99
100
weight loss include decreased food or energy intake, local or systemic disease, decreased absorption, taste changes and medications as causes of cachexia. Also, weight loss has been linked to chronic induction of acute phase reactants by HIV. Increases in tumour necrosis factor (TNF) alpha, interlukin-1, Interlukin-6 and interferon have been documented in AIDS patients without a secondary infection, a situation similar to every chronic infection.149 The SBP and DBP were significantly lower among HIV patients than that of apparently healthy subjects and patients with CVD. This observation was in line with the findings by Danbauchi et al150 who also found that the SBP and DBP were higher in HIV negative controls than in their HIV positive patients in their study. This difference in SBP and DBP between the patients with HIV and controls could be related to the weight loss of the HIV/AIDS patients in this study. Their mean weight was significantly lower than that of the control subjects. Weight loss has been shown to be associated with a reduction in blood pressure in both hypertensive and normotensive individuals.151,152 The exact mechanism of the effect of weight loss on blood pressure is unknown; however there are several proposed possible biologic pathways. Among these is the fact that the renin-angiotensin-aldosterone pathway is over-activated in obese individuals. Hence obese individuals have higher renin activity and higher aldosterone concentrations than leaner individuals and a greater tendency of having elevated blood pressure.153,154 Also, obese individuals may have greater inhibition of natriuretic peptides system. Thus the functional effects of vasodilatation and natriuresis mediated by this system are suppressed with attendant sodium retention and elevation of blood pressure.155
Hypertension is considered an important modifiable risk factor in preventive medicine. In Sub-Saharan Africa, little is known of the epidemiology of hypertension among HIV-infected individuals. The estimated prevalence of hypertension in this study in patients with HIV/AIDS was 22.0%. The 22.0% in this study is higher than 13.1% in HIV-infected patients
101
observed by Carlos et al.156 The finding of higher prevalence of hypertension might be due to the study design because hypertension was taking as a cardiovascular disease and apparently healthy subjects with hypertension were excluded. Many studies from the developed countries reported the prevalence of hypertension in patients with HIV individuals to be between 8 and 39%157,158 and 20% to 25% before the introduction of HAART.62 This dissimilarity might be due to study design and differences in population studied.
Chronic inflammation is a cardinal feature of HIV infection. Abnormalities of lipid metabolism are common in HIV-infected patients and tend to be accentuated in those receiving antiretroviral therapy, particularly with protease inhibitors (PIs).159, 160Tumour necrosis factor (TNF) and interferon alpha (IFN-α)- mediated inhibition of serum lipoprotein lipase activity are suspected as the cause of hypertriglyceridaemia and low LDL-C.159,160 Prevalence of dyslipidaemia was significantly higher in patients with HIV/AIDS than apparently healthy controls (19.0 vs 0.0%, p<0.001). This is in keeping with findings of Mondy et al161 that found higher prevalence of lipids abnormality in their HIV patients. The majority of dyslipidaemia in patients with HIV/AIDS in this study was accounted for by low levels of HDL (11.0%) followed by high level of triglycerides (7.0%), only one (1.0%) patient had a total cholesterol above the upper limit24 This might be due to the fact that LDL-C and total LDL-Cholesterol tend to fall following seroconversion in patients with HIV infection, as demonstrated in the study that involved male patients with HIV infection by Riddler et al.38 Previous studies have also found low levels of HDL and high serum triglycerides level in patients with HIV/AIDS38, 39
Prevalence of abnormal fasting glucose (impaired fasting glucose and diabetics) was significantly higher in patients with HIV/AIDS compared to apparently healthy controls (20.0% vs 3.0%, p<0.001). Pancreatic beta-cell function, or insulin secretion, might be affected by HIV infection or its treatment. This is comparable to Brown et al162 who
102
demonstrated a DM prevalence of 14% vs 5% comparing men in the Multicenter AIDS Cohort Study (MACS) study with HIV-negative controls. Also, Triant et al163 found a prevalence of DM using International Classification of Diseases, ninth revision, of 11.5% vs 6.6% in HIV-infected patients of both genders and all ages in a large US healthcare system.
