Jordi Tor

Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538)

Objective:To define genotypic and phenotypic resistance patterns following prolonged therapy with the protease inhibitor ritonavir (ABT-538). Design:Seven HIV-1-infected patients, all but one previously treated with dideoxynucleoside analogues (zidovudine, didanosine, zalcitabine), were treated for 1 year with ritonavir. Methods:Direct solid-phase sequencing of the protease gene starting from plasma derived viral RNA followed by comparison to phenotypic drug resistance data. Results:The most frequent amino-acid substitutions occurring upon administration of the protease inhibitor were V82A/F (substrate binding site), I54V (flap region), A71V and L10I. Additional mutations found in more than one patient were I15V, M36I, I84V and I93L. Mutation L63P was found both in pre- and post-ritonavir samples. Phenotypic drug resistance assays confirmed resistance to ritonavir in post-treatment samples (~170-fold) and showed cross-resistance to indinavir (~30-fold) and partially to saquinavir (~fivefold). At 1 year of treatment, one patient without known resistance-associated mutations in the protease gene still showed a substantial rise in CD4 cell count accompanied by a more than 2.4 log decrease in RNA viral load. However, at week 78, mutations R8Q, E34K, R57K, L63P and I84V were detected and the treatment benefit was partially lost. Conclusions:Long-term treatment with ritonavir is associated with the emergence of multiple mutations in the HIV-1 protease gene. The mutations L10I, I54V, L63P, A71V, V82A/F and I84V correspond to known drug-resistance mutations for ritonavir and other protease inhibitors. Phenotypic resistance to ritonavir was detected in a majority of ritonavir-treated patients at 1 year of treatment. In addition, long-term ritonavir treatment selects for cross-resistance to the protease inhibitors indinavir and saquinavir. This argues against sequential therapy with several protease inhibitors. Delayed resistance in one patient was accompanied with a prolonged increase in CD4 cell count and decrease in viral load suggesting a temporary benefit of treatment.

Early HCV dynamics on Peg-interferon and ribavirin in HIV/HCV co-infection: indications for the investigation of new treatment approaches

Objectives: To describe the 28-day hepatitis C virus (HCV) kinetics under Pegylated-interferon (Peg-IFN) + ribavirin (RBV) therapy in HIV/HCV co-infected patients. To evaluate the predictive value of early virological response (EVR) of achieving a sustained virological response (SVR). To investigate the baseline mutations in the interferon sensitivity determining region (ISDR)2209–2248 in the non-structural 5A protein of HCV according to genotype. Methods: Open, prospective trial including 28 co-infected patients with directly observed treatment with Peg-IFN + RBV. We assessed the predictive values of EVR (⩾ 2 log10 of HCV decay or a negative qualitative test) at days 1, 7, 28 and in week 12 of the SVR. Results: The SVR in an intention-to-treat analysis was 28.6% (genotype 1, 1/13; genotype 3, 6/10; genotype 4, 1/5). Patients who reached SVR presented a significantly faster HCV plasma viral load reduction compared to non-responders from the first 24 h [−1.06 log10 (interquartile range, −1.7 to −0.4) versus –0.05 log10 (interquartile range, −0.4 to +0.14) respectively; P = 0.002]. The median HCV viral load at week 12 was significantly different from that at baseline in responder and transient responders but not in non-responder patients. The positive predictive value was 100% within the first month and the best negative predictive value was 92% and 88.8% at weeks 4 and 12 respectively. The only genotype 1 responder patient had eight mutations in ISDR2209–2248. Conclusions: A very early HCV viral decay is observed in responder patients. An early virological response assessment at week 4 and 12 might be a useful tool in the clinical management of the co-infected population.

Significant reductions of HIV prevalence but not of hepatitis C virus infections in injection drug users from metropolitan Barcelona: 1987–2001

OBJECTIVES To characterize trends from 1987 to 2001 in the prevalence of HIV and HCV infections among 2219 injection drug users (IDUs) starting treatment for substance abuse in two large hospitals in metropolitan Barcelona. METHODS The study population comprised IDUs with HIV tests completed from 1987 to 2001 and admitted for detoxification. Testing for HCV started in 1991 (n=1132). Characterization of temporal trends was carried out using logistic regression methods. Stratification was used to describe possible heterogeneities of the temporal trends. RESULTS The overall prevalence of HIV, HCV, and HBV (HBsAg+) was 55%, 88%, and 7%, respectively. Adjusted by duration of IDU, sex, and age at initiation, the prevalence of HIV infection declined significantly (p<0.001) from 1989 to 2004. The substantially higher prevalence of HCV showed a decline (p=0.065) of lesser magnitude. The decline of HIV infection was consistently observed among those with duration of IDU of less than 10 years. In turn, the decline of HCV was restricted to those with short duration of IDU (<4 years) because the prevalence of HCV infection was close to 100% for durations longer than 4 years in all calendar periods. CONCLUSIONS Preventive interventions and treatment for substance abuse might have contributed to the waning of the HIV epidemic in Spain. However, the extremely high levels of HCV infection and the underlying prevalence of HIV might lead to a large health burden of liver disease.

Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART.

Objective:To analyse incidence and determinants of tuberculosis in HIV-seroconverters before and after the introduction of HAART. Methods:Data from a multicenter cohort study of 2238 HIV-seroconverters between the 1980s and 2004 were analysed and censored by December 2004. Calendar year at risk intervals were pre-1992, 1992–1996 and 1997–2004. Incident tuberculosis was calculated as cases per 1000 person-years (p-y). Survival analyses using Kaplan–Meier and multivariate Cox regression allowing for late-entry were used. Proportional hazards assumptions were checked with tests based on Schoenfeld residuals. Results:Overall, 173 (7.7%) patients developed tuberculosis over 23 698 p-y at a rate of 7.3 cases per 1000 p-y [95% confidence interval (CI), 6.3–8.5]. Incident tuberculosis was higher in intravenous drug-users (IDUs), 12.3 per 1000 p-y compared with persons infected sexually, 3.8 per 1000 p-y (P < 0.001), and persons with clotting disorders (PCD), 2.7 per 1000 p-y (P < 0.001). A decreasing tuberculosis incidence trend was observed from 1995 in all categories. Highest tuberculosis rates, 44 per 1000 p-y, were observed prior to 1997 in IDUs infected with HIV for 11 years. In multivariable analyses women were less likely to develop tuberculosis [relative hazard (RH), 0.62; 95% CI, 0.41–0.96; P < 0.05) and IDUs were more likely to develop tuberculosis (RH, 3.0; 95% CI, 1.72–5.26, P < 0.001). In the HAART era, the hazard of developing tuberculosis was 70% lower (RH, 0.31; 95% CI, 0.17–0.54; P < 0.001). Before 1997, the risk of tuberculosis increased with time since HIV seroconversion, whereas it remained nearly constant in the HAART era. Conclusions:Since the mid-1990s important decreases in tuberculosis have been observed in HIV-seroconverters that probably reflect the impact of both HAART and tuberculosis control programmes.

Accuracy of Simple Biochemical Tests in Identifying Liver Fibrosis in Patients Co-Infected With Human Immunodeficiency Virus and Hepatitis C Virus

BACKGROUND & AIMS We assessed the ability of 3 simple biochemical tests to stage liver fibrosis in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS We analyzed liver biopsy samples from 324 consecutive HIV/HCV-positive patients (72% men; mean age, 38 y; mean CD4+ T-cell counts, 548 cells/mm(3)). Scheuer fibrosis scores were as follows: 30% had F0, 22% had F1, 19% had F2, 23% had F3, and 6% had F4. Logistic regression analyses were used to predict the probability of significant (>or=F2) or advanced (>or=F3) fibrosis, based on numeric scores from the APRI, FORNS, or FIB-4 tests (alone and in combination). Area under the receiver operating characteristic curves were analyzed to assess diagnostic performance. RESULTS Area under the receiver operating characteristic curves analyses indicated that the 3 tests had similar abilities to identify F2 and F3; the ability of APRI, FORNS, and FIB-4 were as follows: F2 or greater: 0.72, 0.67, and 0.72, respectively; F3 or greater: 0.75, 0.73, and 0.78, respectively. The accuracy of each test in predicting which samples were F3 or greater was significantly higher than for F2 or greater (APRI, FORNS, and FIB-4: >or=F3: 75%, 76%, and 76%, respectively; >or=F2: 66%, 62%, and 68%, respectively). By using the lowest cut-off values for all 3 tests, F3 or greater was ruled out with sensitivity and negative predictive values of 79% to 94% and 87% to 91%, respectively, and 47% to 70% accuracy. Advanced liver fibrosis (>or=F3) was identified using the highest cut-off value, with specificity and positive predictive values of 90% to 96% and 63% to 73%, respectively, and 75% to 77% accuracy. CONCLUSIONS Simple biochemical tests accurately predicted liver fibrosis in more than half the HIV/HCV co-infected patients. The absence and presence of liver fibrosis are predicted fairly using the lowest and highest cut-off levels, respectively.

Survival of HIV-Infected Injection Drug Users (IDUs) in the Highly Active Antiretroviral Therapy Era, Relative to Sex- and Age-Specific Survival of HIV-Uninfected IDUs

BACKGROUND In the era of highly active antiretroviral therapy (HAART), it remains unclear whether human immunodeficiency virus (HIV)-infected injection drug users (IDUs) have durations of survival similar to those for comparable HIV-uninfected IDUs. The goal of this study was to compare survival durations of HIV-infected and HIV-uninfected IDUs for the period 1987-2004.Methods. Demographic data, drug use characteristics, and biological markers were obtained at the time of admission to a substance abuse treatment program. The outcome of interest was the duration of survival after admission, and the primary exposure was HIV infection. Vital status was ascertained by means of the mortality register by the end of 2004. Three calendar periods, which were defined on the basis of use of specific therapies, were considered: 1987-1991 (the antiretroviral monotherapy era), 1992-1996 (the dual combination therapy era and the era when methadone was introduced in Spain), and 1997-2004 (the era of HAART and of established methadone programs). We used Cox regression methods allowing for late entries to handle the contribution of persons who survived a given period and entered the following period with nonzero time. We compared HIV-uninfected and HIV-infected IDUs with adjustments for age, sex, and duration of follow-up after admission. RESULTS A total of 1209 IDUs were admitted to the hospital during the period from January 1987 through December 2004, and 1181 were eligible for the study. The majority (81.3%) of patients were men. The mean age (+/- standard deviation) at admission was 27.8+/-5.6 years, and the mean duration of injection drug use (+/- standard deviation) was 7.6+/-5.0 years. The prevalences of HIV and hepatitis C virus infections were 59.0% and 92.3%, respectively, and the total duration of follow-up was 10.116 person-years. Although survival duration for HIV-uninfected IDUs in 1997-2004 was similar to the duration in earlier periods, the duration for HIV-infected IDUs improved significantly since 1997 (P<.01). Furthermore, among patients admitted in the last period, the survival durations for HIV-uninfected and HIV-infected IDUs was virtually the same (relative hazard, 0.89; 95% confidence interval, 0.44-1.81). CONCLUSIONS The duration of survival of HIV-infected IDUs has improved substantially since 1997, reaching rates similar to the rates for HIV-seronegative IDUs who accessed the health care system in the era of HAART.

Impact of Medical Comorbidity and Risk of Death in 680 Patients with Alcohol Use Disorders

BACKGROUND The association between alcohol use disorders and increased risk of mortality is well known; however, there have been few systematic evaluations of alcohol-related organ damage and its impact on survival in younger alcoholics. Therefore, we assessed medical comorbidity with a clinical index to identify subgroups of alcoholic patients at high risk of premature death. METHODS Hospital-based cohort of alcohol-dependent patients admitted for detoxification between 1999 and 2008 in Barcelona, Spain. At admission, sociodemographic characteristics and a history of alcohol dependence and abuse of illegal drugs were obtained through clinical interviews and questionnaires. Medical comorbidity was assessed with the Cumulative Illness Rating Scale (Substance Abuse) (CIRS-SA). Dates and causes of death were obtained from clinical records and death registers. Survival was analyzed using Kaplan-Meier methods, and Cox regression models were used to analyze the risk factors for premature death. RESULTS Median age of the patients (686 total, 79.7% men) was 43.5 years (interquartile range [IQR], 37.8 to 50.4), average alcohol consumption was 200 g/d (IQR, 120 to 280 g/d), and duration of alcohol use disorder was 18 years (IQR, 11 to 24). Medical comorbidity by CIRS-SA at admission showed that the organs/systems most affected were liver (99%), respiratory (86%), and cardiovascular (58%). After median follow-up of 3.1 years (IQR, 1.5 to 5.1), 78 (11.4%) patients died with a mortality rate of 3.28 × 100 person-years; according to Kaplan-Meier estimates, 50% (95% confidence interval [95% CI], 24 to 69%) of patients with severe medical comorbidity died in the first decade after treatment. In multivariate analysis, severe medical comorbidity (hazard ratio [HR], 5.5; 95% CI, 3.02 to 10.07) and being treated with methadone at admission (HR, 2.60; 95% CI, 1.50 to 4.51) were independent risk factors for premature death. CONCLUSIONS Systematic assessment of alcohol-related organ damage is relevant for the identification and treatment of those at increased risk of death.

