José L. Casado

Validation of a simplified medication adherence questionnaire in a large cohort of HIV-infected patients: the GEEMA Study

Objective To assess the effectiveness of the simplified medication adherence questionnaire (SMAQ) in identifying non-adherent patients. Design Prospective observational study of adherence. The six-item SMAQ was developed. The following aspects were evaluated: (i) criterion validity, comparison with electronic adherence monitoring; (ii) construct validity, association between adherence, as defined by the SMAQ, and virological outcomes; and (iii) reliability, internal consistency and reproducibility. Patients A group of 3004 unselected HIV patients who had initiated nelfinavir therapy combined with other antiretroviral drugs [21% naive, 15% protease inhibitor (PI)-naive, 64% PI-experienced] between January 1998 and December 1999 were enrolled in 69 hospitals in Spain. The SMAQ was administered at months 3, 6 and 12. Results The SMAQ showed 72% sensitivity, 91% specificity and a likelihood ratio of 7.94 to identified non-adherent patients, compared with the medication-event monitoring system (40 patients evaluated). At month 12, 1797 patients were evaluated, of whom 32.3% were defined as non-adherent; viral load < 500 copies/ml found in 68.3% of the adherent, and 46% of the non-adherent patients. A logistic regression analysis of PI-naive patients was performed, including age, sex, baseline viral load > 5 log10/ml, CD4 cell count < 200 × 106/l, and non-adherence as independent variables. Non-adherence was the only significant risk factor in failing to achieve virological suppression. Cronbachs alpha internal consistency coefficient was 0.75, and overall inter-observer agreement was 88.2%. Conclusion The SMAQ appears to be an adequate instrument with which to assess adherence in HIV-infected patients, and may be applied in most clinical settings.

Influence of Liver Fibrosis on Highly Active Antiretroviral Therapy—Associated Hepatotoxicity in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a known risk factor for hepatotoxicity in patients receiving highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the role of HCV-related liver fibrosis in HAART-associated hepatotoxicity. METHODS In a prospective study involving 107 patients who underwent liver biopsy, fibrosis was graded according 5 stages, from F0 (no fibrosis) to F4 (cirrhosis). Hepatotoxicity was defined as an increase in levels of aspartate aminotransferase and alanine aminotransferase to >5 times the upper limit of normal, or a >3.5-fold increase if baseline levels were abnormal. The incidence of hepatotoxicity was compared with liver fibrosis stage and with time and composition of HAART. RESULTS Overall, 27 patients (25%) had hepatotoxic events (5.1 events/100 person-years of therapy). The incidence was greater for patients with stage F3 or F4 fibrosis (38%) than for those with stage F1 or F2 fibrosis (15%; 7.6 vs. 3 events/100 person-years; relative risk, 2.75; 95% confidence interval, 1.08-6.97; P=.013). Duration of HCV infection, duration of HAART, diagnosis of acquired immunodeficiency syndrome, HCV load, HCV genotype, and nadir CD4(+) cell count did not affect the risk of hepatotoxicity. Of the 86 patients who received nonnucleoside reverse-transcriptase inhibitors (NNRTIs), 11 (13%) developed liver toxicity. In these patients, fibrosis stages F1 and F2 were associated with similar rates of toxicity (3 events/100 person-years for patients who received nevirapine, 3.3 events/100 person-years for those who received efavirenz, and 3.4 events/100 person-years for those who received non-NNRTIs). There was a greater incidence among patients with F3 or F4 fibrosis who received NNRTIs (11.7 events/100 person-years for patients who received nevirapine, and 8.6 events/100 person-years for those who received efavirenz), compared with those who received non-NNRTIs (4 events/100 person-years). CONCLUSIONS HAART-associated hepatotoxicity correlates with liver histological stage in patients coinfected with HIV and HCV. There was no difference in hepatotoxicity risk for different antiretroviral therapies in patients with mild-to-moderate fibrosis.

Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio

Background A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events. Methods Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts. Results We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3). Conclusions The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

Long-Term Outcomes among Antiretroviral-Naive Human Immunodeficiency Virus–Infected Patients with Small Increases in CD4+ Cell Counts after Successful Virologic Suppression

To evaluate the frequency and predictive factors of discordant immune response, we performed a prospective cohort study of 288 antiretroviral-naive human immunodeficiency virus (HIV)-infected patients who initiated highly active antiretroviral therapy (HAART) and maintained complete virus suppression for > or =24 months. The median CD4+ cell count was 186x10(6) cells/L, and the median HIV RNA level was 5 log(10) copies/mL. After 24 months of therapy, 42 (16.5%) of 255 patients had a median CD4+ cell count increase of <100x10(6) cells/L. By logistic regression analysis, previous injection drug use was associated with a CD4+ cell count increase of <100x10(6) cells/L (risk ratio [RR], 2.326; 95% confidence interval [CI], 1.077-5.023; P=.032); inclusion of a protease inhibitor (PI) in the HAART regimen reduced the risk of poor immunologic recovery (RR, 0.160; 95% CI, 0.061-0.417; P<.001). Failure of the CD4+ cell count to increase was relatively common among antiretroviral-naive patients in the year after the initiation of HAART and the achievement of complete virus suppression. PI-containing regimens provided better immunologic response.

Intensification of Antiretroviral Therapy with a CCR5 Antagonist in Patients with Chronic HIV-1 Infection: Effect on T Cells Latently Infected

Objective The primary objective was to assess the effect of MVC intensification on latently infected CD4+ T cells in chronically HIV-1-infected patients receiving antiretroviral therapy. Methods We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation. Results Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4+ or CD8+ counts, although a significant decrease was found in the proportion of HLA-DR+/CD38+ CD4+ and CD8+ T-cells. LPS and sCD14 levels increased. Conclusions Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results. Trial Registration ClinicalTrials.gov NCT00795444

Pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

Background: Hepatitis C virus (HCV) and HIV coinfection constitutes an important epidemiological and clinical problem. We evaluated the safety and efficacy of Pegylated interferon α2b (Peg-IFN) and a fixed dose of ribavirin in the treatment of chronic hepatitis C in HIV coinfection. Methods: Open, prospective study in HCV–HIV coinfected patients with persistently elevated alanine aminotransferase (ALT) levels and a liver biopsy showing either portal or bridging fibrosis. Therapy included Peg-IFN (50 μg weekly) with ribavirin 800 mg for 48 weeks. The primary end point was sustained virological response (SVR). Univariate and multivariate analyses were performed to determine factors associated with response. Results: By intent-to-treat analysis, 11 of 35 patients (31%) reached SVR. SVR was significantly better for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05). By multivariate logistic regression analysis, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95% confidence interval (CI), 1.1–31.7; P < 0.005]. A decrease of at least 1.5 log10 HCV RNA at week 12 of therapy was highly predictive of SVR (OR, 49.9; 95% CI, 4.9–508.2; P < 0.001). Most patients developed adverse events, although only six patients (17%) discontinued treatment due to toxicity. Conclusions: The combination of low doses of Peg-IFN plus a fixed dose of ribavirin resulted in a rate of SVR similar to that obtained with higher doses of the drugs in HIV-infected patients and lower than those obtained in non-HIV patients. Response at week 12 may be useful to help guide therapy in HCV–HIV co-infected patients.

Recomendaciones GESIDA/SEFH/PNS para mejorar la adherencia al tratamiento antirretroviral en el año 2004

El cumplimiento incorrecto del tratamiento antirretroviral (TAR) constituye el factor principal de fracaso terapeutico. Los factores que han demostrado estar relacionados con la adherencia de forma mas relevante incluyen la complejidad del tratamiento, los efectos secundarios, los problemas psicologicos, la adiccion activa a drogas y/o alcohol, la falta de soporte sociofamiliar y las actitudes y creencias del paciente acerca del tratamiento. La monitorizacion del cumplimiento debe formar parte de la atencion habitual del paciente con infeccion por el virus de la inmunodeficiencia humana (VIH), deben utilizarse metodos factibles, adaptados a la realidad del hospital y lo mas universalmente aplicables. Puede considerarse un minimo aceptable la asociacion de un cuestionario validado y el registro de dispensacion del servicio de farmacia. Todo paciente que inicie o cambie el tipo de TAR debe realizar un programa de educacion sanitaria sobre el tratamiento, a cargo de profesionales sanitarios con experiencia y conocimiento del manejo de pacientes con infeccion por VIH. Debe procurarse la maxima disponibilidad del equipo asistencial (medicos, farmaceuticos y profesionales de enfermeria) para resolver las dudas y problemas que se presenten a lo largo del tratamiento. En los pacientes en los que no se alcancen niveles de cumplimiento adecuados, se deben intentar estrategias de intervencion, basadas en aspectos psicoeducativos y de asesoramiento personal, con capacidad para adaptar el esquema del TAR a los habitos de vida del paciente y proporcionando estrategias de resolucion de problemas. En determinadas situaciones sera necesario resolver la comorbilidad, por lo tanto el enfoque debe ser pluridisciplinar. Son aconsejables pautas mas sencillas en cuanto a numero de comprimidos y a dosis diarias.

CD4 cell recovery during successful antiretroviral therapy in naive HIV-infected patients: the role of intravenous drug use.

We evaluated the impact of HIV risk practice on immune reconstitution in a prospective cohort of 288 patients (176 former injecting drug users) who maintained complete virus suppression for more than 24 months. Significant differences in CD4 cell counts at 6 and 24 months were detected. Multivariate analysis showed that drug use was an independent predictor of poor immunological recovery. Injection drug abuse impairs short and long-term CD4 cell recovery in HIV-positive patients initiating successful highly active antiretroviral therapy.

Plasma drug levels, genotypic resistance, and virological response to a nelfinavir plus saquinavir-containing regimen.

Objective To determine the importance of resistance and drug levels in the response to a dual-protease inhibitor (PI) combination. Methods Prospective study of 62 HIV-positive patients who switched to a salvage regimen including nelfinavir plus saquinavir. Virological response was defined as a decrease in viraemia > 0.5 log10 after 24 weeks. Optimal PI levels were defined as those above the protein binding-corrected 95% inhibitory concentration (IC95), as estimated in the presence of 50% human serum. Results Baseline median HIV load was 4.78 log10 copies/ml. The median number of mutations in the protease gene was nine (range, 2–25), predominantly at residues 82 (52%), and 90 (40%). After 24 weeks, 45% of patients had responded and 19% were < 50 copies/ml. A higher number of mutations in the protease gene (12 versus 8;P = 0.001), and the L90M mutation (36% versus 67%;P = 0.001) were associated with treatment failure. Trough levels of nelfinavir and saquinavir were two- and fivefold, respectively, greater than those reached when used as the only PI (2480 and 260 ng/ml, respectively), and they were above the estimated protein-corrected IC95 in 96% and 32% of cases. Thus, the Cmin : IC95 ratio ranged from 0.1 to 10 for nelfinavir and from 0.12 to 3.24 for saquinavir. Suboptimal PI levels were associated with a poorer response, but there was no correlation between optimal drug levels and a better response. Conclusion Genotypic resistance predicts the virological response to a nelfinavir–saquinavir salvage regimen. Our data suggest that higher than optimal drug levels could be necessary to control the replication of many PI-resistant viruses.

Extent and importance of cross-resistance to efavirenz after nevirapine failure

The objective of this study was to evaluate the activity of efavirenz after the failure of a nevirapine-containing regimen. This prospective study included 47 patients with plasma HIV loads >1000 copies/ml, and who had received nevirapine for at least 16 weeks, included in an efavirenz-based salvage regimen. The main outcome measure was virological response, defined as an HIV RNA level decrease of at least 1 log(10) copies/ml after 24 weeks, according to genotypic and phenotypic resistance to efavirenz. Phenotypic resistance was defined as a >10-fold increase in the IC(50). The median CD4(+) cell count was 236 x 10(6)/liter and the median HIV RNA level was 4.5 log(10) copies/ml. Mutations known to decrease susceptibility to nonnucleoside reverse transcriptase inhibitors were observed in 79% of patients, predominantly at residues 181 (49%), 103 (40%), and 106 (19%), but phenotypic resistance to efavirenz was seen in 62% of cases. All the strains with the K103N mutation showed high-level resistance to efavirenz, in contrast with 20% of those carrying exclusively the Y181C mutation. By week 24, 38% of patients had responded and 19% had achieved an undetectable HIV load. Virological failure was observed in patients with phenotypic resistance to efavirenz (67 vs. 11%; relative risk [RR], 4; 95% confidence interval [CI], 1.07-14.89; p = 0.04), or in presence of the K103N mutation (52 vs. 17%; RR, 1.77; 95% CI, 1.12-2.79; p = 0.02), and these results remained unchanged after adjusting for HIV load, or by resistance to the accompanying drugs in the salvage regimen. A previous longer period of nevirapine therapy was significantly associated with the emergence of efavirenz resistance (288 vs. 170 days, p < 0.01). We conclude that genotypic and/or phenotypic resistance assays permit the sequential use of nonnucleoside reverse transcriptase inhibitors in the clinical setting. Our data suggest that an early change after nevirapine failure could avoid the emergence of efavirenz resistance.