Retrospective-Prospective Study of Safety and Efficacy of Sofosbuvir based Direct Acting Antivirals in HIV/HCV Coinfected Participants with Decompensated Liver Disease Pre or Post Liver Transplant

Abstract

Direct acting antiviral (DAA) therapy has transformed the management of human Immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multi-center prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6–29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; 8 required 2 or more courses of therapy. Ninety-three% achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and 3 post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.

1. INTRODUCTION

Liver transplantation (LT) for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection was initially a controversial indication for liver transplantation because of poor responses to interferon-based therapies and worse outcomes post-transplant¹. Natural history studies have demonstrated accelerated rates of hepatic fibrosis and complications of cirrhosis as compared to HCV monoinfected people². As a result, liver disease is a leading cause of death among people living with HIV (PLWH)². Although historically HIV was considered a contraindication for LT, studies have shown acceptable transplantation outcomes and minimal HIV-related complications in antiretroviral (ARV) treated patients³. Nevertheless, PLWH are not only less likely to receive a LT than non-infected patients, but they are also at a higher risk of death during the waiting period prior to LT³. While Model for End-Stage Liver Disease score (MELD) appears to be an accurate a predictor of death in PLWH⁴, increased mortality maybe a due to accelerated MELD in PLWH⁵. However, advances in direct-acting antiviral (DAA) therapy over the last years have shown that HCV/HIV coinfected patients without decompensated liver disease, respond as well as HCV monoinfected patients⁶. At the same time, the demand for liver transplantation in this challenging cohort of patients has been increasing, as the prevalence of HCV has been reported to be between 23–33% in HIV infected people⁷.

Prior to the widespread acceptance of the efficacy of DAAs for curing HCV in 2015, LT for people co-infected with HCV/HIV had essentially come to a standstill in the US. Although excellent transplant outcomes for LT were reported for LT performed for HIV-infected recipients in the absence of HCV coinfection⁸, results from American and European cohorts in HCV- and HIV-infected recipients showed a 5-year survival of approximately 50%^3,9,10. The poor survival rates in the HIV/HCV cohort were a consequence of multisystem organ failure in the setting of recurrent HCV infection post-transplant. This low 5year survival was the threshold that triggered most transplant programs to stop performing liver transplants in persons with HIV/HCV coinfection, based on the considerations of optimal use of scarce donor organs. Furthermore, in the US, risk adjusted center specific outcomes following transplant centers are reported by the Scientific Registry of Transplant (SRTR), and in turn are used by government agencies to regulate transplant activities. HIV infection was not included in the SRTR risk stratification, and consequently worse outcomes in the HIV/HCV cohort caused poor center specific results. This prompted most centers to stop transplantation in this cohort due to the poor center specific results as well as concerns of utilization of a scarce resource. This practice prompted the STOP-coinfection (STOP-CO) clinical trial reported here to study the impact of DAA therapy on improving the dismal outcomes in the HIV/HCV cohort. Since DAA therapy is well tolerated in HIV/ HCV infected patients, we sought to study the safety and efficacy of DAA both pre- and post-LT settings in a multicenter cohort study.

2. MATERIALS AND METHODS

2.1. Study Design

STOP-CO was a multi-center prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV coinfected participants pre- or post-LT. The study was designed to prospectively assign ledipasvir-sofosbuvir to participants awaiting transplant or ≥1 month post-transplant. During the course of the trials, DAAs became widely available and the standard of care for the target study population. Only 7 participants could be enrolled in the prospective arm of this study with ledipasvir-sofosbuvir. Therefore in 2017 the study was amended to include retrospective participants who had been treated with any sofosbuvir based therapy after 2014, either post-LT or pre-LT participants with decompensated liver disease.

2.2. Participants

The study population included adults living with HIV with chronic HCV and end-stage liver disease (ESLD) pre-LT and any stage of liver disease post-LT. The study was implemented at 7 designated sites across the United States. Participants were HIV-positive on a stable antiretroviral (ART) regimen for at least 4 weeks pre-treatment. The retrospective portion of the study enrolled participants treated with sofosbuvir-based DAAs for any duration since 2014 were eligible. HCV genotypes 1, 4, 5 or 6 were included with at least one serum HCV RNA ≥ 1000 IU/mL prior to treatment. Pre-LT participants had a pre-treatment Child’s Pugh Turcotte (CPT) score ≥ 7 and a pre-treatment laboratory MELD ≥ 6 and ≤ 30 and included both listed LT candidates and participants who had decompensated cirrhosis not listed for LT. Inclusion criteria for post-LT participants were a LT after 2000 and DAA treatment initiated ≥ 1 month after LT. Prospective participants were accrued from 12/2016–11/2018. Additional exclusion criteria for prospective participants were chronic hepatitis B infection, a history of any other clinically active chronic liver disease, and prior treatment for HCV within one month of screening. Retrospective participants were enrolled between 4/2018 and 6/2019. Information about type of SOF-based therapy in the retrospective participants was not collected for this study. The study was approved by the institutional review boards at all participating sites and all patients signed informed consent prior to enrolment (NCT trial number NCT02533934).

