Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: A hospital-based study.

BACKGROUND: Atherosclerotic Cardiovascular Disease (ASCVD) is an emerging problem among People living with HIV/AIDS (PLWHA). The current study aimed at determining the risk of ASCVD among PLWHA using the Pooled Cohort Equation (PCE) and the Framingham Risk score (FRS).
METHODS: A hospital-based study was carried out from January 2019 to February 2020 in PLWHA. The prevalence of ASCVD risk was determined in individuals aged between 20 to 79 and 40 to 79 years using the FRS and PCE as appropriate. Chi-square, univariate and multivariate logistic regressions were employed for analysis.
RESULTS: The prevalence of high-risk ASCVD for subjects aged 20 and above using both tools was 11.5 %. For those aged 40 to 79 years, PCE yielded an increased risk (28%) than FRS (17.7%). Using both tools; advanced age, male gender, smoking, and increased systolic blood pressure were associated with an increased risk of ASCVD. Younger age (adjusted odds ratio, AOR) 0.20, 95%CI: 0.004, 0.091; P< 0.001), lower systolic blood pressure (AOR 0.221, 95%CI: 0.074, 0.605 P< 0.004), and lower total cholesterol (AOR 0.270, 95%CI: 0.073, 0.997; p<0.049) were found to be independent predictors of reduced risk of ASCVD. Likewise, younger age (40 to 64 years), female gender, and lower systolic blood pressure were significantly associated with lower risk of ASCVD among patients aged 40 to 79 years using both PCE and FRS.
CONCLUSIONS: A considerable number of PLWHA have been identified to be at risk for ASCVD. ASCVD risk was significantly associated with advanced age, male gender, higher blood pressure, and smoking using both FRS and PCE. These factors should therefore be taken into account for designing management strategies.

Introduction

The Human Immunodeficiency Virus (HIV) associated morbidity and mortality have declined significantly since the introduction of Antiretroviral Therapy (ART) [1], which extended the life expectancy of People Living with HIV/AIDS (PLWHA). However, Cardiovascular Diseases (CVDs) and related other non-communicable diseases remain an increased concern among PLWHA [2, 3]. On top of this, the etiology of Atherosclerotic Cardiovascular Disease (ASCVD) in PLWHA is also multi-factorial [4]. Several risk factors for CVDs in PLWHA including age, dyslipidemia, diabetes mellitus, hypertension, family history, sedentary life, cigarette smoking, and cocaine use have been reported [5, 6].

Heart attack, ASCVD, stroke, and other forms of CVDs have been reported to be nearly doubled in PLWHA compared to the general population, despite well-control of HIV-infections with combination ARTs (cARTs) [7-9]. This could be attributed to complexity of the management as well as the need for lifetime intervention [10]. It is therefore prudent to adequately determine the risk of such CVDs for proper monitoring as well as improving outcomes of cART [11].

ASCVD has become the major factor, limiting life expectancy, and causing death in participants age 45 years and above [12]. The intensity of efforts to prevent CVDs depends on the absolute risk of ASCVD, which can be calculated either using the Pooled Cohort Equation (PCE) or the Framingham Risk Score (FRS) [13, 14]. PCE and FRS have been considered as reliable and accurate benchmark for assessing cardiovascular risks in the general population [15]. Indeed, the 10 year PCE & FRS estimations are the most widely used tools for ASCVD risk evaluation [16, 17] and both share similar variables to determine the risk, even though few variations exist [3, 10, 18].

The PCE was designed to determine the risk among population age 40 to 79 years, whereas the FRS was designed to evaluate ASCVD risk among people age 20 to 79 years as well as age 40 to 79 years [19, 20].

The risk can be classified as low-risk (<10%), moderate risk (10–20%), and high-risk (>20%) using FRS [21], and as low risk (<7.5%) and elevated-risk (≥ 7.5%) using PCE [18]. The prevalence of ASCVD is reported to be in the range of 70–90% for the low-risk, 20–30% for the moderate risk, and 0–20% for the high-risk using FRS [22-25]. The overall prevalence of elevated ASCVD risk using either of the tools was approximately 25% [26].

Although CVD is an emerging and significant cause for morbidity and mortality in HIV-infected patients, the main guidelines of HIV therapy are still focusing on HIV and opportunistic infections, with little or no emphasis on non-communicable diseases [27]. Moreover, though the issue is well investigated in developed countries, there is paucity of such data in resource-constrained regions such as sub-Saharan Africa, particularly Ethiopia. Thus, the present study aimed at determining the risk and outcome of ASCVD among PLWHA using PCE and FRS.

Methods

Study setting

This was a hospital-based study conducted in PLWHA on follow-up care between January 2019 and February 2020 at Zewditu Memorial Hospital, Addis Ababa, Ethiopia. It was the first hospital that commenced and initiated the subsidized fee-based scheme of ART service in Ethiopia in 2003. Currently, there are about 7,674 active adults and 2,558 children in its follow-up nest [28].

Patients and sampling

Patients were sampled from newly registered as well as existing PLWHA on follow-up care at ZMH. Adult (aged 20 years and above) HIV positive patients and willing to participate were included. Severely ill patients as well as pregnant and breastfeeding women were excluded from the study. Sample size was calculated using the formula for descriptive studies: Sample size (n) = [DEFF*Np (1-p)] / [(d2/z21- α/2*(N-1) +p*(1-p)]: where N is population size (7674); P (≅ 25% ± 5%) is the estimated prevalence for ASCVD in HIV- infected population obtained from the literature [23]; DEEF, design effect (1.5); d, precision (0.1); and z21- α/2, 1.96. Considering 10% contingency (lost to follow-up and defaulters). An estimated sample size of 314 was obtained using the aforementioned assumptions. A systematic random sampling technique was used to recruit study participants. The sample interval (K) was calculated using the formula N/n (7674/314≅24). The first participant was selected using a lottery method from patients having an appointment during the first day. Since the number of adult ART clinics in the hospital were four; every six (24/4) volunteer participants were then enrolled in the study. Negative response and refusal to continue participation following prior consent was managed by enrolling the next participant automatically.

