Effects of exercise training on cardiovascular risk within HIV-infected adults in Malawi, Africa

Background: Antiretroviral therapy (ART) has successfully improved survival rate among people living with human immunodeficiency virus (HIV) infection (PLHIV), especially in Sub-Saharan Africa (SSA). Seventy percent (70%) of the global population of PLHIV reside in SSA. However, chronic viral infection and ART use, alongside specific ART regimens, have been linked to nearly 15% of cardiovascular disease (CVD) cases within four countries in SSA. Due to limited evidence from comprehensive screening studies in SSA, it remains difficult to understand the CVD risk attributable to ART treatment and regime switching, viral infection and other strong, independent, lifestyle-related risk factors such as poor cardiorespiratory fitness (CRF) and sedentary behaviours, among PLHIV.Notably, physical activity (PA), structured exercise therapy (ET) and lifestyle modification targeted interventions have been shown to be effective in improving CRF and reducing CVD risk in healthy adults, PLHIV and those with established CVD. However, access to such gold-standard interventions in SSA is challenging, and there is limited literature available regarding the effects of PA/ET on CVD risk among PLHIV on ART in healthcare settings in resource-constrained Malawi, SSA.Broadly, the thesis aimed to assess the effects of ET and lifestyle modification on CRF and global cardiovascular risk among PLHIV in both primary and secondary CVD prevention care settings in Blantyre, Malawi. The project also aimed to assess the effects of delivering a low-cost, supervised and structured ET on improving CRF and lowering CVD risks among PLHIV in Malawi. Furthermore, the thesis aimed to examine the accuracy of the Framingham CVD risk algorithm for PLHIV on ART in Malawi. Lastly, the project aimed to engage the PLHIV in designing a peer-led community-based CVD prevention intervention delivery approach in this resource constrained setting.Methods:Given this thesis focuses on designing and delivering supervised ET to higher risk clinical groups in resource-limited settings, an initial validation study of CRF measurement (Chapter 4) was conducted in young, African adults. Overall, this novel validation study supported the use of Chester step (CST) and Incremental Shuttle walk (ISWT) submaximal tests in assessing CRF outcomes by comparison to criterion maximal Treadmill-based walking testing with expired gas analysis. Specifically, the submaximal ISWT with portable gas analysis; or CST without gas analysis, were both highly valid when assessing CRF, as defined by maximal oxygen consumption (VO2max), in young adults of African descent.Chapter 5 presents a secondary data analysis of a randomised controlled trial (RCT) amongst 60 participants with chronic heart failure (CHF) aged 18 years and above, who were recruited from the Queen Elizabeth Central Hospital (QECH) for a cardiac rehabilitation (CR) study (Namanja et al., 2024). This study compared the effects of structured 12-week exercise training CR versus usual care on CRF outcomes in patients with CHF. This was a post hoc evaluation of participants living with and without HIV infection. The PLHIV were well-distributed amongst different sexes (males n=14, 51.9%) and most (n=18, 66.7%) reported being on ART for >5 years.The mean left ventricular ejection fraction (EF) between people living with and without HIV was comparable (54.0±10.9% versus 52.03±10.5%, respectively, p=0.47). The EF classes were also comparable with larger proportions in both groups (63% and 51.5%, respectively) having heart failure preserved EF (HFpEF). The CRF measure in this QECH study was the six-minute walk distance (6MWD), a valid, reliable and most widely applied submaximal test of functional capacity in CHF. This is the first study, in SSA, to compare physiological responses to ET between cardiac patients living with and without HIV.A cross-sectional study of CVD risk was then undertaken of PLHIV and adults without HIV infection in Malawi (Chapter 6). Initially, a total of 316 PLHIV (aged 18 to 65 years) on ART (for >6 months) attending the ART clinic at Ndirande health centre (NHC), Blantyre, were screened for conventional CVD risk factors. Thereafter, a dataset from Malawi’s large, cross-sectional epidemiological database (Malawi epidemiological research unit [MEIRU]), with age and gender matched 316 PLHIV and 316 non-HIV adults, was extracted and utilised to (i) compare and better characterise the global CVD risk in the SSA region and (ii) examine the CVD risk factor effects attributable to HIV infection and ART treatment. To the investigators’ knowledge, this is the first study to comprehensively assess the CVD risk among PLHIV, on a relatively large sample size and focusing on key factors highly associated with chronicity of HIV-infection and ART use.Using higher 30-year Framingham CVD risk scores, together with a novel CVD risk measure, namely the visceral adiposity index (VAI), higher CVD risk participants (n=48) (from the Ndirande distribution) were identified. These higher CVD risk PLHIV from the Ndirande cohort were selected for a RCT of supervised, structured exercise intervention or usual care lifestyle modification/education advice (Chapter 7). Participants were randomised, using a concealment method, into a low-cost, structured, 14-weeks supervised ET (n=24) or a personalised cardio-protective lifestyle enhancing advice (n=24). The primary variables constituted predicted peak oxygen consumption (Pred.VO2peak), composite 30-year CVD risk, VAI and quality of life (QoL) outcomes. Secondary measurements included blood markers for chronic inflammation, cardiometabolic metabolism, anthropometric measures, and CVD risk knowledge and perception. Such measures make this study outstanding among the other few studies that have conducted similar investigations between 2008 and 2015 in SSA. Participants were screened at baseline and end of intervention. The ET constituted both aerobic and strength exercises prescribed at 40-80% of VO2peak (or 12-16 Borg-20 scale) and 60-80% and 40-60% of one repetition maximum for upper and lower extremities, respectively. The group-based circuit interval ET was delivered at NHC three times a week, for 14 weeks duration. The usual care was delivered via face-to-face on commencement at the hospital, and subsequently once a week for 14 weeks via a phone call and short message service. This study is also the first to be done in Malawi, on primary prevention of CVD on PLHIV.Chapter 8 describes the CVD knowledge and risk perception of PLHIV, and their perceptions on accessing CVD preventive interventions with special focus on a peer-led community-based intervention delivery approach. Two focus group discussions were conducted on randomly selected (n=20) participants a week after the intervention period. The novel findings of this study helped in designing an acceptable approach to delivering such an intervention in this setting, which will be assessed for feasibility, effectiveness and sustainability post this thesis. Descriptive and inferential statistics were conducted using SPSS version 29. Deductive thematic analysis was performed on qualitative data, and NVivo software assisted with data management within the Ndirande RCT. The studies were approved by the research ethics committees at the Kamuzu University of Health Sciences in Malawi (p.06/23-0105) and the University of Hull in the United Kingdom (FHS 22-23.18), and it was registered in the Pan African Clinical Trial Registry (PACTR202310853413416). The QECH-CR study was originally approved by the Kamuzu University of Health Sciences (p.10/20/3167), and the conduct of secondary analysis on this dataset was approved by the University of Hull research ethics committee (FHS 22-23.67).Results:Among 316 PLHIV in Ndirande, dyslipidaemia (82.3%) (specifically low concentrations of high-density lipoprotein cholesterol [HDL-c] [74.1%] and high triglycerides [56.6%]), undiagnosed high blood pressure (36%), high VAI (74.4%) and sedentary lifestyles (61.7%) were highly prevalent. Whereas the majority of PLHIV recruited were only classified as having low or moderate Framingham 30-year CVD risk (91.8%). The cross-sectional studies showed that the global 30-year Framingham CVD risk scoring method may underestimate the emerging CVD risk among PLHIV, by not capturing biomarkers underlying the pathophysiology of the CVD atherogenic process. Specifically, HIV infection and the inherent side-effects of the medications used to supress viral load, may exacerbate lipodystrophy or atherogenic dyslipidaemia, hypertension, insulin resistance/glucose intolerance and chronic sub-clinical inflammation. Over 70% of the RCT participants were classified into a moderate CVD risk class, yet they had markedly higher VAI (incorporating higher abdominal adiposity and TAG, with lower HDL-c) and arterial stiffness (SI) indices. Therefore, there is need to further consider how best to assess the CVD risk and CVD risk algorithms for PLHIV.The RCT of supervised, structured exercise intervention or usual care lifestyle modification/ education advice showed that 14-weeks of ET led to improvements in the CRF measures (Pred.VO2peak, VO2Submax), and functional capacity (ISWT walking distance) of the enrolled participants. Participants who received the ET intervention perceived that their health improved significantly, also with trends towards improved domains of QoL namely vitality, social functioning, and role limitations due to emotional health were observed in favour of ET. Additionally, ET led to improvements in biomarkers of CVD risk namely hs-CRP, HbA1C, HDL-c and TAG. Overall, CVD risk perception and unknown risk perception, and knowledge on CVD risk factors also showed improvement. Collectively, these RCT findings suggest that low-cost, structured and short-duration ET intervention is an effective CVD primary preventive measure in PLHIV within resource constrained settings. Participants