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Summary from CROI 2018 for viral Hepatitis
HCV micro-elimination in HIV/HCV coinfection: successes and challenges
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Jurgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany
Correspondence:
Prof. Dr. J.K. Rockstroh
Department of Medicine I
University of Bonn
Sigmund-Freud-Str. 25
53105 Bonn
Germany
Introduction
At this year CROI in Boston data was presented from the Swiss HCVree trial which suggests that offering HCV treatment to all diagnosed HIV/HCV coinfected individuals within the Swiss HIV Cohort may be successful in reducing new incident infections by almost 50% as well as reducing the burden of chronic HCV by over 90% (1). Similar results have been reported at last year CROI in Seattle where again an increased uptake of DAA therapy in Netherlands with over 75% of all HIV/HCV coinfected MSM being cured caused a reduction in new infections by around 50% (2-5). Thereby, two studies now exist which indeed promise that HCV micro-elimination may be achievable in well-identified patient populations. Clearly, the challenge to overcome is the high risk of reinfection in particular in HIV coinfected MSM with reinfection rates of almost 25% after two years of follow-up after a first resolved or successfully treated episode of acute HCV (6). Interesting data was presented in Boston showing that 97% percent of study sequences from Swiss acute HCV infections were located in MSM clusters (7). HCV Transmissions were frequently linked to other European regions suggesting that even after implementation of successful national elimination treatment plans reinfection can occur in neighboring countries with less advanced national treatment plans (7). Moreover, an increasing risk for HCV transmission may also come from HIV-negative MSM. Various studies reported at CROI looked at HCV prevalence and incident infections in HIV-negative MSM entering PREP studies showing that the acute HCV epidemic has now also invaded the HIV-negative MSM population (8,9). Clearly, early treatment of acute HCV will become crucial for achieving micro-elimination in order to limit transmission possibilities. Data from the NEAT-ID foundation PROBE-C cohort looked at the natural course of acute HCV infection in HIV-coinfected individuals (10). Indeed only 11% of all patients were able to clear HCV infection spontaneously which implies that the overwhelming portion of patients will go on to develop chronic HCV infection. Early intervention appears advisable in order to prevent further onward transmission of HCV. The new algorithm provided by the NEAT-ID group, which also has been used in the EACS guidelines, therefore recommend a second HCV-RNA assessment 4 weeks after initial diagnosis. In case there is no 2-log decline in HCV-RNA levels at this time point, a chronic course of HCV becomes very likely and therefore early HCV treatment intervention is recommended.
Other important topics covered response to DAA therapy in HIV/HCV coinfected patients versus HCV monoinfected subjects as well as the impact of switching antiretroviral therapy prior to commencing DAA therapy in HIV/HCV coinfected subjects in order to minimize toxicity or overcome drug-drug interactions (11-12). Furthermore, data in HCV monoinfection was presented on rescue DAA therapy in prior all oral DAA failures (13). In the field of HBV interesting data was presented on outcomes of HBV therapy in HBV/HIV coinfection including TAF as well as a first case report on a newly acquired HBV infection in a patient on ABC/3TC/Dolutegravir fix-dose combination (14,15).
Fueling the HCV epidemic: Low rates of spontaneous clearance of acute HCV in HIV coinfection
With no DAA currently licensed for the treatment of acute hepatitis C (AHC) and with the high drug prices the question becomes eminent which patients will resolve their AHC infection spontaneously and which patients should be offered timely DAA therapy. The large PROBE-C cohort captures data on acute HCV episodes throughout various European countries and offers the opportunity to evaluate rates of spontaneous clearance of acute HCV coinfection in a large European cohort (10). Acute HCV infection was defined as a documented current or past acute hepatitis C infection with detectable HCV-RNA with an estimated duration less than 52 weeks at diagnosis as defined below:
• First HCV RNA positive AND
• Prior negative anti-HCV antibody or HCV-RNA test within 12 months OR
• rise of liver transaminases above 2.5 x ULN within the past 12 months with prior normal transaminases during the year before AND
• exclusion of other causes of acute hepatitis
Between 2007 and 2017 464 AHC episodes were documented in HIV-infected patients with at least 12 months of follow-up and without immediate treatment initiation (>4 weeks duration) from Austria, Denmark, France, Germany, Great Britain and Spain (10). The baseline characteristics of the study population are shown below in table 1.
Table 1: Baseline characteristics of the PROBE-C cohort
The cohort was an almost exclusively MSM patient group with mostly genotype 1a infections and to a lesser extent also genotype 4 infections. The high median maximum ALT underlines the acute HCV diagnosis. Patients were well controlled for HIV with over 90% being suppressed and on average depicting a CD4-count above 500/μl. Figure 1 shows the rate of spontaneous clearance for the study group.
