In this randomized trial involving patients with chronic hepatitis C who were also infected with the human immunodeficiency virus (HIV), peginterferon alfa-2a plus ribavirin was more effective than ...interferon alfa-2a plus ribavirin or peginterferon alfa-2a plus placebo (rates of sustained virologic response, 40 percent, 12 percent, and 20 percent, respectively).
The rates of response were not as high as in previous studies involving HIV-negative patients.
Potent antiretroviral therapy has reduced the morbidity and mortality associated with untreated human immunodeficiency virus (HIV) infection.
1
,
2
At the same time, the pattern of morbidity and mortality among HIV-infected persons has shifted, and clinicians responsible for the care of HIV-infected persons have been confronted with new challenges. Complications associated with concurrent hepatitis C virus (HCV) infection have emerged as one of the most frequent and complex issues in the care of patients with HIV infection and the acquired immunodeficiency syndrome (AIDS).
3
,
4
The current standard of care for chronic infection with HCV in persons without other infections is pegylated . . .
Interferon-based therapies combined with ribavirin are effective for chronic hepatitis C, but many patients do not have a response and side effects are common. Pegylated interferons are more ...efficacious than standard interferons. In this large trial, peginterferon alfa-2a plus ribavirin resulted in a higher rate of sustained virologic response (56 percent) than interferon alfa-2b plus ribavirin (44 percent) and peginterferon alfa-2a alone (29 percent). Side effects occurred less often with peginterferon alfa-2a plus ribavirin than with interferon alfa-2b plus ribavirin.
Peginterferon alfa-2a plus ribavirin appears to be better treatment than interferon alfa-2b plus ribavirin.
Although the mechanism of action of ribavirin remains speculative,
1
the current standard of care for patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapies.
2
–
7
Unfortunately, some patients, particularly those with more resistant hepatitis C virus (HCV) genotypes, do not respond to these agents.
Two types of pegylated interferon, which differ in their pharmacokinetic and chemical properties, have been developed. Both have demonstrated significantly superior efficacy to non-pegylated interferons in several controlled clinical trials.
8
–
12
Peginterferon alfa-2b (a 12-kD linear polyethylene glycol moiety) plus ribavirin produced significantly improved sustained virologic responses as compared with interferon alfa-2b . . .
HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of ...spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.
Background Integrase strand transferase inhibitors (INSTI), including raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), have demonstrated better efficacy and tolerability than other ...combination antiretroviral therapy (cART) classes in clinical trials; however, studies of sustainability of INSTI-containing therapy in the long-term are sparse. The purpose of this study was to provide an epidemiological overview comparing the outcome performance of different INSTI-based regimens longitudinally, including the metrics of efficacy, safety, convenience, and durability among a large, nationally representative cohort of persons living with HIV in Italy. Methods We selected subjects in the MaSTER cohort (an Italian multicenter, hospital-based cohort established in the mid-1990s that currently has enrolled over 24,000 PLWH) who initiated an INSTI-based regimen either when naïve or following a regimen switch. Cox proportional hazards regression models were fitted to evaluate associations between therapy interruptions and age, sex, nationality, transmission risk group, viral suppression status, CD4 + T-cell count, diagnosis year, cART status (naïve or experienced), and hepatitis coinfection. Results were stratified by cART INSTI type. Results There were 8173 participants who initiated an INSTI-based cART regimen in the MaSTER cohort between 2009 and 2017. The population was majority male (72.6%), of Italian nationality (88.6%), and cART-experienced (83.0%). Mean age was 49.7 (standard deviation: 13.9) years. In total, interruptions of the 1st INSTI-based treatment were recorded in 34% of cases. The most frequently cited reason for interruption among all three drug types was safety problems. In the survival analysis, past history of cART use was associated with higher hazards of interruption due to poor efficacy for all three drug types when compared to persons who were cART naïve. Non-viral suppression and CD4 + T-cell count < 200/mm.sup.3 at baseline were associated with higher hazards of interruption due to efficacy, safety, and durability reasons. Non-Italian nationality was linked to higher hazards of efficacy interruption for RAL and EVG. Age was negatively associated with interruption due to convenience and positively associated with interruption due to safety reasons. People who injects drugs (PWID) were associated with higher hazards of interruption due to convenience problems. Hepatitis coinfection was linked to higher hazards of interruption due to safety concerns for people receiving RAL. Conclusion One-third of the population experienced an interruption of any drugs included in INSTI therapy in this study. The most frequent reason for interruption was safety concerns which accounted for one-fifth of interruptions among the full study population, mainly switched to DTG. The hazard for interruption was higher for low baseline CD4 + T-cell counts, higher baseline HIV-RNA, non-Italian nationality, older age, PWID and possible co-infections with hepatitis viruses. The risk ratio was higher for past history of cART use compared to persons who were cART naive, use of regimens containing 3 drugs compared to regimens containing 2 drugs. Durability worked in favor of DTG which appeared to perform better in this cohort compared to RAL and EVG, though length of follow-up was significantly shorter for DTG. These observational results need to be confirmed in further perspective studies with longer follow-up. Keywords: HIV, Integrase inhibitors, Antiretroviral therapy, Survival analysis, MaSTER cohort
: Dolutegravir (DTG) is recommended by international guidelines as a main component of an optimal initial regimen of cART (combination antiretroviral treatment) in people living with HIV (PLWH) and ...in case of switching for failure or optimization strategies. However, studies on the performance of DTG-containing regimens and indications for switching therapies in the long term are sparse. The purpose of this study was to evaluate prospectively the performance of DTG-based regimens, using the metrics of "efficacy", "safety", "convenience" and ''durability'', among a nationally representative cohort of PLWH in Italy.
