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The arrival of coronavirus disease (COVID-19) in Europe exploded initially in North Italy and soon thereafter at several other major European cities, including Madrid. Indeed, Madrid was the epicenter of SARSCoV-2 infection in Spain, with a dramatic surge of cases since mid-March 2020.

Hepatitis delta virus (HDV) infection is a neglected disease despite causing the most severe form of viral hepatitis. Over 15 million people are infected worldwide. IFN-α is largely inefficient and poorly tolerated. The discovery of sodium taurocholate cotransporting polypeptide as the cell receptor for HBV (and consequently for HDV) has allowed development of viral entry inhibitors (i.e., myrcludex-B). More recently, prenylation inhibitors (i.e., lonafarnib) that disrupt virion assembly are being tested. At this time, sustained suppression of HDV replication is the primary goal of hepatitis delta treatment, being associated with normalization of liver enzymes and histological improvement. The lack of persistent forms of HDV-RNA could provide unique opportunities for hepatitis delta cure using specific antivirals, even in the face of persistent HBV cccDNA.

Liver disease is the major complication of chronic HCV infection. However, extrahepatic complications are common (50–75%), including mixed cryoglobulinaemia and B-cell lymphomas. Given that chronic hepatitis C has become curable using expensive oral direct-acting antivirals (DAAs), it seems worth revisiting the whole spectrum and burden of disease in HCV carriers. Herein, we update the most clinically significant medical complications associated with chronic hepatitis C and the evidence of benefits that would derive from a wide use of curative DAA therapies. Chronic HCV infection is associated with a broad spectrum of clinical conditions, including distinct rheumatic disorders (polyarthritis, sicca syndrome), lymphoproliferative conditions (mixed cryoglobulinaemia, monoclonal gammapathies and B-cell lymphomas) and damage at other organs due to persistent systemic inflammation, leading to renal, bone, neurological and/or cardiovascular disease. Eradication of HCV with DAAs is associated with amelioration and/or resolution of most liver-related and extrahepatic complications. Ultimately, gains in quality of life and survival favour treating everyone with hepatitis C regardless of liver fibrosis stage.

Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values.To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials.Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0.A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p0.001). In multivariate analysis, serum HCV-RNA6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03).Serum HCV-RNA6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.

Patients infected with HIV are at increased risk for cardiovascular disease despite successful antiretroviral therapy. Likewise, chronic hepatitis C virus (HCV) infection is associated with extrahepatic complications, including cardiovascular disease. However the risk of cardiovascular disease has not been formally examined in HIV/HCV-coinfected patients. A retrospective study was carried out to assess the influence of HCV coinfection on the risk of cardiovascular events in a large cohort of HIV-infected patients recruited since year 2004. A composite event of cardiovascular disease was used as an endpoint, including myocardial infarction, angina pectoris, stroke or death due to any of them. A total of 1136 patients (567 HIV-monoinfected, 70 HCV-monoinfected and 499 HIV/HCV-coinfected) were analysed. Mean age was 42.7 years, 79% were males, and 46% were former injection drug users. Over a mean follow-up of 79.4 ± 21 months, 3 patients died due to cardiovascular disease, whereas 29 suffered a first episode of coronary ischaemia or stroke. HIV/HCV-coinfected patients had a greater incidence of cardiovascular disease events and/or death than HIV-monoinfected individuals (4% vs 1.2%, P = 0.004) and HCV-monoinfected persons (4% vs 1.4%, P = 0.5). After adjusting for demographics, virological parameters and classical cardiovascular disease risk factors (smoking, hypertension, diabetes, high LDL cholesterol), both HIV/HCV coinfection (HR 2.91; CI 95%: 1.19-7.12; P = 0.02) and hypertension (HR 3.65; CI 95%: 1.34-9.94; P = 0.01) were independently associated with cardiovascular disease events and/or death in HIV-infected patients. Chronic hepatitis C and hypertension are independently associated with increased cardiovascular disease risk in HIV-infected patients. Therefore, treatment of chronic hepatitis C should be prioritized in HIV/HCV-coinfected patients regardless of any liver fibrosis staging.

Roughly 10 % of HIV-positive individuals worldwide have concomitant chronic hepatitis B virus (HBV) infection, with large differences between geographical regions and/or risk groups. Hepatitis B is a preventable infection with vaccines. However, it cannot be eradicated once acquired, resembling HIV and in contrast with HCV. In developed countries, hepatitis B exhibits particular features in the HIV population. First, HBV infection is less frequently misdiagnosed than in the general population. Second, nucleos(t)ide analogs active against HBV are widely used as part of antiretroviral combinations and are taken by most HIV patients. Lastly, as the HIV population ages given the success of antiretroviral therapy, non-AIDS co-morbidities are becoming a major cause of disease, for which specific drugs are required, increasing the risk of interactions and hepatotoxicity. Furthermore, concern on HBV reactivation is rising as immunosuppressive drug therapies are increasingly been used for cancers and other non-malignant conditions. In this scenario, new challenges are emerging in the management of hepatitis B in HIV-positive individuals. Among them, major interest is focused on failures to suppress HBV replication, HBV breakthroughs and reactivations, the meaning of isolated anti-HBc, screening for liver cancer, and the complexity arising when hepatitis viruses C and/or D are additionally present. This review will focus on these challenges and the major advances in HBV coinfection in HIV.

Background Sustained HCV clearance after hepatitis C therapy is associated with reduced liver-related complications and death. It is unknown if treatment may provide any clinical benefit in patients that fail therapy. This could be particularly relevant in HIV–HCV-coinfected patients, in whom liver disease progresses more rapidly. Methods This was a retrospective study of clinical end points in a large cohort of HIV–HCV-coinfected patients with compensated liver disease followed since 2004. Patients were stratified into three groups: treated and cured, treatment failures and non-treated. Follow-up ended at the time of last visit, first liver decompensation event or death. Results A total of 527 HIV–HCV-coinfected patients were examined, of whom 339 (64.3%) had been treated with pegylated interferon/ribavirin. During a mean follow-up of 70.5 months, hepatic decompensation events or liver-related deaths occurred less frequently in cured patients (4/138; 2.9%) than in treatment failures (28/201; 13.9%) or untreated (25/188; 13.3%) patients ( PConclusions Sustained HCV clearance following pegylated interferon/ribavirin therapy is associated with a reduced incidence of liver complications and death in HIV–HCV-coinfected patients. In the subset of patients with baseline advanced liver fibrosis, treatment provides clinical benefit despite lack of sustained virological response. The transient antiviral and/or anti-inflammatory effect of interferon, more recognizable in IL28B-CC carriers, could explain this finding.

Long-term experience in the treatment of HIV-infected individuals has shown indirect benefits of early initiation of antiretroviral therapy, particularly in preventing HIV transmission. With the advent of direct-acting antivirals for the treatment of hepatitis C, the strategy of treatment-as-prevention has become feasible. However, economic, clinical, ethical, and public health issues arise from the concept of using therapeutic interventions only as prevention strategies.

The introduction of direct-acting antivirals (DAA) has revolutionized the hepatitis C field. Most hepatitis C patients can now be cured, including those coinfected with HIV. However, drug-drug interactions (DDI) between DAA and antiretrovirals (ARV) should be known to prevent either toxicity due to drug overexposure or treatment failures due to low drug concentrations. Areas covered: Clinically significant DDI may be classified as major (when co-administration should be contraindicated) or minor (when they require close monitoring, changes in drug dosage or in timing). Strategies for preventing and managing DDI influence response rates in HIV/HCV-coinfected patients. Pharmacokinetic evidence of interactions from clinical trials and reports from real-world experience are discussed. Expert opinion: The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact HCV and HIV boosted protease inhibitors, and most non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide analogue polymerase inhibitors, most HCV NS5A inhibitors and HIV integrase inhibitors (e.g., dolutegravir), do not or only marginally affect CYP450, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to-treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations.

For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

Despite the availability of both effective preventive vaccines and oral antivirals, over 250 million people are chronically infected with the hepatitis B virus (HBV). Globally, chronic hepatitis B is the leading cause of hepatocellular carcinoma, which represents the third cause of cancer mortality, accounting for nearly 1 million annual deaths. Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss. Thus, treatment has to be given lifelong to prevent viral rebound. A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors. Some of them exhibit higher potency than current oral nucleos(t)ides. Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731, ARO-HBV and REP-2139. To date, only treatment with ARO-HBV and with REP-2139 have resulted in HBsAg loss in a significant proportion of patients. Combination therapies using distinct antivirals and/or immune modulators are expected to maximize treatment benefits. The current goal is to achieve a ‘functional cure’, with sustained serum HBsAg after drug discontinuation. Ultimately, the goal of HBV therapy will be virus eradication, an achievement that would require the elimination of the cccDNA reservoir within infected hepatocytes.

Introduction: Human genetic testing is rapidly entering into most medical disciplines, mainly as a way to predict hereditary conditions including predisposition to cancers or degenerative diseases. Another area of interest for human genomics is to ascertain the therapeutic effect and prevent potential toxicities and/or drug-drug interactions of medication.Areas covered: Several human genotypes have been associated with differences in the metabolism and transport of antiretroviral agents that ultimately affect drug exposure. The accelerated discovery of new gene mutations and polymorphisms that influence the effects of antiretroviral drugs provides a unique opportunity for a personalized medicine approach in the management of lifelong HIV therapy.Expert opinion: Integration of human genomic screening into HIV clinical management will be cost-effective, maximizing the benefit of drugs with the lowest risk of side effects for a given patient.

The potency, tolerability and convenience of antiretroviral agents have all significantly improved over the past years, making lifelong HIV therapy easier. However, several specific needs are still unmet, including low daily pill burden, friendly metabolic profile, lack of (or few) drug interactions and high resistance barrier.Updated summary of evidence-based information about the efficacy and safety of the most recently approved or forthcoming antiretroviral agents is provided. All data on antiretrovirals in the most advanced development stages available in peer-reviewed journals or presented at international meetings has been reviewed.Dolutegravir displays greater barrier to resistance and requires simpler administration than other currently existing drugs within the same class. Newer pharmacoenhancers (i.e., cobicistat), CCR5 antagonists (i.e., cenicriviroc) and nucleotide prodrugs (i.e., tenofovir alafenamide fumarate) show promising results and will expand the current HIV armamentarium. The development of newer once-daily, single-tablet coformulations will further improve drug adherence and maximize the success of antiretroviral therapy.

Background Because of their high cost, the use of direct-acting antivirals (DAAs) is being restricted by many governments to chronic HCV-infected individuals with advanced liver fibrosis. However, response rates are lower and toxicities more frequent in this subset of patients. Methods All HIV–HCV-coinfected patients followed for at least 3 years at one reference clinic were identified. Liver fibrosis progression (LFP) was defined as a shift from Metavir F0–F2 to F3–F4 estimates (>9.5 KPa) using elastometry. Results A total of 527 HIV–HCV-coinfected patients were identified, of whom 344 had F0–F2 at baseline. Pegylated interferon/ribavirin therapy was given to 205 patients with null/mild fibrosis, of whom 92 (44.9%) achieved sustained virological response (SVR). After a mean follow-up of 53 months, LFP occurred in 5.4% SVR, 25.7% non-SVR and 18% untreated patients ( P=0.005). In multivariate analysis, only achievement of SVR prevented LFP (adjusted hazard ratio 2.1; 95% CI 1.1, 4.1; P=0.01). In 139 untreated patients, only greater baseline elastometry values predicted LFP in multivariate analysis (adjusted hazard ratio 1.84; 95% CI 1.03, 3.3; P=0.03). The area under the receiver operating characteristic (AUROC) curve was 79%. A discriminant threshold of 7.1 kPa gave 68% sensitivity and 82% specificity. Conclusions In the absence of successful treatment, more than 20% of HIV–HCV-coinfected patients with null/mild liver fibrosis progress to advanced fibrosis within 5 years. Patients with >7.1 kPa (Metavir F2) display the highest risk. Therefore, all coinfected patients with any significant liver fibrosis should be considered as candidates for new DAA-based therapies.

Chronic hepatitis C virus (HCV) infection occurs globally in 20 % of HIV-seropositive patients. In coinfected individuals, HCV-related liver disease is a leading cause of morbidity and mortality. The advent of new direct-acting antivirals (DAA) has been particularly awaited for this population, in whom treatment with peginterferon plus ribavirin depicts limited efficacy and poor tolerability. However, pharmacologic interactions, drug resistance, medication adherence and pricing are major challenges using DAA in HIV/HCV-coinfected patients. Moreover, if the benefit of new antiviral therapies for hepatitis C wants to be recognized at population scale, underdiagnosis and access to particularly difficult to reach populations must be ensured.

Liver disease is currently one of the leading causes of hospitalization and death in HIV-positive individuals. Coinfection with the hepatitis C virus (HCV) is a major contributor to this trend. Besides hepatic damage, which is enhanced in the presence of HIV-associated immunosuppression, HCV may contribute to disease in coinfected individuals by potentiating immune activation and chronic inflammation, which ultimately account for an increased risk of cardiovascular events, kidney disease, and cancers in this population. Fortunately, hepatitis C therapeutics has entered a revolutionary era in which we hope that most patients treated with the new oral direct-acting antivirals (DAA) will be cured. However, many challenges preclude envisioning a prompt elimination of HCV from the coinfected population. Issues that should be addressed include the following: (1) rising incidence of acute hepatitis C in men who have sex with men, and expansion/recrudescence of injection drug use in some settings/regions; (2) adverse drug interactions between antiretrovirals and DAA; and (3) high cost of DAA, which may lead many to defer or fail to access appropriate therapy.

Background Achievement of early viral suppression is important in patients with chronic HCV infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far. Methods All consecutive individuals who initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV RNA (Results A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, body mass index, baseline HCV RNA, HCV subtype 1a (45% versus 42%) and IL28B-CC alleles (29% versus 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% versus 44%). Conversely, more patients on BOC than TLV had previously failed pegylated interferon plus ribavirin (82% versus 64%). RVR was achieved by 82% of patients on TLV versus 59% on BOC ( P=0.001). Multivariate logistic regression analysis confirmed that TLV use was the strongest predictor of RVR (OR 3.54 [95% CI 1.23, 10.24]; P=0.02), others being HCV subtype 1b versus 1a (OR 3.26 [95% CI 1.17, 9.09]; P=0.02) and low baseline HCV RNA (OR 0.41 [95% CI 0.16, 1.03]; P=0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR. Conclusions Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV RNA responses.

Introduction: The number of HIV patients receiving antiretroviral therapy is increasing worldwide, as new infections continue to occur and access to drugs is scaling up in most developing regions. Due to the efficacious nature of combination antiretroviral therapy in most drug-adherent patients, the concerns on the safety profile of these lifelong medicines have attracted great attention. Areas covered: Side effects of antiretroviral agents can be clinically symptomatic or manifest only as laboratory abnormalities. Drug-related toxicities can be grouped by antiretroviral drug class or damage of distinct body organs/systems. By mechanism, antiretroviral-associated adverse events generally result from hypersensitivity reactions, direct cytopathic effect, or idiosyncratic phenomena. Expert opinion: A good knowledge of the toxicity profile of antiretroviral agents is warranted for HIV care providers in order to prevent and avoid unwanted complications.

Background: Outbreaks of acute hepatitis C in HIV-positive men who have sex with men (MSM) are being reported in large cities in western countries along with increasing rates of sexually transmitted diseases. Methods: All HIV individuals attended at a large outclinic in Madrid within the last 5 years were examined. Incident syphilis was diagnosed based on rapid plasma reagin (RPR) reactivity, being negative previously or showing >4-fold increase. Acute hepatitis C was diagnosed based on HCV antibody seroconversion and/or positive serum HCV-RNA after being negative within the last year. Results: A total of 859 episodes of syphilis and 19 of acute hepatitis C were diagnosed during the study period. Syphilis was recognized in 65/2,094 (3.1%) individuals attended in 2008 and rose up to 261/2,512 (10.4%) in 2012 (P < 0.001). Acute hepatitis C was diagnosed in only one subject in 2008 but rose up to 7 in 2012 (P = 0.12). All 19 HIV patients with acute hepatitis C were MSM. Syphilis was diagnosed concomitantly in seven. All eight individuals who were treated with peginterferon/ribavirin were cured, whereas only one untreated experienced spontaneous clearance (P = 0.004). Two clusters of infections by HCV genotypes 4 and 1a were identified by phylogenetic analyses. Conclusions: The incidence of acute hepatitis C is low but steadily increasing in HIV-positive MSM in Madrid (

Background Advanced liver fibrosis frequently develops in patients with chronic hepatitis C coinfected with HIV. Non-invasive techniques for staging liver fibrosis, such as transient elastometry, may allow both periodic monitoring and examination of large patient populations. Methods A programme of liver fibrosis assessment using transient elastometry has been ongoing at our institution since 2004. All HIV-HCV-coinfected patients having ≥2 examinations separated by >18 months were included. Liver fibrosis progression (LFP) was defined as an increase in liver stiffness from 9.5 kPa (Metavir F3-F4), or an increase >30% in patients with baseline Metavir F3-F4. Results A total of 545 HIV-HCV-coinfected patients were analysed (mean age 41 years, 71% male, 81% intravenous drug users, mean body mass index 23.3 kg/m2, 4.2% hepatitis B surface antigen-positive, 8.4% alcohol abuse, mean CD4+ T-cell count 519 cells/μl). At baseline, 527 patients were on antiretroviral therapy, with the most frequent third drug being atazanavir (19.7%), efavirenz (15.9%), lopinavir (13.1%) or nevirapine (7.2%). A total of 99 (18%) patients experienced LFP during a mean (sd) follow-up of 70.9 (15.7) months. Use of protease inhibitors (OR 4.93, 95% CI 1.73, 14.0; P=0.03) and male gender (OR 5.12, 95% CI 1.37, 19.1; P=0.01) were associated with LFP. By contrast, the achievement of HCV clearance following pegylated interferon/ribavirin (PEG-IFN/RBV) therapy (OR 0.27, 95% CI 0.1, 0.79; P=0.02) was protective. Lopinavir exposure was significantly associated with LFP (OR 1.02, 95% CI 1.0, 1.04; P=0.03), whereas nevirapine was protective (OR 0.94, 95% CI 0.9, 0.99; P=0.02). Conclusions The use of protease inhibitors, mainly lopinavir, is associated with increased LFP in HIV–HCV-coinfected patients. By contrast, nevirapine therapy and, particularly, HCV clearance with PEG-IFN/RBV significantly reduce LFP.

Several HCV polymerase inhibitors are in advanced stages of clinical development. They are nucleos(t)ide and non-nucleoside analogs. Nucleos(t)ides inhibit viral replication acting as chain terminators whereas non-nucleosides block allosterically the HCV polymerase. Sofosbuvir is an uridine analog and currently the most promising HCV polymerase inhibitor, being active across all HCV genotypes. It has good tolerability and a robust barrier to resistance. In contrast, non-nucleoside analogs have low to moderate antiviral potency, a low barrier to resistance and inhibit only HCV genotype 1.Studies conducted with distinct HCV polymerase inhibitors as part of interferon-free combinations have opened a new landscape in which shorter treatment duration and all-oral regimens are envisioned as the future curative treatment for most chronic hepatitis C patients.Antiviral drug development for HCV is progressing at a feverish pace. Amongst HCV polymerase inhibitors, sofosbuvir has positioned as unique companion with ribavirin as therapy for most HCV genotypes 2 or 3, and along with NS5A inhibitors for other HCV genotypes. Non-nucleoside HCV polymerase inhibitors are being developed only as part of all-oral combinations with protease inhibitors. The expected high cost of DAAs will preclude their prompt and wider use, allowing room for using alternative cheaper options in easier-to-treat patient populations.

The concentration of circulating viral RNA at baseline and during antiviral therapy predicts response in both HIV infection and chronic hepatitis C.Retrospective review of longitudinal plasma HCV-RNA determinations in untreated chronic hepatitis C patients. As comparison, longitudinal plasma HIV-RNA measurements were performed in untreated HIV individuals.A total of 3169 HCV-RNA determinations over 43.0±31.6 months were available for 818 chronic hepatitis C patients. For 333 HIV individuals, 1998 HIV-RNA measurements were examined over 27.3±17.5 months. Overall 44% consecutive specimens had0.5 log variation in HCV-RNA values compared to 23% for HIV-RNA (p0.001). These rates were 15% and 4%, respectively, for variations1 log (p0.001). In multivariate analysis (odds ratio, 95% confidence interval, p), the likelihood of experiencing HCV-RNA variations0.5 log IU/mL was greater in patients with lower HCV-RNA (0.35 per log[0.26-0.47], 0.001), HIV coinfection (2.57[91.56-4.23],0.001) and IL28B-CC (1.87[1.28-2.74], 0.001).Fluctuation in circulating HCV-RNA may be clinically meaningful in a substantial proportion of chronic hepatitis C patients. It may influence the best time to prescribe antiviral therapy. Moreover, decisions based on early viral kinetics, such as early stopping rules, may require testing of baseline specimens the closest to treatment initiation.

There is scarce information about the impact of antiviral treatment on subsequent progression of liver fibrosis in HIV-infected patients with chronic hepatitis C who experience different outcomes following peginterferon-ribavirin therapy. We conducted a retrospective study of a cohort of HIV/HCV-coinfected patients with longitudinal assessment of liver fibrosis using elastometry. Patients were split out into four groups according to the prior peginterferon-ribavirin response: sustained virological response (SVR), relapse (R), partial response (PR) and null response (NR). A group of untreated, coinfected patients was taken as control. Significant liver fibrosis progression (sLFP) was defined as a shift from baseline Metavir estimates ≤ F2 to F3-F4, or by30% increase in liver stiffness in patients with baseline F3-F4. Conversely, significant liver fibrosis regression (sLFR) was defined as a shift from baseline Metavir estimates F3-F4 to ≤ F2, or by30% reduction in liver stiffness in patients that kept on F3-F4. A total of 498 HIV/HCV-coinfected patients were examined. They were classified as follows: 138 (27.7%) SVR, 40 (8%) R, 61 (12.2%) PR, 71 (14.3%) NR and 188 (37.8%) naive. After a mean follow-up of 53.3 months, sLFP occurred less frequently in patients with SVR (7.2%) compared with R (25%; P = 0.002), PR (23%; P = 0.002), NR (29.6%; P0.001) and naïve (19.7%; P = 0.002). Conversely, sLFR was 26.1% in SVR compared with 10% in R (P = 0.03), 14.8% in PR (P = 0.06), 16.9% in NR (P = 0.07) and 10.6% in naïve (P0.001). Sustained clearance of serum HCV-RNA following a course of antiviral treatment is the major determinant of liver fibrosis regression in HIV/HCV-coinfected patients.

Background Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV– HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. Methods Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. Results A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals ( P≤0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. Conclusions Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV–HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

The results from clinical trials testing new direct-acting antivirals (DAAs) for chronic hepatitis C were the major focus of interest at the 2012 annual meeting of the European Association for the Study of the Liver. Besides triple combinations, in which any one of the new DAAs is given along with peginterferon-α/ribavirin, clinical trials exploring interferon-free oral regimens combining several DAAs attracted major attention. The good tolerance, broad hepatitis C virus (HCV) genotype activity, and high resistance barrier of sofosbuvir make this nucleotide analogue one of the most promising DAAs. Among HCV protease inhibitors, the safety, potency, and convenient dosing of simeprevir, asunaprevir, faldaprevir, and ABT-450/r were particularly highlighted. Among NS5A inhibitors, the good performance of daclatasvir encourages further clinical development. Finally, intriguing results were released about the role of interleukin 28B (IL-28B) polymorphisms using interferon-free regimens, indirectly supporting the role of innate immunity for clearing HCV definitively.

Co-infection with either HIV or HBV in chronic hepatitis C patients is common, since all these viruses share transmission routes and geographical distribution. Interaction between these viruses generally amplifies liver damage, increasing the risk of developing end-stage liver disease and hepatocellular carcinoma. HIV-HCV co-infection is associated with poorer response to antiviral therapy. New antivirals against HCV are eagerly awaited for this population. HBV-HCV dual infections are less common. The principles guiding indication of therapy in monoinfected patients should be followed considering which virus replicates in persons with serological markers of dual HBV-HCV infection. Although there is growing evidence supporting the use of direct acting antivirals (DAA) in dually infected patients with active HCV replication, prospective trials should be conducted to demonstrate their benefit, assessing carefully the rate and clinical consequences of HBV rebounds.

Introduction: HIV therapy has evolved rapidly since the 1990s; the arrival of more potent and safer antiretroviral drugs has transformed HIV infection into a chronic condition, which is rarely fatal. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are frequently used as a third agent – as part of a triple-combination therapy. Side effects and low barriers to resistance have been the major drawbacks of NNRTIs. Rilpivirine (RPV) is a next-generation non-nucleoside analogue, the unique features of which might favor choosing this drug over other NNRTIs. RPV is the latest NNRTI approved for the treatment of HIV infection. Along with its high efficacy and good safety profile, data on pharmacokinetics and drug interactions make RPV particularly attractive. Areas covered: This article aims to provide an in-depth analysis of the main features and data available from recent clinical trials that have tested the performance of RPV. Expert opinion: RPV is a safe and efficacious antiretroviral drug with a bett...

The approval of directly acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection will represent a major breakthrough for the 180 million persons infected worldwide. Paradoxically, hepatitis C is the only human chronic viral disease that can be cured, as all other pathogenic viruses infecting humans either display self-limited courses or establish non-eradicable persistent infections. Until now, treatment of chronic hepatitis C consisted of the combination of peginterferon-α plus ribavirin, which provided limited rates of cure and was associated with frequent side effects. Several DAA have been identified that inhibit the NS3 protease, the NS5B polymerase or the NS5A replication complex, and have entered the final steps of clinical development. These molecules, coupled with significant progress made in the recognition of more potent and safe interferon forms (e.g. interferon-λ) and host protein targets (e.g. alisporivir), are opening a new era in hepatitis C therapeutics. The expectations are so great that, to some extent, it is reminiscent of what happened in 1996 in the HIV field when the introduction of the first protease inhibitors as part of triple combinations revolutionized antiretroviral therapy. To maximize treatment success and reduce the likelihood of drug resistance selection, a proper individualization of hepatitis C therapy will be required, choosing the most convenient drugs and strategies according to distinct viral and host profiles. The complexity of HCV therapeutics has reached a point that presumably will lead to the birth of a new specialist, the HCV doctor.

The first cases of AIDS in Spain were reported in 1982. Since then over 85,000 persons with AIDS have been cumulated, with 60,000 deaths. Current estimates for people living with HIV are of 145,000, of whom 20% are unaware of it. This explains the still high rate of late HIV presenters. Although the HIV epidemic in Spain was originally driven mostly by injection drug users, since the year 2000 men having sex with men (MSM) account for most new incident HIV cases. Currently, MSM represent over 80% of new yearly HIV diagnoses. In the 80s, a subset of young doctors and nurses working at Internal Medicine hospital wards became deeply engaged in attending HIV-infected persons. Before the introduction of antiretrovirals in the earlier 1990s, diagnosis and treatment of opportunistic infections was their major task. A new wave of infectious diseases specialists was born. Following the wide introduction of triple combination therapy in the late 1990s, drug side effects and antiretroviral resistance led to built a core of highly devoted HIV specialists across the country. Since then, HIV medicine has improved and currently is largely conducted by multidisciplinary teams of health care providers working at hospital-based outclinics, where HIV-positive persons are generally seen every six months. Antiretroviral therapy is currently prescribed to roughly 75,000 persons, almost all attended at clinics belonging to the government health public system. Overall, the impact of HIV/AIDS publications by Spanish teams is the third most important in Europe. HIV research in Spain has classically been funded mostly by national and European public agencies along with pharma companies. Chronologically, some of the major contributions of Spanish HIV research are being in the field of tuberculosis, toxoplasmosis, leishmaniasis, HIV variants including HIV-2, drug resistance, pharmacology, antiretroviral drug-related toxicities, coinfection with viral hepatitis, design and participation in clinical trials with antiretrovirals, immunopathogenesis, ageing, and vaccine development.

HIV protease inhibitors (PIs) are potent antiretroviral drugs that represent a pivotal component of highly active antiretroviral therapy (HAART). PIs have evolved over the years to gain in potency, convenience, tolerability and genetic barrier to resistance.Updated summary of evidence-based information about the efficacy and safety of PIs on initial, simplification and rescue interventions in HIV patients.Review of available data reported in peer-reviewed journals, medical conferences and treatment guidelines.Due to their characteristics, PIs are, and will remain, a cornerstone component in most lines of antiretroviral therapy. The antiviral activity, tolerability and convenience of PIs have improved significantly in recent years. Differences between compounds within this class may favour their use in specific situations, such as the friendly metabolic profile of atazanavir in patients with cardiovascular disease or the high genetic barrier of darunavir or tipranavir in heavily pretreated individuals with HIV.

Chronic hepatitis C virus (HCV) infection has become a curable disease. More than 90% sustained virologic response rates have been obtained with 8-24 weeks of treatment with distinct combinations of direct-acting antivirals (DAA) in most registration trials. However, outcomes in real-world patients tend to be lower and treatment of special patient populations is often challenging.We address the treatment of chronic hepatitis C with DAA in major special patient populations, such as HIV-positive persons, transplant recipients, patients with advanced cirrhosis, renal insufficiency, hepatitis B or D coinfection, injection drug users (IDUs) and prior DAA failures.Drug interactions between DAA and medications given to persons with HIV infection or transplant recipients can result in treatment failure and adverse events. Severe organ dysfunction as in kidney insufficiency or decompensated cirrhosis may lead to DAA overexposure and toxicities. Dysfunctional social circumstances and behavior are associated to poor drug adherence and increased risk for HCV re-infection in active IDUs. Finally, DAA response might be impaired by viral interference in patients with hepatitis B or D coinfection or drug resistance in HCV either at baseline or after prior DAA failures.

Roughly 20% of HIV-positive persons worldwide are coinfected with hepatitis C virus (HCV). The recent advent of direct-acting antivirals (DAA) that cure most hepatitis C patients has attracted much attention. Knowledge on drug interactions between DAA and antiretrovirals (ARV) may allow maximizing antiviral efficacy while minimizing drug-related toxicities.We review the most frequent side effects and clinically significant drug interactions between DAA and ARV. We further discuss how they can be prevented and managed in HIV/HCV-coinfected patients.The safety profile of current DAA and the most recently approved ARV is quite favorable. Interactions between DAA and ARV could be frequent in clinical practice. The most common drug interactions affect drug metabolism by inducing or inhibiting the cytochrome P450 system, leading to abnormal drug exposures. Throughout this mechanism HCV and HIV protease inhibitors interact, especially when co-formulated with ritonavir as a pharmacoenhancer, and non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide polymerase inhibitors, and most HCV NS5A inhibitors (i.e., ledipasvir) and HIV integrase inhibitors (i.e., dolutegravir), do not or only marginally affect CYP450, and therefore are free of significant drug interactions. Exposure to HIV and HCV nucleos(t)ide analogues (i.e., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (i.e., P-glycoprotein).

Serum HCV RNA rebound beyond 24 weeks after completing hepatitis C therapy has been rarely reported. From 744 patients treated for chronic hepatitis C at our institution, 4 became HCV-RNA-positive again between weeks 36 and 48 post-treatment. Epidemiological and phylogenetic analyses supported very late HCV relapse instead of re-infection in two of them. This observation may have important implications in the pathogenesis and therapeutics of HCV infection.

Junto al dramapersonal que supone el diagno´stico de la infeccio´n por VIH, esta´ elgasto farmace´utico que controlar la infeccio´n supone de por vida.Por ello, el desarrollo de estrategiasque permitan la prevencio´ndenuevas infecciones por VIH debe ser considerado una prioridad. Sibien la vacunacio´n supone una herramienta de gran utilidad ente´rminos de salud pu´blica en la contencio´n de otras epidemias, enla actualidad no se dispone de ninguna vacuna eficaz frente al VIH,y es muy improbable que lo este´ en el pro´ximo lustro

Background Accelerated liver fibrosis and more frequent hepatic decompensation events and liver-related deaths are characteristically seen in chronic hepatitis C patients coinfected with HIV compared with HCV-monoinfected individuals. Quantitative estimates of long-term clinical benefits derived from curing HCV with antiviral therapy in coinfected patients are scarce, despite being needed for accurate cost-effectiveness decisions using expensive direct-acting antivirals in this population. Methods We retrospectively examined all HIV–HCV-coinfected patients followed at one reference clinic in Madrid since 2004. Liver fibrosis was measured longitudinally using elastometry; changes above 30% in kilo-pascal units were considered as significant. Results A total of 568 HIV–HCV-coinfected patients were examined. Pegylated interferon/ribavirin therapy had been given to 396 (69.7%) of whom 138 (34.8%) had achieved sustained virological response (SVR). Mean follow-up was of 6.8 (±1.5) years for hepatic events and 4.4 (±0.8) years for liver fibrosis. Hepatic decompensation events, liver-related deaths and significant liver fibrosis progression occurred less frequently in SVR than in non-treated/treatment failures. Although regression of liver fibrosis occurred in most SVR patients, fibrosis significantly progressed in 7.2% of them, in association with higher plasma HIV RNA ( P=0.005) and longer exposure to HIV protease inhibitors ( P=0.009). Conclusions Achievement of SVR dramatically reduces the risk of hepatic decompensation events and liver-related deaths in HIV–HCV-coinfected patients. Although liver fibrosis generally improves following HCV cure, worsening may occur in association with uncontrolled HIV replication and prolonged exposure to protease inhibitors. Thus, periodic assessment of liver fibrosis is warranted after SVR and screening for liver cancer should continue in coinfected patients with advanced liver fibrosis.

Background: Hepatitis delta virus (HDV) produces the most severe form of chronic viral hepatitis. We explored whether prolonged tenofovir exposure might be beneficial on hepatitis delta in HIV-infected patients. Methods: All HIV-infected patients with hepatitis delta followed at our institution since year 2000 were retrospectively examined. Serum HBV-DNA and HDV-RNA were quantified using commercial assays. Liver fibrosis was measured using elastometry. Results: A total of 19 HIV/delta patients were identified. All were viremic for HDV and 11for HBV. After a median tenofovir exposure of 58 months, all had undetectable HBVDNA and 10 (53%) had undetectable HDV-RNA. The median drop in HDV-RNA in the remaining nine HDV viremic patients at the end of follow-up was 2.4log copies/ml. A reduction above 30% in liver stiffness occurred in six out 10 (60%) patients who achieved undetectable HDV-RNA, whereas hepatic stiffness did not change in the remaining HDV viremic patients (P ¼0.03). Serum HBsAg concentrations did not decline significantly, although HBsAg seroclearance occurred in three patients, all of whom became negative for HDV-RNA. Conclusion: Long-term exposure to tenofovir significantly reduced serum HDV-RNA apart from completely suppressing HBV-DNA in HIV-infected patients with hepatitis delta. This virological benefit is accompanied by significant improvements in liver fibrosis. 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2014, 28:2389‐2394

Antiretroviral therapy has evolved dramatically and more potent, safer and convenient drugs have replaced former compounds. Dolutegravir (DTG) is the most recently approved integrase inhibitor. It displays attractive properties such as one pill once daily (QD) dosing, high barrier to resistance and clean safety profile. Moreover, it is planned to be marketed, co-formulated with abacavir (ABC) and lamivudine (3TC) as a single-tablet regimen (STR). The availability of this QD single pill represents a significant step further for a large number of HIV-infected persons.Updated summary of evidence-based information on efficacy and safety of DTG along with ABC and 3TC. All information available on antiretrovirals in the most advanced stages of clinical development reported in peer-reviewed journals or at international meetings has been reviewed.The combination of DTG, ABC and 3TC displays a high efficacy, superior to many other antiretroviral combinations, including other convenient STR. The good safety profile, low potential for drug interactions and high resistance barrier of DTG- ABC-3TC are unique features than make this co-formulation the preferred choice as HIV therapy in multiple clinical scenarios, including most treatment-naïve and treatment-experienced patients, as part of switch strategies, and in patients with underlying serious medical conditions such as kidney abnormalities, liver disease, metabolic disturbances or neuropsychiatric conditions.

Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals, mainly among those with sexually risky behaviors. Although HBV vaccination is mandatory in all HIV-infected persons with negative HBV markers, lower rates of protection due to abnormal immune responses are achieved. HIV accelerates the course of liver disease caused by chronic HBV infection, leading rapidly to end-stage hepatic illness and increasing the risk of hepatocellular carcinoma. Treatment of HIV including nucleos(t)ide analogues active against HBV highly improves outcomes, especially when tenofovir is part of the antiviral regimen. The use of lamivudine as the only active anti-HBV agent in HIV-HBV co-infected patients should be limited to individuals with low serum HBV-DNA levels. Otherwise, selection of drug resistance may eliminate any clinical benefit, produce cross-resistance to other antivirals, and favor the emergence of HBV vaccine escape mutants.

BACKGROUND A quarter of individuals acutely infected with hepatitis C virus (HCV) clear the virus spontaneously. Once chronic infection is established, HCV elimination generally can only be achieved using specific antiviral therapy, such as peg-interferon-ribavirin. Herein, we report a group of chronically HIV/HCV-coinfected patients that cleared HCV spontaneously while being treated only with antiretrovirals. METHODS Retrospective analysis of all HIV-infected individuals with positive HCV antibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid. RESULTS From a total of 2366 HIV-infected individuals, 618 (26%) were HCV-Ab+, of whom 387 (62%) were positive for serum HCV-RNA. Individuals HCV-Ab+/HCV-RNA-negative were grouped into two categories--those that had eliminated HCV following a course of antiviral treatment (n = 198, 86%) and those who had cleared the virus spontaneously (n = 33, 14%). Eight with spontaneous clearance were HBsAg+ and might have cleared HCV as a result of viral interference. However, six (24%) out of the remaining 25 did so after being serum HCV-RNA+ for longer than 6 months (median 5.6 years, range 1.3-12 years). All harbored alleles and had undetectable plasma HIV-RNA on HAART around the time of HCV clearance. CONCLUSION Spontaneous HCV clearance may occur in a subset of chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC. Given that antiretrovirals do not display any direct anti-HCV activity, recovery of innate immune responses could be responsible for these late HCV clearance episodes. Thus, periodic testing of serum HCV-RNA may be warranted in chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC alleles.

Background. Coinfection with hepatitis viruses is common in individuals infected with human immunodefi-ciency virus (HIV) and has become a leadingcause ofcomplications and death in those receiving antiretroviral ther-apy (ART).Methods. We retrospectively examined the effect of coinfection with hepatitis B, C, and/or D viruses (HBV,HCV, HDV, respectively) on liver decompensation events (ascites, variceal bleeding, encephalopathy, and/or hepa-tocellularcarcinoma) and liver-related mortalityin HIV-positivepatients on regular follow-up since theyear 2004 ata reference HIV clinic in Madrid, Spain.Results. A total of 1147 HIV-infected patients (mean age, 42 years; 81% males; 46% intravenous drug users,85.4% on ART) were analyzed. Mean follow-up was 81.2±17.8 months. At baseline, 521 patients (45.4%) wereHCV-antibody positive, 85 (7.4%) were hepatitis B surface antigen positive, and 17 (1.5%) were anti-HDV positive.A total of 233 HIV/HCV-coinfected patients received antiviral therapy for HCV, of whom 106 (45%) achieved sus-tained virologic response (SVR). Overall, 15 patients died of liver-related complications and 26 developed hepaticdecompensation events. Taking as controls the 524 HIV-monoinfected patients, HDV coinfection (adjusted hazardratio [AHR], 7.5; 95% confidence interval [CI], 1.84–30.8; P=.005) and baseline liver stiffness (AHR, 1.1; 95% CI,1.07–1.13; P

Around 10–15% of the 35 million people living with HIV worldwide have chronic hepatitis C virus (HCV) infection and are prone to develop liver-related complications. Exposure to HCV is almost universal among injecting drug users and is on the rise among homosexual men. Response to peginterferon-ribavirin therapy is generally lower in coinfection compared to HCV monoinfection. For this reason, the advent of direct-acting antivirals (DAA) is eagerly awaited for this population. The results of trials using DAA in coinfection show that treatment response rates are similar to those obtained in HCV monoinfection. Thus, HIV should no longer be considered as a “special” population, as long as antiretroviral therapy is given and drug interactions are taken into account. Envisioning HCV eradication from the HIV population faces major challenges ahead, including identification of the large number of undiagnosed individuals, and ensuring wide access to the best but often expensive HCV medications. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication”.

Liver disease is currently one of the leading causes of death in HIV individuals. Hepatic fibrosis largely mediates this effect and infection with hepatitis C virus (HCV) is the most common cause. Few studies have examined so far the predictive value of liver fibrosis staging on mortality and liver decompensation in HIV/HCV-coinfected patients.A prospective programme of liver fibrosis assessment using transient elastometry has been ongoing at our institution since 2004. Data from all HIV/HCV-coinfected patients who underwent a transient elastometry examination and have at least 18 months of follow-up were selected for the current analysis.A total of 545 HIV/HCV-coinfected patients were examined (mean age 41 years, 71% men, 81% IDUs, mean BMI 23.3 kg/m2, HBsAg+ 4.2%, alcohol abuse 8.4%, mean CD4 cell count 519 cells/μl). The mean follow-up was 70.9 ± 15.7 months. During follow-up, 12 patients (2.2%) died, four of them due to hepatic complications. Liver-related events (ascites, encephalopathy, oesophageal varices or hepatocellular carcinoma) appeared in 53 patients (10%). In the multivariate analysis, baseline liver stiffness was the strongest predictor of liver-related complications [odds ratio (OR) 1.12, 95% confidence interval (CI) 1.08-1.16, P0.0001] and of all-cause mortality (OR 1.09, 95% CI 1.01-1.19, P = 0.02). The achievement of sustained virological response following peginterferon/ribavirin therapy during the study period was protective against the development of liver-related events (OR 0.02, 95% CI 0-0.23, P = 0.01).Liver fibrosis staging, as measured by transient elastometry, predicts liver-related complications and all-cause mortality in HIV/HCV-coinfected patients on antiretroviral therapy.

Chronic hepatitis C is a leading cause of clinical complications and mortality in individuals infected with human immunodeficiency virus (HIV). Approval for the first direct-acting antiviral (DAA) against the hepatitis C virus (HCV) has been eagerly awaited for treating patients coinfected with HIV/HCV. The use of first-generation HCV protease inhibitors is challenged by complicated dosing schedules, frequent serious toxicities, unwanted drug interactions, drug resistance, and high cost. First-generation DAAs will eventually be replaced by more potent, well-tolerated, and convenient agents. HIV/HCV co-infection will become restricted to individuals without proper access to health care.

The approval of the first protease inhibitors as treatment for hepatitis C virus (HCV) infection is rapidly transforming the way patients with chronic hepatitis C are managed. Treatment regimens are moving to combinations given for shortened periods, excluding poorly tolerated subcutaneous interferon, and providing rates of cure exceeding 75%. The recognition of HCV infection as a systemic disease, not limited to producing liver damage, in which extrahepatic complications play a major role as the cause of morbidity and mortality, is prompting the treatment of a growing number of HCV-infected individuals. However, new challenges are emerging, including the need to diagnose a substantial proportion of asymptomatic carriers, the risk of potentially harmful drug-drug interactions and the high cost of medications. The future will probably see a progressive marginalization of residual HCV populations, with increasing over-representation of illegal immigrants, alcohol abusers, intravenous drug users and the mentally disabled.