Several studies have described disorders related to abnormal glucose metabolism in the context of HIV infection including insulin resistance/impaired glucose tolerance and frank diabetes.63 The epidemiology of the impaired glucose tolerance is currently not totally elucidated.63
Weight loss and/or wasting were among the most frequently occurring AIDS-defining conditions in the pre-HAART era. Pre HAART wasting syndrome accounted for about 18%
of the new diagnoses of AIDS in the early 1990s164 The prevalence of underweight in this study was significantly higher in patients with HIV/AIDS compared to apparently healthy subjects (p<0.001).
The prevalence of smoking in patients with HIV/AIDS in this study was significantly higher than that of apparently healthy subjects. Smoking has been reported to be independently associated with adverse HIV-related outcomes in the context of HAART, including the development of clinical AIDS, lower CD4 counts, a trend toward higher viral loads, and poorer health-related quality of life.75 HIV-infected patients tend to engage in smoking as a measure to fight depression. Also, HIV infection is seen in the company of social vices which smoking is among.
The prevalence of 12.0% in this study is comparable to 7.8% reported by Iliyasu et al165 from the Northern Nigeria though much lower than 22.1% reported by Desalu et al166 and higher than 2.9% observed in Benin republic.167 The differences in the rates might be the reflection of baseline characteristics and geographical prevalence of smoking in the general population.
The rate in this study is consistent with the overall prevalence of smoking in the general
103
population in Nigeria (10.49% for male adults and 2.60% for female adults), 2009 survey, according to a Word Bank report, published in 2010.168,169 Smoking has been shown in several studies in developed counties to be common among HIV-infected people, with rates of 20% to as high as 74% depending on the studies and the location.73 The prevalence in this study was not as high as that reported in the studies from the developed nations. This low prevalence was in keeping with smoking prevalence in the general population in Nigeria and also might be due to the fact that the majority of the recruited HIV patients were females.
Human immunodeficiency virus (HIV) can affect any part of the heart. This is supported by the fact that different studies across the globe demonstrated higher prevalence of cardiac abnormalities in patients with HIV than controls.170-173
Pericardial effusion generally occurs in advanced HIV disease and is usually mild and asymptomatic.101 Various aetiological factors and possible pathophysiologic mechanisms of pericardial effusion in people with HIV/AIDS have been enumerated earlier. The prevalence of pericardial effusion in HIV/AIDS was significantly higher than that of the apparently healthy controls. Also, in comparison with CVD patients the prevalence of pericardial effusion was significantly higher in HIV-infected patients. Majority of the pericardial effusion seen in this study were mild and asymptomatic, this finding is consistent with findings from other previous studies26, 101, 172
The 9.0% prevalence rate of dilated cardiomyopathy observed in this study is comparable to 8.5% reported by Ayaskanta et al171 but higher than 6% and 5% reported by Moreno et al173 and Olusegun et al172 respectively. There are various aetiological factors to DCM in HIV/AIDS; these include direct infection and injury of myocytes by HIV, toxicity caused by cytokines as a result of chronic inflammation, coinfection with cardiotropic viruses, postviral autoimmunity, and toxicity related to antiretroviral therapy as earlier mentioned. In this study, advanced immunological compromise was possibly the only factor associated with
104
DCM because all the cases of DCM from this study were from HIV patients with CD4 count below 200cells/mm3.
Several studies have demonstrated left ventricular systolic and diastolic dysfunction in HIV/AIDs. In this study, 18.0% of HIV patients had systolic dysfunction. In comparison to the apparently healthy subjects, it might be due to the fact that aetiology (like hypertension) of left ventricular dysfunction in addition to HIV itself was higher in patients with HIV infection. This is similar to 14.5% reported by Herskowitz et al.29 Reports by Okehialam and Anjorin93 also observed that systolic dysfunction was common among HIV/AIDS patients they studied. The occurrence of left ventricular systolic and diastolic dysfunction in HIV/AIDS patients reflects varying degrees of myocardial damage. Factors involved in the pathophysiology of left ventricular dysfunction in HIV/AIDS include myocardial infection by HIV itself, opportunistic infections, other infections of viral origin, autoimmune response, cardiotoxicity due to drug treatment or the use of illegal drugs, nutritional deficiencies, and overexpression of cytokines. It should be noted that most of these patients with systolic dysfunction were asymptomatic in this study confirming earlier reports by Barbaro et al89 that it could exist asymptomatically in patients. In view of this, periodic cardiac examination will be helpful for early detection of subclinical heart condition. HIV infection appears to cause cardiac chambers enlargement because both the right and left heart dimensions were more than that of the apparently healthy controls. This trend was similarly observed by Nzuobontane et al88 and Danbauchi et al174 in their studies comparing HIV positive patients with HIV negative controls. In view of the increase in the dimensions of the left ventricle in the HIV patients, it is not surprising that the prevalence of left ventricular systolic dysfunction was significantly higher in them than in the apparently healthy controls since cardiac contractility generally tends to reduce with increased ventricular dilatation. Similar trend of reduced LVEF was also reported by Barbaro et al89 and Nzuobontane et al.88
105
Left ventricular diastolic dysfunction has been shown to be a common finding in HIV/AIDS.
Left ventricular diastolic dysfunction occurred more commonly than left ventricular systolic dysfunction with a prevalence of 32.0% in this study. Factors like hypertension and DCM were among possible reasons for this higher prevalence of left ventricular diastolic dysfunction in comparison to apparently healthy subjects. The prevalence of left ventricular diastolic dysfunction was lower in HIV-infected compared to CVD patients perhaps because of clusters of cardiovascular risk factors in CVD patients. The prevalence of 32.0% of left ventricular diastolic dysfunction in HIV-infected is similar to 32.32% and 30.0% reported by Olusegun et al172 and Danbauchi et al94 respectively. Most of the patients in this study were asymptomatic as was also observed in earlier studies.89 Higher prevalence rates of 53.8%
were reported by Arroja et al175 and 85.7% by Longo-Mbenza et al176 The degree of difference in the proportional rates might probably be related to patient selection since larger percentage of patients in those previous studies had advanced disease.
The two cases of isolated right ventricular disease were seen in patients with HIV/AIDS who had history of chronic cough and were on treatment for pulmonary tuberculosis. These patients also had elevated pulmonary artery pressure on Doppler echocardiography. As part of possible aetiology of pulmonary hypertension was chronic pulmonary disease observed in the two patients, none of the two sets of controls had features suggestive of pulmonary hypertension or isolated right ventricular disease. Right ventricular hypertrophy in isolation, with or without right ventricular dilation and/or failure, is relatively uncommon in HIV-infected individuals.101 When it does occur, is usually related to pulmonary disease116 which was the situation in this study.
Rhythm abnormalities and sudden death are well recognized in patients with HIV infection.98 The prevalence of cardiac arrhythmias in patients with HIV/AIDS was significantly higher than that of the apparently healthy controls (20.0% vs 8.0%). This in addition to HIV itself
106
might be due to higher prevalence of hypertension, DCM, left ventricular dysfunction in HIV-infected patients in comparison to AHS. Anderson et al98 also reported prevalence of 20.0% in their study. It is noteworthy to state that any of the cardiovascular diseases associated with HIV can be complicated with cardiac arrhythmias.99 Valvular abnormality was observed more in HIV-infected patients in comparison to apparently subjects, this might be due factors like left ventricular systolic, left ventricular diastolic dysfunction, hypertension and pulmonary hypertension that were seen with higher frequency in HIV-infected patients in comparison to apparently healthy subjects.
Smoking was significantly prevalent in male patients with HIV/AIDS when compared to females (26.3% vs 3.2%). This might be due to the fact that cultural practice in the locality where the study was conducted doesn’t encourage smoking in women. This is comparable to report by Desalu et al177 and is also consistent with pattern of smoking observed in the general population in the country.168, 169 There was no statistical significance between smoking and the age groups in this study. This is contrary to report by Desalu et al166 who demonstrated positive correlation between smoking in HIV patients and advancing age (40-49years). The majority of the studied HIV-infected patients in this study were younger than those studied by Desalu et al166 and this might account for the difference.
Hypertension has been described as the commonest CVD risk in Nigerians, and the risk of developing CVD in individuals with hypertension is independent of other CVD risks.178 Hypertension was observed more in male patients with HIV/AIDS than females (36.8% vs 12.9%) in this study. Carlos et al in their study observed higher prevalence of hypertension in male HIV-infected patients compared to females.156 The prevalence of hypertension in patients with HIV/AIDS was higher in those above 44 years of age, though not reaching level of statistical significance. This is consistent with the fact that blood pressure rises with
107
advancing age and the report from Onwubere et al178 that found higher prevalence of hypertension in those above 50 years of age.
The occurrence of dyslipidaemia in both males and females HIV infected patients was not significantly different which is consistent with previous studies179,180 There was no significant difference among the age groups.
The prevalence of left ventricular systolic dysfunction and left ventricular diastolic dysfunction were significantly higher in male HIV-infected patients compared to their female counterparts. These findings might be due to the higher prevalence of hypertension and smoking in male HIV-infected patients in this study181-183 The higher prevalence of left ventricular dysfunction in male HIV-infected individuals is contrary to the findings by Robert et al184 who found out that female sex was associated with the development of left ventricular diastolic dysfunction. Robert et al184 study was on adolescents and measurement of blood pressure was not part of the study design.
The HAART regime impedes viral multiplication which allows for an increase in the population of the CD4 positive lymphocytes. The study shows that the two groups of patients were different with respect to their immunological status. This observation is consistent with report by Olawumi et al185 in a longitudinal study of HIV/AIDS patients on HAART. Their study shows that HIV patients on HAART were associated with increase in CD4 count.
The prevalence of pericardial effusion and DCM was statistically not different in the two groups, though were higher in HAART nạve group than those on HAART. This was different from observations from Danbauchi et al94 in their comparison of echocardiographic findings between stage III/IV HIV patients who were HAART-nạve and patients on HAART. Danbauchi et al94 found a higher prevalence of pericardial effusion and DCM in the patients who were not on HAART. The difference between their findings and the findings in
108
this study might be due to differences in patient characteristics, considering the fact that their patients who were not on HAART were all in advanced stages of illness while the patients in this study who were not on HAART were consecutively recruited and effectively comprised patients in different stages of disease. Diastolic dysfunction occurred more frequently in HAART nạve HIV-infected patients than in those on HAART. This is consistent with findings by Danbauchi et al.94
HAART did not affect pulmonary artery pressure from this study. This is consistent with the findings and conclusions of the Swiss HIV Cohort study and the prospective French National Study186 The two studies concluded that though PAH was commoner in HIV/AIDS patients with profound immunodeficiency, HAART did not prevent the development of PAH.186 This study did not show significant difference in the prevalence of cardiac arrhythmia and IHD between the two groups. This might partly be due to short duration of therapy for those on HAART. Studies have revealed that even though HAART prolong life, cardiac involvement seemed not to change from those not on it with long term use of therapy.187 The serum lipids in HIV-infected patients on HAART and HAART naive were statistically similar. This might be due to the fact that none of the recruited HIV patients was on protease inhibitor containing combination which is a major contributory factor to lipid abnormality.43,44 This is similar to the finding by Oduola et al.180The two groups had similar prevalence of hypertension this might be due in part to the fact that none of the HIV-infected individuals was on PI-containing combination. Protease inhibitors have been demonstrated to cause elevated blood pressure.62
The measurement of the CD4 count is the most commonly available immunological tool of disease severity in centres offering HIV/AIDS care in this country. Facilities for more sensitive investigations like the HIV viral load estimation are presently limited to only a few
109
centres in Nigeria. Federal Medical Centre, Ido-Ekiti, the location of this study is yet to have facility for the measurement of viral load. Patients with HIV in this study were stratified into three groups; those who had CD4 count <200 cells/mm3, CD4 count of 200-499 cells/mm3 and CD4 count ≥500 cells/mm3 to evaluate the relationship between conventional cardiovascular risk factors/cardiac diseases and CD4+ counts in patients with HIV.
All the twelve HIV-infected patients with smoking history had CD4 count below 200cells/mm.3 This is consistent with the findings by Desalu et al166 who in their study observed that CD4 count below 200cells/mm3 was associated with smoking among HIV-infected patients. This observation might be due to the fact that smoking is associated with adverse HIV-related outcome including the development of clinical AIDs, lower CD4 counts, a trend toward higher viral loads, and poorer health-related quality of life.75 Larger proportion of HIV patients with weight loss were those with CD4 count below 200cells/mm3 in this study. This is the fact that with progressive immunosuppression, wasting becomes increasingly prominent. This is similar to report by Idindili et al.188
Cardiac abnormalities occurred more frequently in the group with CD4 count < 200 cells/mm3. This is similar to the findings by Nzuobontane et al88 who however used a CD4 count cut-off of 100 cells/mm3 when classifying their patients. The pathophysiologic mechanisms by which the virus causes cardiac disease get more pronounced as the disease progresses and the individual’s immunity declines. A similar trend was observed with respect to the prevalence of pericardial effusion, DCM, left ventricular systolic dysfunction, left ventricular diastolic dysfunction and cardiac arrhythmias which occurred more frequently in the group with CD4 count <200 cells/mm3. Correspondingly, the left ventricular ejection fraction and left ventricular fractional shortening were significantly lower in those with CD4 count <200 cells/mm3. This observed relationship between CD4 count and left ventricular systolic function is comparable to findings by Nzuobontane et al.88 Prevalence of pericardial
110
effusion was more frequent in those with CD4 count below 200cells/mm3. This is in keeping with several studies that demonstrated increasing frequency of pericardial effusion with progressive decline in CD4 count.171,189 All the pericardial effusion observed in this study were small and asymptomatic, which is in agreement with findings by Blanchard et al.189 This might be due to the fact that profound immunological decline is associated with significant inflammation which has been implicated in the pathogenesis of pericardial disease in HIV infection.
Dilated cardiomyopathy occurs late in the course of HIV infection and is usually associated with significant immunological decline26,88,172 similar trends were observed in this study. All the nine HIV-infected patients with DCM were those with CD4 count below 200cells/mm3. It is unclear how HIV enters CD4 receptor negative cells such as myocytes. Cells like dendritic cells are said to play a pathogenic role in the interaction between HIV and cardiac myocyte and in the activation of multi-functional cytokines that contribute to progressive and late myocardial tissue damage.109 Left ventricular systolic and left ventricular diastolic dysfunction occurred more in HIV-infected patients with CD count below 200cells/mm3. This is consistent with previous studies90,172 Asymptomatic left ventricular dysfunction and increased left ventricular mass in both adults and children with HIV infection independently predict accelerated mortality.109
Isolated right ventricular dilatation was seen in two HIV-infected patients CD4 counts below 200mm/mm3 who were on treatment for pulmonary tuberculosis. The association of right ventricular disease with immunological decline is in keeping with the finding by Olusegun et al172 who observed profound immunosuppression in their subject that had isolated right ventricular dilation. Longo-Mbenza et al190 also observed association with low CD4 count and isolated right ventricular disease. The two cases of pulmonary hypertension were seen in the same HIV-infected patients with isolated right ventricular dilatation. Occurrence of