: We selected all PLWH in four centers of the MaSTER cohort who initiated a DTG-based regimen either when naïve or following a regimen switch between 11 July 2018 and 2 July 2021. Participants were followed until the outcomes were recorded or until the end of the study on 4 August 2022, whichever occurred first. Interruption was reported even when a participant switched to another DTG-containing regimen. Survival regression models were fitted to evaluate associations between therapy performance and age, sex, nationality, risk of HIV transmission, HIV RNA suppression status, CD4+ T-cell count, year of HIV diagnosis, cART status (naïve or experienced), cART backbone and viral hepatitis coinfection.
: There were 371 participants in our cohort who initiated a DTG-based cART regimen in the time frame of the study. The population was predominantly male (75.2%), of Italian nationality (83.3%), with a history of cART use (80.9%), and the majority initiated a DTG-based regimen following a switch strategy in 2019 (80.1%). Median age was 53 years (interquartile range (IQR): 45-58). Prior cART regimen was based mostly on a combination of NRTI drugs plus a PI-boosted drug (34.2%), followed by a combination of NRTIs plus an NNRTI (23.5%). Concerning the NRTI backbone, the majority comprised 3TC plus ABC (34.5%), followed by 3TC alone (28.6%). The most reported transmission risk factor was heterosexual intercourse (44.2%). Total interruptions of the first DTG-based regimen were registered in 58 (15.6%) participants. The most frequent reason for interruption was due to cART simplification strategies, which accounted for 52%. Only 1 death was reported during the study period. The median time of total follow-up was 556 days (IQR: 316.5-722.5). Risk factors for poor performance of DTG-containing-regimens were found to be: a backbone regimen containing tenofovir, being cART naïve, having detectable HIV RNA at baseline, FIB-4 score above 3.25 and having a cancer diagnosis. By contrast, protective factors were found to be: higher CD4+ T-cell counts and higher CD4/CD8 ratio at baseline.
DTG-based regimens were used mainly as a switching therapy in our cohort of PLWH who had undetectable HIV RNA and a good immune status. In this type of population, the durability of DTG-based regimens was maintained in 84.4% of participants with a modest incidence of interruptions mostly due to cART simplification strategies. The results of this prospective real-life study confirm the apparent low risk of changing DTG-containing regimens due to virological failure. They may also help physicians to identify people with increased risk of interruption for different reasons, suggesting targeted medical interventions.
Background/Aims To evaluate the off-treatment durability of response in HBeAg-negative chronic hepatitis B patients who achieved a protocol-defined ‘ Response ’ (HBV-DNA < 0.7 MEq/mL and ALT < 1.25 × ...ULN) with entecavir at 48 weeks and the efficacy of entecavir in patients treated beyond one year. Methods Entecavir-treated and lamivudine-treated patients who achieved a protocol-defined ‘ Response ’ were evaluated off-treatment for HBV-DNA < 300 copies/mL and ALT normalisation. Entecavir- and lamivudine-treated patients who achieved a protocol-defined ‘ Virological Response ’ (HBV-DNA < 0.7 MEq/mL but ALT ⩾ 1.25 × ULN) at 48 weeks, continued blinded treatment until they achieved Response or 96 weeks, whichever came first. Results Among ‘ Responders ’ who discontinued treatment after 48 weeks, 7/257 (3%) entecavir-treated and 10/201 (5%) lamivudine-treated patients sustained HBV-DNA below 300 copies/mL at 24-weeks off-treatment. Among the 54 patients who continued blinded treatment in the second year, 7/26 (27%) entecavir-treated and 6/28 (21%) lamivudine-treated patients normalised ALT and 22/26 (85%) entecavir-treated and 16/28 (57%) lamivudine-treated patients maintained HBV-DNA < 300 copies/mL at end-of-dosing. The safety profiles of both drugs remained comparable through a second year of treatment. Conclusions The majority of protocol-defined Responders relapsed after 1 year when treatment was discontinued. Treatment with entecavir beyond 1 year provided continued virological and biochemical benefit.
Summary Background Bacterial brain abscesses remain a serious central nervous system problem despite advances in neurosurgical, neuroimaging, and microbiological techniques and the availability of ...new antibiotics. The successful treatment of brain abscesses requires surgery, appropriate antibiotic therapy, and eradication of the primary source; nevertheless many controversial issues on the management of this serious infection remain unresolved. Controversial issues The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group – a panel of multidisciplinary experts – was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues were: (1) Which patients with bacterial brain abscesses can be managed safely using medical treatment alone? (1a) What is the efficacy in terms of outcome, tolerability, cost/efficacy, and quality of life of the different antibiotic regimens used to treat bacterial cerebral abscesses? (1b) Which antibiotics have the best pharmacokinetics and/or tissue penetration of brain and/or brain abscess? 2) What is the best surgical approach in terms of outcome in managing bacterial brain abscesses? Results are presented and discussed in detail. Methods A systematic literature search using the MEDLINE database for the period 1988 to 2008 of randomized controlled trials and/or non-randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle–Ottawa Quality Assessment Scale for case–control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence and strength of recommendation was applied.
Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed ...to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis.
ClinicalTrials.gov NCT00751595.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and ...immune activation may hamper anti-HCV response in HIV/HCV patients.
98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.
71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014).
In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
