People with HIV more likely to develop high blood pressure after starting an integrase inhibitor

People with HIV taking integrase inhibitors were more likely to develop high blood pressure than those taking non-nucleoside reverse transcriptase inhibitors (NNRTIs), a large international cohort study has reported.

People taking protease inhibitors were also at greater risk of developing high blood pressure, the study found.

A previous AIDS diagnosis, a CD4 count below 350, older age or a body mass index of 30 or above (clinically obese) at the beginning of the follow-up period each independently predicted the development of high blood pressure.

Raised blood pressure (hypertension) is common in older people and people who are overweight. Smoking, high alcohol consumption, illicit drug use and raised lipid levels also increase the risk of high blood pressure. A meta-analysis of studies in people with HIV estimated that 35% of people living with HIV taking antiretroviral treatment have high blood pressure.

High blood pressure increases the risk of various forms of cardiovascular disease, including stroke, heart failure, heart attack and atrial fibrillation, as well as raising the risk for chronic kidney disease and dementia. Maintaining a normal blood pressure contributes to the prevention of cardiovascular disease.

Numerous factors associated with HIV including metabolic changes and inflammation might contribute to the development of high blood pressure, but the precise pathways are uncertain. Previous research has shown that some antiretroviral drugs, including older protease inhibitors, are associated with an increased risk of high blood pressure.

Weight gain associated with integrase inhibitor treatment might also a be risk factor, but previous studies have shown conflicting results and may not have followed participants for long enough to determine if specific treatments increase the risk of developing high blood pressure.

To investigate the link between antiretroviral drug classes and the development of high blood pressure in a diverse population of people with HIV, the RESPOND cohort collaboration identified everyone starting or switching treatment in 17 cohorts in Europe and Australia.

These cohorts follow 32,085 people with HIV. Participants were eligible for inclusion in this analysis if they had started treatment or switched to a regimen containing two nucleoside analogues and either a non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor or an integrase inhibitor between January 2012 and January 2019. The analysis excluded people treated with the newest antiretroviral drugs (doravirine, bictegravir or cabotegravir) owing to insufficient numbers. The study excluded people with high blood pressure at baseline or with missing blood pressure measurements.

A total of 4,606 people were eligible for inclusion (73% male, 69% White, 50% gay or bisexual men, 33% heterosexual and 10% people who inject drugs). Forty-six percent were starting their first regimen while 54% switched to a new regimen during the follow-up period. Existing cardiovascular disease and risk factors for cardiovascular disease were rare in the study population with the exception of smoking (38% smoked).

The median CD4 count was 508 and the median age was 43 years.

Among all study participants, 68% received an integrase inhibitor, 17.5% an NNRTI and 13% a protease inhibitor. The most commonly used integrase inhibitors were dolutegravir (1,929), elvitegravir (777) and raltegravir (458). NNRTIs included rilpivirine (487) and efavirenz (320); the most common protease inhibitor was darunavir (461). Most participants who switched treatment changed to an integrase inhibitor (84%) and approximately three-quarters switched from a protease inhibitor.

The median blood pressure measurement at baseline was 120/78 mmHg and did not differ according to regimen. During a median follow-up period of 1.5 years, 23% of participants developed hypertension. Hypertension was defined as two consecutive diastolic measurements on separate days over 140mmHg and/or two consecutive diastolic measurements over 90mmHg, or a single measurement over either of these levels followed by the initiation of anti-hypertensive medication within six months, or the initiation of anti-hypertensive medication without a recorded blood pressure measurement.

People taking an integrase inhibitor had 76% higher incidence of hypertension (adjusted Incidence Rate Ratio 1.76, 95% CI 1.47-2.11) compared to people taking an NNRTI, with a trend towards a higher incidence in previously untreated people (aIRR 1.92 versus 1.42). There was no significant difference in the incidence of hypertension between people taking integrase inhibitors or boosted protease inhibitors.

Multivariable analysis showed that apart from the class of antiretroviral third agent, several other factors were associated with an increased incidence of hypertension. A baseline CD4 count below 350, older age, type 2 diabetes, a body mass index of 30 or over, a prior AIDS diagnosis or being treatment-naive each modestly increased the risk of developing high blood pressure, but with the exception of age these factors had a less pronounced effect than treatment with an integrase inhibitor rather than an NNRTI. People aged 55 and over were more than twice as likely to develop high blood pressure compared to people aged 35 and under.

The study also showed that the risk of developing hypertension was highest in those with blood pressure that was already above optimal levels (120/80). The incidence of hypertension was more than three times higher in people with a systolic blood pressure over 130 or a diastolic pressure over 85 compared with people in the optimal range (<120/<80). US guidelines issued in 2017 define hypertension as a blood pressure measurements of 130/80, with any measurements over 120/80 described as 'elevated'.

The study investigators say that people with traditional risk factors for hypertension or a prior AIDS diagnosis should receive blood pressure checks regularly, as should people who have blood pressure in the sub-optimal range.

They say that the mechanism leading to increased blood pressure in people taking integrase inhibitors is uncertain. RESPOND cohort investigators are carrying out a separate analysis to investigate further the relationship between integrase inhibitors, weight gain and hypertension, and the study authors say that further research is also needed to look at the hypertension risks associated with individual integrase inhibitors.