Mortality of HIV-positive and HIV-negative heroin abusers as a function of duration of injecting drug use

Objective: To determine the incidence of mortality of injecting drug users as a function of the duration of injecting drugs and HIV status, and to assess how these effects vary according to age at initiation and calendar period (before and after 1992). Methods and Design: Cohort of 376 intravenous heroin users admitted to detoxification between February 1987 and January 1990. Setting: Patients referred from outpatient clinics of metropolitan Barcelona. Duration and characteristics of drug use were determined by interviews. Blood samples were collected during admission and analyzed for HIV, CD4+ cell count and different biologic parameters. Assessment of vital status and causes of death were obtained by hospital charts, death certificates, and autopsies. Results: The study population consisted of 299 men and 77 women, whose mean age at entry was 26 years, mean duration of injecting drug use before admission 6.1 years; HIV seroprevalence at entry 70.2%. By the end of the follow‐up (median 5.6 years), 21.8% of individuals had died (26.6% in HIV‐positive, and 10.7% in HIV‐negative injecting users). Based on Kaplan‐Meier estimates, 10%, 20%, and 30% of HIV negative patients died by 8.7, 11.3 and 14.3 years, respectively, after initiating injecting drugs. The corresponding survival times for the seropositives were substantially lower: 6.6, 8.5, and 11.6 years, respectively. Overall, the survival time was significantly (p < .05) decreased by 22% in HIV‐positive injecting drug users. Older age at initiation of injecting drug use was significantly (p < .05) associated with mortality in HIV‐positive heroin users but it showed the opposite direction among HIV‐negative people. Death rates in HIV‐positive patients of the same duration of drug use were similar in periods before and after 1992 (relative hazard (RH) = 0.97; 95% confidence interval: 0.58‐1,61). Although not statistically significant, the hazard of death in HIV‐negative injecting drug users was substantially lower after 1992 (RH = 0.59). Conclusions: Before introduction of potent antiretroviral therapies, HIV infection further increased rates of mortality that had already been heightened by injecting drug use. Furthermore, HIV infection modifies the effect of age at initiation and eliminates the seemingly downward trend of mortality in HIV‐negative people.

Error diagnóstico en urgencias: relación con el motivo de consulta, mecanismos y trascendencia clínica

BACKGROUND AND OBJECTIVE: We intended to analyze the relation between the main symptom at hospital admission and the diagnosis mistake, assessing the reasons and clinical implications. PATIENTS AND METHOD: We analyzed hospitalized patients from the emergency room to the medical wards. We collected: age, sex, time, main symptom at admission, diagnosis at admission and final diagnosis, days of hospitalization and mortality. We established two groups: patients with a concordant diagnosis and patients with a wrong diagnosis, and we compared the characteristics of them. In each case of a wrong diagnosis, we analyzed the reason of the mistake and the clinical consequences. RESULTS: We found a wrong diagnosis in 42 (6.2%) cases. Fever, as main symptom at admission, had a significant higher rate of mistake than other symptoms. No differences were found in the other variables analyzed. Most frequently omitted diagnosis were infectious diseases, pulmonary embolism and heart failure. Main causes of mistake were a deficient clinical evaluation and X-ray interpretation. The mistake implied a delay in the specific treatment in 42.8% cases. CONCLUSIONS: Diagnostic mistakes in the emergency room are more frequent in patients attending with fever. They are mostly related to deficient clinical evaluation or wrong interpretation of X-ray findings. Although these mistakes usually lead to a delay in the treatment, no increase in the days of hospitalization or mortality is observed.

Unhealthy Alcohol Use, HIV Infection and Risk of Liver Fibrosis in Drug Users with Hepatitis C

Aim To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. Patients and Methods Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. Results A total of 472 (83% M, 17% F) patients were eligible. The median age at admission was 31 years (Interquartile range (IQR) 27–35 years), and the median duration of drug use was 10 years (IQR 5.5–15 years). Unhealthy drinking (>50 grams/day) was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76–1.87) than in the HCV-monoinfected patients (0.75, IQR 0.56–1.11) (p<0.001). In the multivariate analysis, unhealthy drinking (p = 0.034), lower total cholesterol (p = 0.042), serum albumin (p<0.001), higher GGT (p<0.001) and a longer duration of addiction (p = 0.005) were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001), a lower CD4 cell count (p = 0.006), higher total bilirubin (p<0.001) and a longer drug addiction duration (p<0.001) were significantly associated with higher FIB-4 values. Conclusions Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations