Plasma ribavirin trough concentrations at week 4 predict hepatitis C virus (HCV) relapse in HIV-HCV-coinfected patients treated for chronic hepatitis C.

The influence of ribavirin trough concentrations (RBV C(trough)) on the risk of hepatitis C virus (HCV) relapse was retrospectively analyzed in 99 HIV-HCV-coinfected patients who achieved end-of-treatment response with pegylated alpha interferon plus weight-based RBV. The independent predictors (odds ratio [OR] [95% confidence interval (CI)]) of HCV relapse were RBV plasma C(trough) of <2.5 microg/ml (4.5 [1.3 to 15.5]), baseline serum HCV RNA (2.5 [1.2 to 5.1]), and HCV genotype 1 or 4 (13.3 [2.6 to 66.7]). Monitoring of RBV C(trough) may permit early adjustment of RBV dosage to avoid HCV relapse.

High sensitivity of specific genotypic tools for detection of X4 variants in antiretroviral-experienced patients suitable to be treated with CCR5 antagonists.

OBJECTIVES: Evaluation of the reliability of several V3-based genotypic predictors to infer viral tropism in patients infected with B and non-B strains of HIV-1. METHODS: Several genotypic tropism predictors were evaluated in plasma (RNA) samples from 198 HIV-1-infected patients, taking as gold standard the results of the phenotypic recombinant virus assay Phenoscript((R)). In addition, for 37 B subtype HIV-1 patients the phenotypic results from plasma samples were also compared with tropism predictions based on V3 amplification from paired peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 150 paired genotypic/phenotypic results were obtained from plasma specimens. Concordance values ranged from 63% to 85%, depending on the genotypic algorithm used. The best predictors in terms of sensitivity/specificity to detect X4 variants were WebPSSM(X4/R5) (77%/87%), Geno2pheno(FPR) (=) (5%) (80%/77%) and an algorithm combining the '11/25' and 'Net charge' rules, termed Garrido's rule (80%/79%). The performance of genotypic predictors was better testing B than non-B clades. The overall sensitivity ranged from 28% to 94%, reaching 100% in subtype B antiretroviral-experienced patients using WebPSSM(SI/NSI), Geno2pheno(FPR) (> or =) (5%) and Garrido's rule. Conversely, the sensitivity when testing non-B subtypes was poorer, ranging from 17% to 67%. Interestingly, the correlation between genotypic and phenotypic results was better when testing PBMCs than plasma using all genotypic predictors. CONCLUSIONS: Genotypic tools based on V3 sequences may provide reliable information on HIV-1 tropism when testing clade B viruses, especially in antiretroviral-experienced patients. The sensitivity to detect X4 variants using genotypic tools may improve by testing proviral DNA instead of plasma RNA.

Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial.

BACKGROUND: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half-life might allow once-daily (qd) administration. METHODS: Consecutive HIV-infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir. Patients were randomly assigned to raltegravir 800 mg qd, 400 mg bid, or twice daily for the first 3 months and then once daily. RESULTS: A total of 222 patients completed 24 weeks of follow-up on raltegravir (149 once-daily arm, 35 twice-daily arm, and 38 twice-daily to once-daily arm). At inclusion, mean CD4+ count was 574±308 cells/µL. Within 24 weeks, 13 (5.9%) patients experienced virological failure: 12 (6.4%) in the once-daily arms, and 1 (2.9%) in the twice-daily arm (P = .18). The rate of virological failure was 16.2% (12/74) in patients with prior nucleoside reverse transcriptase inhibitor (NRTI) resistance but only 0.7% (1/148) in the rest (P < .001). CONCLUSION: A switch from PIs to raltegravir in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen when comparing raltegravir twice daily or once daily in this context, although once-daily dosing tended to perform less well.

The benefit of simplification from tipranavir/ritonavir 500/200 bid to 500/100 bid guided by therapeutic drug monitoring.

Despite being among the most potent protease inhibitors, the use of tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.

Use of different inhibitory quotients to predict early virological response to tipranavir in antiretroviral-experienced human immunodeficiency virus-infected patients.

Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of > or = 1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (C(trough))/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society-USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hépatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR-) [LHR+ = sensitivity/(1-specificity); LHR- = (1-sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV C(trough), vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV C(trough), and 1.3 for the IAS-USA and RESIST scores. The values of LHR- were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV C(trough). HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.

Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists.

BACKGROUND: Genotypic tools may allow easier and less expensive estimation of HIV tropism before prescription of CCR5 antagonists compared with the Trofile assay (Monogram Biosciences, South San Francisco, CA, USA). METHODS: Paired genotypic and Trofile results were compared in plasma samples derived from the maraviroc expanded access programme (EAP) in Europe. A new genotypic approach was built to improve the sensitivity to detect X4 variants based on an optimization of the webPSSM algorithm. Then, the new tool was validated in specimens from patients included in the ALLEGRO trial, a multicentre study conducted in Spain to assess the prevalence of R5 variants in treatment-experienced HIV patients. RESULTS: A total of 266 specimens from the maraviroc EAP were tested. Overall geno/pheno concordance was above 72%. A high specificity was generally seen for the detection of X4 variants using genotypic tools (ranging from 58% to 95%), while sensitivity was low (ranging from 31% to 76%). The PSSM score was then optimized to enhance the sensitivity to detect X4 variants changing the original threshold for R5 categorization. The new PSSM algorithms, PSSM(X4R5-8) and PSSM(SINSI-6.4), considered as X4 all V3 scoring values above -8 or -6.4, respectively, increasing the sensitivity to detect X4 variants up to 80%. The new algorithms were then validated in 148 specimens derived from patients included in the ALLEGRO trial. The sensitivity/specificity to detect X4 variants was 93%/69% for PSSM(X4R5-8) and 93%/70% for PSSM(SINSI-6.4). CONCLUSIONS: PSSM(X4R5-8) and PSSM(SINSI-6.4) may confidently assist therapeutic decisions for using CCR5 antagonists in HIV patients, providing an easier and rapid estimation of tropism in clinical samples.

[Malignancies in HIV infected patients: study of 139 cases]. / Tumores en pacientes con infección por el virus de la inmunodeficiencia humana: estudio de 139 casos.

BACKGROUND AND OBJECTIVE: Since the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has been altered by an increasing survival. Following this, neoplastic diseases have become more common in HIV positive patients. The purpose of this study was to describe the types of tumor, clinical features and prognosis of HIV infected patients with malignant diseases. PATIENTES AND METHODS: A descriptive study of epidemiological and clinical features was undertaken at Hospital Carlos III, in Madrid. Information was collected on age, sex, risk factors for HIV, HBV/HCV coinfection, malignancies, diagnosis of AIDS, viral load and CD4 cell counts at diagnosis, antiretroviral therapy and mortality. A total of 139 HIV-infected patients were identified who had at least one malignancy. Statistical analysis was performed using SPSS 15.0 package. RESULTS: Types of malignancy were Kaposi's Sarcoma (n=43, 30.9%); non-Hodgkin lymphoma (n=42, 30.2%); gynecologic malignancy (n=16, 11.5%); Hodgkin's disease (n=15, 10.8%); hepatocellular carcinoma (n=7, 5%) and others (n=16, 11.5%). Mean age at diagnosis was 40 years (IC 95% 38.51-1.50). Male/female ratio was 3.63. Patients with HBV or HCV coinfection were 1.4% and 35.3% respectively. Risk factor for HIV was MSM (n=64;46%), IDUs (n=48; 34.5%) and heterosexual (n=26; 18.7%). Viral load was undetectable in 27 cases (19.4%); CD4 cell count was<200 cell/mcl in 58 cases (41.7%). There were 77 (55.4%) patients on HAART when cancer was diagnosed. Mean time on HAART was 23.31 months. Ten patients (7.2%) developed a secondary tumor. Twelve years survival was 20%. CONCLUSIONS: Increased survival of HIV-infected patients receiving HAART makes it possible the development of secondary tumors and AIDS- unrelated malignancies, sometimes related to another virus.

