Prevalence and Patterns of Adverse Drug Events Among Adult Patients with Human Immune Virus Infection on Dolutegravir-Based Antiretroviral Drug Regimens in Amhara Comprehensive Specialized Hospitals, Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study

Introduction

Antiretroviral therapy (ART) refers to any HIV treatment that uses a combination of two or more drugs to effectively suppress viral load and preserve immunofunction.¹ The initiation of ART has made HIV infection a chronic manageable disease for many patients.² Nowadays, patients receiving ART have access to a wide choice of therapeutic alternatives and have strong long-term survival chances. ART has unquestionably been successful, but there are still safety and efficacy issues with many medications, especially in individuals with baseline virus loads >100,000 copies/mL.³

Integrase strand-transfer inhibitor–based regimens are currently among the suggested and preferred first-line ARTs for the treatment of HIV1 infection, due to their benign side-effect profile, minimal drug–drug interactions, and virological efficacy. Dolutegravir (Dtg) is a new-generation integrase strand-transfer inhibitor that is recommended as the core first-line drug for the treatment of HIV patients due to its specific benefits over other antiretroviral medicines currently on the market.⁴ It is anticipated that Dtg will have a strong barrier to resistance based on in vitro investigations and clinical trials in ART-naïve individuals.³ Initiation of Dtg presents a significant opportunity for an efficient and longer-lasting treatment.⁵

All first-line regimens are now being switched over to this combination in a number of sub-Saharan African nations, including Ethiopia. Because levels of safety, efficacy, and associated factors vary across measures, patient subgroups, clinical stages, clinics, regions, and health-care systems, it is crucial to characterize these in each setting. As a result, measuring patient-reported outcomes like side-effect profile and positive outcomes is essential, especially in resource-limited countries.⁶ Hence, weighing the advantages and disadvantages of a Dtg-based regimen is crucial in everyday clinical practice to assist, maintain, and increase patient well-being. Evidence on the new regimen is still required for low- and middle-income nations in order to make the best use of scarce resources.

In general, switching to a Dtg regimen necessitates careful monitoring of its therapeutic effectiveness. However, data on Dtg adverse drug events (ADEs) are limited in developing countries, such as Ethiopia. Therefore, the purpose of this study was to assess the prevalence and pattern of Dtg-based ART regimens among adult HIV patients. The study’s conclusions may then help policymakers create interventions that are supported by the best available scientific evidence. This will also be advantageous to patients and the general public, aiding in the provision of health counseling and support by families and medical experts. It will also serve as a baseline for researchers who are interested in conducting in-depth studies.

Methods

Study Design, Period, and Setting

A multicenter retrospective follow-up study was conducted from January 1, 2019 to December 31, 2021. The study was conducted in Amhara region’s comprehensive specialized hospitals. These include Debre Tabor, the University of Gondar, Felege Hiwot, and Debre Markos comprehensive specialized hospitals. These are located 592 km, 727 km, 492 km, and 300 km from Addis Ababa, respectively. The hospitals serve more than 2.7 million, 7 million, 5 million, and 3.5 million people from the catchment area, respectively. Apart from other services, all the comprehensive specialized hospitals have provided ART services for adult HIV-infected patients since 2005. From January 1, 2019 to December 31, 2021, a total of 530 HIV-infected adult patients were initiated on Dtg-based ART regimens.

Population

All HIV-infected patients aged ≥18 years who had initiated Dtg-based ART at Amhara region comprehensive specialized hospitals were considered the target population, and all HIV-infected patients aged ≥18 years who had initiated Dtg-based ART from January 1, 2019 to December 31 2021 in selected Amhara region comprehensive specialized hospitals were considered the study population.

Eligibility Criteria

All HIV-infected patients aged ≥18 years who had initiated and had been on treatment for at least 6 months were included, and adult HIV-infected patients who had incomplete charts or did not have a minimum of one follow-up visit were excluded from the study.

Sample-Size Determination

Sample size was determined by single proportion formula considering assumptions of confidence level of 95%, margin of error 5%, and 50% prevalence of ADEs):

where n= number of samples, z= standard score at 95% CI which is 1.96.

The total sample size was 384. After adding 10% for incomplete charts, the final adequate sample size was 423.

Sampling Procedure

Initially, the numbers of adults ≥18 years of age initiated on Dtg-based ART from January 1, 2019 to December 31, 2021 were taken from the database of each hospital. After that, the sample size was proportionally allocated based on the number of patients who were receiving Dtg-based ART in each hospital: 140 of 175 from the University of Gondar Hospital, 88 of 110 from Felege Hiwot Hospital, 127 of 160 from Debre Markos Hospital, and 68 of 85 from Debre Tabor Hospital. A total of 423 medical charts were retrieved, of which 51 were excluded due to exclusion criteria. Finally, computer-generated simple random sampling was employed to select the study participants (Figure 1).

Figure 1 Schematic presentation of sampling procedure to assess prevalence and patterns of adverse drug events. Abbreviations: ARCHs, Amhara region comprehensive specialized hospitals; ART, antiretroviral therapy; DMCSH, Debre Markos Comprehensive Specialized Hospital; DTCSH, Debre Tabor Comprehensive Specialized Hospital; Dtg, dolutegravir; FHCSH, Felege Hiwot Comprehensive Specialized Hospital; n, total sample size; N, total source population; UoGCSH, University of Gondar Comprehensive Specialized Hospital.

Data-Collection Tool and Procedures

A data-abstraction tool was adapted from an Ethiopian Federal Ministry of Health ART guideline. Charts were accessed based on medical record numbers. Then, data on sociodemographic variables, baseline clinical and laboratory-related factors, and treatment-related factors of HIV-infected children were collected using Kobo Toolbox software after designing all of the questionnaires in this software and installing them on smartphones. The data were collected by four trained BSc nurses from March to April 2022. Data were extracted from the charts using the data-abstraction tool.

Study Variable

• Occurrence of ADEs (yes/no).

Operational Definition

According to the World Health Organization, an ADE is defined as a list of patient-reported symptoms recorded on their charts as a result of Dtg use that must be confirmed by a physician as being due to Dtg use and also including all available laboratory test results.^7–9

Data Quality Assurance

A pretest was conducted on 10 patients and their charts at the University of Gondar Hospital before the actual data collection. After that, the necessary amendments were made. Data quality was also guaranteed with proper recruitment, and 1 day’s training was also given to data collectors in each hospital concerning the use of software, the data-abstraction tool, and the data-collection process. The principal investigator and supervisor closely supervised the data-collection process on-site and/or on the server and gave prompt feedback to the data collector. At the end of each data-collection day, data completeness and consistency were cross-checked by both the principal investigator and the supervisor. All four data collectors had basic and comprehensive HIV care-and-treatment training and the supervisor had ART mentoring certificates.

Data Processing and Analysis

Data were checked, coded, and cleaned, then exported to SPSS 25 for analysis. The prevalence of ADE was estimated using simple descriptive summary statistics, such as frequency and proportion. Tables and text are used to present the results of the analyzed data.

Ethics

Ethics clearance was obtained from the University of Gondar College of Medicine and Health Sciences School of Nursing Ethical Clearance Review Committee (January 9, 2022, ECRC 245/2022). A consent waiver was obtained from the ethics committee. Then, the data were collected after getting a permission letter from each hospital. Since the study was done through the review of medical records, the individual patients would not be subjected to harm as long as confidentiality were kept. To keep confidentiality, the patients’ clinical records were reviewed anonymously and names and unique ART numbers were not included in data collection. Information obtained from patient medical records was kept confidential and used merely for this particular study. This study was in compliance with the Declaration of Helsinki.

Results

Sociodemographic and Baseline Clinical and Laboratory Characteristics of the Participants

A total of 423 medical records of adult patients who were on Dtg-based antiretroviral regimens were retrieved. After excluding 51 charts due to exclusion criteria, we had 372 charts for the final analysis. Of these, nearly two-thirds 247 (63.4%) were female and the mean age was 29.28±11.6 years. A majority of the participants(220, 59.1%), were urban dwellers, and 117 (31.5%) hadhad a primary school education. At the timet of the survey, the mean overall duration on Dtg-based ART was 1.9±0.6 years, more than two-thirds of the participants 262 (70.4%) had a baseline CD4 count above the threshold, and a majority of the participants were classified as WHO clinical stage I and II (Table 1).