Data collection

Detailed information about the participants was obtained through laboratory tests, clinical examination/measurement, patient interviews, and chart review. The instrument for a face-to-face interview was adapted from the structured questionnaire used by the WHO stepwise approach to non-communicable disease risk factor surveillance (STEPS-2014) [29]. The questionnaire included information related to socio-demographic characteristics (age, gender, religion, civil status, address, educational level, occupation, monthly income), clinical characteristics (Family History of CVD, Viral Load, CD4 Count, Time Since ART Initiated, WHO Staging, ART Medication Regimen, and Frequency of ART Medication Switch), tobacco use (active, passive and smoking history), alcohol consumption (active, alcohol use history), coffee, and khat use. The questionnaire was pre-tested prior to the actual data collection and appropriate modifications were performed accordingly.

The online version of PCE calculator (originally created by the American College of Cardiology/American Heart Association) was used with prior permission, and the online free version of the FRS tool (originally created by the National, Heart, Lung, and Blood Institute) was accessed from the GlobalRPH.com.

Data analysis

Data were cleaned, coded, double-entered, and analyzed using IBM SPSS Statistics software version 25 for Windows. All categorical variables were coded as 0 (for female and no responses) and (1 for male and yes responses). To make comparison easier, the risk calculated using FRS was treated as dichotomous (low and elevated risk) by considering moderate and high risk as elevated risk. Hence, low-risk (<10% for FRS or <7.5% for PCE) was coded as “0” and elevated-risk (≥ 10% for FRS or ≥ 7.5% for PCE) as “1”. Permission was obtained from ClinCalc.com to use the online calculator.

Variables including age, gender, lipid profile (total cholesterol & HDL), systolic blood pressure, smoking status, and blood pressure medications were used to calculate the risk of ASCVD in both PCE and FRS. In addition, race for PCE and LDL for FRS were used [18, 30].

Determination of the risk of ASCVD among patients aged 20 to 79 years (n = 288) was carried out using the FRS tool. A separate determination of the risk for patients aged 40 to 79 years was also carried out using both tools.

Chi-square, univariate, bivariate, and multivariate log-linear regression analyses as well as the Pearson’s chi-square with continuity correction and odds ratio (OR) with the corresponding 95% confidence interval (CI) were used to estimate the relations, associations, and interactions between variables. The outputs of bivariate analysis with p-value ≤ 0.20 were further analyzed in multivariate logistic regression to control the effect of confounders. Statistical significance was considered at p-value ≤0.05.

Ethics statement

The study was approved by several Institutional Review Boards, including the Muhimbili University of Health and Allied Sciences, Office of the Director of Research and Publications, Dar es Salaam, Tanzania (Ref. No. 2018-04-23/AEC//Vol. XII/88), School of Pharmacy (ERB/SOP/41/11/2018), College of Health Sciences (Meeting number 08/2018), Addis Ababa University, and City Government of Addis Ababa Health Bureau, (Ref no. A/A/HB/344438/227), Addis Ababa, Ethiopia. The study was carried out under the tenets of the Declaration of Helsinki. Patients provided written informed consent before they participated in the study. Confidentiality and anonymity were maintained by restricting data access and removing identifiers.

Results

Enrolment

Initially, 314 patients were enrolled. However, 26 participants were later excluded for a variety of reasons: 10 were defaulter (unknown reasons); 4 due to critical illness (three due to high blood pressure, one due to high blood sugar); and 2 discontinued due to change of address (Fig 1). Hence, data for 288 patients were used for analysis.

Fig 1

Enrolment, screening and follow up.

Sociodemographic and clinical characteristics

The sociodemographic and clinical characteristics of patients, as determined by FRS, are depicted in Table 1. Majority of the patients were female (69.4%) and under 50 years of age (69.4%). Close to half (45.1%) were married and a third of them (32.3%) completed high school education. About 12% of the patients had an elevated-risk for ASCVD. Chi-square analysis revealed that the male gender (93.9%) had a significantly elevated-risk (χ2 = 35.881, p<0.001) than the female gender (6.1%). Likewise, the risk increased with age, with patients aged ≥50 years (93.9%) having a significant elevated-risk for ASCVD (χ2 = 67.233, p<0.001) than those under 50 years of age. Although married participants (51.5%) and low-income generating group (81.8%) tended to have an increased risk for ASCVD, it failed to reach a statistical significance (Table 1).

Table 1

Socio-demographic characteristics of HIV-infected patients with 20 and above years of age on ART follow up care at Zewditu Memorial Hospital, Addis Ababa, Ethiopia.

Socio-demographic	ASCVD risk using FRS		χ2-value	P value
	Low risk (%)	Elevated risk
Number (%)	255 (88.5)	33 (11.5)
Gender
Female	160 (62.7)	2 (6.1)	35.881*a	p<0.001
Male	95 (37.3)	31 (93.9)
Age
20–49	198 (77.6)	2 (6.1)	67.233*a	p<0.001
≥50	57 (22.4)	31 (93.9)
Civil status
Never married	49 (19.2)	4 (12.1)	1.138#a	p = 0.768
Married	113 (44.3)	17 (51.5)
Divorced	55 (21.6)	7 (21.2)
Widowed/r	38 (14.9)	5 (15.2)
Educational status
No formal education	34 (13.3)	1 (3.0)	7.944#a	p = 0.159
Primary (1-6th grade)	58 (22.7)	7 (21.2)
Secondary Junior (7-8th grade)	24 (9.4)	3 (9.1)
High school (9-12th grade)	87 (34.1)	9 (27.3)
College/university diploma	37 (14.5)	10 (30.3)
College/ University Degree/master or above	15 (5.9)	3 (9.1)
Occupational status ‡
A-list (intermediate to high income)	38 (14.9)	6 (18.2)	5.211#a	p = 0.74
B-list (small to intermediate income)	171 (67.1)	16 (48.5)
C-list (non-income generating)	46 (18)	11 (33.3)

n = 288; Data presented as % prevalence

*Continuity Correction is computed for a 2x2 table

#Pearson Chi-square; ASCVD, atherosclerotic cardiovascular disease; FRS, Framingham Risk Score

‡ Classification is based on ISEC (International Socio-Economic Classes) [31]. A-List (Higher-level professional; Higher level manager and entrepreneur; Lower-level professional; Lower-level manager; Clerical routine non-manual worker; Sales and service routine non-manual worker). B-List (Small self-employed with employee; Small self-employed without employer; Small self-employed in agriculture; Manual supervisor; Skilled manual worker; Semi- and unskilled manual worker. C-List (Agricultural laborers; Retired; Students; unemployed).