Changing patterns in HIV reverse transcriptase resistance mutations after availability of tenofovir.

Assessment of 1177 human immunodeficiency virus (HIV) resistance genotypes at an HIV/AIDS clinic showed a decrease in the incidence of the K65R mutation, from 15.2% of isolates during the period 2002-2004 to 2.7% of isolates during the period 2005-2006 (P < .001), despite elevated and stable rates of tenofovir use. A reduction in the rate of coadministration of didanosine (from 41.6% of patients in 2004 to 0.8% of patients in 2006; P < .001) largely explained this observation.

Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy: frequency, predictors and outcome.

BACKGROUND: The rate, predictors and outcome following episodes of low-level viral rebound (LLVR) in HIV patients on highly active antiretroviral therapy (HAART) are unknown. METHODS: Retrospective assessment of all HIV patients who experienced LLVR episodes on HAART at one institution from January 1999 to December 2006. LLVR was defined as plasma HIV-RNA between 51 and 500 copies/mL after at least two consecutive undetectable plasma viral load measurements made during the last 6 months. Virological failure was defined as plasma HIV-RNA >500 copies/mL. RESULTS: Out of 2720 HIV patients on successful HAART during the 8 year study period, 779 (28.6%) developed at least one LLVR episode. Only 655 patients who kept unchanged their HAART regimen following LLVR episodes were further examined. After 12 weeks, undetectable viraemia was regained in 458 (71%), which were considered as blips. In contrast, 66 (9%) LLVR episodes were followed by virological failure, and drug resistance mutations developed in most cases, mainly rtM184V (66%) and rtK103N (29.5%). Plasma HIV-RNA remained between 51 and 500 copies/mL at 12 weeks in the remaining 131 (20%) patients with LLVR episodes. In the multivariate analysis, only plasma HIV-RNA levels at the time of LLVR predicted subsequent virological failure. CONCLUSIONS: Episodes of LLVR in HIV patients on successful HAART are relatively common and represent transient events (blips) in most cases (71%). Keeping the same treatment regimen, virological failure follows in <10% of the cases. Plasma HIV-RNA level at the time of LLVR is the best predictor of subsequent failure.

Subtype variability, virological response and drug resistance assessed on dried blood spots collected from HIV patients on antiretroviral therapy in Angola.

BACKGROUND: Subtype variability may influence treatment response and selection of drug resistance mutations in HIV-positive patients on antiretroviral therapy. PATIENTS AND METHODS: A retrospective study was performed on specimens collected on dried blood spots (DBS) from HIV-positive individuals receiving antiretroviral therapy in Luanda, Angola. HIV-RNA, drug resistance mutations and subtypes were examined in 294 HIV-positive patients treated with two nucleoside analogues (NA) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI). RESULTS: Overall, 217 (74%) had <1000 HIV-RNA copies/mL after a median of 12 months (range 7-24) of therapy. CD4 count was significantly higher in subjects with undetectable viraemia compared with viraemic patients (294 versus 220 cells/mm3; P = 0.003). Reverse transcriptase and/or gp41 genes could be genotyped in only 45 (58%) of viraemic patients, probably due to poor storage conditions of DBS. The most frequent resistance mutations were M184V (70%) and K103N (39%); 65% had mutations conferring resistance to both NA and NNRTI. Only five patients did not show resistance mutations. A wide HIV-1 subtype heterogeneity was found: 6 C (18.2%), 2 F (6%), 2 H (6%), 1 D (3%), 1 G (3%), 8 CRF02_AG (24.2%), 2 CRF06 (6%), 1 CRF01_AE (3%), 1 CRF14_BG (3%), 1 CRF25 (3%) and 1 CRF19 (3%). HIV clade could not be assigned in 7 (21%). CONCLUSIONS: Nearly three-quarters of HIV-positive individuals who began an NNRTI-based triple regimen in Angola showed undetectable viraemia after a median of 12 months of therapy, a rate similar to that reported in Western countries. Specimens collected on DBS may allow monitoring of treatment response in resource-limited regions, although adequate temperature and humidity storage conditions are important to ensure RNA stability and further successful testing.

Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trial.

BACKGROUND: Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile. Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk. METHODS: SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/ritonavir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up. RESULTS: A total of 189 patients were recruited and took at least the first dose of the assigned treatment arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All patients received the PI along with two nucleoside analogues. Virological failure occurred in 12 patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in median total cholesterol (-19 mg/dL) and triglycerides (-80 mg/dL) was observed after 48 weeks of atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without ritonavir boosting. CONCLUSIONS: The replacement of lopinavir/ritonavir by atazanavir provides an overall significant reduction in total cholesterol and triglycerides, without increased risk of virological failure.

Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements.

BACKGROUND: The choice of antiretroviral drugs has evolved over the last decade. Recognition of trends and determinants of changes may help to make predictions on prescription patterns. METHODS: Longitudinal analyses were performed every 6 months from 1996 to 2006, of all HIV-infected individuals who attended at one HIV/AIDS referral centre located in Madrid, Spain. RESULTS: A total of 2602 different individuals attending during the study period were examined over 23 consecutive time-points. The number and proportion of patients under antiretroviral therapy significantly increased in the period 1996-99, with a plateau since then around 1100 patients, which represented around two-thirds of the patients seen at each time-point after the year 2000. The proportion of patients under antiretroviral therapy having undetectable viraemia significantly increased from 34.5% in 1996 to 80% in 2006. The relative use of nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) has risen in recent years, while prescription of non-nucleoside reverse transcriptase inhibitors has declined compared with the period 1999-2001, when it peaked. Among NRTIs, the use of zalcitabine, stavudine and didanosine has dramatically declined or vanished, while zidovudine, lamivudine, abacavir and tenofovir have gained relevance. Among PIs, indinavir and nelfinavir have almost disappeared, being replaced by ritonavir-boosted PIs, mainly atazanavir and lopinavir. After its first introduction in the year 1999, efavirenz has been generally preferred over nevirapine. CONCLUSIONS: The choice of antiretroviral drugs has evolved during the last decade, with safety and convenience issues driving most changes in prescription patterns, while antiviral success has dramatically increased.

Update on the treatment of chronic hepatitis C in HIV-infected patients.

Liver disease is currently the second leading cause of death in HIV-infected persons in Western countries. Hepatitis C virus infection accounts for the majority of cases of hepatic illness in this population. Although great progress has been made in the treatment of chronic hepatitis C in HIV-positive patients, many challenges still remain unsolved. The combination of pegylated interferon plus ribavirin is the current treatment of choice in hepatitis C virus/HIV-coinfected patients, regardless of hepatitis C virus genotype. However, the limited efficacy of this therapy in the HIV setting makes necessary the development of new strategies and/or drugs for the treatment of hepatitis C infection. Several anti-hepatitis C virus compounds are currently under investigation, although most are still in the early stages of clinical development. There is a relatively large group of patients who will be unable to be treated with the current hepatitis C virus medication based on interferon, mainly due to contraindications such as serious neuropsychiatric or cardiovascular history. However, for those without contraindications, treatment should be provided with no restrictions at the start (e.g. asking unnecessarily for a liver biopsy), and reassessed at weeks 4 and 12, considering virologic responses. Treatment should only be continued in early virologic responders. The use of standard doses of ribavirin (1000-1200 mg/day) and for at least 12 months seems crucial to maximize the effect of current hepatitis C treatment in the HIV setting, while no further benefit seems to derive from using higher than recommended pegylated interferon dosages. In patients with rapid virologic response (undetectable viremia at week 4) to anti-hepatitis C therapy, shorter periods of therapy (24 weeks) may be advisable in hepatitis C genotypes 2 and 3. Finally, adequate selection of candidates and careful selection of concomitant antiretroviral medications must be encouraged. Patients with low CD4 percentages (< 15%) should be deferred for treatment and HAART prioritized in order to improve CD4 counts. When possible, nucleoside analogs such as zidovudine, stavudine, and abacavir should be replaced by others having no deleterious interactions with ribavirin (e.g. tenofovir, lamivudine, or emtricitabine). Didanosine should never be coadministered with ribavirin due to potential life-threatening complications.

Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia.

BACKGROUND: Hyperbilirubinemia is frequently seen in patients treated with atazanavir (ATV). Polymorphisms at the uridin-glucoronosyl-transferase 1A1 (UGT1A1) and multidrug resistance 1 (MDR1) genes may influence, respectively, bilirubin and ATV plasma concentrations. PATIENTS AND METHODS: HIV-infected individuals receiving ATV 300 mg daily plus ritonavir 100 mg daily at one clinic were examined. ATV plasma concentrations were measured at steady state. MDR1-3435C>T and UGT1A1 polymorphisms were examined in DNA extracted from blood mononuclear cells. RESULTS: A total of 118 patients (all Caucasian) were analysed. The median ATV plasma concentration was 465 ng/ml [interquartile range (IQR), 233-958]. MDR1-3435 genotypes were as follows: CC (32%), CT (47%) and TT (21%). CC patients showed higher ATV minimum concentration than those with CT/TT genotypes: 939 ng/ml (IQR, 492-1266) versus 376 ng/ml (IQR, 221-722) (P = 0.001). In multivariate analyses, having at least one T allele at MDR1-3435 was independently associated with lower ATV plasma concentrations (beta: -427 [95% confidence interval (CI), -633 to -223]; P < 0.001). The proportion of patients with grade 3-4 hyperbilirubinemia varied with distinct UGT1A1 genotypes: 80% for 7/7, 29% for 6/7 and 18% for 6/6 (P = 0.012). In the multivariate analysis, having at least one 7 allele at UGT1A1 was independently associated with severe hyperbilirubinemia (odds ratio, 2.96; 95% CI, 1.29-6.78; P = 0.01). CONCLUSIONS: Polymorphisms at MDR1-3435 significantly influence ATV plasma concentrations, as does being Caucasian patients with CT/TT genotypes, having lower ATV levels, even using ritonavir boosting. On the other hand, although ATV plasma concentrations directly correlate with bilirubin levels, the risk of severe hyperbilirubinemia is further increased in the presence of the UGT1A1-TA7 allele.

Mitochondrial DNA depletion in HIV-infected patients with chronic hepatitis C and effect of pegylated interferon plus ribavirin therapy.

