After the introduction of antiretroviral therapy (ART), the world successfully achieved higher viral suppression and a lower viral load burden, followed by a reduction in mortality and morbidity associated with HIV and an improvement in the quality of life of people living with HIV (1, 2). But, now a days, the care given to this population is complicated by the emergency of other comorbidities introduced by HIV itself and as a result of ART toxicities (3, 4). Exposure to ART for a longer duration of time enhances the susceptibility of these patients to developing these comorbidities, in which atherosclerotic cardiovascular disease (ASCVD) gains the most attention due to its association with the morbidity and mortality of people living with HIV (5–8).

Several studies have revealed that hyperuricemia and chronic inflammation have been proposed as potential mechanisms through which HIV and ART cause ASCVD (9, 10). Uric acid, the end product of purine metabolism, has been associated with metabolic syndrome, and it induces endothelial dysfunction, both of which are the main risk factors for ASCVD in general as well as in people living with HIV (9–16). Increased the activity of the pentose phosphate pathway (PPP) and increase the production of ribose 5-phosphate which stimulate purine nucleotide phosphorylase for nucleotide synthesis, that in turn increased the production of uric acid as well as ART-induced mitochondrial toxicity subsequently increased lactate which compete with uric to be excreted were the possible ways for hyperuricemia seen in treated HIV patients (17–19).

Hyperuricemia was increasingly seen among people living with HIV on ART than in the general population, which indicates people living with HIV are at greater risk of cardiovascular disease (CVD) than HIV-negative people, which means attention must be given to these people to prevent CVD (20). An increased risk of having hyperuricemia was seen among treatment-naive compared to treatment experienced people living with HIV (21, 22). It is observed that hyperuricemia was also detected in HIV patients taking HAART (23, 24). Accordingly, a study from Italy reported that 25.2% of people living with HIV on HAART developed elevated serum uric acid levels (12). The potential to cause an altered level of uric acid was different for different ART classes. Patients treated with stavudine, didanosine, and protease inhibitors had significantly increased levels of uric acid. However, tenofovir is associated with reduced levels of uric acid, and abacavir has a neutral effect on uric acid concentration (25).

Studies have reported that patients treated with dolutegravir (DTG) have elevated levels of uric acid (26, 27). Another study also showed people living with HIV on ritonavir-boosted protease inhibitors, especially ritonavir-boosted atazanavir (ATV/r), were observed to be hyperuricemic (28, 29).

Research into CVD risk factors has identified a number of inflammatory biomarkers, such as interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) (30–32). A study from Italy showed an increased hsCRP level was detected in people living with HIV on combination antiretroviral therapy (cART), which makes hsCRP a useful additional biomarker to predict the risk of HIV patients developing CVD (33, 34). The risk of elevated hsCRP levels was higher among people living with HIV than HIV-negative populations, but the risk was higher for treatment-naïve patients (35, 36). Another study showed similar hsCRP levels were observed during pre-ART and 36 weeks after commencing ART (37). However, one study from Ghana reported that 32.5% of patients on ART have increased hsCRP levels greater than or equal to 3 mg/L (31). A study from France complains that the use of ATV/r containing ART enhances inflammation due to its effect on activation of NF-kB and increased levels of different inflammatory biomarkers (38). It is speculated that the use of integrase strand transfer inhibitors (INSTI) is associated with reduced inflammation, which is determined by elevated levels of different inflammatory biomarkers including hsCRP levels (39). Inflammation as measured by hsCRP levels is reduced after patients switch to INSTI from boosted-protease inhibitors (40, 41). However, a conflicting result was posted, which indicates the association of INSTI including DTG with increased inflammation (42–44).

Several factors contributed to hyperuricemia and increased inflammation measured by hsCRP, such as duration of HIV and HAART, age, obesity, alcohol intake, smoking, region, ethnicity, and low CD4 cell count (45–47).

The DTG is a new integrase inhibitor that has been recommended by the World Health Organization (WHO) as the preferred first-line regimen for people living with HIV (48). ATV/r is widely used as a second-line therapy in Ethiopia (49). DTG is effective, has high antiviral potency, and can be used without pharmacological enhancements (50, 51). As a result of this, most of the patients are on a regimen containing these ARTs.

Despite this, there is no well-documented evidence that shows the level of uric acid and hsCRP among patients taking DTG and ATV/r-based regimens in sub-Saharan Africa, including Ethiopia. The current WHO guideline does not include uric acid monitoring in patients taking these regimens, but they are useful biomarkers to detect and prevent the early occurrence of CVD. Therefore, the present study is designed to assess the serum level of uric acid, hsCRP, and their associated factors among adult HIV patients taking DTG and ATV/r-based antiretroviral therapy at Jimma University Medical Center, Southwest Ethiopia.