Association studies

The calculated risk using both tools is presented in Table 2. Accordingly, individual aged 65 to 79 years had a significantly higher risk for ASCVD than their younger compatriots (40–64 years) in both PCE (χ2 = 20.758, p<0.001), and FRS (χ2 = 28.207, p<0.001) methods. Characteristics such as blood group, WHO staging, and family history did not have significant contribution to ASCVD risk. Smoking was also identified as a significant predictor of ASCVD in both tools, though one cell had a count of less than 5% (Table 2). Hence, Fisher’s Exact Test was used in place of Pearson Chi-square.

Table 2

The risk for atherosclerosis cardiovascular disease using the Pooled Cohort Equation and the Framingham Risk Score in HIV-infected patients aged 40 to 79 years at Zewditu Memorial Hospital, Addis Ababa, Ethiopia.

Characteristics		ASCVD risk using PCE		χ2-value	P value	ASCVD risk using FRS		χ2-value	P value
		Low risk	Elevated risk			Low risk	Elevated risk
Number (%)		134 (72)	52 (28)			153 (82.3)	33 (17.7)
Age (Year)	40–64	134 (100)	43 (82.7)	20.758*a	p<0.001	139 (90.8)	17(51.5)	28.207*a	p<0.001
	65–79	0 (0)	9 (17.3)			14 (9.2)	16 (48.5)
Gender	Female	72 (53.7)	13 (25.0)	11.331*a	p = 0.001	83 (54.2)	2 (6.1)	23.496*a	p = 0.001
	Male	62 (46.3)	39 (75.0)			70 (45.8)	31 (93.9)
Civil status	Never married	18 (13.4)	5 (9.6)	0.679#a	p = 0.787	19 (12.4)	4 (12.1)	0.207#a	p = 0.976
	Married	65 (48.5)	28 (53.8)			76 (49.7)	17 (51.5)
	Divorced	27 (20.1)	10 (19.2)			30 (19.6)	7(21.2)
	Widowed	24 (17.9)	9 (17.3)			28 (18.3)	5 (15.2)
Educational status	No formal education	23 (17.2)	6 (11.5)	7.140#a	p = 0.068	28 (18.3)	1 (3.0)	13.575 #a	p = 0.004
	Primary (1-6th grade)	32(23.9)	9 (17.3)			34(22.2)	7 (21.2)
	Secondary Junior/high school (7-12th grade)	60(44.8)	21 (40.4)			69(45.1)	12 (36.4)
	College/University (diploma/degree)	19(14.2)	16 (30.8)			22(14.4)	13 (39.4)
Family history b	No	110 (82.1)	47 (90.4)	1.379*a	p = 0.240	126 (82.4)	31 (93.9)	1.959*a	p = 0.162
	Yes	24 (17.9)	5(9.6)			27 (17.6)	2(6.1)
Blood type	A	45 (33.6)	15 (28.8)	3.955#a	p = 0.138	52 (34.0)	8 (24.2)	1.556#a	p = 0.459
	B & ABg	45 (33.6)	12 (23.1)			47 (30.7)	10(30.3)
	O	44 (32.8)	25 (48.1)			54 (35.3)	15 (45.5)
The WHO staging at baseline	Stage I	18 (13.4)	7 (13.5)	1.867#a	p = 0.601	22 (14.4)	3 (9.1)	1.253#a	p = 0.740
	Stage II	26 (19.4)	12 (23.1)			32 (20.9)	6 (18.2)
	Stage III	70 (52.2)	22 (42.3)			73 (47.7)	19 (57.6)
	Stage IV	20 (14.9)	11 (21.2)			26 (17.0)	5 (15.5)
TB prophylaxis	No	117 (87.3)	48 (92.3)	0.51*a	P = 0.479	134 (87.6)	31 (93.9)	0.553*a	p = 0.457
	Yes	17 (12.7)	4 (7.7)			19 (12.4)	2 (6.1)
ART class regimen	2 NRTIs +1 INI	68 (50.7)	25 (48.1)	3.925#a	P = 0.141	84 (54.9)	9 (27.3)	8.624#a	p = 0.013
	2 NRTIs + 1 NNRTI	43 (32.1)	23 (44.2)			48 (31.4)	18 (54.5)
	2NRTIs + 1PI d	23 (17.2)	4 (7.7)			21 (13.7)	6 (18.2)
ART regimen as 1st, 2nd, and 3rd line	1st line	111 (82.8)	48 (92.3)	1.999*a	P = 0.157	132 (86.3)	27 (81.8)	0.150*a	p = 0.699
	2nd and 3rd linee	23 (17.2)	4 (7.7)			21 (13.7)	6 (18.2)
Change of ART regimen	No change from the baseline	26 (19.4)	15 (28.8)	3.083#a	P = 0.214	31 (20.3)	10 (30.3)	1.894#a	p = 0.388
	Changed one time	58 (43.3)	16 (30.8)			61 (39.9)	13 (39.4)
	Changed two or more timesf	50 (37.3)	21 (40.4)			61 (39.9)	10 (30.3)
Current Medications	ARVs	125 (93.3)	37 (71.2)	14.415*a	p<0.001	135 (88.2)	27 (81.8)	0.506*a	p = 0.477
	ARVs with other medicationsc	9 (6.7)	15 (28.8)			18 (11.8)	6 (18.2)
	Yes	25 (8.7)	55 (24.9)			25 (8.7)	55 (24.9)
Coffee-drinking	No	79 (59.0)	19 (36.5)	6.679*a	P = 0.006	86 (56.2)	12 (36.4)	3.530*a	p = 0.060
	Yes	55 (41.0)	33 (63.5)			67 (43.8)	21 (63.6)
Smoking	No	129 (96.3)	45 (86.5)	4.375e‡	P = 0.039	146 (95.4)	28 (84.8)	2.431e‡	p = 0.041
	Yesh	5 (3.7)	7 (13.5)			7 (4.6)	5 (2.7)

n = 186; Data presented as % prevalence

*Continuity Correction is computed for a 2x2 table

#Pearson Chi-square; ASCVD, atherosclerotic cardiovascular disease; FRS, Framingham risk score; chi-square test); PCE, Pooled Cohort Equation

