Decoding Infection and Transmission 1 (2023) 100005

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Decoding Infection and Transmission

journal homepage: www.keaipublishing.com/en/journals/decoding-infection-and-transmission

Efficacy and safety of directly acting antiviral drugs in HCV patients with
HIV in liver transplantation: A meta-analysis
Tian Zeng a, 1, Peng Huang b, 1, Weilong Tan c, Zepei Feng b, Jianguo Shao d, Xueshan Xia e,
Chao Shen b, Liqin Qian a, Bingqing Wang a, Zhengjie Li a, Chuanlong Zhu a, f, Yun Zhang g, h,
Ming Yue a, *
a
Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
b
Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
c
Institute of Epidemiology and Microbiology, Nanjing Bioengineering(Gene) Technology Center for Medicines, Nanjing, China
d
Department of Gastroenterology, Third Affiliated Hospital of Nantong University, Nantong, China
e
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
f
Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, 570216, China
g
Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Prevention and Control, Nanjing, 210002, China
h
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: HCV/HIV co-infections were initially a contentious consideration for liver transplantation, primarily
HCV due to their suboptimal response to interferon-based treatments and unfavorable post-transplantation outcomes.
Liver transplant The potential concern in this patient group arises from drug–drug interactions between DAAs and ARVs, with
HIV
data on the effectiveness and safety of DAAs in this demographic primarily derived from isolated case studies.
DAA
SVR12
This extensive review assesses the safety and efficacy of DAAs in liver transplants for individuals with concurrent
HIV and HCV infections.
Methods: Conducting a systematic search across multiple databases until April 2023, our primary focus was the
evaluation of outcomes, specifically the proportion of sustained virologic responses at week 12 following therapy
(SVR12). To gauge publication bias, we scrutinized funnel plots and conducted Egger tests.
Results: Nine studies encompassed a participant pool of 269 individuals, with a statistical estimate of SVR12 at
92% (95% CI: 88–95). Subgroup analysis showed that the ratio of binding SVR12 of genotype (GT) 1a was 97%
(95% CI: 87–100), while that of GT3 was 100% (95% CI: 92–100); 88% (95%CI: 80–95) for pre-transplant
treatments; and 95% (95%CI: 91–99) for post-transplant treatments subgroup. A total of 8 patients died dur­
ing SVR12 completion while 269 had a survival rate of 99% (95% CI 97–100). After one year of follow-up, four
studies recorded a 98% survival rate (95% CI 94–100). Egger’s test did not reveal any publication bias.
Conclusion: Administration of DAAs during liver transplantation for HCV patients with HIV infections has a high
efficacy and safety. Early consideration of HCV therapy should be the goal for all liver transplant recipients.

1. Introduction
Worldwide, there are approximately 180 million cases of hepatitis C
virus (HCV) infection, with 71 million individuals suffering from chronic
HCV infections.1,2 Co-infection of HCV with HIV increases the preva­
lence of hepatic fibrosis and cirrhosis-related complications compared to
HCV infection alone, potentially accelerating the progression to
cirrhosis and decompensation.3Initially, HCV/HIV co-infections posed
challenges for liver transplantation (LT) due to their limited response to
interferon-based therapies and suboptimal post-transplant outcomes.
Before the introduction of direct-acting antiviral drugs (DAAs), in­
dividuals co-infected with HIV and HCV faced reduced survival rates at
both the 2- and 5-year marks compared to those with HCV alone (73%
vs. 91% and 51% vs. 81%, respectively). This trend was particularly
pronounced in cases of rapid progression and severe fibrosing chole­
static hepatitis (FCH) linked to hepatitis C.4,5 It’s worth highlighting that

* Corresponding author.
E-mail addresses: yueming@njmu.edu.cn, njym08@163.com (M. Yue).
1
These authors contributed equally to this work and share first authorship.

https://doi.org/10.1016/j.dcit.2023.100005
Received 16 August 2023; Received in revised form 19 October 2023; Accepted 1 November 2023
Available online 16 November 2023
2949-9240/© 2023 The Authors. Published by Elsevier B.V. on behalf of Jiangsu Institute of Parasitic Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
T. Zeng et al.
liver disease emerged as a prominent cause of mortality among people
living with HIV (PLWH).6
Although HIV was historically viewed as a contraindication for liver
transplantation (LT), recent research has showcased positive transplant
results and minimal HIV-related issues among patients receiving anti­
retroviral (ARV) therapy.7 This patient group is increasingly seeking
liver transplantation, with estimated HCV prevalence ranging from 23%
to 33% among those living with HIV.8 The decreased five-year survival
rates in HIV/HCV co-infected individuals are primarily linked to
multi-system organ failure stemming from recurrent HCV infections
after transplantation. This low survival threshold typically leads many
transplant programs to discontinue LT for patients with HIV/HCV
co-infections, raising concerns about meeting the escalating demand for
liver transplantation amid organ shortages. This concern is particularly
acute for people living with HIV (PLWH), who experience higher mor­
tality rates on waiting lists and diminished prospects for receiving a liver
transplant.
In recent years, the introduction of direct-acting antiviral drugs
(DAAs) has resulted in impressively high rates of sustained virological
response (SVR), ranging from 95% to 100%.9–11 Particularly noteworthy
is their performance in the specific subset of patients co-infected with
HCV and HIV, where DAAs have exhibited a comparable level of safety
and SVR to that seen in HCV mono-infections.12 The early administra­
tion of DAAs has shown significant benefits for post-liver transplant (LT)
patients, as well as individuals on the LT waiting list, facilitating their
removal from the list and improving overall outcomes.
Nonetheless, drug–drug interactions (DDIs) between DAAs and ARVs
represent a potential concern within this patient group.13 Currently,
data concerning the effectiveness and safety of DAAs in this de­
mographic mainly stem from isolated case studies. It is imperative to
prioritize research aimed at confirming the optimal timing of DAA
administration, either pre- or post-LT. As a result, this meta-analysis
endeavors to provide a comprehensive evaluation of the efficacy and
safety of DAA treatment in individuals with co-existing HCV and HIV
infections who are undergoing liver transplantation (LT).
2. Methods
2.1. Search strategy
Our study followed the guidelines outlined in the Preferred Report­
ing Items for Systematic Review and Meta-analyses (PRISMA). The data
for this study have been documented in the PROSPERO database under
the registration number CRD42022363169. A thorough and systematic
search was conducted by two independent reviewers in PubMed,
Embase, and the Web of Science databases, with the most recent update
completed in April 2023, without any language restrictions. The search
strategy was (sofosbuvir OR ribavirin OR asunaprevir OR velpatasvir OR
simeprevir OR daclatasvir OR ritonavir OR ombitasvir OR elbasvir OR
ledipasvir OR grazoprevir OR DAA OR direct-acting antiviral OR direct
acting antiviral OR direct acting antivirals OR Antivirals OR Antiviral
Drugs) AND (liver transplantation OR LT OR Hepatic Transplantation
OR Liver Grafting) AND (hepatitis C OR Hepatitis C virus OR Hepatitis C
Like Viruses OR HCV OR Hepatitis C viruses OR Hepaciviruses) AND
(HIV OR Human Immunodeficiency Virus OR AIDS). Manual searches of
references included in the articles and other relevant systematic evalu­
ations were also conducted to find suitable studies to enhance the
sensitivity of the search.
2.2. Selection criteria
Inclusion in the qualitative analysis was contingent upon the
fulfillment of the following criteria: i. inclusion of patients who were
HCV-positive; ii. Confirmation of HIV positivity; iii. Patients on liver
transplant waiting lists or already receiving a transplant; iv. SVR12 was
measurable, and v. Treatment with DAA (including before and after
2
Decoding Infection and Transmission 1 (2023) 100005
transplantation).
Inclusion in the qualitative analysis was contingent upon the
fulfillment of the following criteria: i. HBV infection; ii. Pharmacoki­
netics, or pharmacodynamics studies; iii. Cost-effectiveness; iv. Edito­
rials, or reviews; v. Meta-analyses; vi. Conferences; vii. Case reports; viii.
Studies without HCV RNA load; and ix. No SVR12 data.
2.3. Outcomes
The primary focus of measurement was SVR12, which was defined as
the sustained absence of plasma HCV RNA, below the lower limit of
quantification (LLOQ), for a consecutive 12-week duration post-
treatment. This definition encompassed both DAA treatment adminis­
tered after liver transplantation and DAA treatment administered before
liver transplantation.
2.4. Study selection and data extraction
Study selection and data extraction were carried out independently
by two investigators, TZ and ZPF.The criteria for study inclusion and
exclusion were predefined and strictly adhered to. Initial screening of
study titles and abstracts, and subsequent identification as well as full
text re-screening of potentially eligible studies was performed. The
extracted data were: single center or multi-center studies (setting),
publication type, study type, region, year, name of first author, DAA
treatment, post-LT time to DAA initiation, duration of DAAs treatment,
sample size, HCV genotype (GT), MELD score before DAA treatment,
CD4+T cell counts before DAA treatment, immunosuppression regimen,
percentage of patients without detection of HIVRNA, SVR12, and AEs/
SAEs. The third reviewer had access to the full text and participated in
discussions when information and evidence were imprecise or when
there were disagreements between the two reviewers.
2.5. Quality assessment
The non-randomized research methodology index (MINORS),36
which is an index composed of eight non comparative research meth­
odology items, was used to evaluate the quality of studies. Each item has
a score of 0–2, and 16, which is a relatively ideal score, indicates that the
study has the highest quality of research, while 24 is the highest score for
a comparative study.
2.6. Statistical analysis
Effect sizes were obtained by inverse variance analysis with 95% of
the corresponding incidence of event sets. Freeman-Tukey double
arcsine transform was used to estimate incidences in cases of 0 or 100%
events. Heterogeneity among the included studies was assessed using
Cochran Q-statistics and I^2 statistics. In cases of significant heteroge­
neity, defined as I^2 ≥ 50%, we employed the random effects model;
otherwise, we utilized the fixed effects model. Subgroup analyses were
conducted to identify potential sources of heterogeneity. To assess
publication bias, both funnel plots and Egger’s test were employed.
Sensitivity analysis was conducted to evaluate the impact of each indi­
vidual study on the effect size. ,A p-value of less than 0.05 is considered
statistically significant and all tests were two-tailed. The statistical an­
alyses were performed using meta package (version 5.5.0) in R Studio
(version 4.2.1).37
3. Results
3.1. Basic information and study selection
The inclusion criteria were met by a total of 1992 studies. A total of
1556 thesis titles and abstracts were identified by deletion of 436
duplicate studies. Then, 56 articles were selected for full text reading, of
T. Zeng et al.
which 47 were excluded on different grounds. Ultimately, nine papers
were included in the review (shown in Fig. 1).14–22 The nine articles,
conducted between 2016 and 2020, were from five regions: the United
States (3 articles), Germany (1 article), Spain (3 article), France (1
article) and Italy (1 article) (Tables 1 and 2). Four DAAs articles before
liver transplantation and five DAAs articles before and after liver
transplantation involving 269 patients.
3.2. Quality of included studies
The scores from the quality assessment can be found in Supple­
mentary Table 1. MINORS was used to assess the 9 studies. Scores
11–16, 5–10, 0–4 indicate a bias risk ranging from low to high.23 Among
these, median MINORS score of 12 was found to have a low risk of bias.
3.3. Efficacy of outcomes
Incidences of SVR12 in DAA for patients with HCV in liver trans­