2.3. Efficacy Outcomes

The primary study endpoint was proportion of participants achieving SVR defined as HCV RNA <lower limit of quantification (LLOQ) at ≥ 12 weeks after the end of sofosbuvir-based DAA therapy (SVR_ever). Secondary endpoints included reversal in decompensation (defined by decrease in MELD score at last follow-up), change in liver fibrosis as determined by standard of care liver staging method, HIV and HCV viral breakthrough or relapse, and alanine aminotransferase (ALT) normalization. Two indirect markers of liver fibrosis were used: aspartate aminotransferase to platelet ratio (APRI) and Fibrosis-4 (FIB-4). These measures can be calculated per the published literature with upper limit of normal designated as 40 U/L^11,12. Transient elastography to assess liver stiffness was performed, if available, in post-DAA therapy using Fibroscan®, with a requirement of 10 valid values and interquartile range (IQR) <30% of median.

2.4. Safety Outcomes

Safety and tolerability were assessed by discontinuation rates, frequency of anemia requiring blood transfusion or growth factors, and survival. All serious adverse events that occurred while the participant was on treatment or in follow up were also recorded.

2.5. Data Handling Conventions

For missing data, imputation methods were not used, except for the endpoints as discussed below. For the analysis of the post-baseline categorical efficacy endpoint, if a data point was missing and was preceded and followed in time by values deemed success, then the missing data point was termed a success, otherwise the data point was deemed a failure. Any participant with missing data due to premature discontinuation of the study medication was considered a failure at the time points on, or following, the date of discontinuation. If no HCV RNA values were obtained after the last dose of study medication, the subject was considered a treatment failure for the SVR endpoints. If laboratory results for a subject were missing for any reason at a time point, the participant was excluded from the calculation of summary statistics for that laboratory value at that time point. Missing Day 0 results were replaced with a screening result, if available.

2.6. Statistical Analysis

For the primary efficacy endpoint (SVR_ever) analysis, an exact Clopper-Pearson 95% confidence interval was computed for the SVR_ever rate. For the secondary analysis, the proportion of participants with HCV RNA below the LLOQ over time (including other SVR endpoints) were calculated. Descriptive statistics in the form of counts and percentages for categorical variables, medians and interquartile (IQR) ranges for continuous variables, as well as counts and percentages for categorical variables, were done for all characteristics at baseline and at each relevant follow up time point. Chi-square and Kruskal-Wallis tests were used to compare continuous and categorical variables respectively. All analyses were conducted using SAS (Version 9.04.01.M3).

3. RESULTS

Sixty-eight HIV/HCV coinfected participants were enrolled, 42 with decompensated ESLD (hereafter referred to as pre-LT) and 26 were treated post liver transplant (post-LT). There were 7 prospective participants (1 pre-LT and 6 post-LT) who received ledipasvir-sofosbuvir and 61 retrospective participants (41 pre-LT and 20 post-LT) who received sofosbuvir-based therapy. As shown in Table 1 the majority of participants were male, all had genotype 1 chronic HCV, 53 were genotype 1a and 13 1b. A significant number had hypertension, diabetes and obesity. Demographic characteristics were generally similar between those treated pre- and post-LT and those treated prospectively or retrospectively. Body mass index (BMI) was higher in the pre-LT group, with more participants having BMI over 30 than in the post-LT group (p=0.028). As expected, those with decompensated liver disease (pre-LT) had higher bilirubin (p=0.002), international normalized ratio (INR) (p=0.003), APRI (p=0.004), FIB-4 (p<0.001) and MELD (p=0.006) and lower albumin (p=0.006) and platelets (p<0.001). All donor livers were HCV negative. Post-LT participants had lower estimated glomerular filtration rates (p=0.019) and higher ALT (p<0.001). All participants were on stable ART and four participants had baseline HIV RNA over 40 copies/mL (62, 70, 125 and 132 copies/mL). Median CD4 count was 236 (IQR, 81–389) cells/mm³ at baseline. Nucleoside analogs and integrase inhibitors were the most common (58.8%) ART. Overall 91.2% of participants were on nucleoside analogs, 79.4% on integrase inhibitors, 30.9% on protease inhibitors and 10.3% on non-nucleoside reverse transcriptase inhibitors.

