Is CD4 + T‐cell recovery ‐ Associated with hypertension during initial antiretroviral therapy in human immunodeficiency virus patients?

There is something refreshing at this time, when both lay press as well as the scientific and medical communities are obsessed with the COVID‐19, to remind ourselves there are also other diseases. One such disease, human immunodeficiency virus (HIV) disease, affects now almost 40 million people and had claimed about 32 million lives. ¹ The advent of antiretroviral therapy (ART) had changed the course of the disease from a relentless progressive disease culminating in acquired immunodeficiency syndrome (AIDS), opportunistic infections and subsequent death to a manageable chronic disease. Nevertheless, this huge achievement comes with a price tag, increased cardiovascular disease, ² driven to a great extent by hypertension. As reviewed by Fahme et al, ³ the increased prevalence of hypertension in this context is undebatable, yet, the mechanisms by which ART‐treated HIV subjects develop hypertension is not that clear. Several mechanisms had been proposed including gut microbiome alterations, immune reconstitution, lipodystrophic effects, HIV related renal disease, protease inhibitors induced arterial stiffness, or some direct ART effects. In this issue of the Journal of Clinical Hypertension, Reis et al ⁴ studied prospectively about 500 HIV patients and 500 non‐HIV infected control subject in Tanzania, who had been attending public HIV clinics in the city of Mwanza. The controls were HIV uninfected subjects designated as "treatment supporters" required for ART in Tanzania.

This study has several advantages, it is prospective, fairly large reasonably representative sample of fairly young subjects (median age 36 interquartile range from 26‐43 years), blood pressure (BP) was measured 3 times in an unobserved yet structured fashion increasing its validity, and directly measured height weight and waist circumference. None of the participants were taking antihypertensive therapy. At baseline BP was correlated with age, male gender, body mass index (BMI) and low fruits consumption, quite similar to what happens in most clinical environments. They describe several interesting findings: BP at baseline was lower in the HIV patients than in the uninfected controls, decreased during the first 6 months of ART in both groups to rise later to higher levels in the HIV patients than those of the controls, this rise of BP is accompanied by rise of BMI, weight circumference and hemoglobin, as well as rise of CD4 + T cells. Another finding was that low BP < 90 mm Hg systolic was associated with increased mortality, a rather expected finding as low BP is frequently associated with poor health, and indeed of the 17 people who had such a BP and had died of whom 5 had had tuberculosis with immune reconstitution inflammatory syndrome. Unfortunately, the BMI of these patients is not described.

In a multivariable logistic regression model, patients who had baseline systolic BP < 120 mmHG, the rise in CD4 + cells as well as rise of hemoglobin and weight circumference were significantly associated with a greater BP rise. BMI was excluded from the model because of collinearity with waist circumference; nevertheless, weight may rise in recovering patients first and waist circumference later.

The authors attempt to explain the greater rise of BP in the HIV patients by way reconstitution of immune functions associated with the increase of CD4 + T cells and their putative role in hypertension. Notwithstanding such a theory, the concomitant rise of weight, hemoglobin, and these T cells points probably to the ART induced recovery from HIV effects. The greatest rise is most notable in those with lowest CD4 + cells as a marker of disease stage, where the sickest responders are likely to have the greatest effect on both HIV disease markers such as CD4 + T cells and other parameters of disease such as weight, hemoglobin levels, and BP. Indeed, hypertension in HIV patients was not always associated with HIV disease markers such as CD4 + T cells and viral load levels. ⁵ In a different study in Tanzania, admittedly in a rural rather than urban setting, hypertension was common among HIV treatment naïve patients and increased subsequently in association with age, BMI, and reduced estimated glomerular filtration rate, but not with either ART or CD4 + T‐cell counts. ⁶

Additionally, other mechanisms may be in action, higher arterial stiffness was found to be associated with some forms of ART. ⁷ ART has profound effect on components of the metabolic syndrome through a variety of metabolic effects including insulin resistance, which may affect BP and cardiovascular risk which may now be the major determinant of outcome in treated HIV patients. ⁸ Insulin resistance in turn may cause hypertension and was found to be its predictor even in young lean subjects. ⁹

Prolonged ART use has been associated with a higher prevalence of systolic hypertension, ¹⁰ and an association between hypertension and higher waist‐hip ratio has also been suggested. ¹¹ , ¹² However, these studies are based on older patients living with HIV and older ART regimen. It is important to further investigate the role of ART on hypertension and other cardiovascular risk factors. For example, weight gain has recently emerged as a major concern with respect to new integrase inhibitor medicines such as dolutegravir. In the ADVANCE trial, ¹³ which was conducted in South Africa, dolutegravir and TAF containing regimen were associated with weight gain, which was more severe in female patients and patients with lower CD4 counts. Dyslipidemia has also been observed with some protease inhibitors, efavirenz (NNRTI) and elvitegravir/cobicistat (integrase inhibitor). ¹⁴ In the present study, 80% of patients were treated with tenofovir‐lamivudine‐efavirenz, 6% received tenofovir‐lamivudine‐dolutegravir, and 14% other treatments; the contribution of ART itself to weight and BP was not analyzed. Further studies need to address the effect of HIV on hypertension, with regard to the effect of different ART regimens on weight gain and subsequent BP elevation.

It is likely that the rise of CD4 + T cells in the study of Reis et al ⁴ is rather an epiphenomenon of improvement of HIV infection state, and the rise of BP during ART is in line with other such epiphenomena such as BMI and hemoglobin levels, all well‐known markers of infectious disease improvement.

CONFLICT OF INTEREST

None.

Bursztyn M, Israel S. Is CD4 + T‐cell recovery ‐ Associated with hypertension during initial antiretroviral therapy in human immunodeficiency virus patients?. J Clin Hypertens. 2020;22:1563–1564. 10.1111/jch.13976