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Integrase inhibitors are the most recently approved family of antiretroviral agents for the treatment of HIV infection. As with other antiretroviral agents, under pharmacological pressure, the virus selects resistance mutations if viral suppression is incomplete. Mutations are selected in the integrase gene, specifically in positions proximal to the catalytic center. Because clinical experience with these drugs is scarce, information on resistance is limited. Virologic failure with raltegravir is associated with selection of primary mutations such as N155H (40%) and distinct changes in position Q148 (28%). Less frequently, Y143R (6.6%) and E92Q are selected. The most frequently observed mutations in failure with elvitegravir are E92Q, E138K, Q148R/K/H and N155H, and less frequently S147G and T66A/I/K. The most common resistance pattern seems to be E138K + E147G + Q148R. There is a high grade of cross resistance between raltegravir and elvitegravir, making sequencing between these two drugs impossible.

Human immunodeficiency virus (HIV) entry into cells is the first step in the viral replication cycle, which has been explored as a new therapeutic target. A better knowledge of the mechanisms involved in the entry process has led to the development of agents, which may inhibit each of the different steps of the viral entry process: attachment of the gp120 to the CD4 cell receptor; binding of the gp120 to CCR5 or CXCR4 coreceptors; and the fusion of viral and cell membranes. Entry inhibitors are the latest family of antiretroviral compounds, being enfuvirtide, a fusion inhibitor, the first approved. Several other entry inhibitors are currently in clinical development and hopefully soon will be part of the therapeutic armamentarium against HIV.

ObjectivesHIV outcomes centre primarily around clinical markers with limited focus on patient-reported outcomes. With a global trend towards capturing the outcomes that matter most to patients, there is agreement that standardizing the definition of value in HIV care is key to their incorporation. This study aims to address the lack of routine, standardized data in HIV care.MethodsAn international working group (WG) of 37 experts and patients, and a steering group (SG) of 18 experts were convened from 14 countries. The project team (PT) identified outcomes by conducting a literature review, screening 1979 articles and reviewing the full texts of 547 of these articles. Semi-structured interviews and advisory groups were performed with the WG, SG and people living with HIV to add to the list of potentially relevant outcomes. The WG voted via a modified Delphi process - informed by six Zoom calls - to establish a core set of outcomes for use in clinical practice.ResultsFrom 156 identified outcomes, consensus was reached to include three patient-reported outcomes, four clinician-reported measures and one administratively reported outcome; standardized measures were included. The WG also reached agreement to measure 22 risk-adjustment variables. This outcome set can be applied to any person living with HIV aged > 18 years.ConclusionsAdoption of the HIV360 outcome set will enable healthcare providers to record, compare and integrate standardized metrics across treatment sites to drive quality improvement in HIV care.

BackgroundLittle is known about the influence of ongoing barriers to care in the persistence of hepatitis C virus (HCV) viremia after treatment with direct-acting antivirals (DAAs) among people living with human immunodeficiency virus (PLWH).MethodsWe conducted a retrospective cohort analysis of PLWH treated through the standard of care in 3 Western countries, to investigate the predictors of HCV treatment failure (clinical or virologic), defined as having a detectable serum HCV ribonucleic acid within 12 weeks after DAA discontinuation. In addition to HCV and liver-related predictors, we collected data on ongoing illicit drug use, alcohol abuse, mental illness, and unstable housing. Logistic regression analyses were used to identify predictors of HCV treatment failure.ResultsBetween January 2014 and December 2017, 784 PLWH were treated with DAA, 7% (n = 55) of whom failed HCV therapy: 50.9% (n = 28) had a clinical failure (discontinued DAA therapy prematurely, died, or were lost to follow-up), 47.3% (n = 26) had an HCV virologic failure, and 1 (1.8%) was reinfected with HCV. Ongoing drug use (odds ratio [OR] = 2.60) and mental illness (OR = 2.85) were independent predictors of any HCV treatment failure. Having both present explained 20% of the risk of any HCV treatment failure due to their interaction (OR = 7.47; P < .0001). Predictors of HCV virologic failure were ongoing illicit drug use (OR = 2.75) and advanced liver fibrosis (OR = 2.29).ConclusionsPeople living with human immunodeficiency virus with ongoing illicit drug use, mental illness, and advanced liver fibrosis might benefit from enhanced DAA treatment strategies to reduce the risk of HCV treatment failure.

BackgroundOne of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents.ObjectiveTo evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV.MethodsIn this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents.Primary endpointthe percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 ×  upper limit of normal (ULN) if baseline ALT ≤ ULN or >3.5 ×  baseline if baseline ALT>ULN in the maraviroc versus the placebo arm.ResultsAt week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group.ConclusionsThe use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment.

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5–10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15–25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct‐acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow‐up, we propose that HIV‐HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta. [ABSTRACT FROM AUTHOR]

Sexually transmitted infections (STIs) have become the second in the global rating of infectious diseases after respiratory infections. Globally, over 1 million, new STI is diagnosed every day. Although four conditions are the most representative and of obligatory declaration (gonorrhea, syphilis, chlamydia, and human immunodeficiency virus [HIV]), there are many other prevalent STI, including trichomona, herpes simplex, papillomavirus, and viral hepatitis. Herein, we perform a narrative and retrospective review, analyzing information from public databases from distinct Spanish government institutions. STI significantly declined in Spain during 2020 as a result of lockdown and social isolation measures dictated in response to the COVID-19 pandemic. After releasing restrictions, a major STI rebound occurred in 2021. Increases were 49% for gonorrhea, 45% for HIV, 39% for chlamydia, and 32% for syphilis. Based on nationwide statistics, we build a narrative review of the recent STI surge after COVID-19. In summary, we propose a holistic approach to confront the current re-emergence of STI. On one hand, new innovative medical advances must be implemented, including new rapid tests, novel vaccines, pre-exposure prophylaxis beyond HIV, and long-acting antivirals. On the other hand, information to citizens needs to be reformulated with interventions aimed to build a healthier society, alike it has been undertaken with tobacco, alcohol, diet, and lifestyle. STI determines important sexual, reproductive, and maternal-child health consequences. To promote human well-being or flourishing, the education of adolescents and young adults should be aligned with human ecology. Therefore, it is urgent to address new approaches in sexual health that represent a clear benefit for individual persons and society. In this way, favoring a cultural evolution aimed to delay the age of first sexual intercourse and the avoidance of multiple sex partners should be prioritized. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection is a major cause of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented in Spain two decades ago, and potent oral antivirals entecavir and tenofovir were introduced around 2007. Aim: To assess the clinical benefits of these interventions nationwide. Methods: Including HBV as a diagnosis, we performed a retrospective study of all hospitalisations in Spain the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2017. Results: From 73,939,642 nationwide hospital admissions during the study period, 129,634 (0.17%) included HBV as diagnosis. Their number doubled from 2007 to 2017 and the median age increased from 44 to 58 years. Most HBV admissions recorded chronic hepatitis B. In‐hospital death occurred in 6.4%. Co‐infection with HIV or hepatitis C virus occurred in 11.9% and 23.3%, respectively. Patients with HIV‐HBV co‐infection had significantly greater mortality than individuals with HBV mono‐infection. The rate of HBV hospitalisations significantly increased over time with a transient drop around 2007, coincident with the arrival of new potent oral antivirals. Although the proportion of HBV hepatic decompensation events has declined, the rate of liver cancer continues to rise. The small subset of patients with hepatitis delta superinfection increasingly and disproportionately accounts for hepatic decompensation events and liver cancer. Conclusion: Hospital admissions of individuals with HBV infection are increasing in Spain. While hepatic decompensation events declined following the introduction of potent oral nucleos(t)ide therapy, HBV‐related liver cancer is rising. No benefit of oral antiviral therapies is seen on hepatitis delta. [ABSTRACT FROM AUTHOR]

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is major cause of decompensated cirrhosis and liver cancer. The advent of curative new antiviral therapies since year 2015 has dramatically improved the prognosis of HCV patients. The real‐life clinical benefits at country level of these therapies have not yet been assessed. This is a retrospective study of all hospitalizations in Spain including HCV as diagnosis using the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2019. From 81,482,509 nationwide hospital admissions recorded during the study period, 1,057,582 (1.29%) included HCV as diagnosis. The median age of HCV hospitalized patients was 54 years old. Males accounted for 63.2% of cases. Most HCV admissions recorded chronic hepatitis C whereas acute hepatitis C was reported in less than 3%. In‐hospital death occurred in 6.4% of HCV admissions. Coinfection with HIV or hepatitis B virus was seen in 14.8% and 6.4%, respectively. Patients hospitalized with HIV‐HCV coinfection represented 14.8% of cases and were on average 17 years younger than HCV‐monoinfected individuals. The rate of HCV hospitalizations significantly increased until 2005, and then stabilized for one decade. A significant reduction was noticed since 2015. However, whereas the proportion of HCV‐associated hepatic decompensation events declined since then, liver cancer diagnoses increased. In conclusion, hospital admissions of HCV individuals significantly declined in Spain since 2015 following a wide prescription of new oral direct‐acting antivirals. This reduction was primarily driven by a fall of hepatic decompensation events whereas HCV‐related liver cancer continues rising. [ABSTRACT FROM AUTHOR]

