---
title: "Hyperuricemia and Gout in People Living with HIV: Systematic Review and Meta-analysis Protocol"
id: "plos-one-6-urate-dysregulation-hyperuricemia-and-gout-among-people-living-with-hiv-a"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-6-urate-dysregulation-hyperuricemia-and-gout-among-people-living-with-hiv-a"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355217"
published_at: "2026-07-31T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Hyperuricemia and Gout in People Living with HIV: Systematic Review and Meta-analysis Protocol
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-6-urate-dysregulation-hyperuricemia-and-gout-among-people-living-with-hiv-a
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355217)
- **Published At:** 2026-07-31T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This protocol outlines a systematic review and meta-analysis to quantify global **hyperuricemia** and **gout** burden among adults living with HIV (PLHIV) using observational studies to May 2026. - Searches will cover PubMed/MEDLINE, EMBASE, Web of Science, and CINAHL with no year, language, or geographic limits. - Eligible designs include cross-sectional, cohort, and case-control studies reporting prevalence or incidence of hyperuricemia or gout; small case series (<10) and non-quantitative reports are excluded. - Participants are adults (≥18 years) with documented HIV; mixed cohorts are eligible if adult-specific data are extractable or adults comprise ≥80%. - The protocol will subgroup by ART class (pre-ART, PI, NNRTI, INSTI/dolutegravir era) to examine drug-specific associations, and will extract CD4 count, viral load, metabolic comorbidities, and HIV duration as potential correlates. - Risk of bias will be assessed using the Joanna Briggs Institute Prevalence checklist for prevalence studies and the Newcastle–Ottawa Scale for case-control/cohort studies. - Pooled prevalence will be estimated with a random-effects DerSimonian–Laird model using Freeman–Tukey double-arcsine transformation for prevalence data; heterogeneity assessed with I2 and Cochran’s Q. - Planned subgroup and sensitivity analyses include ART class, geographic region, CD4 categories, and study quality. - The review is registered on PROSPERO (CRD420261360734) and follows PRISMA-P 2015 guidance. - No primary datasets were generated; funding and competing interests were not reported as affecting the work.
## Clinical Analysis & Structured Key Points
Urate dysregulation (hyperuricemia and gout) among people living with HIV: A protocol for a systematic review and meta-analysis | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Abstract Introduction Approximately 39.9 million people are living with HIV worldwide, most in sub-Saharan Africa. Effective antiretroviral therapy has shifted attention to metabolic comorbidities, and emerging evidence links integrase inhibitors such as dolutegravir to elevated serum uric acid, yet the global burden of hyperuricemia and gout in this population is unquantified. Methods and analysis This protocol describes a systematic review and meta-analysis of observational studies (cross-sectional, cohort, and case-control) published from inception to May 2026. We will search PubMed/MEDLINE, EMBASE, Web of Science, and CINAHL. Studies involving adults (≥18 years) living with HIV that report the prevalence or incidence of hyperuricemia or gout will be included. Two independent reviewers will screen studies, extract data, and assess risk of bias using the Joanna Briggs Institute Prevalence Critical Appraisal Checklist and the Newcastle-Ottawa Scale (NOS). Primary outcomes are the pooled prevalence of hyperuricemia and gout in PLHIV. Secondary outcomes include risk factors associated with urate dysregulation (ART regimen, Cluster of Differentiation 4 [CD4] count, viral load, metabolic comorbidities, and HIV duration), and gout as an immune reconstitution inflammatory syndrome (IRIS) manifestation. A random-effects meta-analysis using the DerSimonian-Laird method with Freeman-Tukey double-arcsine transformation for prevalence data will be performed in R software. Heterogeneity will be assessed using the I 2 statistic and Cochran’s Q test. Subgroup analyses will explore variation by ART class (pre-ART, PI, NNRTI, INSTI/dolutegravir era), geographic region, CD4 category, and study quality. PROSPERO Registration Number CRD420261360734. Citation: Pitua I, Otto KA, Lwembawo KD, Nantalaga KC, Nampiinga MG, Ndyomugabe M, et al. (2026) Urate dysregulation (hyperuricemia and gout) among people living with HIV: A protocol for a systematic review and meta-analysis. PLoS One 21(7): e0355217. https://doi.org/10.1371/journal.pone.0355217 Editor: Junzheng Yang, Guangdong Nephrotic Drug Engineering Technology Research Center, Institute of Consun Co. for Chinese Medicine in Kidney Diseases, CHINA Received: April 5, 2026; Accepted: July 19, 2026; Published: July 31, 2026 Copyright: © 2026 Pitua et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. Funding: The author(s) received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Introduction Globally, approximately 39.9 million people were living with HIV (PLHIV) as of 2023, with sub-Saharan Africa bearing over 65% of the world’s HIV burden [ 1 , 2 ]. The sustained scale-up of antiretroviral therapy (ART) has transformed HIV from a near-uniformly fatal infection into a chronic, manageable condition, dramatically extending life expectancy in affected populations [ 3 , 4 ]. However, longer survival has exposed a new epidemiological layer: the rising burden of non-communicable comorbidities driven by persistent immune activation, chronic inflammation, and ART-related metabolic toxicities. Among these, urate dysregulation which involves both hyperuricemia and gout; its principal clinical manifestation, is emerging as an under-recognized but clinically important comorbidity in PLHIV [ 5 – 7 ], consistent with genetic evidence that metabolic traits, including triglycerides and HDL cholesterol, are causally associated with serum uric acid and gout risk [ 8 ]. Gout is the most common inflammatory arthritis globally, with a pooled worldwide prevalence of approximately 1–4% in the general adult population and an increasing burden in low- and middle-income countries (LMICs) [ 9 ]. It arises from chronic monosodium urate crystal deposition in joints and periarticular tissues, driven primarily by sustained hyperuricemia [ 10 ]. In PLHIV, multiple pathophysiological mechanisms converge to elevate serum uric acid: (i) increased purine turnover resulting from accelerated lymphocyte apoptosis and viral replication; (ii) impaired renal urate excretion secondary to HIV-associated nephropathy and ART nephrotoxicity; and (iii) direct uricogenic effects of specific ART agents, particularly ritonavir-boosted protease inhibitors, stavudine, and didanosine [ 5 – 7 ]. More recently, dolutegravir-based regimens, now the WHO-recommended backbone for first-line ART globally, have been associated with hyperuricemia in several sub-Saharan African cohorts, raising important questions about metabolic monitoring protocols in the post-tenofovir era [ 5 – 7 ]. In Uganda, a cross-sectional study at Kiruddu National Referral Hospital identified a hyperuricemia prevalence of 21.3% among PLHIV on predominantly dolutegravir-based regimens [ 7 ]. In Ethiopia, multi-centre data documented a prevalence as high as 46.5% among those on dolutegravir-based first-line ART [ 5 ]. These rates substantially exceed those reported in HIV-negative general populations in the same regions, signalling a population-specific risk that demands systematic quantification. Gout in PLHIV presents additional clinical complexity. The only published case-control study specifically designed to measure gout prevalence in an HIV cohort, conducted in Brighton, United Kingdom, identified a point prevalence of 2.2%, substantially higher than the estimated 1.0% in the general adult UK population with hypertension conferring a nearly five-fold increased risk [ 11 ]. Ritonavir-boosted protease inhibitor use was established as a risk factor as early as 2005, with an odds ratio of 22 in a retrospective London cohort [ 12 ]. Gout has also been described as a rare but distinct manifestation of immune reconstitution inflammatory syndrome (IRIS) following ART initiation, presenting as severe polyarticular flares in the context of Cluster of Differentiation 4 (CD4) recovery [ 13 , 14 ]. Primary studies of urate dysregulation in PLHIV remain few and heterogeneous. Reports from Africa, Asia, and the Americas describe hyperuricemia and gout frequencies ranging from under 1% to over 40%, reflecting differences in study populations, ART regimens, biochemical thresholds, and geographic context [ 5 – 7 , 15 – 18 ]. Documented gout rests largely on small case series and individual case reports, the studies rarely stratify by ART class, and few are from sub-Saharan Africa. Despite this growing literature, no systematic review or meta-analysis has pooled these estimates, examined the sources of heterogeneity, or synthesized the risk-factor landscape. This gap undermines the development of clinical monitoring guidelines for urate dysregulation in PLHIV, particularly in sub-Saharan Africa, where dolutegravir-based ART is now universal, rheumatology services are severely limited, and gout is often misdiagnosed as septic or reactive arthritis [ 19 , 20 ]. Because dolutegravir-based regimens are now the World Health Organization preferred first-line therapy globally, an integrase-inhibitor uric acid signal would carry implications well beyond sub-Saharan Africa, including high-income settings where gout prevalence is already high. A preliminary search of PROSPERO, the Cochrane Database of Systematic Reviews and MEDLINE (via PubMed) identified no completed or ongoing systematic review on hyperuricemia or gout among people living with HIV. Existing reviews of metabolic complications in people living with HIV concentrate on dyslipidemia, insulin resistance, and weight gain and do not synthesize urate outcomes. Urate dysregulation merits separate synthesis because it follows a distinct mechanism involving renal and intestinal urate handling and purine metabolism, carries a specific and modifiable drug signal centred on integrase inhibitors, sits outside standard ART monitoring, and is clinically actionable through an inexpensive assay and treatable disease. A dedicated synthesis is therefore needed to guide monitoring policy. This protocol describes a systematic review and meta-analysis that will, for the first time, synthesize the global evidence on the prevalence of hyperuricemia and gout in PLHIV, examine how ART class influences urate dysregulation, and identify clinical and demographic correlates that clinicians can use to identify at-risk patients. By framing hyperuricemia and gout under a unified framework of urate dysregulation, we recognize that both conditions exist on a pathophysiological continuum and that their combined synthesis is necessary to fully characterize the burden and to inform rational management strategies. Findings will be particularly relevant to clinical practice in sub-Saharan Africa, where the intersection of HIV, dolutegravir-based ART, and metabolic comorbidities creates a growing, underappreciated rheumatological challenge. Methods This protocol has been drafted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 guidelines [ 21 ]. The full PRISMA-P checklist is provided in S2 File . The review was registered with PROSPERO (CRD420261360734) before the searches were run. Eligibility criteria Study design. We will include observational studies using cross-sectional, prospective or retrospective cohort, and case-control designs that report quantitative data on the prevalence or incidence of hyperuricemia or gout in PLHIV. Case reports and series with fewer than 10 participants will be excluded. Conference abstracts, reviews, editorials, qualitative studies, and animal studies will also be excluded. There is no restriction on publication year, language, or geographic setting. Participants (P). Adults aged 18 years and above with documented HIV infection, regardless of ART status, CD4 count, WHO clinical stage, or HIV-1 subtype. Studies that mix paediatric and adult populations will be eligible if adult-specific data can be extracted or if adults constitute ≥80% of the study population. Where a study includes mixed adult and paediatric participants and reports neither the proportion of adults nor adult-specific data, we will contact the corresponding authors with up to two requests. If usable data are not obtained within four weeks, the study will be excluded. Index Condition/Exposure (I). HIV infection, with or without specific ART regimens. We will specifically characterize the ART class effect by subgrouping studies into: (i) pre-ART/ART-naive era; (ii) protease inhibitor (PI)-based regimens; (iii) non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; and (iv) integrase strand transfer inhibitor (INSTI)-based regimens, particularly dolutegravir. ART exposure will be classified by the regimen the participant was receiving at the time of serum urate measurement (current regimen). Prior ART history will be extracted where reported. Studies reporting only initial or sequential regimens will be recorded as such and examined in a sensitivity analysis, and study populations whose relevant regimen cannot be determined will be excluded from the ART-class stratified analyses. Comparators (C). For prevalence estimates, comparators are not required but will be recorded where reported: HIV-negative individuals drawn from the same population, or PLHIV on different ART regimens. For risk factor analyses, PLHIV without hyperuricemia or gout will serve as the internal comparator group. Outcomes (O). Primary outcomes: Pooled prevalence of hyperuricemia, defined as serum uric acid >7.0 mg/dL (416 μmol/L) in men or >6.0 mg/dL (357 μmol/L) in women [ 22 , 23 ], or as defined by the individual study with the applied cut-off reported. Pooled prevalence of gout, defined by clinical diagnosis, the American College of Rheumatology and the European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria, or crystal-confirmed diagnosis. Eligible studies are expected to define hyperuricemia using varying serum urate thresholds. We will record the exact threshold and assay reported in each study, apply standard sex-specific cut-offs (>7.0 mg/dL [416 µmol/L] in men and >6.0 mg/dL [357 µmol/L] in women) as the primary definition, and extract mean or median serum urate where reported so that prevalence can be re-derived at a common threshold. Gout will be accepted as defined by each study (ACR/EULAR criteria, physician diagnosis, or crystal confirmation), recorded by ascertainment method. The effect of these threshold choices is examined in a pre-specified subgroup analysis comparing standard and alternative cut-offs. Secondary outcomes: Risk factors and correlates of hyperuricemia and gout in PLHIV: specific ART agents/classes (protease inhibitors, dolutegravir, stavudine, didanosine), CD4 count, viral load, duration of HIV infection, duration of ART, metabolic comorbidities (hypertension, obesity/overweight, diabetes mellitus, chronic kidney disease, dyslipidemia), and demographic variables (age, sex). Gout as an immune reconstitution inflammatory syndrome (IRIS) manifestation: this will be summarized narratively as a descriptive case synthesis rather than pooled, given that the available evidence comprises case reports and small case series. Serum uric acid levels (mean/median) in PLHIV versus HIV-negative controls where reported. Study setting. Any healthcare or community setting globally. Studies from all income settings and geographic regions will be eligible. Information sources The following electronic databases will be searched systematically from inception to May 30, 2026: PubMed/MEDLINE EMBASE (via Elsevier) Web of Science (Core Collection) CINAHL (Cumulative Index to Nursing and Allied Health Literature) To supplement electronic database searches, we will: (i) hand-search reference lists of all included studies; (ii) review reference lists of relevant narrative reviews and book chapters; (iii) search Google Scholar for the first 100 results of a structured search; and (iv) contact corresponding authors of included studies to identify unpublished or ongoing studies with available data. Search strategy A comprehensive, structured search strategy will be developed for each database in consultation with a trained medical librarian. Search terms will incorporate Medical Subject Headings (MeSH), Emtree terms, and free-text keywords, combined using Boolean operators (AND, OR, NOT). The strategy will combine two conceptual blocks: (i) HIV/PLHIV, and (ii) urate dysregulation (hyperuricemia and gout). To manage the anticipated volume of irrelevant records, the primary search will apply validated “NOT” operators to exclude animal-only studies and non-eligible publication types and screening will be conducted in Covidence, which uses machine learning-assisted reprioritisation after approximately 50–100 records are reviewer-classified. An example PubMed search string is provided below; full database-specific search strings are provided in S1 File . Example PubMed Search String (See S1 File for all database strings): (“HIV Infections”[MeSH] OR “HIV”[MeSH] OR “Human Immunodeficiency Virus” OR “PLHIV” OR “people living with HIV” OR “antiretroviral”) AND (“Hyperuricemia”[MeSH] OR “Gout”[MeSH] OR “Arthritis, Gouty”[MeSH] OR “Uric Acid”[MeSH] OR hyperuricemia OR hyperuricaemia OR gout OR “gouty arthritis” OR “uric acid” OR “serum urate” OR “urate dysregulation”) Study selection Search results will be exported to Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) for automated deduplication. Two independent reviewers (IP, JNO) will screen titles and abstracts against the eligibility criteria. Full-text articles of potentially eligible studies will be retrieved and assessed independently by the same reviewers using a standardized inclusion/exclusion checklist. During extraction, overlapping populations and duplicate publications will be identified by comparing author lists, recruitment sites, and enrolment periods. Where cohorts overlap, the report with the largest sample or most complete outcome data will be retained, and the basis for each decision will be recorded in a table of excluded duplicates. Disagreements at both stages will be resolved through discussion or, if unresolved, adjudication by a third reviewer (KAO). A PRISMA 2020 flow diagram [ 24 ] will document the number of records identified, screened, assessed for eligibility, and included in the review, with reasons for exclusion at the full-text stage. Data extraction Data will be extracted by two independent reviewers (IP and JNO) into a standardized Microsoft Excel form, piloted on five randomly selected studies before formal extraction commences. Discrepancies will be resolved by consensus or third-reviewer arbitration (KAO). Where studies report insufficient data, corresponding authors will be contacted by email up to twice over four weeks. Case-control studies will contribute only to risk-factor and association outcomes, such as the association between ART class and hyperuricemia, and will not be included in prevalence pooling. The following data items will be extracted: Study characteristics. Author(s), year of publication, country, geographic region (sub-Saharan Africa, South/Southeast Asia, Latin America, Europe/North America, other) Study design (cross-sectional, prospective cohort, retrospective cohort, case-control) Data collection period, healthcare setting (hospital, community, ART clinic) Funding source and conflict of interest disclosures Participant characteristics. Sample size, mean/median age and age range, sex distribution HIV clinical stage (WHO staging), median CD4 count and range, proportion virally suppressed ART status and specific regimen: naive, on PI-based, NNRTI-based, or INSTI-based ART Duration of HIV infection and ART exposure, comorbidities (hypertension, diabetes, CKD, obesity) Outcome data. Definition of hyperuricemia applied and sex-specific cut-off values (mg/dL or μmol/L) Definition of gout (clinical, ACR/EULAR criteria, crystal-confirmed) and diagnostic method Number of participants with hyperuricemia and/or gout; crude prevalence estimate with 95% CI Mean/median serum uric acid level and standard deviation/IQR Risk factors assessed and adjusted/unadjusted odds ratios (OR) or prevalence ratios (PR) with 95% CIs Data on gout as IRIS manifestation: time from ART initiation to gout presentation, joints involved, CD4 recovery Quality assessment (risk of bias) Two reviewers will independently assess study quality using validated tools: For cross-sectional and cohort studies reporting prevalence data: the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data [ 25 ], which evaluates nine domains including sampling frame appropriateness, sample size justification, and validity of the measurement instrument. For case-control and cohort studies examining risk factors: the Newcastle-Ottawa Scale (NOS) [ 26 ], evaluating selection of study groups, comparability, and ascertainment of outcome/exposure. Studies will be classified as low, moderate, or high risk of bias. High-risk-of-bias studies will be retained in the primary analysis but excluded in sensitivity analyses. Risk of bias will be summarized using traffic-light plots generated in the robvis R package
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