Development of a risk score to guide targeted hepatitis C testing among human immunodeficiency virus patients in Cambodia

Table 1 Harm and benefit of hepatitis C virus testing and not testing

Harm of testing (false positives)	Benefit of testing	Harm of not testing (false negatives)	Benefit of not testing
Low, but existing:	High (for some):	High (for some):	Important in some contexts:
Cost of tests, human resources (lab & counseling)	If diagnosed positive: good treatment available (high cure rate, few side effects, short /life-saving for cirrhotic patients/ but treatment often not urgent)	Denial of live-saving, highly efficacious and affordable treatment	Cost-saving in resource-constrained environment with many competing interests
Stress related to waiting for results	Impact on further transmission (but less weight in HCV populations with low risk profile)
Budget allocated to HCV testing not available for other health priorities
Divert resources /timely access from those most in need (in case of testing all)

HCV: Hepatitis C virus.

Table 2 Characteristics of the derivation cohort, including the candidate predictors

Characteristics	Missing values	n = 3045	Candidate predictor
HIV patients with HCV coinfection, n (%)	0	106 (3.5)
Male, n (%)	0	1,307 (42.9)	√
Age, yr, median (IQR)	0	42.5 (36.3-48.1)	√
Key populations1, n (%)	0	31 (0.1)
Receiving ART, n (%)	0	2,972 (97.6)
On NNRTI-based ART, n (%)		2,728 (91.8)
On PI-based ART, n (%)		232 (7.8)
Other, n (%)		12 (0.4)
Duration on ART, years, median (IQR)	0	6.9 (4.4-9.1)
HIV viral load < 50 copies/mL, n (%)	368	2,517 (96.6)
CD4, cells/µL, median (IQR)	11	464 (339-609)
Poor CD4 recovery on ART2, n (%)	13	117 (4.0)	√
ALT, IU/L, median (IQR)	0	28 (20-43)	√
AST, IU/L, median (IQR)	0	26 (21-36)	√
Platelets, × 109 cells/L, median (IQR)	0	266 (221-312)	√
APRI, median (IQR)	0	0.29 (0.21-0.41)	√
Fatigue, myalgia/arthralgia, or anorexia/weight loss, n (%)	0	301 (9.9)	√
Diffuse pruritus, n (%)	0	120 (3.9)	√
Diabetes mellitus, n (%)	6	113 (3.7)	√
Hepatitis B surface antigen positive, n (%)	0	311 (10.2)
Partner or household member with liver disease, n (%)	10	185 (6.1)	√

¹homosexual, history or current injecting drug user, or history or currently engaged in sex work.

²CD4 below200 after 3 years or more on ART.

ART: Antiretroviral therapy; NNRTI: Non-nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; APRI: AST-to-platelet ratio index; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.

Table 3 Crude and adjusted likelihood ratios of the candidate predictors for hepatitis C virus coinfection

Predictor variables after dichotomization	Number of HIV patients	Outcome events, n (%)	Crude likelihood ratios (LHR)		Adjusted likelihood ratios (aLHR)
			Positive LHR	Negative LHR	Positive aLHR	Negative aLHR
Male gender	1307	45 (3.4)	0.99	1.01	-	-
Age ≥ 50 years	601	45 (7.5)	2.55	0.71	2.18	0.72
Platelets < 200 × 109 cells/L	442	49 (11.1)	3.46	0.62	1.69	0.82
AST ≥ 30 IU/L	1190	88 (7.4)	2.21	0.28	1.48	0.53
ALT ≥ 40 IU/L	887	69 (7.8)	2.33	0.49	-	-
APRI ≥ 0.45	633	78 (12.3)	3.88	0.33	2.42	0.48
Having diabetes	113	13 (11.5)	3.76	0.90	2.14	0.94
Presenting fatigue OR myalgia/arthralgia OR anorexia/weight loss	301	21 (7.0)	2.11	0.88	-	-
Generalized pruritus	120	10 (8.3)	2.61	0.94	2.04	0.95
Having a partner OR household member with liver disease	185	10 (10.3)	3.21	0.87	3.62	0.85
Poor CD4 recovery on ART	117	5 (4.3)	1.34	0.99	-	-

In bold the adjusted likelihood ratios ≥ 1.5 or ≤ 0.67. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; APRI: AST-to-platelet ratio index; ART: Antiretroviral therapy; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.

Table 4 Predictors and their weight in the clinical prediction score

Predictor	Score
Age ≥ 50 yr	+1
Having diabetes mellitus	+1
Having a partner and/or household member with liver disease	+1
Presenting generalized pruritus	+1
Platelets < 200 × 109 cells/L	+1
APRI ≥ 0.45	+1
APRI < 0.45	-1
AST < 30 IU/L	-1
Possible range of the score	- 2 to + 6

APRI: AST-to-platelet ratio index; AST: Aspartate aminotransferase.

Table 5 Diagnostic accuracy at different cut-offs of the clinical prediction score

Cut-off	HIV patients, n (%)	Sensitivity, % (95%CI)	Specificity, % (95%CI)	PPV, % (95%CI)	NPV, % (95%CI)
Score ≥ -1	1871 (61.4)	93.4 (86.9-97.3)	39.7 (37.9-41.5)	5.3 (4.3-6.4)	99.4 (98.8-99.8)
Score ≥ 0	926 (30.0)	84.9 (76.6-91.1)	71.6 (69.9-73.2)	9.7 (7.9-11.8)	99.2 (98.8-99.6)
Score ≥ 1	670 (22.0)	74.5 (65.1-82.5)	79.9 (78.4-81.3)	11.8 (9.5-14.5)	98.9 (98.4-99.2)
Score ≥ 2	325 (10.7)	59.4 (49.5-68.9)	91.1 (90.0-92.1)	19.4 (15.2-24.1)	98.4 (97.9-98.9)
Score ≥ 3	103 (3.4)	33.0 (24.2-42.8)	97.7 (97.1-98.2)	34 (24.9-44.0)	97.6 (97.0-98.1)
Score ≥ 4	18 (0.6)	10.4 (5.3-17.8)	99.8 (99.5-99.9)	61.1 (35.7-82.7)	96.9 (96.2-97.5)
Score ≥ 5	4 (0.1)	2.8 (0.6-8.1)	99.97 (99.8-100)	75 (19.4-99.4)	96.6 (95.9-97.2)

In bold the diagnostic accuracy results (number of HIV patients, sensitivity, specificity, PPV, and NPV) for the cut-off at score ≥ 0. This is the cut-off best fitting as threshold-to-test. PPV: Positive predictive value; NPV: Negative predictive value; HIV: Human immunodeficiency virus.