This study explored the levels of uric acid and hsCRP as well as their associated factors among people living with HIV taking dolutegravir and ritonavir-boosted antiretroviral therapy. This is the first study in Ethiopia, given that the drug (DTG) is relatively new for HIV management in Ethiopia.

The prevalence of hyperuricemia among the whole participants was 76.7% (66/172), of which 46.5% (40/86) and 30.2% (26/86) were DTG-treated and ATV/r-treated patients, respectively (p = 0.028). It also found a higher mean level of uric acid among the patients treated by the DTG-based regimen than the ATV/r-based regimens. This observation is comparable to study findings from China (59), Portugal (27), and Japan (26) but is incongruent with another study finding reported from Japan (60). The proportion of treatment-naïve patients (71.6% in their study and with all were treatment-experienced in our study), male participants (91.9 and 51.1% in Japan and our study, respectively), in addition to study design, sociodemographic characteristics and differences in ethnicity might contribute to this incongruency of findings Although individuals of Africans origins had the lowest hyperuricemia and gout risk allele frequencies than Asian descent (61), they may respond differently to ART to result in hyperuricemia.

Consequently, according to our study findings, it was observed that the proportion of patients with increased hsCRP levels ≥2 mg/L was 24.4% (21/86) among patients with a DTG-based regimen and 44.2% (38/86) for patients treated with ATV/r-based regimen (p = 0.006), which was in line with San Francisco (52) and Boston (62). On the contrary, our finding is inconsistent with a study conducted in California (63). The possible reasons for this might be differences in sociodemographic, lifestyle, study design, ART combination, and ART exposure status. For instance, the study from California used TDF plus FTC as the backbone, which is TDF plus 3TC in our study. The participants were treatment-naïve in California and treatment-experienced in our study. In additions, the differences in race (which is whites in California and black Africans in our study) might contribute for this inconsistency of findings. For instance, the elevated levels of hsCRP were seen among African peoples compared to Europe and the United states (34). It is also essential to note that ART response of individuals might be varied due to variation in genetics that contributed for different plasma levels of hsCRP (64). Furthermore, our study was designed to assess factors associated with hyperuricemia and increased hsCRP levels. Accordingly, patients taking ART for more than 24 months were two times more likely to have hyperuricemia. This is similar to studies done in China and Nigeria (23, 65). Patients treated with a DTG-based regimen had a two-fold higher risk of developing hyperuricemia, which was in agreement with a study finding from China (59), which showed the number of patients with hyperuricemia increased with DTG-containing ART. ART-induced mitochondrial toxicity with increased lactate to compete with uric acid excretion by the renal tubules and increased cell turnover followed by increased degradation of nucleotides accompanied by elevated uric acid in the serum were some of the possibilities by which uric acid is elevated in people living with HIV on HAART (66–69). Patients with waist circumferences above the cutoff level had a two-fold increased chance of developing hsCRP levels ≥2 mg/L, which is in line with a study done in Brazil (70). This might be due to the fact that in obese patients, adipocytes produce powerful pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and IL-6, which in turn stimulate the secretion of CRP in the liver and endothelial cells (71). Elevated hsCRP levels increased the risk of HIV patients on HAART for ASCVD, independent of traditional risk factors (33).

The ATV/r was associated with elevated hsCRP levels. This is comparable to study findings from Spain (40) and Italy (72). Ubiquitin-specific protease 18 (USP18) inhibitions lead to activation of nuclear factor kB (NF-kB) signaling, and augmented expression of pro-inflammatory cytokines with elevated inflammatory biomarkers is the possible way by which ATV/r increases the serum level of hsCRP levels (38).

In general, our study showed a higher mean as well as proportion of uric acid with the use of a DTG-based regimen, whereas a higher proportion of hsCRP levels was found among those treated by ATV/r-based regimens. Being on a DTG-based regimen and taking HAART for a long period of time was significantly associated with hyperuricemia. Increased waist circumference and ATV/r-based regimen were identified as significant predictors associated with increased hsCRP levels. Therefore, it is important to consider and evaluate hsCRP levels for patients with increased waist circumference and treated by ATV/r containing ART, along with uric acid levels for patients on HAART for a long duration and taking DTG containing ART, to prevent the risk of having ASCVD. For this, policymakers should take these factors into account when developing public health initiatives on ART side effects management and when strengthening on going non-communicable disease reduction programs. We propose that researchers conduct a prospective cohort study with a larger sample size to determine the exact effects of DTG and ATV/r on serum uric acid and hsCRP levels. Lastly, we suggest a comparative analysis of DTG and ATV/r containing ART in ART-naïve, HIV-positive patients.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by Institutional Review Board of Jimma University with reference number: IHRPG1/5/2021. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

NW: Data curation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing, Conceptualization, Formal analysis, Investigation, Supervision. SN: Conceptualization, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. RU: Formal analysis, Methodology, Software, Supervision, Visualization, Writing – original draft, Writing – review & editing. MJ: Data curation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing.