Association between highly active antiretroviral therapy (HAART) and hypertension in persons living with HIV/AIDS at the Bamenda regional hospital, Cameroon

Introduction The introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV infection has provided different good results: like long-term viral suppression, the decrease of opportunistic infections, and repair of the immune system. Methods We carried out a hospital-based cross-sectional analytic study involving 315 participants 228 were on HAART (group 1) and 87 were HAART-naïve (group 2) at the HIV treatment centre of the Bamenda regional hospital with our study population being all people living with HIV (PLWHIV) in the North West region of Cameroon. The sampling was performed from the 15th of March to the 30th of June 2017. The questionnaire was administered face to face with participants and their vital signs taken. Blood pressure was measured using an automated electronic blood pressure monitor and hypertension (HTN) was considered as systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90mmHg. Results The prevalence of hypertension in the HAART group was 36.44% (n=82, CI: 30.15%-43.10%) compared to that of the HAART-naïve group which was 13.33% (n=12, CI: 7.08%-22.13%, P=0.01). HAART was associated with HTN after controlling for gender, family history of hypertension, body mass index (BMI), smoking and alcohol consumption. The odds ratio of the HAART-treated versus the HAART-naïve was 3.86 (95% CI: 1.98-7.50). We also found an association between TDF/3TC/EFV (OR=2.83), AZT/3TC/NVP (OR=2.82), AZT/3TC+EFV (OR=3.48) and TDF/3TC+NVP (OR=2.36) and HTN whereas those on AZT+3TC+ATV/r (OR=0.84) and TDF+3TC+ATV/r (OR=0.45) were not associated to hypertension. Conclusion Our result suggests that blood pressure should be periodically measured and treated when necessary in PLWHIV on HAART.


Introduction
HIV is a major public health problem in the world today. In 2015, 2.1 million new HIV infections were recorded worldwide, adding up to a total of 36.7 million people living with HIV in the world [1]. About 1.1 million people died of AIDS-related illnesses worldwide [1]. Although the burden of the epidemic continues to vary considerably between countries and regions, sub Saharan Africa remains the most severely affected with 4.4% of persons living with HIV [1]. This percentage accounts for nearly 70% of the people living with HIV worldwide. Whereas concerns of a link between HAART and coronary heart disease (CHD) have increased. An elevated risk of myocardial infarction among people taking HAART has been found in some studies. Investigators have assessed the relationship between the uses of antiretroviral therapy (ART) and components of the metabolic syndrome including dyslipidemia [2], insulin resistance [1,2] and abnormal fat distribution [3]. Despite the scarcity of data on cardiovascular diseases (CVD) in people living with HIV in Africa, a study estimates the prevalence of self-reported CVD risk factors in HIV patients in Africa at 12% [4].
In Uganda, about 18% of HIV-infected adults were found with subclinical atherosclerosis which can be predictive of CVD [5]. Recent data suggest that cardiovascular diseases such as heart failure, coronary artery diseases hypertension and stroke are common and appear to be very frequent in HIV infected population in low and middle income countries [5,6]. HAART and especially protein inhibitors (PIs) seem to be associated with metabolic dysfunction and could increase the risk of cardiovascular events [6]. Recent reports raise increasing suspicion that HAART may also induce hypertension [7][8][9][10][11].
Conflicting results have been reported for the association between HAART and blood pressure and for the association between HAART and the prevalence of hypertension [12,13]. The relationship between HAART and hypertension has not been well studied [13].
Hypertension appears to be linked to insulin resistance; in particular, hypertension seems to be a part of the metabolic syndrome [14].
Interestingly, increase blood pressure has been found to be associated with lipodystrophy [13]; providing thus additional evidence that HAART and hypertension may be linked via pathways involving lipodystrophy or other metabolic disorders [15]. The association between HAART and hypertension has been documented elsewhere [7][8][9][10][11][12][13]. Due to the conflicting results between HAART and hypertension and the lack of data on this subject in the North West region of Cameroon, there is a need to improve our knowledge on the impact of HAART on the possible development of side effects such as hypertension in people living with HIV (PLWHIV) and under ART. This study was carried out with the aim to identify side effects resulting from ART in order to improve the control of HIV/AIDs by putting at the disposal of policy makers and stakeholders' information that could help them to ameliorate the treatment of PLWHIV.
Research question: how can the identification of side effects resulting from HAART help in the management of PLWHIV who are under treatment (HAART) Objective: the main objective of this study was to evaluate blood pressure (hypertension) in PLWHIV and to determine the association between highly active antiretroviral therapy and hypertension in PLWHIV at the Bamenda Regional Hospital.
The specific objectives were: determine the prevalence of hypertension in PLWHIV under HAART and those not treated who attend the Bamenda regional hospital; compare the prevalence of hypertension in these two groups (PLWHIV under HAART and HAARTnaïve clients) of PLWHIV; to determine the association between HAART and hypertension in PLWHIV.
Page number not for citation purposes 3 Methods Study design: this was a hospital based cross-sectional analytic study at the HIV treatment centre of the Bamenda Regional Hospital.
Our study population was all PLWHIV in the North West region. The study was conducted from the 15 th of March to the 30 th of June 2017.
Study area: the study was conducted in the Bamenda Regional

