Background

Over 80% persons living with HIV in low and middle-income countries were taking fixed dose combination tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) by mid-2024, more so countries supported by the U.S. President’s Emergency Plan for AIDS Relief [1,2]. The widespread uptake followed WHO recommendations in 2016 and later 2018 recommending dolutegravir (DTG) anchored anti-retroviral therapy (ART) use as first line and optional second line therapy, respectively [3,4]. The recommendations followed reports of increased resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as well as multiple advantages of DTG including; having a high genetic barrier to resistance, a good side effect profile, high efficacy and less drug-drug interactions [5,6]. Dolutegravir use however has been associated with weight gain when compared to other anchor drugs like non-nucleoside reverse transcriptase inhibitors and protease inhibitors [7–10].

Obesity is a risk factor for dyslipidemia, glucose dysmetabolism, cardiovascular disease and hypertension [11–13]. With mortality and morbidity in persons living with HIV (PLHIV) shifting from AIDS associated opportunistic infections to non- infectious diseases like cardiovascular diseases, renal disease, liver failure and non–AIDS defining malignancies, it is pertinent to understand the risk posed by different ART regimens to inform surveillance decisions as well as ART choice decisions in primary care [14–18]. Whether the weight gain from integrase inhibitors, in particular DTG translates into dyslipidemia, glucose dysmetabolism, cardiovascular disease and hypertension is still subject to research.

There is growing evidence to demonstrate that weight gain noticed in patients on dolutegravir is associated with increased blood pressure as compared to patients on other regimens as demonstrated by two studies with both ART naïve and experienced adults [8,19,20] We sought to evaluate in a Ugandan cohort of PLHIV if weight gain over 48 weeks on TLD correlated with changes in blood pressure. Our cohort was of particular interest because it was composed of younger participants with minimal other risk factors for hypertension.

Methods

Results

Of the 243 patients that completed 48 weeks of follow up in the GLUMED study, 23 patients were diagnosed with hypertension and were on hypertension treatment hence were not included in the final analysis, leaving 220 patients.

Of the 220 patients’ data analyzed, 129 (58.6%) were female. The median age of the participants was 31 years (IQR: 27.0–38.0) with a median CD4 cell count of 319.0 cells/mm³ (IQR: 160.0–524.0). The majority (212 (96.4%)) of the patients were in HIV clinical stage 1 with 3 (1.4%), 4 (1.8%), 1 (0.5%) being in HIV clinical stages 2,3 and 4 respectively. Seven (3.2%) patients had an established diagnosis of active tuberculosis diagnosed at enrollment into HIV care. Overall, 138 (62.7%) had a normal BMI, 48 (21.8%) were overweight, 22 (10.0%) underweight and 12 (5.5%) obese. About half (126 (57.3)) reported not taking alcohol. Most (180 (81.8%) of the patients self-reported as meeting WHO recommendations on physical activity for health. The median serum creatine, fasting LDL, fasting HDL and fasting total cholesterol at baseline were: 0.8 mg/dl, 77 mg/dl, 31.7 mg/dl and 134 mg/dl respectively. At 24 weeks of follow up, 215 (99.5%) patients had viral suppression. (baseline characteristics are summarized in Table 1)

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Baseline clinical and demographic characteristics of the study population.

https://doi.org/10.1371/journal.pone.0325020.t001

Effect of change in weight on change in mean arterial pressure

We found a moderate positive linear relationship between weight gain and MAP over 48 weeks. On linear regression to determine the effect of change in weight over 48 weeks on change in MAP, after adjustment for sex, age, physical activity, and baseline HIV clinical stage in the final model, we found a significant adjusted β co-efficient of 0.62 (0.37, 0.86) (P < 0.001). The observed change in MAP was independent of other factors known to be risk factors for hypertension including baseline BMI, baseline renal function and waist circumference [31–33]. Table 2, Fig 1.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Linear regression evaluating the effect of net weight change from baseline to 48 weeks on change in mean arterial pressure.

https://doi.org/10.1371/journal.pone.0325020.t002

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 1. Scatter plot of change in mean arterial pressure versus change in weight with 95% confidence intervals.

https://doi.org/10.1371/journal.pone.0325020.g001

Fig 1 On linear regression, after adjustment for sex, age, physical activity, andbaseline HIV clinical stage in the final model, the adjusted β co-efficient was 0.62 (0.37, 0.86) (P < 0.001).

Discussion

In this study, we determined the effect of weight gain on blood pressure (expressed as mean arterial pressure) over 48 weeks on TLD. We found a moderate positive linear relationship between weight gain and MAP with an increase of 0.68mmHG for every 1 kg increase in body weight over 48 weeks with consistent findings after adjusting for baseline age, sex, physical activity and baseline clinical stage.

Currently, the most used ART is fixed dose combination TLD in more than 80% PLHIV in low-middle income countries [1,2]. Dolutegravir based ART has been shown to induce weight gain compared to other anchor drugs [7–10]. Increased adiposity one of the characteristics of obesity is known to cause hypertension via various complex interlinked mechanisms including sympathetic nervous system overactivation, stimulation of the renin-angiotensin-aldosterone system, alterations in adipose-derived cytokines, insulin resistance, and structural and functional renal changes [11–13]. Determining if the reported weight gain in patients on TLD correlates with increasing blood pressure can help guide physician choices when individualizing anti-retroviral therapy as well as HIV national programs in designing hypertension surveillance strategies in this group of patients. A positive correlation between dolutegravir- associated weight gain with hypertension has been reported in other larger studies involving both ART naïve and ART exposed PLHIV before and after starting dolutegravir. These studies have had generally older patients with more risk factors for incident hypertension [8,19,20]. One such studies including data from the RESPOND cohort which is a consortium cohort of PLWH with a median age of 43 from 37 countries in Europe and Australia demonstrated that participants receiving INSTIs have a higher incidence of hypertension than those receiving NNRTIs [27]

In our study, we replicated these findings in a relatively younger population (median age; 31 years) with generally minimal other risk factors for hypertension, i.e., at baseline, majority were HIV stage I, were physically active, had normal weight and had normal median creatine levels. With other positive attributes to dolutegravir like having a high genetic barrier to resistance, having less drug- drug interactions, being a once daily drug, good tolerability and low cost of production, DTG is likely to remain part of preferred first line ART for PLHIV. The likely association with hypertension still warrants more research, especially in sub-Saharan Africa where resources for screening as well as treatment for hypertension are still limited. However, this growing evidence to suggest a tendency towards worsening high blood pressure in these patients may warrant intensified blood pressure surveillance in programmatic settings and as well aggressively optimize blood pressure treatment in hypertensive patients on DTG based ART.

Our study had limitations. With our study design, we could not demonstrate if the blood pressure increase we demonstrated is higher than what would be expected in patients on other ART regimens with similar increments in weight given we did not have a comparator group on other ART regimens. Additionally, we also had a limited period of follow-up (48 weeks). Despite the limitations, we had different strengths. Pregnant and breastfeeding mothers who are at risk of gestational hypertension were excluded. We also excluded participants who were on hypertension treatment as well as those with poor adherence to ART as all these could be potential confounders in the hypertension trajectories we report.

Conclusion

We demonstrated a positive linear relationship between weight gain and mean arterial pressure in Ugandan persons with HIV over 48 weeks on tenofovir disoproxil/ lamivudine/ dolutegravir. We provide additional evidence to suggest that the noticed weight gain after starting dolutegravir based ART may be associated with a heightened risk of incident hypertension.

Acknowledgments

We acknowledge the Kampala City Council Authority- Uganda, the Makerere University Infectious Diseases Institute and the Kisenyi Health Center IV (HCIV) administration for authorizing the use of the study site. We also acknowledge the patients that participated in the GLUMED study.