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From this study, the prevalence of PAH among the HIV positive group was 5.6% comprising 5(3.1%) HE and 4(2.5%) HN subjects. When the prevalence of PAH in the HIV positive group (5.6%) was compared to 0(0.0%) in the HIV negative CONTROL group, the difference was statistically significant. This finding is also in-line with reports in the literature. Crothers et al166 in their study on HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era reported that HIV infected patients have a greater incidence of Pulmonary Hypertension compared to general population. Correale et al167 in their study on HIV-aPAH also reported that in comparison with the incidence of idiopathic PAH in the general population (1–2 per million), HIV-infected patients have a 2500-fold increased risk of developing PAH. Hsue et al67 also concluded that HIV-infected persons have a high prevalence of elevated PASP, which is independent of other risk factors for PAH suggesting a causal role of HIV in PAH. Data from this study comparing the TR Vmax and PASP across the 3 groups was also in agreement with the reports above. Fewer number of subjects in the CONTROL group (27, 31) had TR Vmax and PASP values above the median for the study population respectively. More subjects in the HE group (42, 40) and HN group (51, 49) had their TR Vmax and PASP values above the median for the study population. Hsue et al67 also reported similar findings in their study. The reason for the difference in the TR Vmax and PASP between the HIV positive and HIV negative groups is most-likely the effect of the HIV virus which studies 56,67,166,167 have reported. HIV contains some proteins like Negative factor (Nef) and Trans-Activator of Transcription (Tat) which have been shown to induce proliferation and apoptosis of pulmonary endothelial cells.86 They also lead to abnormal pulmonary vascular function.88
5.3 CLINICAL AND DEMOGRAPHIC VARIABLES ASSOCIATED WITH
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The clinical and demographic characteristics of the HE and HN subjects with and without PAH were assessed for relationship with PAH. Statistically significant association was found only with systolic blood pressure in the HN group. Age, sex, BMI, duration of diagnosis, duration of HAART, DBP and SBP for HE group was not associated significantly with PAH in this study.
5.3.1 CLINICAL SYMPTOMS
Six HAART experienced participants had cough. Two of them had elevated PASP. The presence of cough in HAART experienced HIV positive subjects was significantly associated with PASP. Cough has been reported to be a common clinical presentation in HIV infection and HIV-aPAH.34,37 Mehta et al34 reported that 19% of the 131 cases reviewed had cough.
5.3.2 AGE
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Different studies have reported different relationship between age and PAH. Some studies39,76 found a relationship between age and PAH while others31,70 did not find any relationship between age and PAH. In this study, all 9 (5.6%) HIV positive subjects who had elevated PASP were within the age range of 30 - 59 years. The mean age for this study was 47.51 and 45.11 for the HE and HN groups respectively. There was however no relationship between age and PASP in this study. This is different from the report of Isasti et al39 which reported that HIV positive participants who had PAH were older than the patients without PAH (57.7 vs. 46.4 years, p=0.02) and had been on ART for longer (180.0 vs. 92.5 months). Carolyn et al168 reported a population-based evidence of age-related increase in pulmonary artery pressure. The mean age of their study population was 63±11 years. This difference in age between their study population and this study in LUTH (47.51±9.06 for HE group and 45.11±9.22 for HN group) may account for the difference in relationship between age and PAH in the above studies.
However, Mondy et al76 reported that one of the predictors of HIV-aPAH was age >35 years.
No association was found with any other parameter from their study. An average age of 33 years for HIV-aPAH was reported by Mehta et al34 The Swiss HIV study75 and French study10 also reported an average age 38 and 41 years, respectively, for patients with HIV-Related PAH, though the range can span from infancy to old age. This LUTH study data with a mean age of 39.2 and 42.3 years respectively for HE and HN subjects with PAH agrees with studies10,34,75,76
above on the mean age for PAH.
In this study, age was not significantly associated with PAH though all subjects with PAH were within the age range of 30 – 59 years. Reason for this is not clear presently. Quezeda et al31 and Chillo et al70 also did not find any relationship between age and HIV-aPAH in their study.
5.3.3 GENDER/SEX
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Varying reports have been documented on the relationship between sex and PAH. This study had a preponderance of females (78%) who had elevated PASP but this (female sex) had no relationship with PAH. This study report is different from most studies which have reported a male preponderance of HIV-aPAH with a male/female ratio of 1.5: 1.66,34,18,158 This ratio is different from that of HIV negative patients with idiopathic PAH, in whom the female/male ratio is 1.7: 1.33 More recently, however, a slightly marked female predominance in HIV-aPAH patients was suggested by Reinch et al.169 Quezada et al31 after performing multivariate logistic regression analysis, reported that female gender was associated with the presence of PAH but Degano et al75, Zuber et al10 and Nunes et al18 reported that men are slightly more affected by HRPAH (HIV Related PAH) than women (ratio of 1.2:1).
Bigna et al56 and Chillo et al70 however reported no association of HIV-aPAH with sex. On the contrary, Shapiro et al177 in their study on Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension reported that there are similarities and differences between men and women with PAH. They recommended future exploration regarding the role of hormones and sex in causation and survival in PAH.
5.3.4 BODY MASS INDEX (BMI)
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The BMI of HE subjects was not associated with PASP in this study. No association was also found between the BMI of the HN group and PASP on a statistical scale. Shapiro et al177 also found no association between BMI and PAH in their study.
5.3.5 BLOOD PRESSURE [BP] PATTERN OF THE STUDY POPULATION.
SYSTOLIC
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HAART of less than 2 years in duration was not. Chillo et al70 had a lower mean SBP of 118mmHg in their study but most of their subjects had heart failure symptoms and this disease state could account for the lower SBP. When systolic BP within the HAART experienced group was tested for relationship with elevated PASP, a weak, negative, linear relationship was found.
This negative correlation is different from that of HN and CONTROL groups who also had a weak, linear but positive relationship with PASP.
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5.3.6 DIASTOLIC BLOOD PRESSURE (DBP)
Chillo et al70 also found no association between DBP and PAH in their study.
5.3.7 ECHOCARDIOGRAPHIC CORRELATES OF HIV-aPAH
Selected echocardiographic variables were compared across the 3 groups and between HE and HN groups. Variables with statistically significant correlation with PAH include RVOT and MPI (for HE group), ERV, RVOT-AT and RAA (for the HN group).
Right MPI had a weak but positive correlation with PASP in the 2 groups but this was only significant in the HE group. This suggests that worsening MPI is associated with increasing PASP. MPI is an assessment of right ventricular function which utilizes a combination of systolic and diastolic parameters. The reason for the disparity in the significance between the 2 groups is not clear but MPI has been documented to be a surrogate marker of PAH.158,159,181
This association was not significant on multivariate analysis.
RVOT diameter is not one of the known surrogate markers for PAH but in this study it correlated weakly with PASP in both groups. It was however, only significant in the HE group.
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This suggests that increasing RVOT diameter is associated with increasing PASP in the HE group.
In this study, RAA correlated positively (though weakly) with PASP in the 2 groups. This was, however, only significant with the HN group. This suggests that increasing RAA is associated with increasing PASP in the HN group. This association has also been reported in the literature.180 The reason it was not significant in the HE group is not immediately clear. RVOT-AT is another surrogate marker for PAH which also correlated weakly with PASP in both groups. This was however only significant in the HN group. This suggests that worsening RVOT-AT is associated with increasing PASP. This association has also been reported in the literature.158 Also in this study, there was a weak and positive correlation between ERV and PASP in both groups. This suggests that increasing ERV is associated with increasing PASP.
It was however, only significant in the HN group. The reason this was not significant in the HE group is not immediately clear. FAC is one of the indices that are used in assessing individuals with PAH. In this study, FAC had a weak correlation with PASP which not significant in either group. Possible reason(s) for this is not clear presently.
TAPSE, which is a marker of right ventricular dysfunction, can also be a surrogate marker for PAH. In this study, it had no significant correlation with PASP in both HIV subgroups. Reason for this is not immediately clear. However, Forfia et al,181 in their study on Tricuspid Annular Displacement Predicts Survival in Pulmonary Hypertension noted that the measured TAPSE may not change significantly over time (even in those who continue to develop progressive RV failure) and thus may not be a sufficiently reliable marker of RV function to measure serially.181 5.3.8 Independent determinants of Pulmonary artery pressure
In univariate analysis, PAH had varying degrees of relationship with echocardiographic variables in the HE group and these include RVOT and MPI. Similarly, in the HN group, PAH
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had relationship with ERV, RAA and RVOT-AT. However, on multiple linear logistic regression no variable had independent relationship with PASP. Chillo et al70 in their study also did not find any independent predictor of pulmonary hypertension.