) and 687 did have side effects (number of HQ?). Vertical sums in columns 2 and 3 also do not add to the totals on top of table (missing data?). The same is true for many other numbers (but not for all). It is also difficult to understand the meaning of means for some variables (age, CD4 cell count). For example, the “total” mean for age is lower than the mean in those with and without side effects. This should also be explained. It seems that one patient contributed to the mean age several times. To avoid misunderstandings, would suggest separate tables on number of patients and number of responses or some other clear presentation of data. Also, some characteristics on the bottom of Table 1 (viral load, years since ART and diagnosis and CD4 cell count at HQ) are under the subheading “Health questionnaires results” could be moved to another or a new subheading

Author reply: Table 1 has been revised and it has been divided into two sub-tables, Table 1a and Table 1b. We hope that the numbers are now clearer.

3:8:4 The annual HQ data is reported only in percentages, please add the absolute annual number.

Author reply: We have added the annual HQ in Figure 2.

3:8:4 b Please consider moving the sentence starting on line 174 (During the same period….) elsewhere (is not a result of the study).

Author reply: We agree and have removed this sentence.

Reviewer 3.8.5 a+b) In text, there are two figures referred to Fig.2. One in line 180 states that “Fig. 2 shows the percentage….“. The other at line 188 states „Fig2“. Logistic regression:……“. Fig 3.tiff referred in text as Fig.2 Please clarify.

Author reply: We have corrected the manuscript and revised the figures.

3.8.5 c. Any data on the nucleoside backbone usage.

Author reply: We thank the reviewer for this comment which is related to comment 3:6 a. Our intention was never to analyse side effects in relation to individual substances in ART.

3.8.6 a)could you also report the absolute numbers (not only percentages). 3.8.6 b)The vertical (y) and horizontal (x) axis have no titles

Author reply: Figure 2 has now been revised.

3:8:7 Please add the letter for the correlation coefficient before 0.94 and -0.83

Author reply: We have corrected the manuscript and abstract accordingly.

3.8.8 This figure actually repeats the line for fig1.tiff. So, there is no need to have both Fig1.tiff and Fig3.tiff.

Author reply: It is indeed correct that the trend line for Side-effects is expressed in both Figure 1 and Figure 3 and that the information is partly redundant. We have now updated “old” Figure 1 and added more information, it is now the new” Figure 2.

3.9,1 As some variables were omitted from multivariable logistic regression analysis, please provide results of the bivariable analysis in a supplemental table.

Author reply: We thank the reviewer for this comment; however, we would prefer to better explain in the methods section, among the already mentioned variables tested in the model, the criteria for the selection of the variables in the final model. We have therefore added to the methods paragraph “A backward stepwise regression model was used with the significance level for removal from the model set at p<0.20” (lines 158-159).

3.9.2 a.

3.9.2 Fig 2.tiff is incomplete. Figures should also be self-explanatory. No reference categories are included for categorical variables (yes vs no or something else). No units of measurements for age (per 1 year?, per 10-year?), CD4-cell count (per 1 cell? Per 10 cells?), year since HIV-diagnosis (per 1-year?) are mentioned. “Psyche” is jargon. It is difficult to see from Fig. 2.tiff the “negative correlation” between age and side effects, and “positive” for years of diagnosis and CD4 cell count (see lines 199-201). This might be because a small unit of measurement has been used for those continuous variables

Author reply: Following the relevant comments by the reviewer, we have chosen to show the results of the multivariable model in a table (Table 2) rather than in a figure.

3.9.2b. Consider increasing the unit. However, I do assume that “(Fig 3)” mentioned on line 201 is the figure 2.tiff. If so, please correct the reference to figure.

Author reply: Yes thank you, this fault has now been corrected.

3.9,2c It would be useful to readers to have a footnote explaining what an OR < 1 or an OR > 1 means. I suspect that the line range are 95% CI, but this should be mentioned in a footnote.

Author reply: We believe that these relevant comments by the reviewer are met by having Table 2 instead of the Figure. The interpretations of OR<1 or OR>1 are explained in the text.

Author reply: Thank you for the comments. We have revised the tables according to suggestions from you and the other reviewers. We have added descriptive statistics of the extent to which the patients were affected by side effects (lines 208-211). The number of prescriptions is not the same as patients, and we believe that the figure text is now sufficient.

Consider rephrasing the title of Table 4. into “Possible adverse drug events and…….”

Author reply: We have rephrased the title according to the suggestion.

3.9.4 Discussion:

Consider expanding the limitations of the study (not able to make a cause-effect conclusion, no type of side effects recorded….).

Author reply: As suggested, we have now expanded the Limitations.

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PLoS One. doi: 10.1371/journal.pone.0242710.r003

Decision Letter 1

Giuseppe Vittorio De Socio

9 Nov 2020

Longitudinal trends and determinants of patient-reported side effects on ART – a Swedish national registry study

PONE-D-20-19335R1

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PLoS One. doi: 10.1371/journal.pone.0242710.r004

Acceptance letter

Giuseppe Vittorio De Socio

24 Nov 2020

PONE-D-20-19335R1

Longitudinal trends and determinants of patient-reported side effects on ART – a Swedish national registry study

Dear Dr. Svedhem:

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Data Availability Statement

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PERMALINK

Longitudinal trends and determinants of patient-reported side effects on ART–a Swedish national registry study

Åsa Mellgren

Lars E Eriksson

Maria Reinius

Gaetano Marrone

Veronica Svedhem

Roles

Abstract

Introduction

Materials and methods

Results

Conclusions

Background

Material and methods

The InfCareHIV registry and the Health Questionnaire

Study population

Statistical methods

Qualitative interviews

Ethics

Results

Fig 1. Study population and number of Health Questionnaires performed.

Table 1. Patients’ characteristics at their first visit (n = 4,186).

Table 2. Frequency of side effects reported by PLWH on ART in relation to gender, age, route of transmission, origin, CD4-cell count, missed doses of ART, PROs, time on ART and time since HIV diagnosis (9,137 HQs).

Frequency of patient-reported side effects by calendar year

Fig 2. Frequency of patient-reported side effects on the Health Questionnaire in the InfCareHIV Swedish national registry during 2011–2017.

Fig 3. Trend analysis of percentage per year of PLWH prescribed efavirenz or dolutegravir, respectively, and percentage of PLWH reporting side effects.

Multivariable analyses

Table 3. Logistic regression: Determinants for reporting having experienced side effects in 4,186 PLWH based on 9,137 Health Questionnaires from between 2011 and 2017.

Associations between side effects and ART

Table 4. Prevalence of prescribed third agent in PLWH experiencing side effects and of prescribed third agent in ART of PLWH who completed the Health Questionnaire during 2011–2017.

Two themes were identified in the analysis of the qualitative interviews

Table 5. Possible adverse events and experiences that participants described as side effects.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Giuseppe Vittorio De Socio

Roles

Author response to Decision Letter 0

Decision Letter 1

Giuseppe Vittorio De Socio

Roles

Acceptance letter

Giuseppe Vittorio De Socio

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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