The development of high blood pressure (hypertension) after starting antiretroviral treatment in sub-Saharan Africa is common but can be managed with monitoring and low-cost generic drugs, Professor Francois Venter of the University of the Witwatersrand told the 12th International AIDS Society Conference on HIV Science (IAS 2023) in Brisbane, Australia, on Tuesday.
"Mass HIV treatment programmes need to include support and funding for diagnosis and treatment for hypertension," Professor Venter told the conference. In two large studies, between a third and half of participants had high or borderline high blood pressure after four years on treatment.
Another study presented at the conference showed that in cohorts of people with HIV in Europe and Australia, the rate of hypertension was highest in people taking both tenofovir alafenamide and an integrase inhibitor, even after adjusting for weight gain on treatment.
Professor Venter said that more research is needed to tease out the relative contributions of antiretroviral drugs and weight gain after starting treatment to the development of high blood pressure in people with HIV.
Weight gain is common after starting antiretroviral treatment. The ADVANCE study, conducted in South Africa, showed significant differences in weight gain between first-line antiretroviral regimens. People taking dolutegravir gained more weight than people taking efavirenz and weight gain was greatest when dolutegravir was combined with tenofovir alafenamide.
Weight gain increases the risk of developing high blood pressure, which in turn increases the risk of heart attack, stroke and other cardiovascular problems. High blood pressure can also damage the kidneys, affect eyesight and cause erectile dysfunction. As high blood pressure has no symptoms, it can go undetected for years, causing silent damage to blood vessels. High blood pressure before conception increases the risk of developing pre-eclampsia, a dangerous form of high blood pressure, during pregnancy.
Two studies presented at IAS 2023 explored the extent of hypertension in people taking antiretroviral treatment and its association with integrase inhibitor-based antiretroviral treatment.
Francois Venter reported on the prevalence of hypertension in two large studies of integrase inhibitor-based antiretroviral treatment, ADVANCE and NAMSAL, carried out in sub-Saharan Africa (see this report for a detailed description of both studies).
Hypertension in the NAMSAL trial
NAMSAL randomised 613 previously untreated people with HIV in Cameroon to receive either dolutegravir or lower-dose efavirenz (400mg) combined with tenofovir disoproxil and lamivudine. Participants were followed for 192 weeks. During the study, women gained a median of 9kg and men gained a median of 7kg on dolutegravir, most of it in the first 48 weeks of treatment. Participants on efavirenz also gained weight (6kg in women and 4kg in men).
As participants gained weight, blood pressure began to creep up. By week 96, systolic blood pressure had risen by 5mmHg in people taking dolutegravir, and by the end of the study it had risen by 10mmHg. After week 72 of the study, there was a significant difference in mean systolic blood pressure between dolutegravir and efavirenz recipients, so that by week 192, mean blood pressure was 6.5mmHg higher in dolutegravir recipients (p<0.01).
At baseline, similar proportions in the two study arms had high blood pressure (12% and 10%). From week 144 of the study, a significantly higher proportion of dolutegravir recipients had systolic blood pressure above 140mmHg or diastolic pressure above 90mmHg (25 vs 12%, p=0.01) and by week 192, 31% of the dolutegravir group versus 9% of the efavirenz group had high blood pressure (p=0.02). As anti-hypertensive treatment is not provided routinely in primary healthcare in Cameroon, less than 1% of participants started anti-hypertensive treatment during the study.
Hypertension in the ADVANCE trial
The ADVANCE study compared three regimens in 1053 previously untreated people with HIV in South Africa:
- efavirenz (600mg), tenofovir disoproxil and emtricitabine
- dolutegravir, tenofovir disoproxil and emtricitabine
- dolutegravir, tenofovir alafenamide and emtricitabine.
Weight gain was greatest in women receiving dolutegravir with tenofovir alafenamide; they gained a mean of 10kg after 192 weeks, compared to approximately 7kg in men receiving the same combination. Weight gain on the two other combination was less.
Approximately 10% in each study arm were being treated for hypertension at baseline. Thirteen per cent in the dolutegravir/tenofovir alafenamide/emtricitabine arm developed hypertension during the study, compared to 11% in the dolutegravir/ tenofovir disoproxil/emtricitabine arm and 8% in the efavirenz/tenofovir disoproxil/emtricitabine arm.
As in the NAMSAL study, blood pressure increased over time, although the average increase in systolic pressure after four years was smaller in ADVANCE (+2mmHg). This was because once diagnosed, hypertension was routinely treated, so that 94 out of the 100 people newly diagnosed with high blood pressure received treatment for it. Professor Venter said that high blood pressure is easily treated with low-cost generic drugs in South Africa.
At baseline, a substantial proportion of study participants already had hypertension. Thirty-nine per cent in the dolutegravir study arms and 38% in the efavirenz arm had either systolic blood pressure above 135mmHg or diastolic blood pressure above 85mmHg. (Note that the cut-off point for defining high blood pressure varies between studies and countries.) By week 192, people receiving dolutegravir were significantly more likely to fall into this category and the proportion with high blood pressure had grown substantially (54% of dolutegravir recipients compared to 47% of efavirenz recipients, p=0.047).
Using the DAIDS grading system for hypertension, 43% of dolutegravir recipients and 35% of efavirenz recipients had blood pressure in the high normal range (130-139 systolic and 85-89 diastolic) at week 192 (p=0.047). Just over 6% in each arm of the study (6.4%) had grade 1 high blood pressure and 4% in the dolutegravir arms and 2.5% in the efavirenz arm had grade 2 or 3 high blood pressure (seriously elevated).
Although there was a drug-related difference in blood pressure, Professor Venter cautioned that when people receiving anti-hypertensive treatment were excluded from the analysis, a preliminary analysis suggests that hypertension is associated with weight gain rather than treatment. But he said that more data are needed to determine if the development of hypertension is drug-related.
Not all clinical trials of agents in current use reported on blood pressure, he said, and those that did produced mixed findings. But seven observational studies in various populations have shown consistently that hypertension was more likely to be diagnosed in people treated with dolutegravir.
Hypertension in the RESPOND cohort study
Another large study presented at the conference concluded that the risk of hypertension is greater in people treated with an integrase inhibitor and tenofovir alafenamide (TAF). Dr Dathan Byonanebye of the Kirby Centre, University of New South Wales, presented an analysis of the relationship between antiretroviral treatment, weight and blood pressure in 19 observational cohorts in Europe and Australia. The study included people at all stages of treatment and looked at the incidence of hypertension and elevated lipids, adjusted for time-updated body mass index (BMI).
Cohort members were eligible for inclusion in the analysis if they were taking an integrase inhibitor, efavirenz, rilpivirine, boosted darunavir or atazanavir, and had a baseline BMI measurement and at least two follow-up measurements. Participants had at least two blood pressure and lipid measurements.
For the hypertension analysis, 9704 people were eligible for inclusion. Thirty per cent developed hypertension during 39,993 person-years of follow-up. Compared to people who did not take a integrase inhibitor or TAF, those taking both an integrase inhibitor and TAF had a 48% higher rate of hypertension after adjusting for time-updated BMI and other confounding factors. In other words, the type of antiretroviral treatment they took was still associated with their risk of developing high blood pressure, even after adjusting for changes in BMI during the study period.
Treatment with either an integrase inhibitor without TAF, or TAF without an integrase inhibitor, was also associated with a higher rate of hypertension after adjusting for BMI changes, but the increased incidence relative to no integrase inhibitor or TAF was smaller (33% greater for TAF and 25% greater for an integrase inhibitor).
For the dyslipidaemia analysis, 5231 people were eligible for inclusion, of whom just over half (51%) developed dyslipidaemia during 19,547 person-years of follow-up. The current use of TAF with an integrase inhibitor was associated with a 15% increased rate of dyslipidaemia after adjusting for changes in BMI during follow-up. Use of TAF without an integrase inhibitor was not associated with dyslipidaemia.
Venter WF et al. Risks of hypertension with first-line dolutegravir (DTG) and tenofovir alafenamide (TAF) in the NAMSAL and ADVANCE trials. 12th International AIDS Society Conference on HIV Science (IAS 2023), Brisbane, Australia, abstract OALBB0504, 2023.
Byonanebye DH et al. Impact of INSTI and TAF-related BMI changes and risk on hypertension and dyslipidemia in RESPOND. 12th International AIDS Society Conference on HIV Science (IAS 2023), Brisbane, Australia, abstract OALBB0505, 2023.