Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs

Lucy Platt; Silvia Minozzi; Jennifer Reed; Peter Vickerman; Holly Hagan; Clare French; Ashly Jordan; Louisa Degenhardt; Vivian Hope; Sharon Hutchinson; Lisa Maher; Norah Palmateer; Avril Taylor; Julie Bruneau; Matthew Hickman

doi:10.1002/14651858.CD012021.pub2

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Figure 1

Study flow diagram.

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Figure 2

Forest plot of comparison: 1 Current OST versus no OST, outcome: 1.1 HCV incidence adjusted analyses by region.

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Figure 3

Funnel plot of comparison: 1 Current OST versus no OST, outcome: 1.1 HCV incidence adjusted analyses by region.

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Figure 4

Forest plot of comparison: 2 High NSP coverage versus no/low NSP coverage, outcome: 2.1 HCV incidence adjusted analyses by region.

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Figure 5

Forest plot of comparison: 4 Combined OST and high/low NSP versus no OST and low/no NSP, outcome: 4.1 HCV incidence adjusted analyses.

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Analysis 1.1

Comparison 1 Current OST versus no OST, Outcome 1 HCV incidence adjusted analyses by region.

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Analysis 1.2

Comparison 1 Current OST versus no OST, Outcome 2 HCV incidence adjusted analysis by study design.

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Analysis 1.3

Comparison 1 Current OST versus no OST, Outcome 3 HCV incidence unadjusted analyses by different modes of OST provision.

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Analysis 2.1

Comparison 2 Sensitivity analysis: OST versus no OST, adjusted analyses excluding unpublished datasets, Outcome 1 HCV incidence.

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Analysis 3.1

Comparison 3 Sensitivity analysis: OST versus no OST, adjusted analyses excluding studies at critical risk of bias, Outcome 1 HCV incidence.

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Analysis 4.1

Comparison 4 Sensitivity analysis: OST versus no OST, adjusted analyses excluding cross‐sectional studies, Outcome 1 HCV incidence.

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Analysis 5.1

Comparison 5 OST versus no OST, unadjusted analysis, Outcome 1 HCV incidence.

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Analysis 6.1

Comparison 6 High NSP coverage versus no/low NSP coverage, Outcome 1 HCV incidence adjusted analyses by region.

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Analysis 6.2

Comparison 6 High NSP coverage versus no/low NSP coverage, Outcome 2 HCV incidence adjusted analyses by study design.

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Analysis 7.1

Comparison 7 Sensitivity analysis: high NSP versus low/no NSP, excluding unpublished data, Outcome 1 HCV incidence.

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Analysis 8.1

Comparison 8 Sensitivity analysis: high NSP versus low/no NSP, excluding cross‐sectional surveys, Outcome 1 HCV incidence.

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Analysis 9.1

Comparison 9 High NSP coverage versus low/no coverage, unadjusted estimates, Outcome 1 HCV incidence.

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Analysis 10.1

Comparison 10 Low NSP coverage versus no coverage, Outcome 1 HCV incidence, adjusted analyses.

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Analysis 11.1

Comparison 11 Low NSP coverage versus no NSP, unadjusted analysis, Outcome 1 HCV incidence.

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Analysis 12.1

Comparison 12 Combined OST and high/low NSP versus no OST and low/no NSP, Outcome 1 HCV incidence adjusted analyses.

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Analysis 12.2

Comparison 12 Combined OST and high/low NSP versus no OST and low/no NSP, Outcome 2 HCV incidence unadjusted analyses.

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Summary of findings for the main comparison. Current OST versus no OST for people who inject drugs

Current OST versus no OST
Patient or population: people who inject drugs Settings: outpatient Intervention: current OST versus no OST
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No OST	Current OST
HCV incidence adjusted analyses number of HCV seroconversion Follow‐up: mean 440.5 person‐years	—	—	RR 0.50 (0.40 to 0.63)	6361 (12 studies)	⊕⊕⊝⊝ Low^a,b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OST: opioid substitution therapy; RR: risk ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aDowngraded one level due to overall moderate risk of bias in 2 studies, overall serious risk of bias in 6 studies, 2 studies at overall critical risk of bias in 2 studies; not enough information to make judgment in 2 studies. ^bUpgraded one level due to large magnitude of the effect: RR: 0.5.

Summary of findings for the main comparison. Current OST versus no OST for people who inject drugs

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Summary of findings 2. High NSP coverage versus no/low NSP coverage for people who inject drugs

High NSP coverage versus no/low NSP coverage
Patient or population: people who inject drugs Settings: outpatients Intervention: high NSP coverage versus no/low NSP coverage
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No/low NSP coverage	High NSP coverage
HCV incidence adjusted analyses number of HCV seroconversion Follow‐up: mean 269 person‐years	—	—	RR: 0.79 (0.39 to 1.61)	3530 (5 studies)	⊕⊝⊝⊝ Very low^a,b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NSP: needle syringe programmes; RR: risk ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to serious overall risk of bias in all the studies. ^bDowngraded one level due to significant heterogeneity: I²: 77%.

Summary of findings 2. High NSP coverage versus no/low NSP coverage for people who inject drugs

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Summary of findings 3. Combined OST and high NSP versus no OST and low/no NSP for people who inject drugs

Combined OST and highNSP versus no OST and low/no NSP
Patient or population: people who inject drugs Settings: outpatients Intervention: Combined OST and high/low NSP versus no OST and low/no NSP
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No OST and low/no NSP	Combined OST and high NSP
HCV incidence adjusted analyses number of HCV seroconversions Follow‐up: mean 356 person‐years	—	—	RR: 0.26 (0.07 to 0.89)	3241 (3 studies)	⊕⊕⊕⊝ Low^a,b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; NSP: needle syringe programmes; OST: opioid substitution therapy; RR: Risk ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to serious overall risk of bias in all studies. ^bUpgraded one level due to very large magnitude of the effect: RR: 0.26.

Summary of findings 3. Combined OST and high NSP versus no OST and low/no NSP for people who inject drugs

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Table 1. Risk of bias of included studies

Study	Confounding	Selection bias	Measurement of interventions	Departures from intended interventions	Missing data	Measurement of outcomes	Selection of reported result	Overall risk of bias
Aitken 2015 [pers comm]	Critical	Critical	Serious	No info	Critical	Low	No info	Critical
Bruneau 2015 [pers comm]	Moderate	Serious	Moderate	No info	No info	Low	Low	Serious
Craine 2009	Serious	Serious	Serious	No info	Serious	Low	Low	Serious
Crofts 1997	Critical	Serious	Low	No info	Serious	Serious	Low	Critical
Hagan 1995	Serious	Serious	Serious	No info	Low	Low	Low	Serious
Hagan 1999	Moderate	Serious	Low	No info	Low	Low	Low	Serious
Holtzman 2009	Serious	Serious	Moderate	No info	No info	Low	Low	Serious
Hope 2011	Moderate	Moderate	Serious	No info	Low	Low	Low	Serious
Hope 2015 [pers comm]	Moderate	Moderate	Serious	No info	No info	Low	Low	Serious
Judd 2015 [pers comm]	Moderate	Critical	Critical	No info	Critical	Low	Low	Critical
Lucidarme 2004	Moderate	Serious	Serious	No info	Serious	Low	Low	Serious
Maher 2015	Moderate	Serious	Serious	No info	No info	Low	Low	Serious
Mehta 2015 [pers comm]	Moderate	No info	No info	No info	No info	Low	Low	No info
Nolan 2014	Serious	Serious	Moderate	No info	Low	Low	Low	Serious
Page 2015 [pers comm]	Moderate	No info	No info	No info	No info	Low	Low	No info
Palmateer 2014a	Serious	Serious	Moderate	No info	Serious	Low	Low	Serious
Patrick 2001	Serious	Moderate	Serious	No info	Serious	Low	Low	Serious
Rezza 1996	Serious	Low	Serious	No info	Critical	Low	Low	Critical
Roy 2007	Serious	Serious	Serious	No info	Critical	Low	Low	Critical
Ruan 2007	Critical	Critical	Serious	No info	Serious	Low	Low	Critical
Spittal 2012	Serious	Serious	Moderate	No info	Low	Low	Low	Serious
Thiede 2000	Moderate	Moderate	Low	No info	Low	Low	Low	Moderate
Thorpe 2002	Serious	Serious	Serious	No info	Moderate	Low	Low	Serious
Tsui 2014	Moderate	Moderate	Low	No info	Moderate	Low	Low	Moderate
Vallejo 2015	Serious	Serious	Low	No info	Serious	Low	Low	Serious
Van Beek 1998	Critical	Serious	Serious	No info	Critical	Low	Low	Critical
Van Den Berg 2007	Serious	Serious	Moderate	No info	Serious	Low	Low	Serious
White 2014	Moderate	Serious	Moderate	No info	No info	Low	Low	Serious

Table 1. Risk of bias of included studies

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Table 2. Univariable meta‐regression analysis for studies measuring impact of current use of OST on HCV incidence

Variable	Studies	Univariable rate ratio (95% CI)	Ratio of rate ratios (95% CI)	P value	Tau²
Geographic region
Europe	8	0.51 (0.37‐0.70)	1.0 (ref)	—	—
Australia	5	0.55 (0.28‐1.11)	1.12 (0.52‐2.41)	—	—
North America	6	0.69 (0.44‐1.08)	1.42 (0.73‐2.78)	0.53	0.10
Site of recruitment
Service attenders	12	0.67 (0.49‐0.92)	1.0 (ref)	—	—
Community	7	0.49 (0.33‐0.73)	0.73 (0.42‐1.27)	0.256	0.06
Study design
Cross‐sectional	4	0.51 (0.31‐0.85)	1.0	—	—
Prospective cohort	15	0.58 (0.43‐0.77)	1.12 (0.48‐2.61)	0.784	0.10
Females	17	—	1.59 (1.13‐2.29)	0.01	0.04
Prison experience	11	—	1.057 (0.61‐1.79)	0.821	0.43
Experience of homelessness	12	—	1.08 (0.83‐1.40)	0.521	0.23
Injection of stimulants	12	—	0.89 (0.65‐1.22)	0.373	0.17
Daily injection	7	—	0.88 (0.64‐1.22)	0.373	0.17
CI: confidence interval; HCV: hepatitis C virus; OST: opioid substitution therapy.

Table 2. Univariable meta‐regression analysis for studies measuring impact of current use of OST on HCV incidence

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Table 3. Univariable meta‐regression analysis for studies measuring impact of high NSP coverage on HCV incidence

Variable	Studies	Univariable rate ratio (95%CI)	Ratio of rate ratios (95%CI)	P value	Tau²
Geographic region
Europe	5	0.44 (0.24‐0.80)	1.0 (Ref)	—	—
North America	3	1.58 (0.57‐4.42)	3.73 (0.95‐14.7)	0.057	0.41
Recruitment site
Service attenders	3	0.67 (0.28‐1.59)	1.0 (Ref)	—	—
Community	5	0.82 (0.29‐2.32)	0.76(0.12‐4.88)	0.74	0.89
Study design
Cross‐sectional survey	3	0.34 (0.16‐0.75)	1.0 (Ref)	—	—
Prospective cohort	4	1.26 (0.55‐2.93)	3.53 (0.78‐15.86)	0.087	0.48
Females	7	—	2.97(0.38‐23.1)	0.24	0.87
Prison experience	3	—	NA	—	—
Experience of homelessness	6	—	1.01 (0.38‐2.67)	0.976	1.53
Injection of stimulants	7	—	1.08 (0.47‐2.51)	0.827	1.15
Daily injection	5	—	3.66 (0.22‐61.3)	0.239	1.15
CI: confidence interval; HCV: hepatitis C virus; NSP: needle syringe programmes.

Table 3. Univariable meta‐regression analysis for studies measuring impact of high NSP coverage on HCV incidence

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Comparison 1. Current OST versus no OST

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence adjusted analyses by region Show forest plot	12	6361	Risk Ratio (Random, 95% CI)	0.50 [0.40, 0.63]

1.1 North America	5	2245	Risk Ratio (Random, 95% CI)	0.57 [0.42, 0.76]
1.2 Europe	5	3494	Risk Ratio (Random, 95% CI)	0.43 [0.27, 0.68]
1.3 Australia	2	622	Risk Ratio (Random, 95% CI)	0.42 [0.25, 0.72]
2 HCV incidence adjusted analysis by study design Show forest plot	12	6361	Risk Ratio (Random, 95% CI)	0.50 [0.40, 0.63]

2.1 Prospective cohort	10	3467	Risk Ratio (Random, 95% CI)	0.51 [0.40, 0.65]
2.2 Cross‐sectional surveys	2	2894	Risk Ratio (Random, 95% CI)	0.46 [0.23, 0.89]
3 HCV incidence unadjusted analyses by different modes of OST provision Show forest plot	9		Risk Ratio (Random, 95% CI)	Subtotals only

3.1 Ever used OST	3	375	Risk Ratio (Random, 95% CI)	0.81 [0.52, 1.27]
3.2 Interrupted OST use	3	1157	Risk Ratio (Random, 95% CI)	0.80 [0.57, 1.10]
3.3 Detoxification	1	552	Risk Ratio (Random, 95% CI)	1.45 [0.79, 2.66]
3.4 High dose	2	453	Risk Ratio (Random, 95% CI)	0.52 [0.29, 0.94]
3.5 Low dose	2	453	Risk Ratio (Random, 95% CI)	0.85 [0.44, 1.65]

Comparison 1. Current OST versus no OST

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Comparison 2. Sensitivity analysis: OST versus no OST, adjusted analyses excluding unpublished datasets

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	8	5235	Risk Ratio (Random, 95% CI)	0.42 [0.31, 0.58]

Comparison 2. Sensitivity analysis: OST versus no OST, adjusted analyses excluding unpublished datasets

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Comparison 3. Sensitivity analysis: OST versus no OST, adjusted analyses excluding studies at critical risk of bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	9	5782	Risk Ratio (Random, 95% CI)	0.51 [0.40, 0.64]

Comparison 3. Sensitivity analysis: OST versus no OST, adjusted analyses excluding studies at critical risk of bias

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Comparison 4. Sensitivity analysis: OST versus no OST, adjusted analyses excluding cross‐sectional studies

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	10	3467	Risk Ratio (Random, 95% CI)	0.51 [0.40, 0.65]

Comparison 4. Sensitivity analysis: OST versus no OST, adjusted analyses excluding cross‐sectional studies

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Comparison 5. OST versus no OST, unadjusted analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	16	9499	Risk Ratio (Random, 95% CI)	0.57 [0.45, 0.73]

Comparison 5. OST versus no OST, unadjusted analysis

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Comparison 6. High NSP coverage versus no/low NSP coverage

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence adjusted analyses by region Show forest plot	5	3530	Risk Ratio (Random, 95% CI)	0.79 [0.39, 1.61]

1.1 North America	3	627	Risk Ratio (Random, 95% CI)	1.25 [0.63, 2.46]
1.2 Europe	2	2903	Risk Ratio (Random, 95% CI)	0.24 [0.09, 0.62]
2 HCV incidence adjusted analyses by study design Show forest plot	5	3530	Risk Ratio (Random, 95% CI)	0.95 [0.50, 1.82]

2.1 Prospective cohorts	3	627	Risk Ratio (Random, 95% CI)	1.44 [1.01, 2.05]
2.2 Cross‐sectional surveys	2	2903	Risk Ratio (Random, 95% CI)	0.24 [0.09, 0.62]

Comparison 6. High NSP coverage versus no/low NSP coverage

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Comparison 7. Sensitivity analysis: high NSP versus low/no NSP, excluding unpublished data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	4	3245	Risk Ratio (Random, 95% CI)	0.77 [0.28, 2.13]

Comparison 7. Sensitivity analysis: high NSP versus low/no NSP, excluding unpublished data

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Comparison 8. Sensitivity analysis: high NSP versus low/no NSP, excluding cross‐sectional surveys

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	3	627	Risk Ratio (Random, 95% CI)	1.25 [0.63, 2.46]

Comparison 8. Sensitivity analysis: high NSP versus low/no NSP, excluding cross‐sectional surveys

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Comparison 9. High NSP coverage versus low/no coverage, unadjusted estimates

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	7	6455	Risk Ratio (Random, 95% CI)	0.78 [0.39, 1.55]

Comparison 9. High NSP coverage versus low/no coverage, unadjusted estimates

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Comparison 10. Low NSP coverage versus no coverage

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence, adjusted analyses Show forest plot	6	2765	Risk Ratio (Random, 95% CI)	1.43 [0.82, 2.49]

Comparison 10. Low NSP coverage versus no coverage

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Comparison 11. Low NSP coverage versus no NSP, unadjusted analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence Show forest plot	9	3242	Risk Ratio (Random, 95% CI)	1.41 [0.95, 2.09]

Comparison 11. Low NSP coverage versus no NSP, unadjusted analysis

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Comparison 12. Combined OST and high/low NSP versus no OST and low/no NSP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HCV incidence adjusted analyses Show forest plot	3	6197	Risk Ratio (Random, 95% CI)	0.45 [0.22, 0.94]

1.1 High NSP coverage	3	3241	Risk Ratio (Random, 95% CI)	0.26 [0.07, 0.89]
1.2 Low NSP coverage	2	2956	Risk Ratio (Random, 95% CI)	0.87 [0.44, 1.68]
2 HCV incidence unadjusted analyses Show forest plot	4	6427	Risk Ratio (Random, 95% CI)	0.47 [0.27, 0.80]

2.1 Combined OST and high NSP versus no OST and low/no NSP	4	3356	Risk Ratio (Random, 95% CI)	0.29 [0.13, 0.65]
2.2 Combined OST and low NSP versus no OST and low/no NSP	3	3071	Risk Ratio (Random, 95% CI)	0.76 [0.44, 1.33]

Comparison 12. Combined OST and high/low NSP versus no OST and low/no NSP

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