Table 1.

Pre DAA treatment characteristics of HCV/HIV Coinfected participants

	Total Cohort	Treated Pre-Liver Transplant	Treated Post-Liver Transplant
N	68	42	26
Age at treatment (68)*	56.6 (52.3–61.4)	56.4 (52.7–60.4)	57.2 (52.2–61.7)
Male (68), n (%)	53 (77.9)	31 (73.8)	22 (84.6)
Race (68), n (%)
African American	32 (47.1)	21 (50.0)	11 (42.3)
White	24 (35.3)	13 (31.0)	11 (42.3)
Asian	3 (4.4)	2 (4.8)	1 (3.8)
Other	9 (13.2)	6 ()	3 ()
Hispanic (60) n(%)	12 (19.4)	8 (21.6)	4 (16.0)
Blood Type (58), n (%)
O	29 (50.0)	19 (59.4)	10 (38.5)
A	24 (41.4)	12 (37.5)	12 (46.2)
B	4 (6.9)	1 (3.1)	3 (11.5)
AB	1 (1.7)	0 (0.0)	1 (3.8)
Obese BMI>30 (67), n (%)	10 (14.9)	3 (7.3)	7 (26.9)
Diabetes (68), n (%)	16 (23.5)	8 (19.0)	8 (30.8)
Hypertension (68), n (%)	40 (58.8)	22 (52.4)	18 (69.2)
Dyslipidemia (68), n (%)	6 (8.8)	3 (7.1)	3 (11.5)
Total Bilirubin (61), median (IQR)	1.20 (0.70–2.00)	1.50 (1.00–2.30)	0.80 (0.40–1.20)
ALT (60), median (IQR)	45.5 (29.0–83.0)	32.5 (27.0–56.0)	80.5 (47.0–115.0)
AST (60), median (IQR)	60.5 (41.0–95.0)	58.0 (38.0–73.0)	69.5 (42.0–123.0)
Albumin (58), median (IQR)	3.35 (2.90–3.90)	3.20 (2.80–3.50)	3.70 (3.30–4.10)
Mean Log10 HCV RNA (68)	5.92 +/− 1.03	5.71 ± 1.01	6.26 ± 0.98
eGFR (61), median (IQR)	72.3 (55.4–101.3)	86.1 (60.1–105.1)	65.9 (46.6–75.5)
Creatinine (62), median (IQR)	1.20 (0.95–1.46)	1.10 (0.79–1.35)	1.25 (1.05–1.50)
INR (44), median (IQR)	1.10 (1.05–1.30)	1.20 (1.10–1.40)	1.10 (1.00–1.15)
Hemoglobin (57), median (IQR)	11.9 (10.7–13.4)	11.9 (10.7–13.3)	11.9 (10.5–13.6)
Platelets (57), median (IQR)	118 (68–160)	84.0 (35.0–119.0)	160 (121–228)
CD4 count (38), median (IQR)	236 (81–389)	297 (134–389)	161 (74–523)
APRI (55), median (IQR)	1.35 (0.86–2.98)	1.90 (1.23–3.91)	0.98 (0.67–1.89)
FIB4 (55), median (IQR)	4.31 (2.63–10.79)	8.83 (4.91–14.35)	2.67 (2.24–3.30)
MELD Na (42), median (IQR)	12.0 (9–15)	14.0 (11–20)	11 (8–13)

^*variable (number available for variable)

3.1. HCV Outcomes

Participants were followed for treatment efficacy at 3 and/or 6 months and assessed at last follow up for current status. The median (IQR) time from end of treatment to current status was 38.5 (26.2–47.5) months. SVR was achieved in 63/68 (93%) of participants. Twenty five of 26 (96%) participants treated post-LT achieved SVR with two treated twice because of non-response (Table 2). The one non-responder treated post-LT died of hepatocellular carcinoma (HCC) 11 months after end of DAA treatment.

Table 2.

Outcome of HIV/HCV Participants by DAA Treatment pre- versus post-Liver Transplant

	Total Cohort	Treated post LT*	Treated pre LT
			All	Subsequent LT^
				yes	No
n	68	26	42	12	30
Treated twice	8	2	6	4	2
SVRever	63	25	38	11	27
History HCC	26	10	16	5	11
Died	13	3	10	2	8
Survival#	80.9%	88.5%	76.2%	83.3%	73.3%

^*LT, liver transplant.

^{^,}treated preLT and subsequently received LT.

^#survival based on crude analysis

Thirty-eight of 42 participants treated pre-LT achieved SVR and 6 participants were treated twice. Of those 4 participants without SVR, 3 had undetectable HCV RNA during DAA therapy; 2 died before testing for SVR and 1 was lost to follow up. One participant failed two treatment regimens pre-LT with pegylated interferon and ribavirin and then ledipasvir/sofosbuvir. He was transplanted for HCC at 33 months after the last DAA treatment, retreated with ledipasvir/sofosbuvir post-LT and successfully cleared HCV. Of the four participants who had detectable HIV VL at baseline, all were treated pre-LT, achieved SVR and did not experience virologic failure of HIV.

3.2. Liver disease outcomes

Median ALT pretreatment was 45.5 U/L (IQR 29.0–83.0) and at last follow-up was 21.0 U/L (IQR 16–34). ALT improved significantly after DAA therapy (Figure 1 A). Fifty one of 66 (77%) participants had normal ALT at last follow up. After HCV treatment, markers of fibrosis improved significantly from pretreatment to 3 and/or 6 months post treatment as shown in Figure 1B and 1C. APRI and FIB-4 were significantly higher in pre-LT participants compared to post-LT participants prior to DAA therapy (APRI p=0.004 and FIB-4 p<0.001). These markers improved significantly in all participants post treatment (p <0.01). Median liver stiffness, performed in 35 participants after DAA therapy within 6 months of current status, was 11.3 (IQR: 4.6–18.7) kPa. Twelve participants had liver stiffness scores reported in fibrosis (F) stage 0–1; 5 were F2; 1 was F3 and 17 were F4, of which 7 were in portal hypertension range (>21kPA). Thirty three of the 42 participants treated pre-LT had MELD available pre and post treatment. MELD improved in 19 (range 1–30 points), was unchanged in 3 and worsened in 11 (2–25 points). Median MELD did not differ significantly between pre and post DAA therapy (Figure 1D).

Figure 1.

Change in ALT (A), APRI (B), FIB-4(C) AND MELD (D) before (solid boxes) and after (open boxes) DAA therapy in all participants (total) and those treated pre-LT and post-LT. Values are shown as median and IQR (error bars). ALT decreased significantly from baseline to current status in all groups: p<0.001 in total cohort and in those treated post-LT, and p=0.04 in those treated pre-LT. APRI decreased significantly in all groups from pre-DAA therapy to post DAA therapy (3 or 6 months post treatment) (p<0.01). FIB-4 decreased significantly in all groups from baseline to post DAA therapy (3 or 6 months post treatment) (p<0.01) and p<0.001 in those treated pre-LT. There was no significantly differences in MELD from before DAA therapy to current status.

Figure 2 depicts the final disposition of all 68 study participants. Twelve of the participants treated pre-LT progressed to LT, in spite of achieving SVR in all but one participant: 5 had HCC and 7 had decompensated liver disease. Four of these 12 had been treated twice pre-LT. MELD at time of transplant was 10 (IQR 8–13) in HCC patients and 14 (IQR 8–21) in those transplanted for decompensated liver disease (Figure 2). Two of those with decompensated liver disease had low MELD as one received a liver for a deceased donor with HIV infection (HOPE act) and another from a live donor. In 33 of the 42 participants treated pre-LT, MELD was available pre and post DAA treatment. For the 12 participants who subsequently went on to LT, MELD pre-LT was used. Figure 3 shows a waterfall plot of the change in MELD in those with pre-treatment MELD <15 (Figure 3A, n=19) and MELD ≥15 (Figure 3B, n=14). We used a MELD of 15 as the generally accepted score at which LT is recommended¹³ and it has been used in peri-transplant HCV monoinfected studies¹⁴. Among the 19 participants with pretreatment MELD<15, 10(53%) had improvement in MELD (−1 to −6); 7(37%) had worsening of MELD (2–15); and 5 (26%) had post DAA treatment MELD ≥15. Among those 14 participants with pretreatment MELD ≥15, 9(64%) had improvement in MELD (−1 to −30); 4(29%) had worsening of MELD (2 to 21); and 6(43%) had MELD <15.

Figure 2.

Cohort flow diagram of HIV-HCV coinfected participants characterized by hepatocellular carcinoma (HCC) status and DAA treatment pre liver transplant (LT) or post-LT. Laboratory MELD (median, IQR) is reported for all participants pre and at current status post DAA. Patients with HCC are shown separately.

Figure 3.

Change in MELD from pre to post DAA treatment in 33 of 42 participants who received DAA treatment pre-LT. 3A depicts the 19 participants with pre-treatment MELD <15 and 3B the 14 participants with pre-treatment MELD ≥15. For the 12 participants who subsequently went on to LT, MELD pre-LT was used. Improvement is denoted by negative scores and worsening by positive scores. Two participants in 3A and 1 in 3B had no change in MELD. Pre and post DAA treatment MELD pre- and post-treatment were not available in 9 participants.

Overall in the total cohort, 13 participants died, 10 treated pre-LT and 3 treated post-LT. Ten of 42 participants treated pre-LT died: 8 of 30 participants who did not receive LT died within 1–49 months after end of DAA treatment. Two of the 12 participants treated pre-LT who went on to receive LT died post LT, one each with graft failure and anoxic brain injury. Three participants treated post-LT died, 2 of recurrent HCC and one of renal failure. Overall crude survival was higher in those treated post liver transplant (88.5%) and those treated pre-LT who received subsequent LT (83.3%) compared to those treated pre-LT without subsequent LT (73.3%). Figure 4A shows a cumulative post-LT survival of 87.9% and 87.9% at 2 and 5 years respectively. Figure 4B shows a cumulative transplant free survival at 2 and 4 years of 85.5% and 42.8% respectively.

Figure 4.

Kaplan Meier Survival Curves of those participants who were treated pre-LT (A: transplant free survival) and those who received liver transplant (B: post-transplant survival). Included are the number of participants at risk and cumulative number of events (death and transplant) over years post DAA therapy (A) and post-transplant (B).

3.3. Side effects

No participants discontinued therapy due to adverse events. Twenty-eight participants experienced 41 serious adverse events during treatment: 11 liver complications (6 complications of ESLD, 2 HCC); 8 infections; 4 neurologic complications; 3 gastrointestinal; 2 renal complications; 7 other (one each polysubstance abuse, ventral hernia, malignancy, gout and fracture, 2 venous thromboses and 6 unknown hospital admissions). Seven participants had ≥2 gram drop in hemoglobin during treatment, but no participants required blood transfusion or growth factors during DAA therapy.

3.4. HIV status

All participants had controlled HIV on ART with occasional low detectable HIV viral load. The 4 participants with detectable HIV VL at baseline subsequently were undetectable during treatment but two different participants had small increase in HIV RNA at 105 and 259 copies/mL during treatment which were considered as clinically insignificant “blips”. At last follow up 5 participants had HIV RNA >40 copies/mL (54, 70, 74, 128 and 174,550 copies/mL). CD4 counts were stable during treatment and at last follow up median CD4 count was 335 cells/mm³ (IQR 194–464).

4. DISCUSSION

In this cohort of HIV/HCV coinfected participants treated before and after liver transplant DAA therapy was safe and well tolerated with high rates of HCV cure. Because DAA became widely available after the initiation of our study, we amended our protocol to include retrospective participants. Only CPT B and C participants (CPT >=7) were included in this large cohort of HCV/HIV coinfected participants. Most studies of HIV/HCV coinfected patients have included only CPT A patients or limited numbers of CPT B and C patients^15–17. Lacombe et al reported a 92% SVR in 407 patients but only 13% were decompensated cirrhotics¹⁸. Rockstroh et al reported a 92% SVR rate in 55 pre transplant patients, 50% of whom were CPT B and C¹⁹. Our study is the largest with decompensated HIV/HCV part²⁰icipants and SVR rates (93%) achieved were as good or better than other studies.

In spite of achieving SVR, 12/42 pre-LT participants went on to require liver transplant. SVR did not lead to improvement in MELD in all participants as has been shown in other studies, both HCV monoinfected^14,21 and HCV/HIV coinfected^14,22. Of the 12 who required liver transplant after DAA treatment, 5 were transplanted for HCC and 7 for complications of ESLD. Thus, cure of their HCV did not preclude worsening liver disease. Some participants were deemed not candidates for LT due to medical or psychosocial issues. Of these participants who did not receive liver transplantation, 90% achieved SVR but 8 subsequently died, all due to ESLD and one with HCC. As in HCV-monoinfected patients with SVR, HCC in HCV/HIV patients is decreased post SVR but may still occur²³. Overall, pre-LT participants received short term benefits with good transplant free survival at 1y from SVR but not at 4y post DAA (Figure 4). SVR was associated with improved indirect markers of fibrosis (APRI and FIB-4) but did not prevent progression of ESLD. In addition, transient elastography data did not correlate with MELD at current status. This highlights what other studies have shown, that transient elastography and FIB-4 may show improve post SVR due to improvement in necroinflammation and may not reflect reversal of fibrosis and does not necessarily correlate with liver biopsy post SVR²⁴.

Our data have broad applicability, not just in the US. While there are few remaining untreated HIV/HCV patients post LT, our results emphasize the need for early engagement of HCV/HIV patients with compensated liver disease, regardless of comorbidities to prevent liver decompensation, HCC and need for LT. Other studies have highlighted the inability to reverse the complications of cirrhosis and prevent liver-related deaths among DAA-treated patients, suggesting there is a “point of no return” in the natural history of decompensated cirrhosis²⁵. However, the “point of no return” in terms of preventing the need for liver transplantation in HIV/HCV coinfected patients with decompensated liver disease cannot be determined from this analysis and improvement in fibrosis was not sufficient to preclude liver transplantation. In this regard, alternate, concomitant strategies to prevent progression of liver disease may need to be employed in patients with decompensated liver cirrhosis. Recent studies have suggested targeting CCR2/5 pathway may be beneficial, particularly for HIV/HCV coinfected patients²⁶. Current guidelines recommend that all HIV/HCV LT candidates be treated pre-LT, whereas for nonHIV patients the recommendation is MELD based^27,28.

This study was limited by the necessity to change the design from a prospective to a retrospective/prospective analysis. It should be emphasized that this change in study design resulted from the urgency in treating the HIV/HCV coinfected liver transplant candidate with DAAs, based on the dismal survival outcome in this cohort. By the time this trial was approved, many of the DAAs for HCV were approved, and centers immediately treated their decompensated HIV/HCV recipients. Nonetheless, the participants enrolled in the retrospective component of the trial would have met the inclusion/exclusion criteria for enrollment in the prospective component. Importantly, we show that outcomes for LT recipients were excellent, with survival rates of 87.9% at 5 years (Figure 4) and provides support for the use of LT as treatment of complications of ESLD in patients with HCV-HIV coinfection. Post-transplant treatment with DAAs was highly successful as noted in other studies^29,30. It is important to note that 2 of the 5 deaths which occurred in the 38 liver transplant recipients in the STOP-CO consortium were from recurrent HCC. Earlier transplantation may have prevented HCC recurrence, and access to HIV-infected deceased donor livers under the HOPE ACT may expand the pool of available livers to allow for earlier transplantation.

DAA therapy given in the peritransplant period was safe and well tolerated. A significant number of participants had serious adverse events which is expected in this fragile cohort of participants with complications of end stage liver disease and post-transplant HCV. This study highlights the success of late DAA treatment in many patients in terms of SVR with variable improvement in MELD. Of equal significance, this data demonstrates that successful management of HCV in the coinfected patient addresses a critical barrier to liver transplantation in this challenging cohort of recipients. The self-imposed moratorium on transplanting HIV/HCV patients, which was appropriately based on poor utilization of a scarce resource²⁷, can safely be lifted at centers that remain hesitant to transplant the HIV/HCV coinfected patient.

Abbreviations:

ALT

alanine aminotransferase

APRI

aspartate aminotransferase to platelet ratio

ART

antiretroviral therapy

ARV

antiretroviral

CPT

Child’s Pugh Turcotte score

DAA

Direct acting antiviral

ESLD

end-stage liver disease

F

Fibrosis stage

FIB-4

Fibrosis-4 score

HCC

hepatocellular carcinoma

HCV

Hepatitis C virus

HIV

human immunodeficiency virus

IQR

interquartile range

LLOQ

lower limit of quantification

LT

liver transplant

MELD

Model for End-Stage Liver Disease score

PLWH

people living with HIV

SRTR

Scientific Registry of Transplant

STOP-CO

stop coinfection

SVR

sustained virologic response