‡ Khat, plant/substance chewed in East-Africa and Middle East as a stimulant or benefit for the purpose of “recreational values”

a. 0 cells (0.0%) had a count of less than 5

b, Family history: History of Cardiometabolic diseases among siblings

c, Other medications include BP lowering drugs, blood sugar lowering agents, lipid lowering agents and antiepileptic and antipsychotics

d, Only one case was on 2 NRTIs + 1INTI +1 PI regimen

e, Only one case was on 3rd line

f, Eleven individual changed 3 times and four participants changed 4 times

g, Fourteen of the cases were with AB blood type

h, 1 cell had a count of less than 5%

‡, Fisher’s Exact Test was used

Logistic regression was utilized to determine predictors of FRS score in both total patients (Table 3) as well as those 40 to 79 years of age (Table 4). When the total patients were considered, younger age (adjusted odds ratio (AOR) 0.20, 95% CI (0.004, 0.091); p< 0.001), lower systolic blood pressure (AOR 0.221 (0.074, 0.605); p< 0.004), and lower total cholesterol (AOR 0.270, 95% CI (0.073, 0.997; p<0.049) were found to be independent predictors of reduced risk for ASCVD (Table 3). Similarly, only younger age (age 40 to 59), the female gender, and lower systolic blood pressure were associated with lower risk for ASCVD among PLWHA age 40 to 79 years using both the FRS (Table 4) and PCE (Table 5).

Table 3

Association between ASCVD risk using FRS and clinical characteristics among people living with HIV/AIDS at Zewditu Memorial Hospital, Addis Ababa, Ethiopia.

Clinical characteristics	ASCVD risk using FRS		COR (95% C.I.)	P value	AOR (95% C.I.)	P value
	Low risk (<10%) n = 255	High risk (>10%) n = 33
Age (year)
≥50	57 (22.4)	31 (93.9)	1.00		1.00
< 50	198 (77.6)	2 (6.1)	.019 (.004-.080)	P < .001	.020 (.004, .091)	p<0.001
CD4 count (cells/μL)
>/ = 500	94 (36.9)	13 (39.4)	1.00		1.00
<500	161 (63.1)	20 (60.6)	.898(.427, 1.889)	P = 0.777	.895 (.309, 2.591)	p = 0.838
Systolic blood pressure (mmHg)
>/ = 130	89 (34.9)	25 (75.5)	1.00		1.00
<130	166 (65.1)	8 (24.5)	.172 (.074, .396)	P<0.001	.221 (.074, .605)	p = 0.004
Total cholesterol (mg/dL)
>/ = 160	164 (64.3)	29 (87.9)	1.00		1.00
<160	91 (35.7)	4 (12.1)	.249 (.085, 0729)	P = 0.011	.270 (.073, .997)	p = 0.049
HDL cholesterol (mg/dL)
<50	173 (67.8)	27 81.8)	1.00		1.00
>/ = 50	82 (32.2)	6 (18.2)	.469 (.186, 1.180)	P = 0.108	.365 (.106, 1.255)	p = 0.110
Duration on ART (year)
>/ = 2 years	229 (89.8)	32 (97)	1.00		1.00
< 2 years	26 (10.2)	1 (3)	.275 (0.036, 2.098)	P = 0.213	.276 (.028, 2.739)	p = 0.271
Blood group
Type ‘O’	82 (32.2)	15 (5.2)	1.00		1.00
Type ‘A’	95 (37.3)	8 (24.2)	.460 (.186, 1.141)	P = 0.094	.635 (.193, 2.083	p = 0.454
Type ‘B’ & ‘AB’	78 (30.6)	(30.3)10	.701 (.297, 1.653)	P = 0.417	1.371 (.418, 4.497)	p = 0.603
Current ARV drug regimens
2NRTIs + 1PI*	48 (18.8)	6 (18.2)	1.00		1.00
2 NRTIs +1 INI	129 (50.6)	9 (27.3)	.323 (.095, 1.097)	P = 0.323	.279 (.062, 1.254	p = 0.096
2 NRTIs + 1 NNRTI	78 (30.6)	18 54.5)	.535 (.180, 1.593)	P = 0.535	1.254 (.304, 5.177)	p = 0.754

n = 288; Data presented as % prevalence; ASCVD, Atherosclerotic Cardiovascular Disease; CI, confidence interval; FRS, Framingham risk score; OR, odds ratio

*two of the cases were on 2 NRTIs+ 1INTI +1 PI) regimen.

Table 4

Association between ASCVD risk using FRS and clinical characteristics among people living with HIV/AIDS age 40 75 years at Zewditu Memorial Hospital, Addis Ababa, Ethiopia.