Figure 1: Virological outcome in the natural course of acute HCV in HIV-coinfection
The rates of spontaneous clearance were strikingly low with only 11.9% being able to clear HCV successfully without therapeutic interventions. Of note of the 88.1% developing chronic HCV infection 245/324 were treated with 75.6% achieving SVR. Overall, 17% (51/300) developed a reinfection. The clinical characteristics of spontaneous clearers versus those who went on to develop chronic infection are shown in table 2.
Table 2: Clinical characteristics of the two patient groups (PV=persistent viremia, SC=spontaneous clearers)
Of note, both patient populations were comparable with regard to age, HCV GT distribution, median HCV RNA level and HIV surrogate markers. Patients who spontaneously cleared however, were significantly more likely to experience a >2log drop in HCV-RNA 4 weeks after diagnosis and first HCV RNA determination. Table 3 looks at the results from univariate and multivariate analysis looking for predictive factors for spontaneous clearance.
Table 3: Results of univariate and multivariate analysis
In multivariate analysis the only factor which remained highly predictive was the >2log decline in HCV RNA 4 weeks after first HCV-RNA determination. This wonderfully supports the current algorithm for treatment of acute HCV from the EACS guidelines, which proposes a second HIV-RNA determination after acute HCV diagnosis. In case of a greater than two log decline in HCV-RNA spontaneous clearance becomes very likely and further monitoring is recommended. In the absence of such a >2 log decline chronic HCV infection is highly likely and treatment with all oral DAA therapy is recommended. The early treatment commencement is also important as it may help to minimize onward transmission of acute HCV in this phase where it is unclear whether treatment should be started or not. The current algorithm for management of acute HCV from the EACS guidelines is shown in figure 2.
Figure 2: Management of acute HCV in HIV-coinfection from the EACS guidelines (see www.eacssociety.org)
New data on treatment of acute HCV with shortened DAA therapy
CROI: A treatment as prevention trial to eliminate HCV in HIV positive men who have sex with men: The Swiss HCVree Trial - e-health assisted behavioral intervention to reduce risk in HCV re-infection in MSM - (03/15/18)
The Dutch Acute HCV in HIV study no. 2 (DAHHS2; NCT02600325) was designed to prove that the all oral DAA fix-dose combination of grazoprevir/elbasvir was effective when given during the acute phase of HCV and in addition that treatment can be shortened during acute HCV to 8 weeks (16). This single-arm, prospective, open-label, multicenter trial included patients with acute HCV genotype 1 or 4 only. Fifteen hospitals referred patients diagnosed with an acute HCV to 1 of the 9 DAHHS study centers spread across the Netherlands and Belgium. Patients received 8 weeks of grazoprevir/elbasvir 100/50mg QD. Therapy was initiated no later than 26 weeks after the estimated day of infection. The primary endpoint was SVR 12 weeks post-treatment in the intention to treat population. Overall, 80 patients were recruited but full data (SVR12) was only available for 63 subjects. Table 4 summarizes the baseline characteristics of the entire study population. The cohort consisted exclusively of male MSM with mostly GT1 infection and well-controlled HIV infection. Figure 3 summarizes the patient flow and main treatment outcome of the study. In the primary endpoint analysis in an ITT population 62/63 patients achieved SVR. The obtained 98% SVR12 rate (exact 95%CI 91-100%) was non-inferior to the SVR12 rate of 93% in the registrational coinfection study with grazoprevir/elbasvir in chronic HIV (HCV coinfected patients (C-EDGE) (17). If reinfection is counted as a failure the ITT population revealed treatment success in 59/63 patients resulting in a SVR12 rate of 94% (exact 95%CI 85-98%) which again was non-inferior to the SVR12 rate of 93% obtained in the C-EDGE trial. In summary, an 8-week course of grazoprevir/elbasvir for treatment of acute HCV in HIV coinfected subjects was highly effective and safe and non-inferior compared to 12 weeks of grazoprevir/elbasvir for chronic HCV in HIV-coinfection.
Table 4: Baseline characteristics of the DHHHS acute HCV study
The Swiss HCVree trial: Is microelimination possible?
The Swiss HIV cohort collects data from almost all HIV-infected subjects in Switzerland and as such offers the perfect opportunity to study changes in HCV epidemiology after DAA treatment implementation. The Swiss HCVree trial is a treatment as prevention trial to eliminate HCV in HIV positive men who have sex with men (1). The hypothesis entering the trial was that if all HCV infected MSM were successfully treated, potentially the reduction in HCV reservoir could prevent new HCV infections, considering the high risk for reinfections in this particular patient population. In Phase A HIV/HCV coinfected subjects with ongoing HCV replication were identified (9 months) (1). HCV-PCR screening was routinely scheduled at the 6-monthly SHCS visit, respectively. Part B of the study was the treat and council phase (9 months). Merck Sharpe & Dohme (MSD) provided DAA treatment with grazoprevir/elbasvir for the study participants. For participants with contraindication to grazoprevir/elbasvir standard of care DAAs were administered. In addition, behavioral intervention was offered in order to help prevent reinfections. Finally, phase C of the study was used to identify and treat new HCV cases. Re-screening was implemented to assess post-intervention prevalence. Figure 4 summarizes the findings of phase A.
Figure 4: Phase A: Systematic population-based HCV screening
Study medication was grazoprevir/elbasvir for 12 weeks. In GT 1a patients with baseline RAS and GT 4 patients with previous failure to IFN/RBV treatment was adjusted to add-on ribavirin and prolongation to 16 weeks. Patients with contraindication to grazoprevir/elbasvir received standard DAA therapy. Overall, 91% of study participants were treated with a remarkably high SVR12 rate of 99.5%. This once again highlights that early intervention comes along with the highest HCV cure rates. Figure 5 shows the course of newly diagnosed infection from phase C of the study. HCV Treatment intervention in the Swiss HCVree trial reduced incident HCV infections by 49% and chronic infections by 92.5% clearly highlighting that micro-elimination in this targeted well-defined patient group is feasible.
CROI: 8 weeks of grazoprevir plus elbasvir for acute hepatitis C virus genotype 1 or 4 infection - the DAHHS 2 study - a single-arm, prospective, open-label, multicenter phase 3b trial (03/12/18)
Figure 5: Newly diagnosed HCV infections over time
How are acute HCV infections linked within the outbreak of acute HCV among HIV-seropositive MSM?
Additional data from the Swiss cohort was presented which classified incident HCV infections in HIV-positive MSM as domestically or internationally acquired and located incident infections in transmission clusters (7). Whole genome sequencing was performed in sixty-six HCV sequences subtype 1a. The NS5B region was compared to sequences from Switzerland from people who inject drugs as well as with international databases. Interestingly, 90% of sequences from acute infections in Swiss MSM were within transmission clusters. Four Swiss dominated (Dominance criteria 80%) transmission clusters estimated to have emerged between Nov-2000 and Jun-2007. But 14% to 44% of sequenced infections were likely acquired by contacts with MSM not living in Switzerland, which suggests that international transmission networks need to be taken into account. Therefore, micro elimination will only work if there is a pan-European effort to end the HCV epidemic among HIV coinfected MSM.
webcast: http://www.croiwebcasts.org/console/player/37299?mediaType=slideVideo&&crd_fl=1&ssmsrq=1522333457582&ctms=5000&csmsrq=838
Risk of HCV in PrEP users: how big is it?
Professor Cotte from France is among the first to present prospective data on acute HCV incidence in PrEP users MSM and in HIV+ MSM enrolled in a large French cohort (8). The DatAIDS cohort covers about 25% of French HIV+ patients in care. HIV+, HCV-negative MSM with serological follow-up in 2016 and HIV-negative, HCV-negative MSM PrEP users enrolled from January 2016 to May 2017 in 13 of the 15 cohort sites were analyzed to assess the incidence of a first acute HCV episode. The incidence of HCV reinfection was determined in patients having cured a previous one. Since PrEP recruitment was highly heterogeneous between sites, a sub-analysis was conducted based on the 5 sites with the highest number of PrEP patients. Among 10,537 HIV+ MSM followed in 2016 in 14 centers, HCV serological status was available in 10,049 (95.4%). 681 patients were already HCV+ when entering the study (prevalence 6.4%) and serological follow-up was available in 2016 for 4,151 HCV-negative patients. Virological follow-up was available for 478 patients who had cured a previous infection. 57 acute HCV infections occurred in 2016 (42 first infections, 15 reinfections). Incidence of first HCV infection, reinfection and overall acute HCV was respectively 1.01, 3.14 and 1.23 /100PY. 930 PrEP-using MSM were enrolled. HCV serology was available in all patients and serological follow-up was available for 916 (972 PY). 17 patients were already HCV-infected when entering the study (prevalence 1.8%), of whom 14 were cured and 3 had an active HCV infection. 12 acute HCV occurred during follow-up (10 first infections, 2 reinfections). Incidence of first HCV infection and overall acute HCV was respectively 1.03 and 1.24 /100PY.
In a sub-analysis restricted to 5 sites contributing to 44% of HIV+ MSM and 90% of PrEP patients, the overall incidence of acute HCV was 1.47 and 1.38 /100PY in HIV+ and PrEP-using MSM, respectively. The HCV incidence for all centers is shown in figure 6.
Figure 6: HCV incidence for all participating centers
Of note, the incidence of acute HCV was comparable between HIV-seropositive and HIV-seronegative PrEP-users suggesting that there is already a reservoir of potentially transmittable HCV in the HIV-seronegative MSM community. This implies that prevention measures also have to address the HIV-negative population.
CROI: HCV incidence in HIV-infected and in PrEP-using MSM (03/27/18)
CROI: New HCV Infections Still Rising Among MSM With HIV in France - (03/21/18)
Additional data of interest were presented from the French Ipergay study (9). In this particular substudy the investigators aimed at assessing the sensitivity of different tests for early diagnosis of acute hepatitis C in high risk MSM. ALT determinations were carried out at each visit. In addition HCV antibody immunoassay 3rd Generation (3thG) was performed at baseline and every 6 months and in case of new onset of an >2.5 fold ALT increase. High risk MSM were included which reported on average 25 sex partners in the last
2 months with on average 15 sex events in the last 4 weeks with 92% unprotected receptive
anal intercourse and 54% engaging in chemsex. Figure 7 describes the study population and summarizes the cases of HCV infections among the IPERGAY participants.
Figure 7: Flow-chart: Description of the number of HCV-infected diagnosed based on HCV serology during the IPERGAY PrEP trial.
CROI: HCV RNA and Antigen Detection for Diagnosis of Acute Hepatitis C Among MSM on PreP..... In the ANRS IPERGAY PrEP trial among high risk MSM - (03/29/18)
The overall conclusions of the study were that HCV antigen immunoassay and plasma HCV RNA test were positive within a median of 2 months before the detection of antibodies and ALT elevation, when patients were asymptomatic and had no increase in ALT in the majority of cases. Therefore, these tests should be used in high risk MSM for early diagnosis of acute HCV and prevention of transmission.
Reinfection with the hepatitis C virus (HCV) has been described in patients with ongoing risk behavior (6). Among men who have sex with men (MSM), users of intravenous (IDU) and non-intravenous drugs (mainly methamphetamine) for sexual enhancement (Chemsex) as well as traumatic sex practices with high risk for blood-blood contacts have been identified as a main risk group for HCV acquisition. The frequency of HCV reinfections after treatment with direct-acting antivirals (DAA) is not well-known. At CROI data on the reinfection incidence rate in HCV mono-infected and HIV/HCV co-infected MSM or patients with IDU from the German hepatitis C cohort (GECCO) were presented (17). The German hepatitis C cohort (GECCO) is a real-world cohort on treatment with all directly acting antiviral agents from nine care centers from Germany since February 2014. Clinical and demographic data is collected from HCV mono- and HIV-HCV coinfected patients. Patients without virological response or that were lost to follow-up were excluded from this analysis. Reinfection was defined as undetectable HCV RNA in a patient that had an undetectable HCV RNA at least 12 weeks after the end-of-treatment (SVR12), or with an HCV-genotype switch before that time point. Out of 2,074 patients, 41 (1.97%) were identified with an HCV reinfection. Reinfection occurred within a median of 63 weeks (range16-180) after end-of-treatment response. The reinfection prevalence was highest in MSM (figure 8), 2 reinfections occurred in HIV negative MSM.
Figure 8: Reinfection rates in the GECCO cohort by HIV transmission risk group.
Within the GECCO cohort, reinfection remains a rare event. However, in subgroups with ongoing risk behavior the HCV reinfection rate remains high, with MSM being more affected than IDUs. In HIV-infected MSM, similar reinfection rates as in the pre-DAA era are observed, again highlighting this subgroup as a target population for close monitoring and specific behavioral interventions.
CROI: Nine of 100 MSM in German Cohort Get HCV Reinfection Every Year in DAA Era - (03/29/18)
Real-life cohort experience with DAA therapy in HIV/HCV coinfection
The efficacy of licensed DAA regimens is assumed to be the same for HCV-monoinfected patients (MoP) and HIV/HCV-coinfected patients (CoP). However, the high SVR rates of DAA regimens and the relatively small number of patients included in registration trials have made it difficult to identify predictors of treatment failure, including the presence of HIV. At CROI results from a large Spanish real life cohort were presented which compared treatment outcomes for LDV/SOF against HCV G1 in treatment-naïve MoP and CoP without cirrhosis (12). In order to make the cohort as homogenous as possible only GT1 patients without cirrhosis were included. Also all patients received the same DAA therapy. The flow chart of study participants is shown below in figure 9. Overall, 1102 HCV monoinfected subjects and 305 HIV/HCV coinfected subjects fulfilled the inclusion criteria and were available for full analysis.
Figure 9: Flow chart
The baseline characteristics for the two groups and by DAA treatment duration are summarized below in table 6.
Table 6: Baseline characteristics
# = median (IQR), ± = n (%), MOP= HCV monoinfected patients, COP = HIV/HCV coinfected patients, TE = transient elastography
Of note, HIV/HCV coinfected patients were significantly younger, more likely to be male and to have a GT1a subtype than the HCV monoinfected subjects in the comparator group. As GT1b has different impact on resistance development and also is often more easy to treat with DAAs this may have an impact on the results. The treatment outcomes for 8 and 12 weeks of LDV/SOF DAA therapy, respectively is shown below in figure 10 a and b.
Figure 10 a and b: Treatment outcomes for 8 (10a) and 12 weeks (10b) of LDV/SOF, respectively.
10a:
It is important to highlight that for 8 week as well as for 12 weeks of LDV/SOF excellent HCV cure rates of above 91.9% were observed in the ITT analysis for the HIV/HCV coinfected subjects, respectively. Nevertheless, SVR rates were significantly lower than in the HCV monoinfected groups. Numerically because of the low patient number however, the difference is driven by very few more relapses (1.0 vs 3.1%) and some more discontinuations. Whether the number of subjects included is sufficiently powered to determine such differences is still unclear and larger patient cohorts need to be investigated whether these findings can be confirmed. Also differences in baseline characteristics may impact differences in treatment outcomes for the different study groups studied.
Data was also presented from a multicenter (N=9), observational clinical registry, which evaluated the outcome of switching antiretroviral therapy versus no change in ART before commencing DAA therapy (11). The study population included patients with HIV/HCV co-infection treated with ledipasvir/sofosbuvir. Cases (ARV switch prior to HCV therapy) and controls (no ARV switch prior to HCV therapy) were enrolled in a 1:1 ratio. Inclusion criteria were: ≥18 years of age and capacity to sign consent, HIV/HCV co-infection, on stable ARV regimen consisting of at least two active ARV for 12 weeks prior to switch (case) or start of DAA therapy (control), evidence of HIV RNA <50 copies/mL prior to switch (case) or prior to start of DAA therapy (control) and having received/initiated a ledipasvir/sofosbuvir regimen. The primary endpoint is HIV treatment failure defined by a combined endpoint of HIV virologic failure (confirmed HIV RNA >50 copies/mL >1 week apart), discontinuation of ARV regimen, lost to follow-up, progression to AIDS, or death. Secondary endpoints include nephrotoxicity and sustained virologic response (SVR12), defined as an undetectable HCV RNA 12 weeks after DAA therapy. Planned analyses include Fischer's exact for differences in proportions. The baseline characteristics are summarized below in table 7.
Table 7: Baseline characteristics
Of note, more switches occurred in patients with boosted PIs and TDF as part of a boosted regimen which makes sense as interactions with TDF and ledipasvir in particular in boosted regimens have been postulated. Less switches were seen in patients on TAF were no interactions are expected. The outcome results are shown below in table 8.
Table 8: Results
No difference in rate of HIV treatment failure or clinical endpoints was seen between patients who switched their antiretroviral therapy and those who remained unchanged on their respective HIV therapy. SVR rates were also comparable and encouragingly high with 99%. Rates of nephrotoxicity also did not differ between study groups. These results show that despite anticipated drug-drug interactions in particular between TDF and ledipasvir no clinical relevant differences in clinical findings were found in those remaining on TDF. Clearly the short duration of HC therapy may limit the clinical impact of DDIs.
CROI: A Multicenter Registry in HIV/HCV Co-infected Patients Initiating Ledipasvir/Sofosbuvir - (03/29/18)
Salvage therapy in prior all DAA failures
Modern all oral DAA therapy comes with very high SVR cure rates on average way above 95%. Nevertheless, the question remains which treatment options exist in those few DAA failures, particularly after emergence of resistance associated variants (RAS). At this year CROI data from the ongoing MEGALLAN-3 study was presented which examined safety and efficacy of a salvage therapy of glecaprevir/pibrentasvir (G/P) + sofosbuvir + ribavirin in prior G/P failures (13). The study included patients with HCV GT1-6, without or with HIV-1 co-infection (ART-naïve or on stable ART) who had experienced virologic failure during or after treatment with G/P in an Abbvie clinical study. Previous G/P treatment was completed or discontinued ≥1 month prior to screening. Patients had to show absence of co-infection with hepatitis B virus as well as absence of decompensated cirrhosis (Child-Pugh B/C). The study design is depicted below in figure 11. Patients who were non-GT3-infected, non-cirrhotic, and naïve to protease inhibitor and/or NS5A inhibitor prior to VF with the G/P regimen received 12-week (Arm A) treatment with the combination regimen; all other enrolled patients who did not meet any of these criteria received the same regimen for 16 weeks (Arm B). Efficacy (primary outcome is SVR at post-treatment (PT) Week 12 [SVR12]), safety, and baseline resistance were assessed.
Figure 11: Study design of the MEGALLAN-3 study
Overall, 2 patients were included into arm A and 21 in arm B. Table 9 summarizes the baseline characteristics.
Table 9: Baseline characteristics of the MEGALLAN-3 study
Most patients had GT1 infection, with one third showing compensated cirrhosis. The baseline polymorphisms at baseline are shown below in table 10.
Table 10: Baseline polymorphisms
All patients had at least NS5A mutations, a quarter already in combinations with a NS3 mutation as well. The treatment outcome results are shown in figure 12.
Figure 12: Results
Overall, only one relapse occurred in a GT1a patient with compensated cirrhosis who had failed SOF/LDV prior to G/P. In conclusion, preliminary data from this study show that HCV-infected patients who experienced virological failure following G/P treatment can achieve high SVR12 rates with G/P + SOF + RBV. Overall, the combination of G/P + SOF + RBV was well tolerated. Indeed it looks as if 3-drug class therapy (NS5A+NSA+Sof) is a great option for salvage therapy. Similar good responses have been described for the licensed 3-drug fix dose combination of Velpatasvir/sofosbuvir/voxilaprevir (18).
CROI: Retreatment of Hepatitis C Infection in Patients Who Failed Glecaprevir/Pibrentasvir (03/09/18)
Anything new about hepatitis B and HIV coinfection?
At this year CROI data on HBV and HIV outcomes in antiretroviral treatment (ART)-naïve and -experienced HIV/HBV-coinfected patients enrolled in 4 Gilead studies of coformulated bictegravir/emtricitabine/TAF (B/F/TAF) were reported (15). All participants enrolled in the 4 studies were tested for HBV serologies at screening and Week 48. Active HBV infection at study entry (prevalent HBV) was defined as HBV surface antigen (HBsAg) positive on or prior to 1st dose date, or HBsAg negative, HBV surface antibody (HBsAb) negative, HBV core antibody (HBcAb) positive, and quantifiable HBV DNA (ie, HBV DNA ≥20 IU/mL) on or prior to 1st dose date. Participants with active HBV infection at screening were excluded from Studies 1489 and 1844 as comparator arms did not include guideline-recommended NRTIs for treatment of HBV in HIV-infected participants. Potential incident HIV/HBV coinfection was defined as participants enrolled in any of the 4 studies who were not HIV/HBV-coinfected at baseline and met the following criteria: HBsAg positive after 1st dose date; HBsAg negative, HBsAb negative, HBcAb positive, and quantifiable HBV DNA (ie, ≥20 IU/mL) after 1st dose date; or Experienced adverse events (AEs) consistent with HBV infection after 1st dose date (eg, acute HBV, HBV infection, and HBV test positive). Overall, within the pooled analysis of from 4 B/F/TAF Studies (n=2414) 14 ART-naïve HBV/HIV patients were identified. The HBV outcome with regard to HBV viral load decline and possible serconversion of HBsAg or HBeAg under F/TAF as dual active HIV/HBV agents are summarized in table 11.
Table 11: HBV Outcomes and HBV DNA Results at Week 48
Overall, B/F/TAF- and F/TAF-containing regimens produced robust HBV antiviral responses in treatment-naïve participants with HIV/HBV coinfection 85% (11/13) achieved HBV DNA <29 IU/mL at Week 48. No participant developed HBV resistance to FTC or TAF; the 2 subjects without HBV DNA < 29 at Week 48 had decreases in HBV DNA from >170,000,000 IU/mL at baseline to <400 IU/mL at Week 48. 15% had HBsAg loss and seroconverted to HBsAb-positive status at Week 48. 25% of HBeAg-positive participants experienced HBeAg loss at Week 48. 100% of participants had HIV-1 RNA <50 copies/mL at Week 48.
In the switch studies an additional 14 patients with chronic hepatitis B coinfection were identified. The HBV DNA outcomess at week 48 are summarized in table 12.
Table 12: HBV DNA outcomes at week 48
B/F/TAF- and F/TDF-containing regimens maintained HIV-1 virologic suppression in HIV/HB-coinfected participants with HIV-1 suppression at study entry. 100% of patients with HBV suppression at baseline had HBV DNA <29 IU/mL at Week 48. 1/4 participants who were HBeAg positive at baseline had HBeAg seroconversion at Week 48 (25%). 100% of participants with Week 48 HIV-1 RNA results had HIV-1 RNA <50 copies/mL at Week 48. In summary, TAF/FTC shows robust anti-HBV antiviral activity in HIV/HBV coinfected subjects.
Of note, one participant randomized to receive DTG/ABC/3TC developed incident HBV infection during the trial. The course of HBV serologies and DNA determinations is shown below in figure 13.
Figure 13: Incident HBV Infection Case, HIV RNA, HBV serologies and HBV DNA Results
As HBV DNA levels were very low upon initial hepatitis B diagnosis no resistance testing was performable at this point.
In summary, no participant treated with B/F/TAF or an F/TAF- or F/TDF-containing regimen acquired HBV infection during the studies but 1 study participant treated with ABC/3TC/DTG had incident HBV infection with confirmed HBV viremia at Week 48.
CROI: High HBV and HIV Suppression With Treatment of HIV/HBV Coinfection in B/F/TAF Studies (03/10/18)
At last year CROI a higher HBsAg seroconversion rate has been reported for HIV/HBV patients on long-term TDF therapy (19). Patients with HIV have a six times higher rate of developing chronic hepatitis B following acute HBV infection. Immune reconstitution under successful ART however, may increase the likelihood of clearing HBV infection successfully after prolonged dual HIV/HBV active nucleoside therapy. At this year CROI similar data but in a much larger cohort was reported from France (14). HIV-infected individuals with chronic HBV infection starting combined antiretroviral-anti-HBV treatment were retrospectively included from the French National Dat'AIDS cohort (NCT02898987). HCV co-infected subjects were excluded. Primary outcomes were confirmed HBsAg loss and Anti-HBs seroconversion. Bayesian analysis was used to study the risk factors for HBsAg clearance. Overall, 1419 HIV/HBV coinfected subjects were included. An HBsAg loss was documented for 97 patients (6,8%) after a median of 45 - 137 months. The estimated time until loss of HBsAg for the various HBV active regimens used is shown below in figure 14.
Figure 14: Kaplan-Meier analysis: estimated time until loss of HBsAg
HBsAg clearance rates were low while on HBV therapy but still higher than has been reported for HBV monoinfected subjects on nucleos(t)ide therapy. A higher CD4 nadir, prompt initiation of HBV therapy, mainly with TDF-based regimen, improved HBsAg clearance and anti-HBs seroconversion.
Summary
•Spontaneous clearance of acute HCV infection in the setting of HIV coinfection is a rare event; almost 90% of acutely infected patients face a chronic course.
•A <2-log drop in HCV RNA 4 weeks after diagnosis of acute HCV is strongly predictive of a chronic course allowing for early DAA treatment initiation.
•An 8-week course of grazoprevir/elbasvir for treatment of acute HCV in HIV coinfected subjects was highly effective and safe and non-inferior compared to 12 weeks of grazoprevir/elbasvir for chronic HCV in HIV-coinfection.
•HCV Treatment intervention in the Swiss HCVree trial reduced incident HCV infections by 49% and chronic infections by 92.5%.
•HCV Transmissions in Switzerland are frequently linked to other European regions suggesting that even after implementation of successful national elimination treatment plans reinfection can occur in neighboring countries with less advanced national treatment plans.
•HCV antigen immunoassay and plasma HCV RNA test are positive within a median of 2 months before the detection of antibodies and ALT elevation, when patients were asymptomatic. Therefore, these tests should be used in high risk MSM for early diagnosis of acute HCV and prevention of transmission.
•Within the GECCO cohort, reinfection remains a rare event. However, in subgroups with ongoing risk behavior the HCV reinfection rate remains high, with MSM being more affected than IDUs.
•In HIV-infected MSM, similar reinfection rates as in the pre-DAA era are observed, again highlighting this subgroup as a target population for close monitoring and specific behavioral interventions.
•Spanish real-world study results analyzing the treatment outcomes for LDV/SOF treatment in treatment-naive HCV GT1 non-cirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C.
•In a real world cohort of HIV/HCV co-infected patients receiving ledipasvir/sofosbuvir, switches in ARVs were not associated with HIV treatment failure. While nephrotoxicity events did occur, these were not more common in controls and were not associated with TDF-containing regimens.
•Preliminary data from this study show that HCV-infected patients who experienced virological failure following G/P treatment can achieve high SVR12 rates with G/P + SOF + RBV. Overall, the combination of G/P + SOF + RBV was well tolerated
•In a pooled analysis of 4 large bictegravir/emtricitabine/TAF (B/F/TAF) studies no participant treated with B/F/TAF or an F/TAF- or F/TDF-containing regimen acquired HBV infection during the studies but 1 study participant treated with ABC/3TC/DTG in the control arm had incident HBV infection with confirmed HBV viremia at Week 48.
•HBsAg clearance rates in HIV/HBV coinfection are low while on HBV therapy but still higher than has been reported for HBV monoinfected subjects on nucleos(t)ide therapy. A higher CD4 nadir, prompt initiation of HBV therapy, mainly with TDF-based regimen, improved HBsAg clearance and anti-HBs seroconversion.
References
1. Braun D et al., for the Swiss HIV Cohort Study. A treatment as prevention trial to eliminate HCV in HIV+ MSM: The Swiss HCVREE trial. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract LB87
2. Boerekamp A et al. Unrestricted DAA access in the Netherlands: Rapid therapy uptake in HIV+HCV+ patients. 24th Conference on Retroviruses and Opportunistic Infections, February 13-16, 2017, Seattle; abstract 136
3. Boerekamp A et al.: Substantial decline in acute HCV infections among Dutch HIV+MSM after DAA roll out. 24th Conference on Retroviruses and Opportunistic Infections, February 13-16, 2017, Seattle; abstract 137LB
4. Boerekamps A et al.: NVHB-SHM hepatitis working group and the Netherlands ATHENA HIV observational cohort. High treatment uptake in HIV/HCV-coinfected patients after unrestricted access to direct-acting antivirals in the Netherlands. Clin Infect Dis. 2017 Nov 23. doi: 10.1093/cid/cix1004. [Epub ahead of print]
5. Boerekamps A et al.: Declining HCV incidence in Dutch HIV positive men who have sex with men after unrestricted access to HCV therapy. Clin Infect Dis. 2017 Nov 23. doi: 10.1093/cid/cix1007. [Epub ahead of print]
6. Ingiliz P, et al. NEAT study group. HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe. J Hepatol. 2017 Feb;66(2):282-287.
7. Salazar-Vizcaya L et al. International versus domestic HCV transmission in MSM: A perspective for the DAA era. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 130
8. Cotte L et al.: HCV incidence in HIV-infected and in PrEP-using MSM. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 590
9. Gras J et al. for the ANRS IPERGAY study group. HCV RNA and antigen detection for diagnosis of acute hepatitis C among MSM on PrEP. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 585
10. Boesecke C et al. for the PROBE-C study group. Fueling the epidemic: Low rates of spontaneous clearance of acute HCV coinfection. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 129
11. Marks KM et al. Multicenter registry in HIV/HCV co-infected patients initiating ledipasvir/sofosbuvir. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 604
12. Berenguer J et al. HIV predicts failure of LDV/SOF in HCV G1 treatment-naïve non-cirrhotic patients. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 607
13. Wyles D et al. Retreatment of hepatitis C infection in patients who failed glecaprevir/pibrentasvir. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 127
14. Gantner P et al. Higher rates of HBsAG clearance with TDF-containing therapy in HBV/HIV coinfection. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 617
15. Rockstroh J et al. High HBV and HIV suppression with treatment of HIV/HBV coinfection in B/F/TAF studies. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 618
16. Boerekamps A et al: 8 weeks of grazoprevir plus elbasvir for acute HCV: A multicentre clinical trial (DAHHS 2). 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 128
17. Ingiliz P, et al.: High incidence of HCV reinfection in MSM in the DAA era. 25th Conference on Retroviruses and Opportunistic Infections, March 04-07, 2018, Boston; abstract 612
18. Bourliere M, et al.: POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376:2134-2146.
19. Boesecke C et al. Increased rates of HBV seroconversion under long-term HBV active therapy in HBV/HIV. 24th Conference on Retroviruses and Opportunistic Infections, February 13-16, 2017, Seattle; abstract 580
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