Selection criteria
Inclusion criteria: for the control group, all newly diagnosed cases in the Bamenda Regional Hospital aged 20 years and above who are not yet on treatment and consented to take part in the study were included in the study. For the intervention group, PLWHIV age 20 years and above who had been on continuous HAART for at least 24 months (2years) were included.
Exclusion criteria: all clients with pre-existing hypertension before HAART initiation whether on anti-hypertensive medication or not were excluded. Clients on oral contraceptives, corticosteroid and other medications whether traditional or modern medication that could affect blood pressure were also excluded. Clients with a family history of hypertension, with a confirmed non-adherence to HAART for 6 months, with confirmed psychological stress or any abnormal physical stress were also excluded. Those who smoke or drink more than 2 bottles of beer a week and who did not give their consent where also excluded. we thus needed 313 participants. To account for potential nonresponse, 344 participants were selected. Thus, Non-respondent was considered to be 10% of the sample size. This gives us a total of N=344 persons.

Data management and statistical analysis
Data quality assessment: each filled questionnaire was checked again to ensure that all the questions are answered and correctly. All the questionnaires were checked daily for completeness and consistency. Those that were not correctly filled were rejected. The completed questionnaires were rechecked to maintain the quality of data.
Statistical analyses: at the end of each day, questionnaires were collected and coded before being transmitted for data entry. Double entries were made and analyzed using EPI Info 7 and Excel 2010.
Descriptive and inferential statistical analysis was used. Uni-variate and multi-variate logistic regression analysis were used to determine if there is an association between HAART and hypertension.
Unadjusted and adjusted odd ratio (AOR) and their corresponding 95% confidence interval were used to examine the strength of association. P values of less or equal to 0.05 was considered significant.
Ethical consideration: the protocol for this study was reviewed and approved by the University of Dschang; more so, authorization to carry out the research was obtained in the research site. Patient's confidentiality was respected and consented participants enrolled in to the study.

Socio-demographic
and clinical characteristics of participants: a total of 315 participants were enrolled in the study, 228 were on HAART (group 1) and 87 were HAART-naïve (group 2 were separated and 1.59% (n=5) were divorce (Figure 1). Age distribution in the study participants: the majority of the participant age ranges between the ages of 36 to 55 years (68.15%). Figure 4 shows the age distribution of all the participants.  Table 2).

Association between HAART and hypertension in PLWHIV: in
our analysis using logistic regression, we observed that being on HAART was significantly and positively associated with having HTN.