Clinical characteristics	ASCVD risk using FRS		COR (95% C.I.)	P value	AOR (95% C.I.)	P value
	Low risk (<10%)	High risk (≥10%)
Number (%)	153 (82.3)	33 (17.7)
Age (year)
60–79	14 (9.2)	16 (48.5)	1		1
40–59	139 (90.8)	17 (51.5)	0.107 (0.045, .257)	p<0.001	0.022 (.004, .115)	p<0.001
Gender
Male	70 (45.8)	31 (93.9)	1		1
Female	83 (54.2)	2 (6.1)	0.054 (0.013, .235)	p<0.001	0.017 (.002, .126)	p < .0001
CD4 count (cells/μL)
>/ = 500	56 (36.6)	13 (39.4)	1		1
<500	97 (63.4)	20 (60.6)	0.888 (0.410, 1.922)	P = 0.763	0.380 (.110, 1.312)	p = 0.126
Systolic blood pressure (mmHg)
>/ = 130	71 46.4)	25 (75.8)	1		1
<130	82 (53.6)	8 (24.2)	0.277 (.118, .653)	P = 0.003	0.190 (.054, .668)	p = 0.010
Total cholesterol (mg/dL)
>/ = 160	107 (69.9)	29 (87.9)	1		1
<160	46 (30.1)	4 (12.1)	0.321 (.107, .965)	P = 0.043	0.302 (.081, 1.131)	p = 0.075
HDL cholesterol (mg/dL)
<40 in male & < 50 in women	63 (41.2)	11 (33.3)	1		1
>/ = 40 in Male & >/ = 50 in Female	90 (58.8)	22 (66.7)	1.40 (.634, 3.091)	P = 0.405	0.308 (.087, 1.095)	p = 0.069
Duration on ART (year)
>/ = 2 years	139 (90.8)	32 (18.7)	1		1
<2 years	14 (9.2)	1 (3.0)	0.310 (.039, 2.446)	P = 0.267	0.571 (.046, 7.145)	p = 0.664
Blood group
Type ‘O’	54 (35.3)	15 (45.5)	1		1	.
Type ‘A’	52 (34.0)	8 (24.2)	0.554 (.217, 1.416)	P = 0.217	0.486 (0.123, 1.924)	p = 0.304
Type ‘B’ & ‘AB’	47 (30.7)	10 (30.3)	0.766 (.134, 1.866)	P = 0.557	0.824 (0.227, 2.998)	p = 0.769
Current ARV drug regimens
2NRTIs + 1PI*	21 (13.7)	6 (18.2)	1	.	1	.
2 NRTIs +1 INI	84 (54.9)	9 (27.3)	0.375 (0.120, 1.171)	P = 0.091	0.149 (0.029, .775)	p = 0.024
2 NRTIs + 1 NNRTI	48 (31.4)	18 (54.5)	1.313 (0.456, 3.776)	P = 0.614	0.450 (.093, 2.177)	p = 0.321

n = 186; Data presented as % prevalence; ASCVD, Atherosclerotic Cardiovascular Disease; FRS, Framingham Risk Score; COR, Crude Odds Ratio; AOR, Adjusted Odds Ratio; CI, Confidence Interval

*two of the cases were on 2 NRTIs + 1INTI +1 PI) regimen

Table 5

Association between ASCVD risk using PCE and clinical characteristics among people living with HIV/AIDS age 40 to 75 years at Zewditu Memorial Hospital, Addis Ababa, Ethiopia.

Clinical characteristics	ASCVD risk using PCE		COR (95% C.I.)	P value	AOR (95% C.I.)	P value
	Low risk (<7.5%)	High risk (≥7.5%)
Number (%)	134 (72.0)	52 (28.0)
Age (year)
60–79	6 (4.5)	24 (46.2)	1		1
40–59	128 (95.5)	28 (53.8)	0.55 (0.020, 0.146)	p<0.001	0.012 (0.002,.066)	p<0.001
Gender
Male	62 (46.3)	39 (75.0)	1		1
Female	72 (53.7)	13 (25.0)	0.287 (0.141, 0.586)	p = 0.001	0.185 (0.054,0.630)	p = 0.007
CD4 count (cells/μL)
>/ = 500	52 (38.8)	17 (32.7)	1		1
<500	82 (61.2)	35 (67.3)	1.306 (0.664, 2.566)	p = 0.439	1.045 (0.385, 2.833)	p = 0.931
Systolic blood pressure (mmHg)
>/ = 130	53 (39.6)	43 (82.7)	1		1
<130	81 (60.4)	9 (17.3)	0.137 (0.062, 0.304)	p < .001	0.034 (0.007, 0.162)	p<0.001
Total cholesterol (mg/dL)
>/ = 160	99 (73.9)	37 (71.2)	1		1
<160	35 (26.1)	15 (28.8)	1.147 (0.562,2.340)	p = 0.707	1.342 (0.499, 3.607)	p = 0.560
HDL cholesterol (mg/dL)
<40 in male & < 50 in women	56 (41.8)	18 (34.6)	1		1
>/ = 40 in Male & >/ = 50 in Female	78 (58.2)	34 (65.4)	1.356 (0.696, 2.641)	p = 0.370	0.635 (0.206, 1.956)	p = 0.429
Duration on ART (year)
>/ = 2 years	125 (93.3)	46 (88.5)	1		1
<2 years	9 (6.7)	6 (11.5)	1.812 (0.611, 5.371)	p = 0.284	1.952 (0.365, 10.437)	p = 0.434
Blood group
Type ‘O’	44 (32.8)	25 (48.1)	1		1
Type ‘A’	45 (33.6)	15 (28.8)	0.587 (0.273, 1.258)	p = 0.171	0.353 (0.116, 1.073)	p = 0.066
Type ‘B’ & ‘AB’	45 (33.6)	12 (23.1)	0.469 (0.210, 1.049)	p = 0.065	0.378 (0.122, 1.170)	p = 0.092
Current ARV drug regimens
2NRTIs + 1PI*	23 (17.2)	4 (7.7)	1		1
2 NRTIs +1 INI	68 (50.7)	25 (48.1)	2.114 (0.665, 6.720)	p = 0.205	1.600 (0.341, 7.515)	p = 0.551
2 NRTIs + 1 NNRTI	43 (32.1)	23 (44.2)	3.076 (0.949, 9.972)	p = 0.061	1.820 (0.372, 8.901)	p = 0.459

n = 186; Data presented as % prevalence; ASCVD, Atherosclerotic Cardiovascular Disease; FRS, Framingham Risk Score; COR, Crude odds ratio; AOR, adjusted odds ratio; CI, Confidence Interval

*two of the cases were on 2 NRTIs + 1INTI +1 PI) regimen.

To see the effect of ART regimen on mean score, ASCVD risk was calculated based on FRS and PCE, and a curve was plotted for age (Fig 2), sex (Fig 3), and blood group (Fig 4). The mean score for the risk based on both FRS was found to be higher with NNRTI-based regimen, age 40–64 years, the male gender, and blood type ‘O’. On the other hand, the highest marginal mean was observed in NNRTI based regimen, the male gender, age 65–79 years, and blood type ‘A’ in the PCE method.

Fig 2

The ASCVD risk based on ART regimen and age interaction among PLWHA age 40–79 years: using the pooled cohort equation (a), and the Framingham risk score (b) estimation.

Fig 3

The ASCVD risk based on ART regimen and gender interaction among PLWHA age 40–79 years: using the pooled cohort equation (a), and the Framingham risk score (b) estimation.

Fig 4

The ASCVD risk based on ART regimen and blood type interaction among PLWHA age 40–79 years: using the pooled cohort equation (a), and the Framingham risk score (b) estimation.

Discussion

This is the first study that attempted to determine the ASCVD risk prevalence and predictors among PLWHA based on both PCE and FRS methods. Several studies investigated the risk of ASCVD in PLWHA using the FRS/PCE tools and reported that both FRS and PCE are equally important in both PLWHA and the general population, although some prefer PCE [3, 17, 18, 32, 33] and others FRS [19, 34]. We used both tools because this is the first study conducted in the country and wanted it to serve as a basis for future similar studies.

The prevalence of elevated risk for ASCVD in all patients based on FRS was 11.5%. It was 28% and 17.7% for those patients 40 to 79 years of age based on the PCE and FRS method, respectively. Since race has been incorporated as a predictor in determination of the risk for ASCVD by the PCE method, an exaggerated prevalence might be seen in such population, as evidenced in the present study (28% for PCE vs. 17.7% for FRS). Moreover, the lower cut-off point used for the PCE method (≥7.5%) could also contribute to the observed higher prevalence.

The prevalence of elevated risk for ASCVD in all patients based on FRS in our study is found to be higher than the Chinese [35], Botswana [36] and Taiwan [37] studies, but lower than the Italian [38] and the US [26] studies. Moreover, the male gender and age ≥50 years were found to be predictors of elevated-risk for ASCVD and this is consistent with studies conducted in the USA [3, 39]. Study design, sample size, population genetics, and study duration could account for the observed discrepancies.

Our study revealed that age plays a major role in the prevalence of elevated ASCVD risk and this is in line with several studies conducted elsewhere [12, 39–41]. In our study, participants with 40 to 64 years of age had a low-risk for ASCVD than those with the age range 65 to 79 years based on both methods and this is in agreement with several studies done globally [10, 12, 23, 37, 42–44]. On the other hand, many other studies have also reported high prevalence of elevated ASCVD risk at 40 to 65 years of age that tended to decline with age above 65 years [44, 45].

Consistent with our finding, there is a sex-based difference in the lifetime risk for ASCVD, being 50% for men and 33.3% for women at 40 years of age and decreasing to 33% for men and 25% for women at 70 years of age [44]. The association of the male gender with increased risk for ASCVD is a subject of controversy. The female sex hormones have been assumed to confer a protective role for ASCVD. However, a recent published study [46] did not provide any evidence for the role of these hormones in ASCVD risk prevention, casting doubt on their protective role. As a result, post-menopausal hormone replacement therapy should not be considered as beneficial for ASCVD prevention strategies. Environmental factors (cigarette smoking and working in hazardous conditions) have also been suggested to play a major role in sex difference of ASCVD distribution [44, 45, 47, 48]. Although females tend to have a lower-risk for ASCVD, its occurrence is associated with poor prognosis and increased risk of mortality [3, 45].

Smoking has been shown to be associated with ASCVD in both PLWHA and the general population [49, 50]. Our study also showed that smoking is a significant predictor of ASCVD in both tools, although the proportion of smokers was less than 5%, which is much lower than other studies conducted elsewhere (23.5%) [51] and 68.7% [49].

Several studies reported that hypertension is an important risk factor for cardiovascular, stroke, and cerbrovascular diseases [52-54]. Mostly hypertension and ASCVD appear together in clinical investigation, although which causes which is a paradox [55]. Lower systolic blood pressure (<130mmHg) in HIV patients was associated with a decreased risk of ASCVD based on FRS and this is comparable with several other studies [56-58]. Systolic blood pressure was also a significant predictor of ASCVD among patients 40 to 79 years of age using both PCE and FRS, suggesting that lowering this pressure to below 130 mmHg could reduce the risk of acquiring ASCVD by 15 to 25%, which is concordant with several studies [16, 59, 60].

Dyslipidemia is considered to be the most frequent risk factor for ASCVD as reported in the literature [58, 61]. A decrease in total cholesterol below 160 mg/dL was associated with a lower risk of ASCVD in all patients in the present study. However, it was not a significant predictor of ASCVD among population age 40 years and above, as reported elsewhere [62].

A significant lower-risk of ASCVD was observed among participants on ART regimen of ‘2 NRTIs +1 INI’ and aged 40 to 79 years using FRS but the PCE-based calculation did not produce any significant association. The lack of association in PCE but not in FRS could be attributed to the difference in the number of lipid variables used by the two methods. FRS uses three different lipids (TC, HDL, and LDL) to predict the risk of ASCVD and cART increase the risk of ASCVD by altering lipid profiles [24, 63].

Between subject analysis for the variables cART, age, gender, and blood group against the risk of ASCVD was performed and the analysis revealed that mean score was highest with NNRTI-based regimen. The association of NNRTIs-based cART with the risk of ASCVD has been widely reported by several studies [64-66], but association was more commonly reported with PI- based cART [66-68]. However, we found no association with PI-based cART, which could possibly be due to the fact that many of the participants were on NNRTIs-based cART until the recent introduction of the integrase inhibitors and/or the small sample size employed.