Background: HIV-1 and HIV-2 differ in their antiretroviral (ARV) susceptibilities and drug resistance mutations (DRMs).Methods: We analyzed published HIV-2 pol sequences to identify HIV-2 treatment-selected mutations (TSMs). Mutation prevalences were determined by HIV-2 group and ARV status. Nonpolymorphic mutations were those in <1% of ARV-naive persons. TSMs were those associated with ARV therapy after multiple comparisons adjustment.Results: We analyzed protease (PR) sequences from 483 PR inhibitor (PI)-naive and 232 PI-treated persons; RT sequences from 333 nucleoside RT inhibitor (NRTI)-naive and 252 NRTI-treated persons; and integrase (IN) sequences from 236 IN inhibitor (INSTI)-naive and 60 INSTI-treated persons. In PR, 12 nonpolymorphic TSMs occurred in ≥11 persons: V33I, K45R, V47A, I50V, I54M, T56V, V62A, A73G, I82F, I84V, F85L, L90M. In RT, 9 nonpolymorphic TSMs occurred in ≥10 persons: K40R, A62V, K70R, Y115F, Q151M, M184VI, S215Y. In IN, 11 nonpolymorphic TSMs occurred in ≥4 persons: Q91R, E92AQ, T97A, G140S, Y143G, Q148R, A153G, N155H, H156R, R231 5-amino acid insertions. Nine of 32 nonpolymorphic TSMs were previously unreported.Conclusions: This meta-analysis confirmed the ARV association of previously reported HIV-2 DRMs and identified novel TSMs. Genotypic and phenotypic studies of HIV-2 TSMs will improve approaches to predicting HIV-2 ARV susceptibility and treating HIV-2-infected persons. [ABSTRACT FROM AUTHOR]

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has hit health-care systems and societies in an unprecedented manner. In 1981, the first cases of AIDS were reported and wide diagnostic testing helped to characterize high-risk groups and the global burden of the epidemic. With Coronavirus Disease (COVID)-19, everything has happened too fast and both cases and fatalities are huge but still uncertain in most places. Diagnostic testing of active and past SARS-CoV-2 infections needs to expand rapidly, ideally using rapid tests. COVID-19 deaths are highly concentrated in the elderly population, with a large proportion of fatalities being "with" rather than "by" SARS-CoV-2 infection. They are often the result of inadequate health care due to overwhelming demands. To date, there is no specific therapy for SARS-CoV-2 infection. Several antivirals are being tested clinically, including remdesivir, at this time the most promising. For others such as lopinavir/ritonavir, neither significant virological nor clinical benefit has been shown. Given the characteristic pulmonary cytokine storm underlying the pathogenic mechanism of severe COVID-19 pneumonia and acute respiratory distress, antiinflammatory agents are being investigated. The benefit of corticosteroids, hydroxychloroquine, etc., is limited. Monoclonal antibodies targeting different pro-inflammatory cytokines, such as tocilizumab, an anti-interleukin 6 agent, are being tried with encouraging results. Ultimately a protective vaccine will be the best response for controlling the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 2 (HIV-2) was isolated in AIDS patients in 1986. Around 1-2 million people are infected worldwide. The virus is less transmissible than HIV-1, being sexual contacts the most frequent route of acquisition. In the absence of antiretroviral therapy, most HIV-2 carriers will develop AIDS; however, it takes longer than in HIV-1 infection. There is no global pandemic caused by HIV-2, as the virus is largely confined to West Africa. Due to historical ties, HIV-2 is also prevalent in Portugal and its former colonies in Brazil, India, Mozambique, and Angola. Other European countries with hundreds to thousands of HIV-2 infections are France, Belgium, and Spain. A few hundred have been reported in North America, mostly in West African foreigners. Globally, HIV-2 infections are steadily declining. Although CD4 declines occur more slowly in HIV-2 than in HIV-1 patients, the CD4 recovery with antiretroviral treatment is smaller in the former. HIV-2 is naturally resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some protease inhibitors. In contrast, HIV-2 is susceptible to all NRTIs and integrase inhibitors. Drug resistance in HIV-2 may develop earlier than in HIV-1 and select for mutations at distinct sites. Misdiagnosis of HIV-2 in patients wrongly considered as HIV-1 positive or in those dually infected may result in treatment failures with undetectable HIV-1RNA. Given the relatively large number of West Africans migrated to the European Union and North America, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded at least once in all HIV-seroreactive persons. This should be stressed in the face of atypical HIV serological profiles, immunovirological disconnect (CD4 cell count loss despite undetectable HIV-1 viremia), and/or high epidemiological risks (birth in or sex partners from HIV-2 endemic regions). Superinfection with any HIV variant may occur in persons infected with the other, since there is no cross-protection. Thus, earlier antiretroviral therapy is warranted for either HIV-1 or HIV-2, given that it would protect from each other superinfection in persons at risk. [ABSTRACT FROM AUTHOR]

Nearly 1 million people become infected every day with any of the four major curable sexually transmitted infections (STIs), namely trichomoniasis, chlamydia, gonorrhea, and syphilis. Despite huge global incidence, STIs remain as neglected diseases. The success of antiretrovirals for halting progression to AIDS in HIV-infected individuals and for stopping HIV transmission to uninfected contacts, either as pre- or post-exposure prophylaxis, has to lead to increased risky sexual behaviors through risk compensation. Recent epidemics and outbreaks of STIs among men having sex with men reflect the global loss of fear to HIV/AIDS.The alarming rising rates of STIs worldwide have been fueled by: (1) rapid spread of drug resistance, that is, for Neisseria gonorrhoeae and Mycoplasma genitalium; (2) unprecedented impact of recreational drugs (chemsex) and internet (apps, websites) for facilitating exposure to multiple sex partners; and (3) growing rates of sexual violence and commercial sex, associated with wars, refugees, migrations, traveling, and sexual tourism. Moreover, there is an increasing appreciation of sexual transmission for other agents, including human T-lymphotropic virus type 1, hepatitis A and C viruses, Zika, and Ebola. For addressing this new scenario for STIs, an expert panel workshop was arranged in Madrid, Spain in May 2018. This review summarizes the discussions at the meeting. [ABSTRACT FROM AUTHOR]

Introduction: Current antiretroviral therapy allows to achieve and sustain maximal suppression of HIV replication in most treated patients. As result, the life expectancy of HIV-infected persons has improved dramatically and is nowadays similar to that of the HIV-negative population. However, oral antiretrovirals have to be taken daily and indefinitely to avoid resumption of HIV replication and selection of drug resistance. Unfortunately, drug adherence is often suboptimal and tends to decline over time. Areas covered: New drugs, formulations and delivery systems are being developed for extended-release of antiretrovirals. At this time, intramuscular cabotegravir and rilpivirine, dapivirine vaginal rings and tenofovir alafenamide subdermal implants are the products in more advanced stages of clinical development. Their pharmacokinetics/dynamics and safety/efficacy are reviewed. Expert commentary: In the absence of eradicative therapy for individuals with HIV infection and protective vaccines for persons at risk, long-term antiretroviral therapy is the best approach for preventing disease progression in patients and halting transmissions, either as result of ‘treatment as prevention’ for HIV carriers or ‘pre-exposure prophylaxis’ for uninfected individuals at risk. In all these scenarios, the advent of long-acting antiretrovirals will expand options for overcoming the challenge of suboptimal drug adherence and reduce the burden of HIV infection. [ABSTRACT FROM AUTHOR]

The International Conference on Viral Hepatitis 2017 brought exciting news on the treatment of viral hepatitis. The most recent estimates of the burden for hepatitis B virus and hepatitis C virus (HCV) infections were presented. The current gaps and prospects for regional and global eradication of viral hepatitis were discussed on the light of the WHO roadmap until 2030. Debates focused on hepatitis C and expectations using the new approved HCV pan-genotypic, once daily, oral direct-acting antivirals (DAAs), glecaprevir-pibrentasvir, and sofosbuvir-velpatasvir-voxilaprevir. The management of difficult-to-cure HCV patients included individuals who had failed prior DAAs, people who inject drugs, patients with decompensated cirrhosis, or renal insufficiency. Special patient populations such as children, pregnant women, persons with acute hepatitis C, or HIV coinfection were addressed separately. The use of HCV treatment as prevention was subject to debate, balancing the benefits on halting transmission and the risk for HCV reinfections and high medication costs. Complementary efforts on behavioral interventions and harm reduction programs were highlighted. Data from both clinical trials and real-world experience (i.e., from the US Veterans) were compared. Further debates addressed hepatic conditions that may alter the management and outcome of viral hepatitis, such as hepatitis B reactivation, non-alcoholic fatty liver disease, liver transplantation, and hepatocellular carcinoma. Finally, the recent data on often neglected hepatitis D and E virus infections were reviewed. [ABSTRACT FROM AUTHOR]

Background: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL).Methods: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models.Results: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients.Conclusions: A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2. [ABSTRACT FROM AUTHOR]

Background: A broader extent of amino acid substitutions in the integrase of HIV-2 compared with HIV-1 might enable greater cross-resistance between raltegravir and dolutegravir in HIV-2 infection. Few studies have examined the virological response to dolutegravir in HIV-2 patients that failed raltegravir.Methods: All patients recorded in the HIV-2 Spanish cohort were examined. The integrase coding region was sequenced in viraemic patients. Changes associated with resistance to raltegravir and dolutegravir in HIV-1 were recorded.Results: From 319 HIV-2-infected patients recorded in the HIV-2 Spanish cohort, 53 integrase sequences from 30 individuals were obtained (20 raltegravir naive and 10 raltegravir experienced). Only one secondary mutation (E138A) was found in one of the 20 raltegravir-naive HIV-2 patients. For raltegravir-experienced individuals, the resistance mutation profile in 9 of 10 viraemic patients was as follows: N155H + A153G/S (four); Y143G + A153S (two); Q148R + G140A/S (two); and Y143C + Q91R (one). Of note, all patients with Y143G and N155H developed a rare non-polymorphic mutation at codon 153. Rescue therapy with dolutegravir was given to 5 of these 10 patients. After >6 months on dolutegravir therapy, three patients with baseline N155H experienced viral rebound. In two of them N155H was replaced by Q148K/R and in another by G118R.Conclusions: A wide repertoire of resistance mutations in the integrase gene occur in HIV-2-infected patients failing on raltegravir. Although dolutegravir may allow successful rescue in most HIV-2 raltegravir failures, we report and characterize three cases of dolutegravir resistance in HIV-2 patients, emerging variants Q148K and Q148R and a novel change G118R. [ABSTRACT FROM AUTHOR]

The article presents the discussion on annual conference on retroviruses and opportunistic infections. Topics include Islatravir being a promising new antiretroviral belonging to a first class of inhibitors of the HIV polymerase; and lenacapavir in borosilicate vials in all ongoing clinical studies as HIV pre-exposure prophylaxis (PrEP).

The International Conference on Viral Hepatitis 2016 brought exciting news on the treatment of viral hepatitis. The conference was mainly focused on the most recent estimates of burden for HBV and HCV; the current gaps and prospects for regional and global HCV eradication; the use of HCV treatment as prevention; and the management of difficult-to-cure hepatitis C patients, including individuals who fail on direct-acting antivirals, people who inject drugs, and those with decompensated cirrhosis or renal insufficiency. Special patient populations, such as children, pregnant women, HIV-coinfected and persons with acute hepatitis C, were addressed separately. Data from both clinical trials and real-world experience were discussed. Further debates focused on hepatic conditions that may alter the management and outcome of viral hepatitis, such as fatty liver disease, liver transplantation, and hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. Objective: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV. Methods: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents. Primary endpoint: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 × upper limit of normal (ULN) if baseline ALT ≤ ULN or >3.5 × baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. Results: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. Conclusions: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment. [ABSTRACT FROM AUTHOR]

Summary: Objective: It is not known whether the probability of achieving sustained virological response (SVR) can be determined on the basis of the magnitude of HCV viral decline over the first 4 weeks of Peg-IFN/RBV treatment of HIV/HCV co-infected patients who fail to achieve a rapid virological response (RVR). Methods: HIV patients co-infected with HCV genotype 1 naïve to Peg-IFN/RBV treatment were included. HCV viral decline from baseline to week 4 was graded. The positive predictive value (PPV) for SVR was evaluated according to the magnitude of HCV viral decline at week 4. Results: One hundred and fifty patients were included. Thirty-four (22.6%) patients achieved RVR, 33 of these (PPV [CI 95%]; 97.05% [86.34–99.85]) achieved SVR. In those patients who did not achieve RVR, the probability to achieving SVR was graded according to the magnitude of viral decline at week 4 (>2 log10 [55.5%], >2.5 log10 [73.3%] and >3 log10 [75%]). The combination of undetectable and magnitude of decline (>2.5 log10) had a PPV for SVR of 89.8% (CI 95%; 0.794–0.964). Conclusions: The combination of undetectable HCV viral load and magnitude of decline at week 4 has a high PPV for SVR and identified a higher number of potential Peg-IFN/RBV responders. [Copyright &y& Elsevier]

Objectives: The rs12979860 variant, linked to IL28B gene, predicts sustained viral response (SVR) to pegylated-interferon/ribavirin (pegIFN/RBV) therapy in Hepatitis C Virus genotype 1 or 4 (HCV-1/4)-infected patients. Recently, a functional variant, ss469415590, in linkage disequilibrium (LD) with rs12979860, has been discovered. Our objective was to assess the value of ss469415590 to predict SVR to pegIFN/RBV in Caucasian HCV-1/4-infected individuals and to compare its performance with that of rs12979860. Methods: 272 Caucasian HCV-1/4-infected patients who completed a course of pegIFN/RBV were genotyped for both rs12979860 and ss469415590 markers. Logistic regression models including factors with univariate association with SVR and each genetic marker were elaborated. The area under the receiver operating-characteristic curve (AUROC) was calculated for each model and both were compared. Results: Both markers were in LD (r2 = 0.82). For rs12979860, 66 (64.0%) CC versus 56 (33.1%) T allele carriers achieved SVR (Adjusted OR = 4.156, 95%CI = 2.388–7.232, p = 4.647×10−7). For ss469415590, 66 (66.0%) TT/TT versus 56 (32.5%) –G allele carriers (Adjusted OR = 4.783, 95%CI = 2.714–8.428, p = 6.153×10−8) achieved SVR. The AUROC of the model including rs12979860 was 0.742 (95%CI = 0.672–0.813) and of that based on ss469415590 was 0.756 (95%CI = 0.687–0.826) (p = 0.780). Conclusions: The ss469415590 variant shows an equivalent performance to predict SVR to pegIFN/RBV than the rs2979860 in Caucasian HCV-1/4-infected patients. [ABSTRACT FROM AUTHOR]

Chronic hepatitis E virus infection with rapid progression to cirrhosis is reported in 2 human immunodeficiency virus (HIV)–infected patients with severe immunosuppression. Monotherapy with ribavirin led to temporary viral response and marked improvement of liver damage. Chronic hepatitis E should be regarded as another opportunistic event within HIV infection.Chronic hepatitis E virus infection with rapid progression to cirrhosis is reported in 2 human immunodeficiency virus (HIV)–infected patients with severe immunosuppression. Monotherapy with ribavirin led to temporary viral response and marked improvement of liver damage. Chronic hepatitis E should be regarded as another opportunistic event within HIV infection. [ABSTRACT FROM AUTHOR]

Summary: Objective: Some experts consider that hepatitis C virus (HCV) genotype 1-infected patients harboring IL28B genotype CC should be treated with interferon (Peg-IFN) plus ribavirin (RBV). This study aimed to assess the rate of sustained virological response (SVR) in these subjects, according to whether they achieve rapid virological response (RVR) or not. Methods: Prospective cohort study conducted at the Infectious Diseases Units of three Spanish hospitals. 220 treatment-naive, HCV genotype 1-infected patients, 160 of them HIV/HCV-coinfected, who initiated dual therapy with peg-IFN plus RBV were analyzed in an on-treatment approach. Results: 29 (18%) HIV/HCV-coinfected and 14 (23%) HCV-monoinfected (p = 0.44) individuals developed RVR. In the overall population, 32 (39%) patients with IL28B genotype CC versus 11 (8%) bearing genotype non-CC achieved RVR (p < 0.0001). In HCV-monoinfected patients with IL28B genotype CC, SVR was observed in 12 (92%) of those who achieved RVR and in 3 (30%) of those who did not (p = 0.0018). The corresponding figures for HIV/HCV-coinfected individuals were 19 (100%) and 14 (35%), respectively (p < 0.0001). Conclusion: Treatment-naïve HCV-genotype 1-infected patients bearing favorable IL28B genotype should not be treated with dual therapy including Peg-IFN plus RBV if they do not achieve RVR. These subjects clearly represent candidates for more effective therapy with direct-acting antivirals. Summary: Some experts consider that hepatitis C virus (HCV) genotype 1-infected patients harboring the favorable IL28B genotype CC should be treated with interferon plus ribavirin. However, patients harboring favorable IL28B genotype should not be considered likely responders to the same extent. This prospective cohort study conducted in 220 treatment-naive HCV-infected patients with or without HIV coinfection patients shows that among the IL28B CC carriers, while the subset of those patients who achieve negative plasma HCV-RNA after 4 weeks (rapid virological response, RVR) of dual therapy have a rate of sustained virological response near to 100%, those who do not present RVR show a response rate lower than 40%. Therefore, treatment-naïve HCV-genotype 1-infected patients bearing favorable IL28B genotype who do not achieve RVR should be considered candidates for more effective therapy with direct-acting antivirals like boceprevir or telaprevir. [Copyright &y& Elsevier]

The article presents the discussion on pandemics caused by RNA viruses. Topics include despite the success of antiretroviral therapy, hospital admissions in HIV individuals still representing a significant health burden in most countries; and helping in predicting the evolution of other human RNA viruses such as SARS-CoV-2 put under pressure with antivirals and/or vaccines.

Background. The risk of liver toxicity during antiretroviral drug use in human immunodeficiency virus (HIV)— positive patients increases in the presence of chronic hepatitis C virus (HCV) infection. It is unknown whether sustained HCV clearance after interferon (IFN)—based therapy might reduce this complication. Methods. The incidence of severe elevations in liver enzyme levels during antiretroviral therapy was retrospectively analyzed in a group of HIV/HCV-coinfected patients after completion of a full course of IFN-based therapy. Hepatic events were recorded according to the achievement of a sustained virological response (SVR), and the presence of advanced liver fibrosis was assessed by transient elastometry. Results. A total of 132 HIV/HCV-coinfected patients were analyzed (66% men; mean age, 38 years). Overall, 33% achieved an SVR and 40% had advanced liver fibrosis after IFN therapy. A total of 49 episodes of liver toxicity occurred during a mean of 35 months of follow-up (9.7% per year) after IFN therapy. The yearly incidence of hepatic events was greater in patients who did not achieve an SVR than in those who did (12.9% vs. 3.1%; P<.001) and in patients with advanced liver fibrosis than in those without it (14.4% vs. 7.6%; P = .001). Drugs involved in hepatic events were dydeoxynucleoside analogues (namely, didanosine and stavudine; 40%) nevirapine (30%), efavirenz (11%), and protease inhibitors (PIs; 8%). In logistic regression analysis, lack of an SVR (odds ratio [OR], 6.13 [95% confidence interval {CI}, 1.83-37.45]; P = .003) and the use of dydeoxynucleosides (OR, 3.59 [95% CI, 1.23-10.42]; P = .02) were independent predictors of hepatotoxicity after IFN therapy. Conversely, regimens containing PIs (OR, 0.07 [95% CI, 0.02-0.30]; P< .01) or efavirenz (OR, 0.13 [95% CI, 0.04-0.44]; P = .001) were associated with a diminished risk of hepatic events. Conclusion. Sustained HCV clearance after IFN-based therapy reduces the risk of liver toxicity during antiretroviral therapy, which should further encourage the treatment of chronic hepatitis C in HIV-coinfected patients. In this population, prescription of PIs or efavirenz decreases and use of dydeoxynucleoside analogues increases the risk of hepatotoxicity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Chronic hepatitis C is frequently seen in HIV-positive subjects infected through needle sharing or transfusion of contaminated blood products. Progression to end-stage liver disease seems to occur faster in these patients. As the life expectancy of HIV-infected persons has dramatically improved since the introduction of highly active anti-retroviral therapies, cirrhosis and eventually hepatocellular carcinoma (HCC) may be recognized at an increasing rate in patients coinfected with HIV and hepatitis C virus (HCV). METHODS: We identified the main features of HIV-infected individuals with end-stage liver disease due to HCV infection and diagnosed with HCC in three HIV/AIDS referral centers, and compared these features to those of a control group of patients with HCV-related HCC but without HIV infection. RESULTS: Seven HIV-infected patients were identified. Of these, six were <45 yr of age and had been intravenous drug users. The mean time between exposure to HCV and the development of HCC was estimated to be 17.8 yr. Two subjects were coinfected with hepatitis B and delta viruses, respectively. Only one individual had been diagnosed of an AIDS-defining condition before the diagnosis of HCC was made. However, all subjects had <500 CD4-I- T cells at the time of HCC diagnosis. Five died within the first 4 months of follow-up. Patients in the control group (n = 31) were significantly older (68.9 ± 8.9 vs 42.2 ± 10.4; p < 0.001) and the duration of HCV infection was significantly longer (28.1 ± 10.9 vs 17.8 ± 2.7; p < 0.05) than in those with HIV-HCV coinfection. CONCLUSIONS: HCC seems to occur at a younger age and after a shorter period of HCV infection in subjects coinfected with HIV. Thus, treatment of CHC should be encouraged in HIV-positive patients, and in those with HCV-related cirrhosis the periodic monitoring of α-fetoprotein and abdominal ultrasonography should be recommended. [ABSTRACT FROM AUTHOR]

The article presents the discussion on the magnitude of huge public health crisis growth during the COVID-19 pandemic. Topics include overdoses being largely caused by synthetic opioids and fueled by the widespread use of fentanyl; and sharing needles during drug injection practices and increasing sexual risk behaviors.

The article focuses on the belief that human immunodeficiency virus (HIV) could be eliminated with the help of genetics and not chemotherapy. It discusses the revelation by Jérȏme Lejeune for the cause of Down Syndrome being trisomy 21, strategy like excision or mutational inactivation, and challenges of body infected cells.

Only a few cases of AIDS-related primary lymphomas of the central nervous system (CNS) show a T-cell phenotype. We have recently studied two intravenous drug users with HIV infection who had primary CNS T-cell lymphomas. In both cases, the enzyme immunoassay (EIA) for HTLVgave a positive result. In the first case, study by western-blot (WB) and specific PCR confirmed the human T-cell lymphotropic virus type I (HTLV-I) infection and serological study by EIA for HTLVof his mother was negative. In the second case, analysis of ante-mortem serum samples by two different WBs showed an indeterminate pattern suggestive of HTLV-I infection, but adequate samples for PCR were not available. We speculate about the possibility that the horizontal transmission of HTLV-I infection could have facilitated the devepolment of a primary CNS T-cell lymphoma in these HIV patients, although they cannot be strictly considered as ATLL cases. [ABSTRACT FROM AUTHOR]

Human retroviruses HIV and HTLV share transmission routes. HIV widely spread in Spain during the 80 s through injection drug use and sex, and nowadays HIV rates in Spain account for one of the largest in Europe. In contrast, HTLV-1 is not endemic in Spain, despite hosting huge numbers of migrants from highly endemic regions. Herein, we report the rate and main features of the HIV-HTLV co-infected population in Spain. A national registry exists in Spain for HTLV since year 1989. Data from standardized case report forms and one centralized lab repository were reviewed, especially for the subset with HTLV-HIV co-infection. Up to December 2018, a total of 369 individuals with HTLV-1 had been diagnosed in Spain. 64% of the population were females, and Latin American individuals accounted for 64.5%. Classical HTLV-associated illnesses were found in 12.7% (myelopathy) and 7.6% (leukemia). HIV coinfection was found in 12 (3.2%). Of those, 3 patients (25%) were female and 39 (75%) were of non-Spanish origin. All but two harbored HIV-1 subtype B, being non-B variants found in the two West Africans. Exposure had been sexual in most cases, being 4 homosexual men. Seven HTLV-HIV co-infected patients had developed AIDS and two had developed myelopathy. There was no evidence for increased HTLV-1 clinical pathogenicity due to HIV coinfection. HIV coinfection is infrequent (<5%) among HTLV-1 carriers in Spain. More than half of co-infected patients come from Latin America. Sexual contact is the most frequent risk behavior, being MSM one third of cases. Late diagnosis explains the high rate (9/12) of clinical manifestations in our HIV-HTLV co-infected population. [ABSTRACT FROM AUTHOR]