Table 1 Socio-demographic, baseline clinical and laboratory characteristic of participants (n=372)

Physician-Confirmed Symptoms from Patient Reports and Laboratory Test Results of Dtg-Related Adverse Events

The prevalence of at least one ADE was 37.6% (95% CI 32.1%–42.1%). Nearly two-thirds (60.7%) of the participants had neuropsychiatric symptoms, followed by gastrointestinal symptoms (23.6%) and hepatic problems (7.14%). Among the neuropsychiatric symptoms recorded by physicians was insomnia (21.4%), and diarrhea had also been reported, confirmed, and recorded by the physicians as a gastrointestinal AED in 12.1% of patients. All ADEs recorded by physicians were mild, and none was severe, life-threatening, or led to hospitalization or death (Table 2).

Table 2 Patient-reported and laboratory test results of Dtg-related adverse events

Discussion

Despite the optimal efficacy and safety profile of Dtg-based regimens demonstrated in clinical trials, recent studies have questioned the tolerability of Dtg because of a high incidence of discontinuation reporting due to toxicity, mainly related to neuropsychiatric events associated with Dtg.^10–16 Even with the upcoming widespread use of Dtg as part of dual regimens in ART-naïve and -experienced patients, as well as being the first-line option in resource-constrained countries like Ethiopia, additional studies are required to accurately estimate the ADE prevalence and tolerability profile of Dtg-based regimens in real-world settings.^15,17,18 This study was intended to assess the prevalence and patterns of Dtg-associated ADEs among adult HIV-infected patients on Dtg-based ART regimens in Amhara comprehensive specialized hospitals, northwest Ethiopia.

The prevalence of at least one ADE among adult patients on Dtg was 37.6% (95% CI 32.1%–42.1%). This finding was in line with a study conducted in Uganda,¹⁹ which reported a prevalence of 33.1% of ADEs among patients on Dtg-based regimens. The similarity might be due to the same study design, outcome measurement, and study population used in the studies. The current study’s figure was higher than in a study conducted in Brazil,²⁰ which revealed that the prevalence of ADEs was 10%. This could be due to a variance in population characteristics and study periods.

A majority of the participants had neuropsychiatric followed by gastrointestinal symptoms. Among the neuropsychiatric ADEs, insomnia was the most commonly reported. This symptom might contribute to poor patient adherence to drug treatment. The current finding is supported by studies from Italy and Brazil,^14,20 but incongruent with former findings^21,22 where insomnia along with depression and mood disorders were the commonest neuropsychiatric symptoms associated with Dtg and resulting in treatment discontinuation and switching.

Nevertheless, the rate of Dtg discontinuation due to ADEs like neuropsychiatric events observed in this study was analogous to several previous studies,^6,14,16 with the highest occurrence reported in a Dutch cohort.¹⁴ In a large-cohort study, although the rates of ADEs leading to treatment discontinuation were similar between Dtg and elvitegravir (7.6% at 12 months), the risk of discontinuing treatment due to neuropsychiatric events was consistently higher for the former (5.6% vs 0.7% at 12 months),^17,18 although the deployment of Dtg in resource-constrained nations is anticipated to be both economical and effective, especially in light of the rising prevalence of pretreatment NNRTI resistance.²³

Strengths and Limitations

This study has described the real‐life setting of Dtg-based ADEs by physician-confirmed and patient reports and laboratory findings. We used a 3-year retrospective design, which helped in assessing both short- and long-term ADEs associated with the use of Dtg. However, the study has its limitations, eg, we used merely descriptive statistics, and some variables were excluded due to incompleteness as the data source was secondary (chart review).

Conclusion and Recommendation

ADEs were relatively low compared to previous studies. This commonest ADEs in laboratory test results and reported by patients were neuropsychiatric symptoms and gastrointestinal symptoms, followed by hepatic and renal. The findings also revealed that all the recorded ADEs were mild and none severe or life-threatening events leading to hospitalization or death. Therefore, we recommend the use of Dtg in clinical settings. Furthermore, a prospective cohort or experimental study shall be conducted to generate more evidence and build a cause–effect relationship regarding symptoms and use of Dtg, and inferential statistics shall be considered by future researchers.