Mariola López

Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients.

To assess the impact of chronic viral liver disease (CVLD) on hospital admissions and death in HIV-infected patients since the introduction of highly active antiretroviral therapy, all hospital charts, from January 1996 to December 2000, in a large HIV/AIDS reference center in Madrid were reviewed. Discharge diagnosis, complications during the inpatient period, and number and causes of death were recorded. A total of 1334 hospital admissions involving 875 HIV-infected individuals was recorded. Up to 82% of them were either active or former intravenous drug users. Overall, 158 (11.8%) were admitted because of complications of CVLD, or developed complications of CVLD during their admission for another reason. The absolute number and proportion of admissions caused by CVLD increased over time, from 9.4% (31 of 330) in 1996 to 16% (46 of 287) in 2000 (p < 0.05). Likewise, the total number and proportion of deaths due to CVLD increased from 9.3% (5 of 54) in 1996 to 45% (9 of 20) in 2000 (p < 0.05). Chronic hepatitis C was the only etiology in nearly three-quarters of patients who were admitted or died of CVLD. In conclusion, the proportion of hospital admissions caused by liver failure in HIV-infected patients has increased in the last 5 years, accounting for 16% of cases in 2000. End-stage liver disease currently represents 45% of causes of in-hospital death among HIV-infected individuals. Therefore, strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons.

Differential Upregulation of Cd38 on Different T-cell Subsets May Influence the Ability to Reconstitute Cd4+ T Cells Under Successful Highly Active Antiretroviral Therapy

Background:Immune activation is an independent surrogate marker of CD4 T-cell depletion in HIV-infected patients. Highly active antiretroviral therapy (HAART) reduces disease progression as a direct consequence of suppressing HIV replication. Immune function does not normalize completely in most subjects on HAART, however, perhaps reflecting residual HIV replication. So far, it is unclear to what extent immune activation may influence the evolution of CD4 T-cell counts in patients on HAART. Patients and Methods:The expression of CD38 on naive and memory subsets of CD4+ and CD8+ T cells was measured quantitatively by flow cytometry in 62 drug-naive HIV-positive and 30 HIV-uninfected controls. In addition, the evolution of this marker as well as that of some virologic parameters (plasma viremia and proviral load) and CD4 counts were assessed in 25 HIV-infected individuals who initiated HAART and were followed for 12 months. Results:The mean level of CD38 on memory CD4+ and CD8+ T cells as well as in naive CD8+ cells was significantly higher in drug-naive HIV-positive subjects than in HIV-negative controls. Moreover, it was highly correlated with viral load titers. In patients on successful HAART, immune activation declined in all T-cell subsets, particularly among memory CD8+ cells. It remained elevated with respect to HIV-negative controls, however, even after 12 months of HAART. There was a significant correlation between the CD8+ T-cell activation decay and the increase of CD4+ T cells on HAART. Patients with the highest decline in CD8 activation were those showing the highest CD4 T-cell gains after 12 months of therapy. Conclusions:The level of CD38 expression on different T-cell subsets is differentially upregulated in drug-naive HIV-infected patients. After successful HAART, immune activation decreases in all T-cell subsets, although it still remains elevated in most cases after 12 months of HAART. The extent of immune deactivation under successful HAART correlates with the ability to reconstitute CD4 counts.

CD38 Expression on CD8 T Lymphocytes as a Marker of Residual Virus Replication in Chronically HIV-Infected Patients Receiving Antiretroviral Therapy

The level of CD8+ CD38+ T lymphocytes in blood correlates with disease progression in HIV-infected individuals, independently of the CD4 count. Effective antiretroviral therapy reduces this lymphocyte subset in parallel with plasma viremia, although CD38 expression on CD8+ cells does not normalize completely in most subjects, and might reflect residual HIV replication. The expression of CD38 on CD8+ cells (as number of CD38 molecules per CD8+ cell) was measured quantitatively by flow cytometry in 200 individuals, of whom 170 were HIV positive and 30 were HIV-uninfected controls. Forty-six HIV-infected subjects were on antiretroviral therapy and had undetectable viral load. The remaining 124 HIV-positive persons were not on therapy and had detectable plasma viremia. The mean level of CD38 on CD8+ cells was higher in HIV-positive, untreated patients than in subjects on antiviral therapy and controls (5023, 2029, and 1978 molecules per CD8+ cell, respectively, p < 0.01). In HIV-positive, untreated subjects, the higher CD38 expression mainly occurred on CD45RO+ CD8+ cells. The level of CD38 strongly correlated with plasma HIV-RNA (r = 0.63, p < 0.001). The levels of CD38 on CD8+ cells declined steadily in HIV-positive subjects after beginning antiretroviral therapy. A few individuals presented viral blips whereas being on antiviral treatment, levels of CD38 on CD8+ cells increased transiently in parallel with episodes of viral replication. Levels of CD38 on CD8+ cells are increased in chronic HIV infection, and strongly correlate with plasma viremia. The slow decline of CD38 expression on CD8+ cells over time in subjects with undetectable plasma viremia while being on antiretroviral therapy suggests that CD38 expression on CD8+ cells could be used as a marker of residual virus replication.

Long-term non-progressors display a greater number of Th17 cells than HIV-infected typical progressors

Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p=0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p=0.001 and p=0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.

Down-Regulation of Interleukin-7 Receptor (CD127) in HIV Infection Is Associated with T Cell Activation and Is a Main Factor Influencing Restoration of CD4+ Cells after Antiretroviral Therapy

BACKGROUND Factors influencing the depletion of CD4(+) cells and the restoration of CD4(+) cells after antiretroviral therapy are not completely understood. Recently, attention has been paid to interleukin (IL)-7 and its receptor (CD127). We analyzed the influence of T cell activation and of suppression of viremia with antiretroviral therapy on this system, as well as its role in CD4(+) cell restoration after long-term antiretroviral therapy. METHODS IL-7 levels and CD127 expression on several subsets of CD4(+) and CD8(+) T lymphocytes and the activation status (CD38) of these cells were examined at baseline and during 24 months of complete viral suppression under highly active antiretroviral therapy (HAART). RESULTS A total of 42 individuals with human immunodeficiency virus (HIV) infection and 10 age-matched, uninfected control subjects were examined. Before HAART, IL-7 levels were increased and CD127 expression was decreased. Down-regulation of CD127 was mainly associated with T cell activation and reverted only partially after suppression of detectable plasma HIV RNA with HAART. In a multivariate analysis, CD127 expression on CD8(+) T cells was the main determinant of the extent of CD4(+) cell gains after successful HAART. CONCLUSIONS The IL-7-CD127 system is impaired in HIV-infected patients. CD127 down-regulation is associated with T cell activation and with CD4(+) cell restoration after HAART.

Differences in Cellular Activation and Apoptosis in HIV-Infected Patients Receiving Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors

The mechanism of CD4(+) T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8(+) T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+) and CD8(+) lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8(+) T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4(+) counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.

Level, phenotype and activation status of CD4+FoxP3+ regulatory T cells in patients chronically infected with human immunodeficiency virus and/or hepatitis C virus

CD4+ regulatory T (Treg) cells have been involved in impaired immunity and persistence of viral infections. Herein, we report the level, phenotype and activation status of Treg cells in patients chronically infected with human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV). Expression of CD25, CD45RA, CD27, CD127 and CD38 was assessed on these cells using polychromatic flow cytometry in 20 healthy controls, 20 HIV‐monoinfected, 20 HCV‐monoinfected and 31 HIV/HCV‐co‐infected patients. Treg cells were defined as CD4+forkhead box P3 (FoxP3)+. The percentage of Treg cells was increased significantly in HIV patients compared with controls. Moreover, there was a significant inverse correlation between CD4 counts and Treg cell levels. Fewer than 50% of Treg cells expressed CD25, with differences in terms of CD127 expression between CD25+ and CD25(–) Treg cells. CD4+Foxp3+ Treg cells displayed predominantly a central memory phenotype (CD45RA–CD27+), without differences between patients and healthy controls. Activated Treg cells were increased in HIV patients, particularly considering the central memory subset. In summary, HIV infection, but not HCV, induces an up‐regulation of highly activated Treg cells, which increases in parallel with CD4 depletion. Hypothetically, this might contribute to the accelerated course of HCV‐related liver disease in HIV‐immunosuppressed patients.

Impact of chronic hepatitis C on HIV-1 disease progression.

Abstract Background: Although there is clear evidence of an accelerated progression of liver fibrosis in HIV-positive patients with chronic hepatitis C virus (HCV) infection, it is unclear whether HCV infection may influence HIV-1 disease progression. We have analyzed the impact of HCV on CD4 counts and plasma HIV RNA in a large group of HIV-positive individuals. Method: Epidemiological data, CD4 counts, and plasma HIV RNA values were recorded from 902 consecutive HIV-1-positive persons who attended our institution since 1998. Results: HCV infection was documented (antibodies and/or HCV RNA) in 72% of the total study population. The higher rates were seen among intravenous drug users (97%) compared to other groups (17% in homosexual men, 23% in patients who acquired HIV heterosexually). In a cross-sectional analysis performed at the first trimester of 2000, the mean CD4 count was lower among HCV-positive than among HCV-negative individuals (518 ± 282 cells/μL vs. 620 ± 302 cells/μL; p < .001). The mean plasma HIV RNA was 11,188 ± 55,301 copies/mL in HCV-positive persons versus 6,352 ± 32,152 copies/mL in HCV-negative persons (p = .03). Undetectable plasma HIV RNA (<50 copies/mL) was recognized in 54% of HCV-positive persons versus 64% of HCV negative persons (p = .04); a similar proportion of patients in each group was on antiretroviral therapy (90% vs. 93%) or HAART (86% vs. 89%). When comparing data from 1998 and 2000, the CD4 count increased an average of 53 cells/μL (11%) in HCV-positive persons versus 111 (19%) in HIV-negative persons during this 2-year interval (p < .05). Plasma HIV RNA on average declined 606 copies/mL (5%) in HCV-positive persons versus 5,788 copies/mL (54%) in HCV-negative persons (p < .05). A significant association between HCV infection and CD4 counts was recognized in the multivariate analysis, which was independent of gender, age, plasma HIV RNA, use of HAART, and adherence to therapy. In contrast, no significant effect of HCV on HIV RNA was found. Conclusion: Hepatitis C may be associated with a poor immunologic outcome in HIV-infected persons. This worst influence is not explained by a lower rate of antiretroviral therapy among HCV-positive persons nor a much poorer drug adherence in this population. Therefore, hepatitis C may act as a direct cofactor for HIV disease progression. If so, treatment of chronic hepatitis C might indirectly benefit HIV disease.

Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4+CD38+ (p = 0.006), CD4+HLA-DR−CD38+ (p = 0.02), CD4+CD45RA+CD27+HLA-DR−CD38+ (p = 0.002), CD8+CD45RA+CD27+CD38−HLA-DR+ (p = 0.02), and CD8+CD45RA+CD27−CD38+HLA-DR+ (p = 0.03). Activation of CD8+ T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.

Coinfection with Hepatitis C Virus Increases Lymphocyte Apoptosis in HIV-Infected Patients

To test the role of hepatitis C virus (HCV) in CD4 cell depletion in human immunodeficiency virus (HIV)-coinfected patients, T cell apoptosis was measured by annexin V labeling in 31 HIV-infected and 30 HIV-HCV-coinfected patients who were not receiving antiretroviral therapy. Apoptosis in naive CD4(+) T cells and in naive and memory CD8(+) T cells was significantly higher in HIV-HCV-coinfected than in monoinfected patients.