Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients.

BACKGROUND: Coinfection with hepatitis viruses is common in individuals infected with human immunodeficiency virus (HIV) and has become a leading cause of complications and death in those receiving antiretroviral therapy (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 hepatocellular carcinoma) and liver-related mortality in HIV-positive patients on regular follow-up since the year 2004 at a 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%) were HCV-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 sustained virologic response (SVR). Overall, 15 patients died of liver-related complications and 26 developed hepatic decompensation events. Taking as controls the 524 HIV-monoinfected patients, HDV coinfection (adjusted hazard ratio [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 < .0001) were associated with a higher rate of liver-related morbidity and mortality. In contrast, SVR following hepatitis C therapy in HIV/HCV-coinfected patients was protective (AHR, 0.11; 95% CI, .01-.86; P = .03). CONCLUSIONS: Hepatitis delta is associated with a high rate of death and liver decompensation events in HIV-infected patients on ART.

Update on HIV/HCV coinfection.

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.

Directly acting antivirals against hepatitis C virus.

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.

COVID-19 in Madrid: Leading Pandemic Control after being the Spanish Epicenter.

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.

Coronavirus and other airborne agents with pandemic potential.

The recent emergence of a novel coronavirus (severe acute respiratory syndrome coronavirus 2) has caused a pandemic, which is the most severe infectious disease outbreak in many decades. Other infective agents such as influenza as well as other neglected viruses such as Lassa virus, Nipah virus or poxviruses are also a cause for concern owing to their attack rate and potential for global spread. Drug-resistant bacteria, such as Mycobacterium tuberculosis, are already a significant public health issue in many countries, and it is expected that they will be expanding in the near future. Finally, airborne bioterrorism agents have high morbidity and mortality rates and should be looked with concern in the current international unrest.

Treatment as Prevention: Should Hepatitis C Learn the Lessons from HIV?

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.

Dual antiretroviral therapy for HIV infection.

INTRODUCTION: 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.

Emerging antiretroviral drugs.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Towards hepatitis C eradication from the HIV-infected population.

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".

Pharmacogenetics of antiretroviral therapy.

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.

Dolutegravir, abacavir and lamivudine as HIV therapy.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy.

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.

Once-daily raltegravir moving ahead.

Raltegravir is a highly potent antiretroviral agent, with arguably one of the most favorable adverse event profiles in the HIV armamentarium. However, its standard twice-daily (BID) dosing schedule makes it less convenient than once-daily (QD) options. Although pharmacokinetic data suggest that QD raltegravir may provide adequate drug levels, the randomized phase III QDMRK trial (Eron, et al. Lancet Infect Dis. 2011;11:907-15) showed that 800 mg QD raltegravir failed to meet the criteria for non-inferiority when compared with 400 mg BID RAL in antiretroviral-naive HIV-infected individuals. 83% of patients in the QD arm achieved undetectable HIV viremia, in comparison with 89% in the BID arm. This was largely due to poorer efficacy among people with high baseline viral load (74 vs. 84%, respectively).

Liver stiffness predicts liver-related complications and mortality in HIV patients with chronic hepatitis C on antiretroviral therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, P < 0.0001] 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). CONCLUSION: Liver fibrosis staging, as measured by transient elastometry, predicts liver-related complications and all-cause mortality in HIV/HCV-coinfected patients on antiretroviral therapy.

Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients.

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

Hepatitis C therapy with HCV NS5B polymerase inhibitors.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Management of hepatitis C in HIV and/or HBV co-infected patients.

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.

Treatment of hepatitis C in patients infected with human immunodeficiency virus in the direct-acting antiviral era.

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.