José M. Bellón

Clinical Outcomes Improve with Highly Active Antiretroviral Therapy in Vertically HIV Type-1–Infected Children

Background. Use of antiretroviral therapy has resulted in a decrease in morbidity and mortality rates in human immunodeficiency virus type 1 (HIV-1)-infected children.Methods. We performed a retrospective study involving 427 children to determine the effectiveness of different antiretroviral therapy protocols on clinical outcome. The follow-up period was divided into 5 calendar periods (CPs): CP1 (1980-1989), before antiretroviral therapy was administered; CP2 (1990-1993), when monotherapy was administered; CP3 (1994-1996), when combined therapy was administered; CP4 (1997-1998), when </=50% of children were receiving highly active antiretroviral therapy (HAART); and CP5 (1999-2003), when >/=60% of children were receiving HAART.Results. Children experienced a progressive increase in the CD4(+) cell count and decrease in the viral load from 1997 onwards. A lower number of AIDS cases and deaths occurred during CP5 than during the other CPs (P<.01), with a relative risk of an absence of AIDS of >20 and a relative risk of survival of >30. The AIDS rate was >50% in CP1; we observed a very strong decrease to 14% in CP2, to 16% in CP3, to 7% in CP4, and to 2% in CP5. The mortality rates in CP2 and CP3 were >6% and thereafter decreased to 0.5% in CP5. The relative risks for no hospital admission in CP4 and CP5 were >3.5. The total rates of hospital admission in CP1, CP2, and CP3 were >30%; we observed a decrease in CP4 and CP5. The duration of hospitalization decreased during the follow-up period, and it was higher in CP1 (~30 days) than in the other periods.Conclusions. We observed that HAART produces a decrease in adverse clinical outcomes (i.e., hospital admission, AIDS, and death) in children with vertical HIV-1 infection in Madrid, Spain.

CD38 Expression in CD8+ T Cells Predicts Virological Failure in HIV Type 1–Infected Children Receiving Antiretroviral Therapy

An observational study of children vertically infected with human immunodeficiency virus type 1 (HIV-1) was performed to determine the role of CD38 expression in CD8(+) T cells as prognostic marker of virological failure in children receiving HAART. We studied 42 children who were receiving antiretroviral therapy and who had an undetectable virus load (uVL), and we found a negative correlation between CD38 expression in CD8(+) T cells and the duration of uVL. We selected 17 HIV-1-infected children with CD38 values close to the baseline level (i.e., the first uVL achieved), and we distributed the children into 2 groups on the basis of median CD38 value in CD8(+) T cells. Children with CD38 values in CD8(+) T cells that were higher than the median had a higher incidence and relative risk of virological failure than did those with values lower than the median. In conclusion, we demonstrate for the first time that CD8(+)CD38(+) T cell count is a good prognostic marker of therapeutic failure in HIV-1-infected children.

Extensive implementation of highly active antiretroviral therapy shows great effect on survival and surrogate markers in vertically HIV-infected children.

We performed a retrospective observational study of 253 children vertically infected with human immunodeficiency virus (1994-2001) to assess the effectiveness of antiretroviral therapies (ARTs) on survival and surrogate markers at the population level. Children were divided into 3 groups according to the ART protocols used during the follow-up period: calendar period (CP) 1 (1994-1996) received combined therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs); CP2 (1997-1998) received implementation of highly active ART (HAART) with 3 drugs (NRTIs, protease inhibitors, and non-NRTIs); and CP3 (1999-2001) received extensive HAART. The children in the CP3 group had statistically significant longer survival periods, lower virus load (VL), highest undetectable VL proportion, and highest CD4+ T cell counts. HAART is effective at the population level at decreasing VL, increasing CD4+ T cells, and increasing the survival in a higher percentage of HIV-infected children.

Association between Exposure to Nevirapine and Reduced Liver Fibrosis Progression in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND We analyzed the effect of exposure to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) on the progression of liver fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus coinfection. METHODS We analyzed data and liver biopsy findings for 201 coinfected patients. Fibrosis was scored following the French METAVIR Cooperative Study Group. We used multinomial logistic regression analysis and the fibrosis progression rate to assess the association between cumulative exposure to antiretroviral drugs and stage of fibrosis. RESULTS The adjusted odds ratio (AOR) and 95% confidence interval (CI) of having a fibrosis stage score of 0 or 1, compared with 3 or 4, increased with each additional year of exposure to HAART (AOR, 1.32; 95% CI, 1.04-1,67), to NNRTIs as a class (AOR, 1.64; 95% CI, 1.18-2.27), to efavirenz (AOR, 1.54; 95% CI, 1.03-2.30), and to nevirapine (AOR, 1.72; 95% CI, 1.15-2.78). This effect was not found with PIs as a class. The AOR (95% CI) of having a fibrosis stage score of 2 versus 3 or 4 increased with each additional year of exposure to NNRTIs (AOR, 1.51; 95% CI, 1.08-2.10) and nevirapine (AOR, 1.58; 95% CI, 1.06-2.37). This effect was not found with highly active antiretroviral therapy, PIs, or efavirenz. The AOR (95% CI) of having a fibrosis progression rate < or = 0.1 versus > 0.1 increased with each additional year of exposure to highly active antiretroviral therapy (AOR, 1.31; 95% CI, 1.07-1.60), to NNRTIs (AOR, 1.33; 95% CI, 1.03-1.70), and to nevirapine (AOR, 1.44; 95% CI, 1.07-1.95). This effect was not found with PIs or with efavirenz. CONCLUSIONS In contrast with previous studies, we found that exposure to NNRTIs was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis progression than was exposure to efavirenz. Prospective work is needed in this area.

Viral Load and CD4+ T Lymphocyte Response to Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: An Observational Study

An observational study was performed involving 95 children with vertically transmitted human immunodeficiency virus type 1 infection to assess the sustainability of undetectable viral loads (VLs) and increased CD4+ T lymphocyte percentages after 48 months of highly active antiretroviral therapy (HAART). The median time to achieve a 10% increase in the CD4+ T lymphocyte percentage was 11.01 months. The median time to achieve an undetectable VL was 6.4 months. At the end of the study, 64.2% of the children had achieved an undetectable VL. Of the patients with an initial VL of >3.6 log10 copies/mL, 74.7% had a decrease in the VL of 1 log10 copies/mL. By contrast, of the patients who presented with an initial VL of >4.6 log10 copies/mL, 37.9% had a decrease of >2 log10 copies/mL. Higher VL at baseline, antiretroviral therapy regimens received before HAART, and multiple drug switches while receiving antiretroviral therapy were all inversely associated with an undetectable VL. A CD4+ T lymphocyte percentage of >25% was directly associated with undetectable VL during the follow-up period. In conclusion, first-line HAART induces beneficial virological and immunological outcome responses in children.

Characterizing immune reconstitution after long-term highly active antiretroviral therapy in pediatric AIDS.

In this study, we sought to characterize the T lymphocyte recovery in vertically HIV-1-infected children who respond to long-term highly active antiretroviral therapy (HAART). A 3-year longitudinal retrospective study was used to perform a cross-sectional study of 32 children rated according to the time course of CD4(+) T cell percentages in response to antiretroviral therapy and CDC clinical classification: (1) long-term asymptomatic (LTA group): 8 children in A1 during the whole follow-up period; (2) responsive to HAART (Rec group): 13 children in C3 before HAART who achieved CD4(+) T cell counts of > 500 cells/mm(3) after 3 years of HAART; and (3) nonresponsive to HAART (Non-Rec group): 11 children in C3 during the whole follow-up period despite 3 years of HAART. We also studied 17 healthy age-matched uninfected children as controls. Lymphoproliferative responses (LPRs) were evaluated by incorporation of [(3)H]thymidine, identification of T cell subsets by three-color flow cytometry, and determination of thymic production of T cells by quantification of T cell receptor rearrangement excision circles (TRECs). Interestingly, the Rec group showed an increase in percentage of CD4(+) T cells and a decrease in viral load, and recovered LPRs to mitogens and recall antigens, with values similar to those of the LTA group. Moreover, the Rec group produced similar percentages and absolute counts of naive (CD45RA(+)CD62L(+)) CD4(+) and CD8(+) T cells, and TRECs similar to those of the LTA group. In particular, the Rec group produced similar percentages of CD8(+)CD28(-)CD57(+) and CD8(+)CD28(-)CD57(-) T cell subsets compared with controls. Our data indicate that among children who have already progressed to AIDS and severe immunodeficiency but who respond to HAART, the immune system can recover and resemble those of nonprogressors or even uninfected children, in quantitative as well as in functional terms.

Virological phenotype switches under salvage therapy with lopinavir-ritonavir in heavily pretreated HIV-1 vertically infected children

Objective: To investigate the effects of salvage therapy with lopinavir–ritonavir on HIV-1 phenotype in heavily antiretroviral experienced HIV-infected children. Design: Twenty antiretroviral experienced HIV-infected children were studied during a mean of time of 16.1 months from initiation of the treatment with lopinavir–ritonavir. Methods: Besides CD4 T cells, viral load and clinical status, we analyzed 91 serial viral isolates to study the phenotype, and biological clones derived from co-cultivation techniques. Results: We observed an increase in CD4 T cells, a statistically significant decrease in viral load and clinical benefits from 3 months after treatment. Ninety per cent of children had SI/X4 bulk isolates in peripheral blood mononuclear cells at study entry. The viral phenotype changed to non syncitium-inducing (NSI)/R5 in 94% of the children after a mean of 5.7 months (95% confidence interval, 2.1–9.3 months) of salvage therapy. The remaining 10% of children had NSI/R5 isolates at entry and at all follow-up study. Similar results were found at the clonal level. Thus, at study entry in PBMC of three children with bulk syncitium-inducing (SI) phenotype, we recovered 65 biologic clones, 56 being SI and nine NSI. After salvage therapy bulk isolates changed to NSI and of 40 biologic clones recovered only five were SI and the rest were NSI. Conclusions: Our data suggest that lopinavir–ritonavir salvage therapy led not only to a viral load decrease but also to a phenotypic change. X4 virus appeared to be preferentially suppressed. Shifts in co-receptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs in vertically infected infants.

Characterizing the immune system after long-term undetectable viral load in HIV-1-infected children

Thirty two HIV-infected children, on highly active antiretroviral therapy (HAART) and >500 CD4+ T cells/mm3, were rated according to the time-course of viral load (VL) during the whole follow-up period (>18 months) in a longitudinal retrospective study. (a) uVL group: 15 children with VL below 400 copies/mL; (b) dVL group: 17 children with higher VL. The uVL group showed higher memory (CD4+CD45RO+) T cells than did dVL group, and higher number of memory activated CD4+CD45RO+HLA-DR+ than did control group (healthy age-matched uninfected children), whereas CD4+CD45RAhi+CD62L+ was similar. However, TCR rearrangement excision circles (TRECs) were higher in uVL group than in dVL group. uVL Group showed CD8+CD45RO+ and CD8+CD45RO+CD38+ higher number than the control group, but lower than the dVL group. The percentage of CD8+CD45RAhi+CD62L+, CD8+CD45RA+, CD8+CD62L+, and CD8+CD28+ was higher in uVL group than in dVL group, and lower than in control group. The uVL group showed higher number of activated (HLA-DR+CD38+, HLA-DR+, HLA-DR+CD38−) CD4+ T cells and lower percentages of CD4+HLA-DR−CD38+ than dVL group. In activated CD8+ T cell, the uVL group had lower CD8+HLA-DR+CD38+, CD8+HLA-DR+, and CD8+CD38+ than the dVL group. Preeffector (CD8+CD57−CD28− and CD8+CD45RA−CD62L−) T cells were lower in the uVL group than in dVL group. In the effector (CD8+CD57+, CD8+CD57+CD28−, and CD8+CD45RA+CD62L−) T cells, HIV-infected-children had higher values than control group. HIV-infected-children who respond to HAART had TRECs reconstitution, decreased immune activation, and lower effector CD8+ T cells. Moreover, successful HAART allow the increment of activated CD4+ T cells.

Association of CD8+ T lymphocyte subsets with the most commonly used markers to monitor HIV type 1 infection in children treated with highly active antiretroviral therapy

In contrast to adults, there is no information about children concerning the effects of the new antiretroviral therapy on the chronic activation and expansion of CD8+ T cells. We have investigated the relationship between blood CD8(+) T cell subsets, with percent CD4+ cells (%CD4), percent CD8+ cells (%CD8), and plasma viral load (VL), in 39 vertically HIV-1-infected children receiving highly active antiretroviral therapy (HAART) (mean age, 7.6 years; range, 2-15.6 years). CD8+ subsets were examined by three-color multiparametric flow cytometry, and VL was quantified by standard assays. There was a strong positive correlation between activated CD8+ T cells and VL. An increase in memory and memory-activated CD8+ T cells correlated with increased VL, whereas nonactivated memory cells and CD28+ CD8+ T cells correlated negatively with VL. Naive and effector cells did not correlate with VL, although the CD8+ CD45RA -CD62L- subset correlated with increased VL. Activated CD8(+) T cells did not correlate with %CD4, but an increase in memory-activated and effector CD8+ T cells was associated with lower %CD4. Increased naive CD8+ and CD28 +CD8+ T cells showed a positive correlation with %CD4 and a negative correlation with %CD8. In conclusion, in HIV-1-infected children receiving HAART, the activation of CD8+ T cells is associated with high VL, whereas CD8 +CD28+ and nonactivated CD8+ memory cells are associated with lower viral load. Naive CD8+ and CD28 +CD8+ T cells are associated with an improved immunological status.

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus

BACKGROUND & AIMS Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.