HIV-hepatitis C virus co-infection is associated with decreased plasmatic IL-7 levels.

We analysed the potential influence of hepatitis C virus (HCV) co-infection over IL-7 levels and thymic function in naive HIV-infected patients and after effective HAART. HIV-HCV-co-infected patients had lower plasmatic IL-7 levels compared with HIV-monoinfected patients. This effect may not be associated either with HCV monoinfection or with the rate of liver injury. These lower levels may explain, at least partly, the lower CD4 cell repopulation of HIV-HCV-co-infected patients after HAART.

Tratamiento de las hepatitis víricas (II). Tratamiento de la hepatitis crónica C / Treatment of viral hepatitis (II). Treatment of chronic hepatitis C

La infección crónica por el VHC es la principal causa de enfermedad crónica hepática, cirrosis y hepatocarcinoma en países occidentales. La hepatitis crónica por VHC transcurre a menudo de modo silente y sólo es descubierta con frecuencia al realizar estudios serológicos o bioquímicos rutinarios. Con frecuencia el intervalo de tiempo entre la infección y el desarrollo de cirrosis excede los 30 años y los síntomas durante todo este tiempo están ausentes hasta que la enfermedad está muy evolucionada. El tratamiento antiviral puede impedir la evolución de la enfermedad y el desarrollo de sus complicaciones. Actualmente el tratamiento estándar de esta infección se basa en la combinación de interferón alfa pegilado y ribavirina. En estos últimos años hemos aprendido también a entender mejor este tratamiento en "poblaciones especiales", como los pacientes infectados por el VIH o los que habían fracasado con otros intentos de tratamiento previo, debido a un mejor conocimiento de la enfermedad y a los ensayos realizados en estas poblaciones. En la actualidad están investigándose muchos fármacos nuevos que pueden tener acción frente al VHC. Es de esperar que en el futuro, todavía lejano, algunos de estos fármacos consigan la erradicación de este virus

Hepatitis C virus infection is the principal cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in the Western World. Chronic hepatitis C is often silent, most of the times discovered only by routine serologic or biochemical testing and the interval between infection and the development of cirrhosis exceed 30 years. Interestingly the complications of chronic hepatitis C virus infection can be prevented by antiviral therapy. At present, the combination of pegylated interferon-alfa and ribavirina has become the standard treatment of chronic hepatitis C. The management of HCV infection in "special populations" (HIV coinfection and HCV therapy-experienced patient) has improved significantly over the past few years, through a better knowledge of the disease and the publication of several clinical trials performed in these patients. At presents, a number of new anti-HCV therapies are in development. Future drugs for HCV infection might make possible to eradicate HCV in future

[Treatment of viral hepatitis (II). Treatment of chronic hepatitis C]. / Tratamiento de las hepatitis víricas (II). Tratamiento de la hepatitis crónica C.

Hepatitis C virus infection is the principal cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in the Western World. Chronic hepatitis C is often silent, most of the times discovered only by routine serologic or biochemical testing and the interval between infection and the development of cirrhosis exceed 30 years. Interestingly the complications of chronic hepatitis C virus infection can be prevented by antiviral therapy. At present, the combination of pegylated interferon-alfa and ribavirina has become the standard treatment of chronic hepatitis C. The management of HCV infection in "special populations" (HIV coinfection and HCV therapy-experienced patient) has improved significantly over the past few years, through a better knowledge of the disease and the publication of several clinical trials performed in these patients. At presents, a number of new anti-HCV therapies are in development. Future drugs for HCV infection might make possible to eradicate HCV in future.

[Treatment of viral hepatitis (I). Treatment of chronic hepatitis B]. / Tratamiento de las hepatitis víricas (I). Tratamiento de la hepatitis crónica B.

In the past 25 years remarkable progress has been made in our understanding of the natural history of chronic HBV. The infection is now perceived as having three consecutive phases: immune tolerance, immune clearance, and inactive carrier status, with possible reactivation episodes. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Five agents are now approved for therapy of chronic hepatitis B: interferon-alpha (standard and pegylated), lamivudine, adefovir and entecavir. All five drugs are effective in suppressing HBV DNA levels and improving serum alanineaminotransferase levels and hepatic histology, but it is still unclear who should be treated, with which agent (or combination of agents), for how long, and what endpoints measure the success or failure of treatment. Until a drug therapy results in lasting virological remission in most patients after a reasonably short period of treatment, individualized treatment decisions will remain key to maximizing efficacy, and chronic HBV infection will continue to be treated as a liver disease rather than as an infectious disease.

Tratamiento de las hepatitis víricas (I). Tratamiento de la hepatitis crónica B / Treatment of viral hepatitis (I). Treatment of chronic hepatitis B

Nuestro conocimiento acerca de la historia natural de la infección crónica por el virus de la hepatitis B (VHB) ha progresado de manera muy importante en los últimos 25 años. La infección se entiende ahora como la sucesión de 3 fases: inmunotolerancia, inmunoaclaramiento y estado de portador inactivo en el que pueden existir episodios de reactivación. Cada vez es mayor la evidencia de que el tratamiento antiviral puede prevenir la progresión a estadios finales de la enfermedad hepática, especialmente en los pacientes que logran una respuesta sostenida. Son cinco los fármacos que están disponibles para el tratamiento de la hepatitis crónica B. Interferón alfa (convencional o pegilado), lamivudina, adefovir y entecavir. Los cinco han demostrado ser capaces de reducir la concentración de ADN del VHB y de las transaminasas y mejorar la histología hepática, pero hasta el momento no está claro quién debe recibir tratamiento, con qué fármacos o combinación de fármacos, durante cuánto tiempo y cuáles son los objetivos que se persiguen. Mientras no dispongamos de fármacos capaces de inducir una remisión duradera en la mayoría de los pacientes tras un razonablemente corto período de tratamiento, la hepatitis crónica B deberá seguir siendo tratada más como una enfermedad hepática que como una enfermedad infecciosa (AU)

In the past 25 years remarkable progress has been made in our understanding of the natural history of chronic HBV. The infection is now perceived as having three consecutive phases: immune tolerance, immune clearance, and inactive carrier status, with possible reactivation episodes. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Five agents are now approved for therapy of chronic hepatitis B: interferon-alpha (standard and pegylated), lamivudine, adefovir and entecavir. All five drugs are effective in suppressing HBV DNA levels and improving serum alanineaminotransferase levels and hepatic histology, but it is still unclear who should be treated, with which agent (or combination of agents), for how long, and what endpoints measure the success or failure of treatment. Until a drug therapy results in lasting virological remission in most patients after a reasonably short period of treatment, individualized treatment decisions will remain key to maximizing efficacy, and chronic HBV infection will continue to be treated as a liver disease rather than as an infectious disease (AU)

Immunovirologic characteristics of human immunodeficiency virus-infected patients consisting mainly of injecting drug users on highly active antiretroviral treatment with prolonged virologic failure.

Immunovirologic parameters of 24 heavily antiretroviral drug-pretreated patients with prolonged virologic treatment failure under highly active antiretroviral therapy, and who harbored highly resistant human immunodeficiency virus (HIV) isolates, were studied in this retrospective cross-sectional study. Most of the patients were injecting drug users (71%) and male (88%). All patients were studied for CD4(+) cell count, HIV viral load, resistance mutations, and viral phenotype. The patients showed a high accumulation of resistance-associated mutations, their CD4(+) cell count and viral load directly correlated with their respective values at initiation of therapy, and the presence of K103N was inversely associated with lower viral load. On the other hand, patients with K103N had the same level of CD4(+) cell count compared with patients without this mutation. Among the patients, a majority with a specific viral phenotype was not present. Rather, a dual-tropic virus was found most frequently, suggesting a preferential suppression of X4-specific strains and less cytopathogenicity during antiretroviral therapy and a greater proportion of R5X4 viruses due to an adaptation to that pressure.

Effect of hepatitis C virus coinfection on humoral immune alterations in naïve HIV-infected adults on HAART: a three year follow-up study.

Whether HAART allows complete recovery of humoral immune function in HIV-infected individuals is still controversial. Our objective was to study the effect of HAART on both B cell repopulation and hypergammaglobulinemia in 72 naïve patients, including 35 HCV-coinfected individuals, during 156 weeks on HAART. The possible role of HCV coinfection on the recovery of the humoral immune system was also investigated. At baseline, HCV-coinfected patients had greater circulant IgG levels than HIV-only-infected patients, while B cell count and CD21(low) B cell subpopulation were similar in both groups. During HAART, HIV-only-infected patients reached normal B cell counts and circulant IgG levels, while HCV-coinfected individuals did not. CD21(low) B cell subpopulation significantly decreased in both groups of patients at week 48 after the initiation of HAART compared to baseline. Thus, B cells remained continuously stimulated in HCV-coinfected patients and this stimulation seemed to be through a CD21-independent pathway.

Genotypic resistance profile in treatment-experienced HIV-infected individuals after abacavir and efavirenz salvage regimen.

Once highly active antiretroviral therapy (HAART) fails to suppress HIV replication and resistant viruses emerge, it is difficult to find a salvage regimen since cross-resistance is high among the available classes of antiretroviral drugs. In this retrospective analysis, genotypic resistance profiles were analysed in 24 patients who switched treatment to abacavir (ABV), efavirenz (EFV), and either a NRTI or a PI at baseline and after 24 weeks of treatment. At baseline, 71% of patients harboured at least one resistance mutation in the protease gene. In the RT gene, 87.5% of the patients showed nucleoside analogue resistance mutations, and an equal 87.5% showed resistance mutations to non-nucleoside analogues. After 24 weeks of treatment, only mutations to nucleoside analogues raised in 95.8% of the patients, while resistance mutations to the other drug classes remained constant. Substitutions conferring cross-resistance within each drug family were very common among this treatment-experienced population. These data also indicate that salvage therapy is likely to remain one of the most important issues in the treatment of HIV infections.

Long-term virological outcome and resistance mutations at virological rebound in HIV-infected adults on protease inhibitor-sparing highly active antiretroviral therapy.

OBJECTIVE: To assess the durability of the undetectability of HIV plasma viraemia (pV) and to determine the factors associated with virological rebound (VR) in HIV-infected adults on protease inhibitor (PI)-sparing highly active antiretroviral therapy (HAART). The development of resistance mutations during virologically successful therapy and VR was also analysed. MATERIALS AND METHODS: One hundred and twenty-six HIV-infected adults on PI-sparing HAART were prospectively followed from April 1998 to December 2002: Group 1, naive for antiretroviral drugs (n = 26); Group 2, previously PI-HAART-exposed patients (n = 19); Group 3, previously exposed to suboptimal therapy (n = 81). Genotypic resistance tests on peripheral blood mononuclear cells or on plasma RNA (when feasible) were carried out when undetectable HIV pV was demonstrated for at least 48 weeks. Additionally, patients showing a therapy adherence >95% developing VR were also tested at rebound, at simplification and during previous suboptimal therapy exposure. RESULTS: The median follow-up time was 630 [329-903] days. VR was considered as two consecutive pV levels >50 copies/mL. Twenty-two (17.5%) patients developed VR. Only therapy adherence <95% was independently associated with VR (adjusted hazard ratio: 8.42; 95% CI: 3.33-21.27). Twenty (40%) of the 50 patients with pV < 50 copies/mL for at least 48 weeks showed at least one thymidine-associated mutation (TAM) but none had NNRTI-resistance mutations. Ten (83.3%) of 12 available adherent patients showing VR harboured NNRTI-resistance-associated mutations; 50% of them were considered as wild-type strains at simplification time. However, the TAM number and resistance mutations profile found on suboptimal exposure were very similar to those found at VR on simplification therapy. CONCLUSIONS: PI-sparing HAART allows maintenance of successful long-term control of HIV replication, adherence to therapy being the main factor associated with VR. However, a small proportion of patients on simplification regimen may develop VR regardless of therapy compliance. VR on PI-sparing HAART is characterized by the emergence of NNRTI cross-resistance mutations. Finally, TAMs 'archived' during previous suboptimal exposures are partially involved in subsequent VR on simplification HAART.

Comparison of thymic function-related markers to predict early CD4 T-cell repopulation in adult HIV-infected patients on HAART.

The aim of this work was to compare thymic function-related markers for predicting early CD4 T-cell repopulation in adult HIV-infected patients under HAART. Forty-three consecutive antiretroviral-naive patients were prospectively analysed for clinical, biochemical, immunological and virological parameters at starting HAART, and followed for 4 weeks and every 12 weeks thereafter. At baseline, all patients underwent a thoracic computer tomography scan, in order to measure thymic volume, as well, T-cell phenotype (naive CD4 and CD8 T cells) and the number of TREC-bearing cells were obtained. CD4 cell repopulation was considered as an increase > or = 200 cells/mm3 above baseline count. Twenty-seven patients (62.8%) increased > or = 200 cells/mm3 above baseline levels during the follow-up. The median time to event was 182 days (84-537 days). On the univariate analysis, to be younger than 36 years, showing a CD4 cell count > or = 272 cells/mm3, a total naive T-cell count > or = 128 cells/mm3, a TREC-bearing cell count > or = 0.74 cells/mm3, and a thymic volume > or =3.07 cc at baseline were statistically associated to the event studied. However, when the multivariate analysis was performed, only thymic volume at baseline was independently associated (P=0.002) to CD4 cell recovery. This co-variable was identified as a positive predictor [hazard ratio, 1.22 (95% confidence interval: 1.16-1.28)]. In summary, data presented herewith show that thymic volume is the best thymic function-related marker for predicting early CD4 T-cell recovery in adult HIV-infected patients under HAART.

Coinfección por el virus de la inmunodeficiencia humana y el virus de la hepatitis C. ¿Se conoce su historia naturalen la era del TARGA? / Human immunodeficiency virus and hepatitis C virus co-infection. Do we know their clinical evolution in HAART era?

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Endogenous IL-7 is associated with increased thymic volume in adult HIV-infected patients under highly active antiretroviral therapy.

OBJECTIVE: Immune reconstitution after highly active antiretroviral therapy (HAART) in HIV-infected patients has led to an increase in the number of new CD4 T lymphocytes. Neolymphopoiesis in the thymus has been proposed as a mechanism in T-cell regeneration. Nevertheless, factors involved in the regeneration of T cells by thymic-dependent pathways in HIV-infected patients under HAART are still unknown and might be of relevance in HIV infection. The aim of this work was to study the role of IL-7 in the thymic rebound of HIV-infected adults under HAART. DESIGN: To study the association between IL-7 and thymic function-related markers, these variables were measured in 49 antiretroviral-naive HIV-infected patients at baseline and at weeks 12, 24, 36 and 48 of treatment. METHODS: Thymic function-related markers: thymic volume, naive phenotype, and T-cell receptor excision circles (TREC) bearing-cells, were evaluated by computed tomography, flow cytometry, and quantitative polymerase chain reaction, respectively. IL-7 levels were evaluated using a high sensitivity colorimetric enzyme-linked immunosorbent assay. RESULTS: At baseline, we found an inverse correlation between IL-7 levels and thymic function-associated parameters: thymic volume, naive T cells and TREC-bearing cells. After 48 weeks of therapy increased levels of thymic function-related markers along with a significant decrease in IL-7 levels were found. IL-7 levels at baseline were the only independently associated variable with respect to changes in thymic volume at weeks 12, 24 and 48 of follow-up. CONCLUSION: These data suggest that IL-7 plays an important role in thymic rebound in adult HIV-infected patients under HAART.

Baseline thymic volume is a predictor for CD4 T cell repopulation in adult HIV-infected patients under highly active antiretroviral therapy.

The objective of the present study was to assess the impact of baseline thymic volume on the CD4 cell repopulation induced by highly active antiretroviral therapy (HAART) in HIV-infected adults. Therefore, 37 previously untreated HIV-1-infected adults were prospectively followed from August 1998 to September 2001. All patients underwent a thorax CT scan at starting HAART to measure thymic volume. The median follow-up time was 189 [87.5-498.5] days. CD4 cell repopulation was considered as an increase > or = 200 cells/mm3 above baseline count. Twenty-one (57%) patients achieved this CD4 repopulation. Baseline thymic volume was the main independent factor associated with CD4 repopulation (P = 0.016); this factor was a positive predictor (adjusted hazard ratio: 1.25 [95% confidence interval 1.1-1.4]). Although, CD4 cell count and non-AIDS diagnosis at baseline were associated with CD4 cell repopulation on the univariate analysis (P = 0.03 and P = 0.02, respectively), no statistical signification was found on the multivariate test. In summary, baseline thymic volume is a predictor of early CD4 cell repopulation in adult HIV-1-infected patients taking HAART.

Evidence of thymic function in heavily antiretroviral-treated human immunodeficiency virus type 1-infected adults with long-term virologic treatment failure.

Thymic function was evaluated in 32 heavily antiretroviral-treated human immunodeficiency virus type 1 (HIV-1)-infected adults with long-term virologic treatment failure by measuring thymic volume, by determining the absolute number of naive T cell phenotypes, and by determining the number of cells carrying T cell receptor excision circles (TRECs). There was a significant inverse correlation between age and thymic volume (r=-0.415; P=.018), and there was a significant direct correlation between thymic volume and total naive T cell counts (r=0.529; P=.002), naive CD4(+) cell counts (r=0.437; P=.012), naive CD8(+) cell counts (r=0.467; P=.007), and TREC levels (r=0.391; P=.027). In conclusion, this study found clear evidence that the thymus of heavily antiretroviral-treated HIV-1-infected adults with long-term virologic treatment failure is actively engaged in thymopoiesis, which generates new naive T cells for the peripheral lymphocyte pool.

T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy.

The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of naïve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-naïve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between naïve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in naïve CD4(+) and CD8(+) T cells, TRECs, and thymic volume. The initial net increases in naïve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken together, our data strongly suggest a thymic role in immune reconstitution, at least in patients with depleted baseline TREC levels. (Blood. 2002;99:3702-3706)

Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy.

The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4(+) cell counts below 300 cells/mm(3) during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.