BACKGROUND: The metabolic stress derived from high levels of virus replication in both HIV and hepatitis C virus (HCV) infections results in mitochondrial DNA depletion, which seems to be enhanced in co-infected patients. The use of nucleoside analogues to treat HIV infection may further increase mtDNA depletion by inhibiting gamma DNA polymerase. Information on the impact of therapy with pegylated interferon (pegIFN) plus ribavirin on mtDNA is scarce and conflicting results have been reported. PATIENTS AND METHODS: Fifty-nine HCV/HIV-co-infected patients (43 on and 16 off antiretroviral therapy) who initiated treatment with pegIFN plus ribavirin were retrospectively analysed. The amount of mtDNA in peripheral blood mononuclear cells (PBMC) was measured at baseline and at the end of HCV therapy. RESULTS: Mean baseline serum HCV-RNA was 5.8 log IU/ml and 56% of patients were infected by HCV genotype 1. An inverse correlation between serum HCV-RNA levels and PBMC mtDNA content was recognized at baseline (r = -0.370; P = 0.006). HCV-RNA suppression at the end of HCV therapy was associated with a significant increase in mtDNA, particularly in patients with baseline HCV-RNA levels greater than 6 log IU/ml (+61 mtDNA copies/cell) and in subjects not taking antiretroviral therapy (+133 mtDNA copies/cell). CONCLUSION: HCV replication correlates with the extent of mtDNA depletion in PBMC, and treatment of chronic hepatitis C is associated with a significant improvement in mtDNA content. This benefit, however, is not recognized when HCV medications are used along with antiretroviral therapy, probably because of a deleterious interaction of these drugs on mitochondria.

Evolution of T-cell responses to hepatitis C virus (HCV) during pegylated interferon plus ribavirin treatment in HCV-monoinfected and in HCV/HIV-coinfected patients.

BACKGROUND: The role of T-cell immunity in chronic hepatitis C virus (HCV) infection remains controversial. As in HIV infection, virus replication could drive or be contained by T-cell immunity. We have examined the effect of HIV coinfection and of suppression of HCV replication with therapy on HCV-specific T-cell responses. PATIENTS AND METHODS: Thirty-five patients with chronic hepatitis C (17 coinfected with HIV) initiating anti-HCV therapy were analysed. HCV-specific responses were assessed at different time points using intracellular interferon-gamma staining in response to a panel of overlapping peptides comprising E2, NS3, NS5a and NS5b HCV proteins. RESULTS: At baseline, HCV-specific responses were significantly lower in HIV-coinfected patients. At week 12 of therapy, CD8+ T-cell responses against all HCV proteins significantly decreased in HCV-monoinfected patients and this was maintained throughout the follow-up period. Although the same trend occurred in the HIV-coinfected group, differences were not significant. CD4+ T-cell responses against NS3 significantly diminished in the HCV-monoinfected group, whereas in coinfected patients CD4+ T-cell responses were low at baseline and did not experience any significant variation. CONCLUSIONS: HCV-specific T-cell responses are lower in HIV-coinfected patients and vanish following complete suppression of HCV replication under successful HCV therapy, suggesting that they are dependent on continuous antiqenic stimulation.

Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards.

The use of abacavir (ABC) may be associated with a hypersensitivity reaction (HSR) that requires discontinuation of the drug. The HLA-B*5701 allele has been linked to this HSR. Information on the strength of this association across distinct geographic regions and ethnicities is scarce. We tested HLA-B*5701 in 53 Spaniards infected with HIV who received ABC treatment. The presence of HLA-B5701 had strong positive and negative predictive values for ABC HSR, 92% and 63%, respectively.

Changing rates and patterns of drug resistance mutations in antiretroviral-experienced HIV-infected patients.

Surveillance of drug resistance mutations in antiretroviral-experienced HIV(+) patients may provide useful information regarding options available for rescue interventions. All resistance tests performed from 1999 to 2005 on antiretroviral-experienced individuals at one reference laboratory in Madrid were examined. Only mutations associated with drug resistance recorded at the September 2006 IAS-USA list were considered. A total of 2137 specimens were analyzed. Overall, 71.1% showed resistance mutations to at least one drug class, 56.1% to at least two, and 21% to all three drug families. Resistance mutations were 65% for NRTI, 44.4% for NNRTI, and 42.5% for PI. Mutations T215Y/F, M184V, and M41L were the most frequent for NRTI. Their rate significantly declined since 1999. K65R significantly increased since 1999 (0.8%) to 2003 (7.3%) but declined up to 3.3% in 2005. For NNRTI, K103N significantly increased from 21.8% in 1999 to 29.5% in 2005 (p < 0.01). The most frequent PI resistance mutations were L90M (24.3%), V82X (19.9%), M46I/L (19.5%), and I54V (17.1%). The presence of five or more was 58.8% in 1999 but declined to 22.2% in 2005. The rate of drug resistance mutations causing NRTI and PI resistance has steadily declined in antiretroviral-experienced patients since 1999. The availability of a large number and/or more convenient NRTI as well as the wide use of ritonavir-boosted PI could explain these observations. However, broad PI cross-resistance was seen in nearly 25% of antiretroviral-experienced patients in 2005. Therefore, there is a still need for new antiretrovirals with different resistance profiles.