Only few studies are available that attempted to determine the risk for ASCVD in HIV-infected adults in Africa. Mosepele et al. [36] reported PCE to classify more participants in the elevated risk category than FRS (14.1 vs. 2.6%) and to a similar extent to those having established subclinical atherosclerosis. Mubiru et al [69] conducted a systematic review to find the most frequently used tool for screening the risk and did not find any detectable differences between lipid and non-lipid as well as HIV-specific and non-HIV-specific factors, although they suggested that the inclusion of HIV and ART history might improve accuracy of risk determination. Similarly, a study done in Tanzania by Kingery et al [70] reported that the lifetime and 10-year ASCVD risk as well as the prevalence of metabolic syndrome was higher in ART-experienced than HIV-negative and ART-naïve subjects. All reports highlighted the need for further studies to better understand the risk of CVD in HIV patients, as the burden of the disease is greater in sub-Saharan Africa.

Limitations of the study

The study may not be used as a representative for the entire PLWHA in Ethiopia as the data were obtained only from a single hospital. The ASCVD risk assessed in this study might not represent an actual ASCVD, as clinical events, or surrogate proofs such as coronary plaque were not determined using computed tomography. The anticipated risk of ASCVD can also be reverted by proper implementation of preventive clinical guidelines during the follow-up period and a healthier life style modification.

Conclusions

This study highlighted that a significant number of PLWHA are at risk for developing ASCVD in the coming 10 years. In both FRS and PCE, ASCVD was significantly associated with advanced age, male gender, low blood pressure, and smoking. ASCVD management strategies should also take into consideration age, gender, smoking status, and blood pressure control. The ASVD risk calculators, PCE and FRS, have similar prediction capacity in PLWHA. However, PCE might yield an exaggerated prevalence of ASCVD due to the race variable and the lower cut-off point for risk stratification incorporated in the tool. Hence, the tools can be used interchangeably or together.

(SAV)

Click here for additional data file.

16 Sep 2021

PONE-D-21-18860

Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: a hospital-based study

PLOS ONE

Dear Dr. Engidawork,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewer and this Editor found that the manuscript has merits, but it cannot be accepted in the present form. Specifically: (1) a comparison of the inferred risk derived from the scores used should be included; (2) please, describe enrolment procedures and inclusion and exclusion criteria; (3) please, describe the criteria for HIV infection diagnosis; (4) please, include the smoking habit in the risk model; (5) describe what is the added value/information specific to the present study, in comparison to other published studies; (6) fully describe the limitations of the study.

Please submit your revised manuscript by Oct 31 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gualtiero I. Colombo, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Review 21- 18860 Plos One

This is a study which assess the prevalence of atherosclerotic cardiovascular disease (ASCVD) risk among a cohort of people living with HIV (PLWHA) in Addis Ababa, Ethiopia. The whole sample includes 288 patients for data analysis. For risk calculation, the authors use two calculators: the Pooled Cohort Equation (PCE) or the Framingham Risk Score (FRS). The results of risk calculation are then reported using both, independently, as well as the analyses of the effect of predictors.

General comments:

The authors should be very careful in all their text that ASCVD risk is assessed in their study, but not ASCVD itself. In more than one place, there is not enough precision on this issue.

I think there could be less acronyms. Please use acronyms if they are frequently used in the text, and try to minimize their use.

A comparison of the risk calculation using both scores would be very helpful, using clinically used values such as low, moderate or elevated risk (or low versus elevated risk). See methodology of : Hernando Knobel 1, Carlos Jericó, Milagro Montero, María L Sorli, Manuela Velat, Ana Guelar, Pere Saballs, Juan Pedro-Botet Global cardiovascular risk in patients with HIV infection: concordance and differences in estimates according to three risk equations (Framingham, SCORE, and PROCAM) AIDS Patient Care STDS . 2007 Jul;21(7):452-7. doi: 10.1089/apc.2006.0165.

Specific comments in the Word document attached.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Review PLOS ONE 21 18860.docx

Click here for additional data file.

27 Sep 2021

Dear Editor,

We are very much thankful for the constructive comments and suggestions of the Editor and Reviewers. The comments are all valuable and very helpful for revising and improving our manuscript. We have attended all the comments and provided point-by-point response as depicted below. Changes introduced are marked in red with visible track changes in the manuscript. An unmarked version of the revised paper without track changes has also been submitted separately labeled as “Revised Manuscript without track change'.

Kind regards,

Ephrem Engidawork (PhD)

Professor of Pharmacology

Editor’s Comment

• Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

o We checked and it adheres to the guideline.

• Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

o We used an instrument developed by WHO and can be accesses, as we have given the reference. We have provided sufficient detail about the instrument in the text.

• We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

o We will submit the requested item after acceptance of the manuscript.

• Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

o It now appears in the Method section.

Review 21- 18860 Plos One

General comments:

• The authors should be very careful in all their text that ASCVD risk is assessed in their study, but not ASCVD itself. In more than one place, there is not enough precision on this issue.

o Thank you. Corrected.

• I think there could be less acronyms. Please use acronyms if they are frequently used in the text, and try to minimize their use.

o Minimized as much as possible.

• A comparison of the risk calculation using both scores would be very helpful, using clinically used values such as low, moderate or elevated risk (or low versus elevated risk). See methodology of: Hernando Knobel 1, Carlos Jericó, Milagro Montero, María L Sorli, Manuela Velat, Ana Guelar, Pere Saballs, Juan Pedro-Botet Global cardiovascular risk in patients with HIV infection: concordance and differences in estimates according to three risk equations (Framingham, SCORE, and PROCAM) AIDS Patient Care STDS . 2007 Jul;21(7):452-7. doi: 10.1089/apc.2006.0165.

• Abstract:

Define AOR

o Explained or defined.

• Introduction

p 9 line 58. “It is therefore prudent to determine the risk of such CVDs for

59 proper monitoring as well as improving outcomes of cART [13].” Suggest to add “… adequately determine …”

o Corrected accordingly.

p10 line 73: “The prevalence of ASCVD using FRS reported to be in the range of 70-90% for the low risk, 20-30% for the moderate risk, and 0-20% for the high-risk [17-20].” Is it the inverse of that? so the authors want to describe the prevalence of cardiovascular risk, or the prevalence of cardiovascular disease? please be specific, since ASCVD is defined here as atherosclerotic cardiovascular disease (and not atherosclerotic cardiovascular disease risk)

o The percentages are correct. The most prevalent form of ASCVD risk is ‘Low risk’. Corrections are also made as per the comment

• Methods:

Enrolment:

o described

What were the inclusion and exclusion for enrolment?

o described

Please in the method, underline that HIV infection was among the inclusion criteria.

o Accommodated

How HIV infection was proven?

o Confirmation of HIV was already made based on laboratory investigation as documented in patients’ charts.

p 13, line 132: “Determination of ASCVD among population aged 20 to 132 79 years (n=288) was carried out using the FRS tool.” Please add the work “risk”. The sentence should be “Determination of ASCVD risk among population aged 20 to 132 79 years (n=288) was carried out using the FRS tool.”

o Accommodated.

• Results:

In the Introduction, the authors mention that “The risk can be classified as low-risk (<10%), moderate risk (10-20%), and high-risk (>20%) using FRS [15], and as low risk (<7.5%) and elevated risk (> 7.5%) using PCE 73 [16].”. However, in Table 1, the risk with FRS seems to be classified as low versus elevated. Please clarify. Please define what is low and what is elevated using FRS.

o Corrected.

Same issue: in the introduction it is written as “ .. low risk (<7.5%) and elevated risk (> 7.5%) using PCE.”. Please, if low and elevated categories are also used for FRS, “FRS” has to be included in the sentence.

o Corrected.

p15 line 169 “The calculated risk using both tools presented in Table 2.” Please, specify in this sentence that it is for participants 40 to 79 years.

o It is already provided in the footnote.

I do not see Smoking as a predictor in any of the tables. Smoking is a predictor of coronary artery disease (CAD) that is difficult to control in comparative studies assessing causes of CAD in HIV-associated atherosclerosis (see Durand et al. JAIDS. 2011;57(3):245-253, as well as Boldeanu et al. Radiology 2021). Please try to specifically assess the role of smoking in the predicted risk.

o We opted to remove the smoking data from our results because we found the expected count was less than 5%, which is because of the smaller number of smokers in the cohort

• Discussion

3rd paragraph: “The prevalence of the risk for ASCVD in all patients based on FRS was 11.5% and it was 28% and 17.7% for those patients 40 to 79 years of age based on the PCE and FRS method, respectively.” Please add the word elevated: The prevalence of elevated risk for ASCVD in …

o Amended.

Please describe which, if any, studies also describe ASCVD and ASCVD risk in the HIV African populations. Please convince the reader that there a need in the literature for another ASCVD risk assessment study such as this one. Explain what is specific of the present study, in comparison to other published studies.

o Revised as per the comment.

Please comment and discuss that ASCVD risk is assessed in this study, however without available data for proven ASCVD (for example, clinical events, or surrogate proofs such as coronary plaque using computed tomography). This is among the limitations of the study.

o Accommodated.

• References:

ref no 8 seems incomplete

if another reference is needed:

Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec's public health insurance database. Journal of acquired immune deficiency syndromes (1999). 2011;57(3):245-253.

o The Reference. Authors name was modified.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

11 Oct 2021

PONE-D-21-18860R1Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: a hospital-based studyPLOS ONE

Dear Dr. Engidawork,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I recommend that the authors discuss how the absence of data on smoking habits may affect their results.

Please submit your revised manuscript by Nov 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gualtiero I. Colombo, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Comment of reviewer (in submission version):

I do not see Smoking as a predictor in any of the tables. Smoking is a predictor of coronary artery disease (CAD) that is difficult to control in comparative studies assessing causes of CAD in HIV-associated atherosclerosis (see Durand et al. JAIDS. 2011;57(3):245-253, as well as Boldeanu et al. Radiology 2021). Please try to specifically assess the role of smoking in the predicted risk.

Answer of authors:

We opted to remove the smoking data from our results because we found the

expected count was less than 5%, which is because of the smaller number of smokers

in the cohort

New comment in R1 :

Please, the removal of smoking data from the results should be discussed in the Discussion section, as well as how this could affect your results, since this predictor seems to be difficult to control in comparative studies assessing causes of CAD in HIV-associated atherosclerosis, and since it is an important predictor of CAD.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Oct 2021

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: a hospital-based study”. The comments are all valuable and very helpful for improving our manuscript. We have seen all the comments carefully and have made correction which we hope meet your expectations. Revised portion are shown with track changes and both the marked and unmarked versions of the manuscript are separately uploaded. The main corrections in the paper and the responses to the Editor’s and reviewer’s comments are as follows:

Comments of the Editor

• Review your reference list to ensure that it is complete and correct. Provide rationale for including retracted articles.

� We checked all the references and they are complete and correct. We have included three references (50-52) to that effect. We did not cite any retracted articles.

Comments of Reviewer 1

• Removal of the smoking data

� We removed the smoking data because the proportion of smokers was too small. We have now changed the tool from Pearson Chi-Square test to Fisher’s exact test and included the smoking data in the association studies.

Kind regards

Ephrem Engidawork (PhD)

Professor of Pharmacology

Submitted filename: Response to reviewers 2 .docx

Click here for additional data file.

3 Nov 2021

Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: a hospital-based study

PONE-D-21-18860R2

Dear Dr. Engidawork,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Gualtiero I. Colombo, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

12 Nov 2021

PONE-D-21-18860R2

Predicting the risk of atherosclerotic cardiovascular disease among adults living with HIV/AIDS in Addis Ababa, Ethiopia: a hospital-based study

Dear Dr. Engidawork:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gualtiero I. Colombo

Academic Editor

PLOS ONE