Cristina Tural

Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy

OBJECTIVE To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of < 500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). RESULTS HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a > or = 50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a > or = 50 cells/microL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. CONCLUSIONS HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus.

Clinical utility of HIV-1 genotyping and expert advice: the Havana trial.

Objective To determine whether HIV-1 genotyping and expert advice add additional short-term virologic benefit in guiding antiretroviral changes in HIV+ drug-experienced patients. Design A two factorial (genotyping and expert advice), randomized, open label, multi-center trial. The patients were stratified according to the number of treatment failures. Patients and methods HIV-1 infected patients on stable antiretroviral therapy who presented virological failure were included into the study. Genotypic testing was performed by using TrueGene HIV Genotyping kit and the results were interpreted by a software package (RetroGram®, version 1.0). An expert advisory committee suggested the new therapeutic approach based on clinical information alone or on clinical information plus HIV-1 genotyping results. Plasma HIV-1 RNA load, CD4+ cell count and adverse events were recorded at baseline and every 12 weeks. Results A total of 326 patients were included. The baseline CD4+ cell count and plasma HIV-1 RNA were 387 (± 224) × 106 cells/l and 4 (± 1) log10 respectively. The proportion of patients with plasma HIV-1 RNA < 400 copies/ml at 24 weeks differed between genotyping and no genotyping arms (48.5 and 36.2%, P < 0.05). Factors associated with a higher probability of plasma HIV-1 RNA < 400 copies/ml were HIV-1 genotyping [odds ratio (OR), 1.7; 95% confidence interval (CI), 1.1–2.8;P = 0.016] and the expert advice in patients failing to a second-line antiretroviral therapy (OR, 3.2; 95% CI, 1.2–8.3;P = 0.016). Conclusions HIV-1 genotyping interpreted by a software package improves the virological outcome when it is added to the clinical information as a basis for decisions on changing antiretroviral therapy. The expert advice also showed virologic benefit in the second failure group.

Sustained virological response to interferon plus ribavirin reduces liver‐related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus

Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end‐stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver‐related or non–liver‐related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow‐up of 20.8 months (interquartile range: 12.2‐38.7), the incidence rates per 100 person‐years of overall mortality, liver‐related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log‐rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver‐related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3‐F4 versus those with F0‐F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect. Conclusion: Our results suggest that the achievement of an SVR after interferon‐ribavirin therapy in patients coinfected with HIV/HCV reduces liver‐related complications and mortality. (HEPATOLOGY 2009.)

Prospective randomized two-arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.

Background: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long‐term period of therapy are necessary. Methods: This is a prospective, randomized, two‐arm controlled study including patients starting their first‐ or second‐line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow‐up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long‐term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long‐term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self‐reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of ≥95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. Results: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence ≥95% (p = .008); 89% of patients in the EG versus 66% controls had HIV‐1 RNA levels <400 copies/ml (p = .026). Overall, 85% of patients with adherence ≥95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p = .008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p = .04), poor effort to take medication (OR, 5.38; p = .03), and high self‐perceived capacity to follow the regimen (OR, 13.76; p = .04). Self‐reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. Conclusions: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patients compliance in the clinical setting.

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults

With the decline in HIV‐associated morbidity and mortality following the introduction of highly active antiretroviral therapy (HAART), liver disease has emerged as a major cause of death in HIV/hepatitis B virus (HBV) and HIV/hepatitis C virus (HCV) coinfected persons. Therefore, screening for underlying viral hepatitis coinfection and the provision of management and treatment recommendations for patients with chronic viral hepatitis are of great importance in preventing, as far as possible, the development of liver disease. With the introduction of new agents for the treatment of hepatitis B and increased knowledge of how best to manage hepatitis C, an update of current guidelines for management of HBV and HCV coinfection with HIV is warranted.

Long-Lasting Remission of Cytomegalovirus Retinitis without Maintenance Therapy in Human Immunodeficiency Virus-Infected Patients

Seven AIDS patients who were receiving suppressive therapy for previously diagnosed cytomegalovirus (CMV) retinitis were offered treatment with protease inhibitors (PIs). Secondary prophylaxis for CMV was discontinued after 3 months of therapy with PIs if patients had >150 CD4 cells/mm3 and a human immunodeficiency virus (HIV) load of <200 copies/mL and if they were negative for CMV as determined by qualitative CMV polymerase chain reaction (PCR). Ophthalmologic exams were done periodically. After a median follow-up of 9 months (range, 9-12), no new episodes of CMV retinitis were observed. CD4 cell counts were >150 cells/mm3 in all cases, HIV loads were <200 copies/mL, and results for qualitative CMV PCRs remained negative. These observations suggest that for selected patients with healed CMV retinitis who have immunologic and virologic evidence of a clinical response to potent combination antiretroviral therapy, temporary discontinuation of a chronic anti-CMV suppressive therapy may not result in further retinal necrosis. However, the long-term immunologic benefit of PIs and hence the safety of prolonged withdrawal of anti-CMV therapy is unknown.

Virological, Immunological, and Clinical Impact of Switching from Protease Inhibitors to Nevirapine or to Efavirenz in Patients with Human Immunodeficiency Virus Infection and Long-Lasting Viral Suppression

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.

Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens.

&NA; We assessed the impact of an efavirenz‐containing regimen versus a protease inhibitor‐containing regimen on quality of life, emotional status, and adherence of HIV‐1‐infected patients. In addition, we sought to define the adverse events associated with these treatments, with a special focus on central nervous system disorders in the efavirenz treatment group. This prospective, randomized, two‐arm, controlled study included 100 patients for whom initial treatment with a protease inhibitorcontaining regimen failed. Patients were randomized to start treatment with two nucleoside retrotranscriptase inhibitors plus efavirenz (group 1; 51 patients) or two nucleoside retrotranscriptase inhibitors plus one or more new protease inhibitors (group 2; 49 patients). Quality of life was assessed by a five‐point item adapted from the HIV questionnaire of the Medical Outcomes Study, emotional status was evaluated by the Profile of Mood State questionnaire, and patients self‐reported adherence. Data were analyzed by both an as‐treated method and an intention‐to‐treat‐last observation carried forward method. Patients in group 1 reported the following findings at week 4: dizziness (66%), abnormal dreaming (48%), light‐headedness (37%), and difficulty sleeping (35%). At week 24, dizziness (13%; p < .001), abnormal dreaming (18%; p = .002), light‐headedness (13%; p = .01), difficulty sleeping (7%; p = .001), and nervousness (13%; p = .01) decreased in these patients. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% of group 1 patients, respectively. Patients in group 2 reported the following findings at week 4: lightheadedness (8%), dizziness (5%), difficulty sleeping (4%), nervousness (4%), and headaches (3%). Patients in group 2 reported the following findings at week 48: difficulty sleeping (4%), nervousness (3%), headaches (3%), and light‐headedness (2%). In group 1, quality of life (p < .001) and emotional status (week 48; p = .004) improved, both of which were better than those in group 2 (p = .001). Both groups maintained high levels of medication adherence, and no significant differences in the number of patients who had viral loads of <200 copies/mL at week 48 were found (78% of group 1 patients vs. 85% of group 2 patients; p = not significant). At week 48, the mean CD4 cell count ± SD was 497 ± 224/mm3 in group 1 and 539 ± 298/mm3 in group 2 (p = not significant). Despite similar immunologic and virologic outcomes, a second‐line efavirenz‐containing regimen improved quality of life of HIV‐1‐infected patients compared with a second‐line protease inhibitor‐containing regimen. However, close follow‐up of patients receiving treatment with efavirenz‐based regimens is recommended, especially for those with previous emotional disturbances due to central nervous system disorders in the short term and those with persistence of a low percentage of these disorders in the long term.

Randomized trial comparing pegylated interferon α‐2b versus pegylated interferon α‐2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients

Although two pegylated interferons (Peg‐IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head‐to‐head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa‐2b (PEG 2b) versus PEG IFN alfa‐2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi‐center, open‐label clinical trial including 182 human immunodeficiency virus (HIV)–hepatitis C virus (HCV) patients naïve for HCV therapy was performed. Patients were assigned to PEG 2b (80‐150 μg/week; n = 96) or PEG 2a (180 μg/week; n = 86), plus RBV (800‐1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV‐RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 through 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 through 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 through 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; ≥2 log reduction from baseline or negative HCV‐RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety. (HEPATOLOGY 2009;49:22‐31.)

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.