Discussion
This study found a significant higher prevalence of hypertension among PLWHIV on HAART than their HAART-naïve counterparts.
HAART was significantly and positively associated to hypertension even after adjusting for confounders. Trends in published research findings on this subject have shown a mixture of association and lack of association between HAART use and hypertension. This study is similar with that of several studies which show a higher prevalence of HTN with HAART [14]. This result supports the fact that HAART can possibly induce hypertension in people under HAART. Our results are not in line with other studies which revealed no significant difference in the prevalence of HTN between patients on HAART and HAARTnaïve people [16] or even a lower prevalence of HTN with NNRTI's use [10]. These differences observed between results of these studies could be due to several factors such as differences in geographical location, study settings, clinical characteristics of the study participants and even study designs. The prevalence of hypertension in our participants on HAART (36.44%) was higher than that found in previous studies [16,17]. This high prevalence can be explained by the fact that participants of our study were on HAART for a long time (7.92 years) compared to the participants of the above studies. This hypothesis is supported by the findings of the Multi-centre AIDs cohort study which suggested a link between the duration of HAART and high blood pressure [18]. This Multi-centre study showed, that prolong HAART (defined as 2-5years in duration) was independently associated with development of HTN, whereas HAART of less than 2 years in duration was not [18]. Contrary to our study which was predominantly composed of females, all the participants of the multi- suggesting that HAART has a significant direct impact on blood pressure. In contrary, other authors like [14,20]  as the control group [16]. Ideally, the control group should be recruited from the same population from which the case arose as seen in the study of Serberg et al. 2005 [18]. All participants in our study were recruited from the same health facility.
Our study showed that TDF/3TC/EFV, AZT/3TC+EFV, AZT/3TC/EFV and TDF/3TC+NVP were associated to hypertension. This might be due to the presence of Tenofovir and Lamivudine in the different regimens. Our results are in line with those of [21], showing that treatment regimens containing Tenofovir/Lamivudine were associated with an increased risk of developing elevated blood pressure compared to those containing Zidovudine/Lamivudine. In another study Gallant et al. (2005) [22] showed that treatment with Tenofovir is associated with declined renal function that could lead to elevation  [14,24]. We did not also distinguish primary from secondary hypertension. Our study did not control for potential confounders such as diabetes, renal disease and dyslipidaemia. Our findings reporting that TDF/3TC/EFV, AZT/3TC+EFV, AZT/3TC/EFV, and TDF/3TC+NVP were associated to hypertension and that HAART regimens containing Atazanavir were not associated to hypertension warrant further investigation ideally in the context of a randomized controlled trial.

Conclusion
This study showed that the prevalence of hypertension in PLWHIV on HAART was twice that of PLWHIV who were not on HAART (HAARTnaïve). Our result shows that PLWHIV and who are on HAART were more likely to have hypertension than those who are not on HAART.
They show also a significant association between HAART and HTN.
The treatment regimens TDF/3TC/EFV, AZT/3TC+EFV, AZT/3TC/EFV and TDF/3TC+NVP were associated to hypertension whereas AZT+3TC+ATV/r and TDF+3TC+ATV/r were not associated to Page number not for citation purposes 7 hypertension. The high prevalence of hypertension, a known cardiovascular risk factor combined to the risk factor of metabolic disorders related to HAART are worrisome and should be monitored periodically and treated when necessary.

What is known about this topic
• Other researchers from different areas carried out research on the prevalence of HTN between patients on HAART and HAART-naïve people and they had conflicting results in others the prevalence was higher in the HAART group than the HAART-naïve group and they found a significant difference between the two groups. Whereas in others there was no significant difference; • Other researchers on other countries worked on the association between HAART and HTN and some say there is an association while others say there is no association; • Another study was carried out to find out which particular therapy is associated to hypertension.

What this study adds
• We found out that the prevalence of hypertension in the HAART group was two times higher than that of the HAARTnaïve group and there was a significant difference between the two groups; • We found a significant and positive association between HAART and hypertension(we are the first to find out this in Cameroon); • We then went further to find out the prevalence of hypertension in the different HAART regimens and we found that the highest prevalence were in clients who took TDF/3TC/EFV and the lowest were in clients who took AZT+3TC+ATV/r; in our study, since all of our clients were on triple therapy it was not possible to assess the association that exist between each regimen and hypertension. But our study found out that TDF/3TC/EFV, AZT/3TC+EFV and TDF/3TC+NVP were associated to hypertension while regimens containing Atazanavir were not associated to hypertension (We are the first to find this in Cameroon).