plantation were reported in all nine studies (269 cases). The combined
effects of the fixed-effect model on SVR12 was 92% (95% confidence
interval: 88–95, I^2 = 4%, p = 0.40) (shown in Fig. 2).
3.4. Subgroup analysis of the overall SVR12 rate
Subgroup analysis was performed on the basis of settings, GTs, DAA
regimens, before and after LT (Table 3). In multicenter studies, the
Fig. 1. The flow diagram of literature screening and following the preferred
reporting items of systematic reviews and meta-analyses (PRISMA).
3
Decoding Infection and Transmission 1 (2023) 100005
SVR12 incidence was 92% (95% CI: 88–95, I^2 = 4%) and in single-
centre studies this number was 92% (95% CI: 87–95). In both groups,
the SVR12 rate was 92%. The 95% CI was 91–99 in the post-transplant
subgroup and 80–95 in the pre-transplant subgroup. In total, 117 pa­
tients of the eight studies recorded GTs for group analyses. In the GTs
subgroup, SVR12 rates in GT1a, GT1b, GT2, GT3 and GT4 were 97%
(95% CI: 87–100), 94% (95% CI: 68–100), 100% (95% CI: 21–100),
100% (95% CI: 92–100), 97% (95% CI: 83–100). Under different DAA
regimens, the SVR12 rate was 98% (95% CI: 90–100) in the SOF/LDV ±
RBV group, 98% (95% CI: 92–100) in the SOF/DCV ± RBV group, 84%
(95% CI: 64–98) in the SOF/SMV ± RBV group, 93% (95% CI: 73–100)
in the SOF/DCV ± RBV group, and 100% (95% CI: 38–100) in the SOF/
DCV group.
3.5. Subgroup analysis of protocols
Various subgroups of DAAs before and after transplantation were
respectively analyzed using GT and DAA. In pre-transplant studies, the
SVR12 rates in GT1a, GT3, and GT4 were 100% (95% CI: 78–100), 100%
(95% CI: 70–100) and 92% (95% CI: 58–100). Among SOF ± RBV, SOF/
DCV ± RBV, and SOF/LDV ± RBV under different DAA regimens, in­
cidences of SVR12 were 93% (95% CI: 53–100), 94% (95% CI: 75–100),
and 71% (95% CI: 38–97), respectively (Table 4).
In post-transplant studies, incidences of SVR12 in GT1a, GT1b, GT3,
and GT4 were 99% (95% CI: 88–100), 98% (95% CI: 73–100), 100%
(95% CI: 87–100), and 99% (95% CI: 83–100), respectively. Incidences
of SVR12 in patients treated with different DAA treatments were 100%
(95% CI: 94–100) in SOF/LDV ± RBV subgroup, 100.0% (95% CI:
97–100) in SOF/DCV ± RBV subgroup, 93% (95% CI: 69–100) in SOF/
SMV ± RBV subgroup, 93% (95% CI: 73–100) in SOF/SMV ± RBV
subgroup, and 100% (95% CI: 21–100) in 3D ± RBV (Table 5).
3.6. Safety
Adverse reactions were clearly documented in five of the nine
studies. In nine studies, a total of 136 adverse events and serious adverse
events were combined with an overall occurrence rate of 71% (95%
confidence interval: 42–94), with 84 cases explicitly reported as adverse
events and serious adverse events by 136 recipients, 48 cases of anemia
reported by 208 recipients, and 31 infections reported by 189 patients.
Eight patients died during SVR12 completion while 269 had a survival
rate of 99% (95% CI 97–100) (shown in Fig. 3). After one year of follow-
up, 4 studies recorded a 98% survival rate (95% CI 94–100) (shown in
Fig. 4).No significant drug–drug interactions were reported.
3.7. Sensitivity analysis and publication bias
The funnel plot combining SVR12 ratio estimates exhibited sym­
metry (shown in Fig. 5). Egger’s test did not reveal any signs of publi­
cation bias (t = − 0.34, p = 0.74). Additionally, sensitivity analysis
indicated that SVR12 rates were not influenced by any individual study
(shown in Fig. 6).
4. Discussion
We performed a meta-analysis to assess the effectiveness and safety
of DAAs in HCV patients with HIV coinfected with LT. It was found that
regardless of gender, age, GTs, DAA regimens, and LT sequencing when
treating patients, DAAs can achieve higher SVR12 rates in target groups.
Some HCV-associated AEs occur with SAEs. Taken together, regardless
of pre-and post-LT procedures, treatment of HCV and HIV patients with
DAAs resulted in highly effective, safe, and stable outcomes.
In this study, the aggregated SVR12 was 92% (95% CI: 88–95),
indicating that the DAA regimen was effective, in tandem with previous
findings.21 No significant differences were observed between subgroups
based on various DAA programs. Regarding GT, we included studies that
T. Zeng et al. Decoding Infection and Transmission 1 (2023) 100005

Table 1
| Characteristics of the studies included in this comprehensive analysis.
Reference study design Region Setting Protocol Drug node year Sample size Duration

event n

Antonini et al. prospective cohort study France, Belgium multicentre post-transplant therapy After LT 2018 28 29 12/24W
Campos et al. prospective cohort study America, Europe multicentre post-transplant therapy After LT 2016 16 20 24/48W
Grant et al. prospective cohort study America Single center post-transplant therapy After LT 2016 7 8 12W
Grottenthaler et al. retrospective study Germany multicentre pre/post-transplant therapy Before/After LT 2018 13 14 12/24W
Guaraldi et al. retrospective study Italy multicentre pre/post-transplant therapy Before/After LT 2017 41 48 12/24W
Londoño et al prospective cohort study Spain Single center pre/post-transplant therapy Before/After LT 2016 11 11 12/24W
Manzardo et al. prospective cohort study Spain multicentre post-transplant therapy After LT 2018 44 47 12/24W
Peters et al. retrospective study America multicentre pre/post-transplant therapy Before/After LT 2020 63 68 NA
Vinaixa et al. retrospective study Spain Single center pre/post-transplant therapy Before/After LT 2018 20 24 12/24W

Setting, single center or multi-center studies; Drug node, the initiation time of DAAs therapy; LT, liver transplant.

Table 2
| Patient characteristics of the studies enrolled in this comprehensive analysis.
Reference Age Gender MELDscore HCV DAA DAAINT Immunosuppressive CD4 Tcell HCV RNA Undetectable
(M%) (before GT regimens (month) agents (cell/mm3) (log10 IU/ HIV-RNA
DAAS) (before mL) (before
DAAS) DAAS)

Antonini et al. 54(50–57) 20 15(10–34) 1a、 SOF/LDV ± 37.5 Tac-based 57.1% 342 6.7 (5.9–7.2) 100%(<12
(69.0) 1b、 RBV,SOF/ (14.4–99.2) (172–483) IU/mL)
3、4 DCV ± RBV
Campos et al. 49(45–52) 15(75) 13(9–20) 1a、 SOF/SMV 20.9 Tac-based 75% 182 6.0 (5.6–7.0) 100%(<25
1b、 ± RBV,SOF/ (9.7–61.1) (138–303) UI/mL)
3、4 DCV ± RBV,
SOF ± RBV
Grant et al. 51 8(100) NA 1a、 SOF/SMV 23.8 Tac-based 100% 259 6.5 (6.3–7.4) 100%(≤50
(40.3–59) 1b、 ± RBV,SOF (11.3–66.3) (159–364) copies/mL)
2 ± RBV
Grottenthaler 48.5 12 13(7–21) 1a、 SOF/DCV ± 35、58 Tac-based 50% NA 5.6(4.5–6.4) NA
et al. (39–64) (85.7) 1b、 RBV,SOF/
4 LDV ±
RBV,3D ±
RBV,SOF ±
RBV
Guaraldi et al. 52(49–53) 38(79) B 16 1a、 SOF/DCV ± 49 (5–142) Tac-based 79% B 356 B 5.64 B 100%/A
(12–20)/A 8 1b、 RBV,SOF/ (239–497)/ (4.48–6.02)/ 92%
(6–10) 2、 LDV ± RBV, A 342 A 6.81
3、4 SOF ± RBV (236–580) (6.04–7 .08)
Londoño et al. 53(47–57) 9(81.8) 9(6–12) 1a、 SOF/LDV ± 61(16–108) Tac-based 42.9% 336 5.86 90.9%(<37
3、4 RBV,SOF/ (217–445) (5.62–7.08) copies/mL)
DCV ± RBV,
SOF/SMV
± RBV,3D
± RBV
Manzardo 47.3(6.36) 36 9.01 1a、 SOF/DCV ± 71.2 Tac-based 61.7% 367 6.29 87.2%(<50
et al. (76.6%) (7.49;10.9) 1b、 RBV,SOF/ [57.2;100] (264–473) (5.84;6.67) copies/mL)
3、4 LDV ± RBV,
SOF/SMV
± RBV,
SMV/DCV
± RBV,3D
± RBV
Peters et al. 56.6 53 12.0(9–15) 1a、 SOF/LDV ± NA NA 236 5.92 ± 1.03 100%(<40
(52.3–61.4) (77.9) 1b RBV,besed- (81–389) copies/mL)
on SOF
Vinaixa et al. 51(10) 21 B 18(2)/A 9 1a、 SOF/DCV ± 24 (120) Tac-based 60% NA B 5.14(5.47)/ 100%
(87.5) (5) 1b、 RBV,SOF/ A 6.49(6.06)
4 LDV ± RBV,
SOF/SMV
± RBV,3D
± RBV,SOF
± RBV

M,male;MELD,Model for End-Stage Liver Disease;DDAINT,Time from transplant to initiation of DAA;SOF,sofosbuvir;LDV,ledipasvir;RBV,ribavirin;DCV,daclatasvir.