[Display omitted] • Defined needs for long-acting (LA) antiretroviral therapy (ART) • Current and future LA ART for HIV prevention and treatment. • Extending antiretroviral (ARV) drugs half-lives. • Optimizing ARV biodistribution to cell and tissue viral reservoirs. • ARV implants, microbicides, and injectable prodrug formulations. • Pathways towards an every six-month LA ART. Adherence to daily oral antiretroviral therapy (ART) is a barrier to both treatment and prevention of human immunodeficiency virus (HIV) infection. To overcome limitations of life-long daily regimen adherence, long-acting (LA) injectable antiretroviral (ARV) drugs, nanoformulations, implants, vaginal rings, microarray patches, and ultra-long-acting (ULA) prodrugs are now available or in development. These medicines enable persons who are or at risk for HIV infection to be treated with simplified ART regimens. First-generation LA cabotegravir, rilpivirine, and lenacapavir injectables and a dapivirine vaginal ring are now in use. However, each remains limited by existing dosing intervals, ease of administration, or difficulties in finding drug partners. ULA ART regimens provide an answer, but to date, such next-generation formulations remain in development. Establishing the niche will require affirmation of extended dosing, improved access, reduced injection volumes, improved pharmacokinetic profiles, selections of combination treatments, and synchronization of healthcare support. Based on such needs, this review highlights recent pharmacological advances and a future treatment perspective. While first-generation LA ARTs are available for HIV care, they remain far from ideal in meeting patient needs. ULA medicines, now in advanced preclinical development, may close gaps toward broader usage and treatment options. [ABSTRACT FROM AUTHOR]

Background 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. Objectives To estimate the rate and predictors of serum HCV-RNA above 6 million IU/mL in chronic hepatitis C patients on care outside clinical trials. Study design 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. Results 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 82.6 IU/L; mean HCV-RNA 6.02 log IU/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 values >6 million IU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects ( p < 0.001). In multivariate analysis, serum HCV-RNA >6 million IU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98–8.19, p < 0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05–3.37, p = 0.03). Conclusions Serum HCV-RNA >6 million IU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection. [ABSTRACT FROM AUTHOR]

Background Toll-like receptor-3 (TLR3) is a cellular receptor that may recognize double-stranded RNA (dsRNA) from viruses, resulting in production of proinflammatory cytokines and interferons, which are important for the adaptive immune response. Objectives To analyze the association between Toll-like receptor-3 ( TLR3 ) polymorphisms (rs3775291 and rs13126816) and virologic response to pegylated interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/HCV coinfected patients. Study design We performed a retrospective study in 321 naïve patients treated with pegIFNα/RBV. Genotyping was performed by using the GoldenGate ® assay with VeraCode ® . The outcome variables were early virologic response (EVR) and sustained virologic response (SVR). Results In a multivariate analysis, rs3775291 A allele decreased the likelihood of achieving EVR (aOR = 0.20; p = 0.018) and SVR (aOR = 0.38; p = 0.024). Regarding rs13126816, the percentage of EVR decreased with each minor A allele ( p = 0.034) in HCV-GT2/3 patients, although no significant association was obtained in the multivariate analysis ( p = 0.076). Regarding TLR3 haplotypes (comprised of rs3775291 and rs13126816), GT2/3 patients with AA haplotype had decreased odds of achieving EVR ( p = 0.030), whereas GG haplotype increased the likelihood ( p = 0.018). Regarding SVR, GG haplotype carriers had increased odds of achieving SVR ( p = 0.019, p = 0.043 and p = 0.070 for all, GT2/3 and GT1/4 patients, respectively). Besides, GT1/4 patients with GA haplotype had lower odds of achieving SVR ( p = 0.039). Conclusions Our study shows the first evidence that two TLR3 polymorphisms (rs3775291 and rs13126816) seem to be related to the HCV therapy response in HCV/HIV coinfected patients. [ABSTRACT FROM AUTHOR]

The article presents a study on the use of genotypic predictive model to assess phenotypic tropism in HIV patients. The study used Trofile™ assay and HIV-1 coreceptor tropism assay (ES Trofile™) with the interpretation in third hypervariable (V3) loop sequences, and employed multivariate logistic regression analysis. Results showed that a genotypic-clinical model predicts HIV-1 tropism with high accuracy and can be used in selecting candidates to treat coreceptor antagonists.

Examines the subdivision of human immunodeficiency virus (HIV)-1 into two groups, M and O which are based on phylogenetic analysis, while focusing on the study of the biologic and genetic characteristics associated with two primary isolates. Replication of all three isolates; What the phylogenetic analysis of V3 loop sequences showed; Circumstances surrounding viral isolation.