Rosario Mata

Increased Regulatory T Cell Counts in HIV-Infected Nonresponders to Hepatitis B Virus Vaccine

Hepatitis B virus (HBV) coinfection is a main cause of liver-related mortality in human immunodeficiency virus (HIV)-infected subjects. Unfortunately, HIV-infected subjects show a low rate of response to standard HBV vaccination (23%-56%), in contrast to rates >90% found in the general population, and the underlying causes (particularly cellular and molecular causes) are still unknown. We hypothesized that an increased frequency of regulatory T (T(reg)) cells could be involved in the low rate of seroconversion in HIV-infected subjects. Forty HIV-infected subjects were enrolled in the Assistance Vaccination Program against HBV of the Infectious Diseases Service from the Virgen del Rocío University Hospital, Seville, Spain. Freshly isolated peripheral blood mononuclear cells from baseline were immunophenotyped for T(reg) cells, CD4, and CD8 T cells in both naive and memory subpopulations and activation degree, as well as recent thymic emigrants. Baseline T(reg) cell frequency was found independently associated with the final nonresponse to HBV vaccine in HIV-infected subjects. Furthermore, a negative correlation between baseline frequency of T(reg) cells and antibody titers in the final response was found. These findings suggest an active role played by T(reg) cells on the immunization antigen-specific T and/or B cell responses with the final consequence of a B cell anti-HBs lower production.

Changes in liver stiffness in patients with chronic hepatitis C with and without HIV co-infection treated with pegylated interferon plus ribavirin

OBJECTIVES To evaluate the changes in liver stiffness measurement (LSM) in patients infected by hepatitis C virus (HCV) under pegylated interferon (Peg-IFN) plus ribavirin therapy. METHODS One hundred and forty-three HCV-infected patients, of whom 97 (68%) were also carrying HIV, who started treatment with Peg-IFN/ribavirin were included in this prospective cohort study. The outcome variable of the study was the change in LSM between baseline and the scheduled date for evaluating sustained virological response (SVR). RESULTS The median (Q1-Q3) LSM values at baseline and at the SVR assessment date were 8.1 (6.2-11.6) kPa and 6.8 (5.2-9.8) kPa (P<0.001), respectively. The median (Q1-Q3) decrease between both timepoints was -1 (-2.75, 0.3) kPa. The baseline LSM decreased ≥20% in 37 (46%) patients with SVR and in 19 (30%) without SVR (P=0.05). In the linear regression analysis, baseline LSM {beta [standard error (SE)] -0.712 (0.044), P=0.004}, alcohol intake ≥50 g/day [beta (SE) 0.202 (0.030), P=0.014] and achievement of SVR [beta (SE) -0.238 (0.026), P=0.029] were independently associated with changes in LSM. CONCLUSIONS LSM decreases significantly among patients with chronic HCV infection who achieve SVR with Peg-IFN/ribavirin. These patients show a higher frequency of LSM reduction ≥20% at the date of SVR evaluation.

Prevalence and resistance mutations of non-B HIV-1 subtypes among immigrants in Southern Spain along the decade 2000-2010

BackgroundMost of the non-B HIV-1 subtypes are predominant in Sub-Saharan Africa and India although they have been found worldwide. In the last decade, immigration from these areas has increased considerably in Spain. The objective of this study was to evaluate the prevalence of non-B subtypes circulating in a cohort of HIV-1-infected immigrants in Seville, Southern Spain and to identify drug resistance-associated mutations.MethodsComplete protease and first 220 codons of the reverse transcriptase coding regions were amplified and sequenced by population sequencing. HIV-1 subtypes were determined using Stanford University Drug Resistance Database, and phylogenetic analysis was performed comparing multiple reported sequences. Drug resistance mutations were defined according to the International AIDS Society-USA.ResultsFrom 2000 to 2010 a total of 1,089 newly diagnosed HIV-1-infected patients were enrolled in our cohort. Of these, 121 were immigrants, of which 98 had ethical approval and informed consent to include in our study. Twenty-nine immigrants (29/98, 29.6%) were infected with non-B subtypes, of which 15/29 (51.7%) were CRF02-AG, mostly from Sub-Saharan Africa, and 2/29 (6.9%) were CRF01-AE from Eastern Europe. A, C, F, J and G subtypes from Eastern Europe, Central-South America and Sub-Saharan Africa were also present. Some others harboured recombinant forms CRF02-AG/CRF01-AE, CRF2-AG/G and F/B, B/C, and K/G, in PR and RT-coding regions. Patients infected with non-B subtypes showed a high frequency of minor protease inhibitor resistance mutations, M36I, L63P, and K20R/I. Only one patient, CRF02_AG, showed major resistance mutation L90M. Major RT inhibitor resistance mutations K70R and A98G were present in one patient with subtype G, L100I in one patient with CRF01_AE, and K103N in another patient with CRF01_AE. Three patients had other mutations such as V118I, E138A and V90I.ConclusionsThe circulation of non-B subtypes has significantly increased in Southern Spain during the last decade, with 29.6% prevalence, in association with demographic changes among immigrants. This could be an issue in the treatment and management of these patients. Resistance mutations have been detected in these patients with a prevalence of 7% among treatment-naïve patients compared with the 21% detected among patients under HAART or during treatment interruption.

Very low prevalence and no clinical significance of occult hepatitis B in a cohort of HIV-infected patients with isolated anti-HBc seropositivity: the BHOI study.

Abstract Purpose: Data on occult HBV infection in HIV patients are conflicting. We aimed to analyse the prevalence and clinical significance of occult hepatitis B in HIV-infected subjects. Method: An open-label, cross-sectional, multicentre study including all subjects with isolated anti-HBc seropositivity from a cohort of 3,030 HIV-infected patients was undertaken. HBsAg and HBsAb were both negative in all cases, and those patients with acute or convalescent hepatitis B were excluded. HBV DNA was quantified by PCR with a detection limit of 20 IU/mL. Results: We found 5 cases (2.5%) of occult hepatitis B among 202 HIV-patients with isolated anti-HBc. The mean HBV DNA was 66 (15–112) IU/mL, none had symptomatic hepatitis, and their features, including aminotransferase levels, were similar to those without occult HBV infection. Conclusions: Occult hepatitis due to HBV is very unusual in HIV-positive patients with isolated anti-HBc. The use of standard regimens of HAART including drugs with activity against HBV might underestimate the prevalence of occult HBV infection. These patients had a very low viral load, no identifiable risk factors, and no greater risk of hypertransaminasaemia or the development of symptomatic hepatitis.

Nevirapine-based antiretroviral therapy is associated with lower plasma hepatitis C virus viral load among HIV/hepatitis C virus-coinfected patients.

1Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain 2Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain 3Seccion de Enfermedades Infecciosas, Hospital Universitario Reina Sofia, Cordoba, Spain 4Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocio, Sevilla, Spain 5Seccion de Enfermedades Infecciosas, Hospital Punta de Europa, Algeciras, Spain 6Servicio de Medicina Interna, Hospital Juan Ramon Jimenez, Huelva, Spain 7Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Virgen de la Victoria, Malaga, Spain 8Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen Macarena, Sevilla, Spain 9Unidad de Enfermedades Infecciosas, Complejo Hospitalario de Jaen, Jaen, Spain 10Grupo HEPAVIR de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)

High Seroprevalence But Low Incidence of HCV Infection in a Cohort of Patients With Sexually Transmitted HIV in Andalusia, Spain

Purpose. To analyze the prevalence and the incidence of hepatitis C virus (HCV) seropositivity in sexually transmitted human immunodeficiency virus (HIV) patients. Methods. Observational study of 1468 sexually transmitted HIV-infected patients from 7 hospitals (Southern Spain). Characteristics of HCV cases, and incidence of HCV seroconversion was assessed. Results. Seroprevalence of HCV was 16.1%, higher among heterosexual than homosexual patients, and similar between heterosexual men and women. Seroincidence was 0.16 cases per 100 patient-years, similar between homosexual and heterosexual patients. HCV patients had a mean CD4 of 523 cells/μL, 82.0% were on highly active antiretroviral therapy (HAART), and 72.0% had undetectable HIV viral load. Serum HCV-RNA was positive in 79.0% cases, and only 16.0% had ever received HCV treatment. Conclusions. HCV seroprevalence among sexually transmitted HIV-infected patients is more frequent than in the general population; however, incidence of HCV infection is currently low. Patients with sexually transmitted HIV coinfected with HCV have their HIV infection well controlled, but HCV infection was treated in few cases.

Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

ABSTRACT We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median Cmax, area under the concentration-time curve from 0 to 24 h, and Cmin plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate Cmin levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

Liver Toxicity of Antiretroviral Combinations Including Fosamprenavir Plus Ritonavir 1400/100 mg Once Daily in HIV/Hepatitis C Virus-Coinfected Patients

Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

Background Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. Methods and Findings Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. Conclusions Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. Trial Registration: ClinicalTrials.gov NCT00553930

Virological and immunological stability in HIV infected patients undergoing partial-treatment interruption

BACKGROUND Partial-treatment interruption in patients with drug-resistant viremia has been associated with stable HIV RNA levels suggesting that interruption of protease inhibitors may be an effective strategy for patients without other therapeutic options while waiting for the development of new drugs. OBJECTIVE Our goal was to maintain virological and immunological stability in patients experiencing virologic failure with multiresistant HIV to allow access to newly developed antiretroviral drugs, and to characterize the impact of partial-treatment interruption on replication capacity and resistance profile. STUDY DESIGN From 2003 to 2004, a group of 12 heavily treated patients was studied. Protease inhibitor treatment was interrupted and patients were treated with nucleoside analog retrotranscriptase inhibitors (Trizivir) and the fusion inhibitor Enfurvirtide to establish the therapeutic benefit and the virologic response. RESULTS Both, CD4 T-cell counts and viral load remained stable for a period of time that enabled all the patients to access rescue treatments (median=13.5 months; IQR: 9-19). The replication capacity of the patient-derived viruses significantly decreased or remained stable during the partial-treatment interruption. The decrease in replication capacity was mainly attributable to the selection of viruses carrying at least two fewer minor mutations in the protease. As of December 2008 10 of 12 patients maintained undetectable HIV RNA levels. CONCLUSIONS Study results indicate that a partial-treatment interruption regimen based on Trizivir with Enfurvirtide augmentation allows for a loss of protease inhibitor resistance mutations as well as for a decrease in the replication capacity of patient-derive HIV protease gene recombinants.