SMV,simeprevir;3D,Paritaprevir/Ritonavir/Ombitasvir;B,before liver transplant;A,after liver transplant.

explicitly recorded GT data, despite the fact that patients with HCV GT3
infection have traditionally been described as being more difficult to
treat than other GTs.24 In subgroup analyses, GT3 SVR12 rates were as
high as 100.0%.The reason for this unusual result, we believe, is due to
the unique characteristics of this population and the limited number of
individuals with GT3 included.
Furthermore, the timing of initiation of DAA treatment in HCV/HIV
patients has not been conclusively established.25,26 In this study, there
were no substantial differences in DAA treatment outcomes between the
pre-transplantation and post-transplantation periods. The SVR12 rates

4
T. Zeng et al. Decoding Infection and Transmission 1 (2023) 100005

Fig. 2. Forest plot of pooled SVR rates of DAAs treatment for HCV recipients with LT.

Table 3
Table 4
| SVR12 by settings, genotypes, regimens,and protocols.
| Subgroup analysis of SVR12 for pre-transplant.
Response SVR12 Heterogeneity P**- Studies
value Response SVR12 Heterogeneity P**- Studies
Total, Rate(95% I2 Pa N value
n/N CI) Total, Rate(95% I2 Pa N
n/N CI)
Overall 243/ 92(88–95) 4% 0.4 9
269 pre-transplant 78/91
By settings 0.63 therapy
Single-center 38/43 92(88–95) 28% 0.25 3 By genotypes 29/33 0.66
Multi-center 205/ 92(87–95) 5% 0.38 6 1a 12/13 100 0% 0.38 3
226 (78–100)
By genotypes 108/ 0.83 1b 1/2 \ \ \ 1
117 2 1/1 \ \ \ 1
1a 44/47 97 0% 0.55 6 3 6/6 100 0% 0.85 2
(87–100) (70–100)
1b 13/15 94 0% 0.58 4 4 9/11 92 3% 0.38 4
(68–100) (58–100)
2 2/2 100 0% 1.00 2 By regimens 40/49 0.53
(21–100) SOF/LDV/ 6/7 93 0% 0.40 3
3 19/19 100 0% 0.91 4 RBV (53–100)
(92–100) SOF/DCV/ 23/26 94 0% 0.95 4
4 30/34 97 21% 0.27 6 RBV (75–100)
(83–100) SOF/RBV 10/15 71(38–97) 45% 0.14 4
By regimens 180/ 0.21 3D/RBV 1/1 \ \ \ 1
201 a
Test of heterogeneity. ** Test for subgroup differences.
SOF/LDV/RBV 54/57 98 0% 0.68 6
(90–100)
SOF/DCV/RBV 73/77 98 0% 0.44 7
(92–100) Table 5
SOF/RBV 29/38 84(64–98) 26% 0.24 6 | Subgroup analysis of SVR12 for post-transplant.
SOF/SMV/RBV 20/23 93 0% 0.77 5
Response SVR12 Heterogeneity P**- Studies
(73–100)
value
3D/RBV 3/3 100 0% 1.00 3
(38–100) Total, n/ Rate(95%CI) I2 Pa N
SMV/DCV/RBV 1/3 \ \ \ 1 N
By protocols 0.54
post-transplant 165/
pre-transplant 78/91 88(80–95) 8% 0.36 5
therapy 178
therapy
By genotypes 79/84 1.00
post-transplant 165/ 95(91–99) 0% 0.77 9
1a 32/34 99(88–100) 0% 0.76 5
therapy 178
1b 12/13 98(73–100) 0% 0.82 3
a
Test of heterogeneity. ** Test for subgroup differences. 2 1/1 \ \ \ 1
3 13/13 100(87–100) 0% 0.91 3
4 21/23 99(83–100) 0% 0.8 5
By regimens 140/ 0.62
were high in both groups. The use of immunosuppressants after organ
152
transplantation can lead to active viral infections and replication. SOF/LDV/RBV 49/50 100(94–100) 0% 0.83 5
Immunological risk is characterized by acute hepatitis, fibrotic chole­ SOF/DCV/ 48/50 100(97–100) 0% 0.58 7
stasis hepatitis and acute/chronic rejection. Therefore, early initiation of RBV
DAA may mitigate these risks. Taken together, our data suggest that SOF/RBV 20/24 93(69–100) 0% 0.96 5
SOF/SMV/ 20/23 93(73–100) 0% 0.77 5
HCV-infected LT candidates do not have an increased risk of transplant RBV
failure due to HIV positivity as the DAA era continues.27 Despite the SMV/DCV/ 1/3 \ \ \ 1
possibility of residual hybridization risk, this enhancement can be RBV
credited to the improved treatment results for hepatitis C in contrast to 3D/RBV 2/2 100(21–100) 0% 1.00 2
the period before the availability of DAAs. The success of DAA therapy a
Test of heterogeneity. ** Test for subgroup differences.
has brought post-transplant survival rates for HIV/HCV co-infected pa­
tients in line with those of individuals without HCV infection. These HIV/HCV co-infection. Moreover, our findings indicate positive
results support liver transplantation as a viable option for those with