Efficacy and safety of a once daily regimen with efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study.

The combination of didanosine (ddI) and lamivudine (3TC) is attractive considering its low cost, potency, tolerability, and convenience (once daily administration), but it is not recommended as first-line therapy for HIV infection. A prospective, multicenter, open, comparative trial was conducted in HIV-infected, antiretroviral-naive persons in Spain who begun a QD regimen with efavirenz (EFV), 3TC, plus ddI, the latter with or without food. A total of 103 patients were recruited in the study. Median baseline CD4 count was 229 cells/microl and plasma HIV-RNA was 4.9 logs copies/ml. In an intent-to-treat analysis, 78 (75.8%) had undetectable viremia at week 48 of therapy, without significant differences when comparing patients on and without fasting ddI (75% vs. 76.6%, respectively). The mean CD4 increase was of 199 cells/microl, with no significant differences between groups. Overall, 29 adverse events were recorded in 23 patients, the majority associated with neuropsychiatric symptoms of EFV. Treatment was discontinued in 10 (9.7%) patients due to adverse events. Virological failure was recognized in only six patients, four taking ddI with and two without food (p = 0.3). Drug resistance mutations were recognised in four of them. Plasma ddI concentrations did not differ significantly between groups. Mitochondrial DNA within peripheral blood mononuclear cells tended to increase in most subjects over 48 weeks of therapy regardless of treatment group. A QD regimen with ddI, 3TC, and EFV shows potency and tolerance similar to that reported using other currently recommended regimens in drug-naive HIV-infected patients. Its efficacy does not seem to be compromised when ddI is administered with food. Therefore, this regimen merits further investigation in larger comparative trials.

[Immigration and HIV-1 infection: clinical manifestations, subtypes and evolution of 78 patients attended during the last 5 years]. / Infección por el virus de la inmunodeficiencia humana tipo 1 e inmigración: manifestaciones clínicas, subtipos y evolución de 78 pacientes ingresados durante los últimos 5 años.

BACKGROUND AND OBJECTIVE: To analyse the characteristics and HIV-1 subtype in a group of HIV+ hospitalised immigrants in our Infectious Diseases Unit. PATIENTS AND METHOD: Clinical reports of 78 immigrants HIV+ were reviewed. HIV-1 subtyping was carried out examining the protease and transcriptase genes by phylogenetic analysis. Statistical study was done by SPSS 11.0 program. RESULTS: 57% of patients come from sub-Saharian Africa. Mainly they had been infected by heterosexual contact. HIV was diagnosed at the hospitalisation time in 35 cases. Only 28% were receiving highly active antiretroviral therapy and 48,7% had CD4+ cells less than 200/microl. The more frequent diagnosed diseases were: tuberculosis (20.5%), candidiasis (24.4%), bacterial pneumonia (19.2%) and malaria (21.8%). HIV-1 subtype B was isolated in 26 patients, none Africans. Twenty nine individuals (52.8%) were infected with HIV-1 non-B subtypes. Relationship between HIV-1 subtype, immunodepression, diagnosed diseases and origin countries was not found apart from malaria. CONCLUSIONS: Most HIV-1 infected immigrants are from Africa, being predominantly infected with HIV-1 non-B subtypes. No relationship between HIV subtype and diagnosed diseases was found.