Josep M. Guardiola

Drug resistance in patients experiencing early virological failure under a triple combination including indinavir.

ObjectiveTo assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir. Patients and methodsPlasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes. ResultsThe mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359 460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients. ConclusionThe overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus

BACKGROUND & AIMS Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.

Treatment of Chronic Hepatitis C in HIV-Infected Patients with Interferon α-2b Plus Ribavirin

One hundred six HIV-infected patients with chronic hepatitis C virus (HCV) infection were randomized to receive ribavirin (RBV) 400 mg bid plus interferon α-2b (IFN-α) at two different doses, 3 mU tiw (control arm) or 5 mU daily for the first 6 weeks, followed by 3 mU tiw until completing 6 months of therapy (induction arm). All patients had CD4 counts above 350 cells/μl and 89% were taking antiretroviral therapy. Adverse effects leading to treatment discontinuation occurred in 12.3% of patients, a rate quite similar to that seen in HCV-monoinfected patients. Negative serum HCV-RNA values (<60 IU/ml) were recorded in 24.7% and 35.5% of patients at 3 and 6 months of therapy. However, in the intent-to-treat analysis, sustained response was reached by only 16% of patients (22.4% in the on-treatment analysis). No differences between treatment arms were noticed. Patients with HCV genotypes 2 or 3 had a 7-fold higher response rate than those with HCV genotypes 1 or 4. Therefore, early, end-of-treatment, and sus...

IFNL4 ss469415590 Variant Shows Similar Performance to rs12979860 as Predictor of Response to Treatment against Hepatitis C Virus Genotype 1 or 4 in Caucasians

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.

Effects of sustained viral response in patients with HIV and chronic hepatitis C and nonadvanced liver fibrosis.

Objective:We assessed the effects of sustained viral response (SVR), after treating with interferon–ribavirin (IF-RB), on mortality, liver-related (LR) events (decompensation, hepatocellular carcinoma), HIV progression, and liver stiffness in HIV/hepatitis C virus (HCV)-coinfected patients with nonadvanced liver fibrosis. Methods:From a cohort of HIV/HCV-coinfected patients treated with IF-RB, we selected those with baseline liver fibrosis stages F0, F1, or F2 according to METAVIR. The study started when IF-RB was stopped and ended at death or at the last follow-up visit. Results:A total of 695 patients were included (HCV genotype 1 or 4, 431; F0, 77; F1, 290; and F2, 328), and 274 patients achieved SVR. After a median follow-up of 4.9 years, the adjusted hazard ratio (aHR) [95% confidence interval (CI)] of LR events or overall death, for patients with SVR taking the group of patients with no SVR as a reference was 0.217 (0.079 to 0.599) (P = 0.003) for the whole cohort with F0 to F2. For patients with F0, the aHR (95% CI) was 0.514 (0.040 to 6.593) (P = 0.609), for patients with F1, the aHR (95% CI) was 0.305 (0.053 to 1.762) (P = 0.185), and for patients with F2, it was 0.075 (0.009 to 0.662) (P = 0.020). We also found that, in comparison with no SVR, SVR was followed by less frequent HIV progression for the entire population (F0 to F2) and less frequent liver stiffness across all categories of fibrosis. Conclusions:SVR in HIV/HCV-coinfected patients with moderate stages of liver fibrosis is associated with a reduction of mortality and LR events, and with a reduction of progression of HIV and liver fibrosis.

Association of ITPA Gene Polymorphisms and the Risk of Ribavirin-Induced Anemia in HIV/Hepatitis C Virus (HCV)-Coinfected Patients Receiving HCV Combination Therapy

ABSTRACT Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = −0.7; 95% CI = −1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.

Effect of accompanying antiretroviral drugs on virological response to pegylated interferon and ribavirin in patients co-infected with HIV and hepatitis C virus

OBJECTIVES The effects of antiretroviral drugs on the response to pegylated interferon plus ribavirin remain uncertain. We evaluated whether antiretroviral drugs affected the response to pegylated interferon plus ribavirin in patients co-infected with HIV and hepatitis C virus (HCV). METHODS We conducted a retrospective analysis of two cohorts of HIV/HCV-co-infected patients treated with pegylated interferon plus ribavirin between 2001 and 2007 in Spain. The outcome measure was sustained virological response (SVR). Logistic regression models were used to test possible associations between non-response and pre-treatment characteristics, including accompanying antiretroviral drugs. RESULTS The study sample comprised 1701 patients: 63% were infected with HCV genotype (G) 1 or 4 and 88% were taking highly active antiretroviral therapy (HAART). Factors independently associated with increased odds of SVR were G2 or 3, HVC RNA <500,000 IU/mL and CDC clinical category A or B. When we adjusted for these prognostic factors and dose of ribavirin/kg, the adjusted odds ratio (AOR) of SVR for patients without HAART was 1.31 [95% confidence interval (CI) 0.91-1.88; P = 0.144]. Taking the backbone of tenofovir and lamivudine/emtricitabine as a reference, we found that, with the exception of regimens including zidovudine, the effect of other nucleoside reverse transcriptase inhibitor backbones had little effect on SVR. The AOR of SVR for zidovudine and lamivudine was 0.65 (95% CI 0.46-0.93, P = 0.017). We carried out several sensitivity analyses, the results of which were consistent with the findings of the primary analysis. CONCLUSIONS Our results suggest that, with the exception of regimens including zidovudine, accompanying antiretroviral drugs have little effect on the virological response to pegylated interferon plus ribavirin in HIV/HCV-co-infected patients.

STARTVerso4: faldaprevir and pegylated interferon α-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV.

Objective:Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon &agr;-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. Design:A phase 3 open-label study (NCT01399619). Methods:Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Results:SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. Conclusions:High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.

IFNL4 rs368234815 polymorphism is associated with innate resistance to HIV-1 infection.

The interferon (IFN)L4 polymorphism rs368234815 is associated with hepatitis C virus (HCV) spontaneous clearance and response to IFN-based treatments. The role of this polymorphism in HIV-1 infection is controversial. We investigated whether genetic variation at IFNL4 is associated to HIV-1 acquisition. The HCV protective allele TT was associated with decreased likelihood of HIV-1 infection in male intravenous drug users [odds ratio (OR): 0.3; P = 0.006], and this association was not modified by the genotype of CCR5. These results suggest that genetic susceptibility to HCV and HIV-1 infection shares common molecular pathways.

Neurofibromatosis and systemic lupus erythematosus. A matter of coincidence

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that is present in one in 4000 individuals and affects ectodermal and mesodermal tissues. It is well known that patients with neurofibromatosis show an increased incidence of various neoplasms, most of these being tumours of neural crest origin, including neurofibromas, leiomyomas, ganglioneuromas, paragangliomas and carcinoids, but it has also been related to smallbowel adenocarcinoma, pancreatic endocrine malignant tumour, and neurofibromatosis of the colon and urinary bladder [1, 2, 3, 4, 5]. Systemic lupus erythematosus (SLE) is an autoimmmune disease with diverse clinical manifestations and characterised by the production of antibodies to components of the cell nucleus, mostly present in young females. The disease shows strong familial aggregation, mainly in first-degree relatives [6]. We report a young female patient with SLE and NF1 while considering the interest of such an uncommon association. A 32-year-old woman, diagnosed in 1997 with neurofibromatosis type 1 (NF1), presented with numerous cafe-au-lait spots and pedunculated lesions without central nervous system involvement. Genetic study revealed a single mutation in exon 37 of the NF1 gene (679C fi A). In October 2002 she was admitted to our hospital with a history of 1 month of fever together with a symmetrical and bilateral polyarthritis of the knee, ankle, wrist, metacarpophalangeal joints 2 and 3, and all proximal interphalangeal joints (PIP). She also presented with oral ulcers, 30 min morning stiffness, Raynaud s phenomenon and alopecia. Physical examination on admission showed tenderness to palpation of the involved joints. Temperature was 38 C, heart rate 96/min. Laboratory studies revealed haemoglobin 13 g/ dI, white blood cell count 6.9·10/l with 3.6·10/l neutrophils and 0.33·10/l lymphocytes, and erythrocyte sedimentation rate 34 mm/h. Renal and liver function tests were normal. Antinuclear antibodies were >1/320 H, 1/320 S, 1/160 N, positive DNA-EIA and complement levels of C3: 43 mg/100ml (85–193) and C4: 11 mg/ 100ml (12–36). RNP, Sm, Ro and La antibodies were negative. Serologies and microbiological studies for CMV, EBV, CVH, BVH, HV-type 6 toxoplasma and tuberculosis were negative. Based on ACR criteria [7] she was diagnosed with systemic lupus erythematosus (SLE) and treatment with oral hydroxychloroquine and prednisone was begun. The most frequent variant of the group is neurofibromatosis type 1 (NF1), which can vary in severity but can affect all organs. The diagnosis of NF1 is based on clinical criteria, but with the development of molecular genetic tests a wide range of mutations have been described, although the large size of the gene has impeded the development of a clinical diagnostic test [8]. The gene for NF1 has been identified by cDNA cloning, and a homology between the NF1 gene product and members of the GTPase-activating protein (GAP) superfamily has been described [9]. The association of NF1 and SLE has been reported elsewhere and it has been debated whether the association was coincidental or related. The cases described to date showed that SLE was already present when NF1 appeared. The hypothesis that virus infections in SLE patients might play a role in the higher susceptibility to tumours or connective tissue diseases has been supported [10, 11, 12]. In contrast to these reports, our patient was previously diagnosed with NF1, and 6 years later with SLE. No data exist in NF1 patients about their susceptibility to develop SLE. Is that therefore a matter of coincidence? Clin Rheumatol (2003) 22: 496–497 DOI 10.1007/s10067-003-0764-8