5
T. Zeng et al. Decoding Infection and Transmission 1 (2023) 100005

Fig. 3. Survival rate of nine studies during DAA treatment.

Fig. 4. Survival rate of Four studies after DAA treatment one year of follow-up.

Fig. 5. Funnel plot for the evaluation of publication bias.

outcomes for liver transplant recipients who are HIV-positive, irre­
spective of their hepatitis C status.
Two of the included nine studies found drug interactions. In his
work, Campos15 examined interactions between antiretroviral therapy
(ART) and medications used to treat HCV, frequently associated with
changes in drug levels due to the induction or inhibition of cytochrome
P450 3A4 enzymes. This mechanism can contraindicate the use of HCV
protease inhibitors (PIs) like simeprevir when plasma levels are reduced
by efavirenz but increased by boosted HIV PIs.28 These interactions are
comparable to the preventable interactions between atazanavir and
simeprevir.29 Another DDI is between the HCV antiviral and tenofovir.
Renal toxicity should be carefully monitored when tenofovir is used in
combination with enhanced PI and SOF-Ledipasvir or emtricitabine/e­
favirenz. When this is likely to happen, alternative solutions should be
initiated.30 The ART regimens can be modified to account for known
DDIs. Progress in liver-friendly ART technologies can improve the
handling of HCV recurrence in HIV patients after liver transplantation.
Consideration is essential when dealing with interactions between
HCV antivirals and immunosuppressants. The combinations of pallipi­
vir/ritonavir with the calcineurin inhibitor should be reduced to avoid
CNI poisoning.31 In addition, improved drug metabolism during HCV
treatment (e.g. liver) leads to a decrease in immunosuppressive levels,
therefore, during and early after therapy, patients may require higher
doses of immunosuppressants.32 Since HCV-HIV LT recipients had a
higher risk of rejection, there was a greater association between rejec­
tion and HCV-HIV LT recipients.28,33 To reduce the risk of rejection,
levels of immunosuppressants should be carefully monitored during
treatment and early after treatment.
Between the start of treatment and SVR12, 8 of 269 people in the
nine studies died. Most of the 8 fatalities were linked to complications
arising from advanced liver disease, none of which were linked to DAA
treatment. In a one-year follow-up conducted across four

6
T. Zeng et al.
Fig. 6. The sensitivity analysis of the SVR12.
studies,15,19,20,27 two patients passed away, resulting in a one-year
survival rate of 98% (95% CI 94–100). Notably, Peters MG21 conduct­
ed a more extensive 5-year follow-up post-treatment. Despite achieving
SVR, 12 out of 42 pre-LT participants, including 5 with HCC and 7 with
ESLD complications, still requested LT. Among the remaining
non-transplant participants, 90% achieved SVR, but eight later suc­
cumbed to ESLD, resulting in a 42.8% survival rate without trans­
plantation at 4 years and an 87.9% survival rate after 5 years of LT. From
this, we can observe that the survival outcomes for individuals without
liver transplantation are discouraging, whereas early treatment with
DAAs can assist HIV/HCV co-infected patients in rejoining the trans­
plant candidate list and undergoing liver transplantation promptly, thus
leading to a higher survival rate. Nevertheless, when the trial received
approval, a multitude of HCV-specific DAAs had already been sanc­
tioned, resulting in the prompt treatment of numerous decompensated
LT patients co-infected with HIV/HCV. The incidence of HCC in in­
dividuals co-infected with HCV and HIV declined after achieving SVR,
mirroring the trend seen in those with HCV monoinfection.21 However,
the risk of HCC remains, indicating that not all end-stage recurrent pa­
tients can avoid liver-related complications or mortality through anti­
viral therapy.38,39 Therefore, it is imperative for all LT recipients to
undergo early hepatitis C treatment before advanced fibrosis develops.
Current guidelines advocate for pre-LT treatment in all candidates
co-infected with HIV and HCV.34,35
This study presents several limitations. Firstly, the absence of ran­
domized controlled trials limits our ability to assess relative risk within
subgroups. Secondly, the study had a relatively small sample size due to
the specific population under investigation. Lastly, the lack of data from
Asian regions among the included studies may constrain the choice of
DAA regimens and the generalizability of our findings across diverse
geographical regions.
Nonetheless, this meta-analysis stands out as the pioneering inves­
tigation into the efficacy and safety of DAA treatment in HIV/HCV co-
infected liver transplant recipients. The analysis meticulously
reviewed nine studies encompassing 269 patients to provide a precise
assessment of SVR12 rates in recipients. Given the minimal heteroge­
neity observed in the majority of these studies, we have confidence in
the reliability and clinical significance of our findings.
5. Conclusion
This analysis demonstrates the effectiveness and safety of DAA in
HCV/HIV-associated liver transplantation. Early HCV therapy should be
the goal for all liver transplant recipients.
Data availability statement
The original contributions presented in the study are included in the
7
Decoding Infection and Transmission 1 (2023) 100005
article Material, further inquiries can be directed to the corresponding
author/s.
Ethics approval and consent to participate
Not available.
Funding sources
The study was funded by the National Natural Science Foundation of
China (82273691,81773499), the Science Foundation for Distinguished
Young Scholars of Jiangsu Province (BK20190106), the Science and
Technology Plan of Hainan Province (Clinical Research Center)
(LCYX202103, LCYX202204, and LCYX202306), the Hainan Province
Science and Technology Special Fund (ZDYF2022SHFZ067), and the
grants from Jiangsu Provincial Medical Key Discipline (Laboratory)
Cultivation Unit and Hainan Province Clinical Medical Center.
Consent for publication
All authors consent for publication.
CRediT authorship contribution statement
Tian Zeng: Conceptualization, Data curation, Investigation, Meth­
odology, Software, Supervision, Formal analysis. Peng Huang:
Conceptualization, Supervision, Writing – original draft, Writing – re­
view & editing, Funding acquisition, Validation. Weilong Tan: Data
curation, Formal analysis, Investigation. Zepei Feng: Data curation,
Investigation, Methodology, Software. Jianguo Shao: Formal analysis,
Project administration, Software, Supervision. Xueshan Xia: Method­
ology, Resources, Software. Chao Shen: Conceptualization, Data cura­
tion, Investigation, Methodology, Software, Supervision. Liqin Qian:
Writing – original draft. Bingqing Wang: Methodology, Software.
Zhengjie Li: Methodology, Resources, Software. Chuanlong Zhu:
Methodology, Resources, Software, Supervision, Validation. Yun
Zhang: Funding acquisition, Project administration, Resources, Super­
vision, Validation. Ming Yue: Funding acquisition, Resources, Super­
vision, Validation, Writing – review & editing.
Declaration of competing interest
Ming Yue is an Editorial Board member of Decoding Infection and
Transmission. She is not involved in the peer-review or handling of the
manuscript, and has no other conflict of interests to declare. All other
authors declare that they have no known competing financial interests
or personal relationships that could have appeared to influence the work
reported in this paper.
T. Zeng et al.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.dcit.2023.100005.
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