José Tomás Ramos

Impact on weight and height with the use of HAART in HIV-infected children.

Background: There are few data on long-term effects of highly active antiretroviral therapy (HAART) on weight and height in HIV-infected children. Objectives: Our objective was to assess the effect of HAART on the weight and height of HIV-infected children over time in the Madrid cohort, and analyze possible factors associated with the effect. Patients and methods: This was a retrospective study of HIV-infected children starting HAART in 1997 or later. Serial measurements of weight, height and body mass index (BMI) were performed and converted to z-scores using the Spanish revised reference data. Changes from baseline in weight, height and BMI at 12, 24, 36, 48 and 60 months were determined. Associations of z-scores at the last visit with immunologic (CD4% above 25%) and virologic responses (more than 50% of samples below 400 copies/mL), CDC (Centers for Disease Control) clinical category, and the presence and type of lipodystrophy (lipoatrophy or lipohypertrophy) were evaluated. Results: Twelve hundred and twelve children, 97% of them vertically-infected, received HAART starting in 1997 for a median of 71 months (4–102 months). Median age at initiation of HAART was 6 years (1 month–18 years). Thirty-nine percentage were antiretroviral naive and 61% had received NRTI therapy previously. Thirty-two percentage and 53% had CDC class C and immunologic class 3, respectively. At the final evaluation, 24% of children remained on their first combination therapy, 39% on the second and 37% had received at least 3 different HAART regimens. Fifty-one percentage were classified as virologic responders. Thirty-nine percentage of children in this study were diagnosed with lipodystrophy. At baseline, median z-score for weight, height and BMI were −0.45, −0.60 and −0.33, respectively. HAART was associated with significant increases in z-scores of weight and height but not BMI at the different time-points analyzed. Virologic nonresponders had significantly lower z-scores for weight and height but not for BMI. CDC class C was associated with lower z-scores for height. No differences in final measurements were observed for baseline CD4, immunologic response or lipoatrophy. Children with lipohypertophy had a significantly higher BMI at the last visit. Conclusions: HIV-infected children experienced a continued catch-up in weight and height 5 years after starting HAART. Virologic control is related to sustained growth.

Opportunistic infections and organ‐specific diseases in HIV‐1‐infected children: a cohort study (1990–2006)

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ‐specific diseases in HIV‐infected children.

High Drug Resistance Prevalence among Vertically HIV-Infected Patients Transferred from Pediatric Care to Adult Units in Spain

Background Antiretroviral treatment (ART) has contributed to increased life expectancy of HIV-1 infected children. In developed countries, an increasing number of children reaching adulthood are transferred to adult units. The objectives were to describe the demographic and clinical features, ART history, antiviral drug resistance and drug susceptibility in HIV-1 perinatally infected adolescents transferred to adult care units in Spain from the Madrid Cohort of HIV-1 infected children. Methods Clinical, virological and immunological features of HIV-1 vertically infected patients in the Madrid Cohort of HIV-infected children were analyzed at the time of transfer. Pol sequences from each patient were recovered before transfer. Resistance mutations according to the InternationaI AIDS Society 2011 list were identified and interpreted using the Stanford algorithm. Results were compared to the non-transferred HIV-1 infected pediatric cohort from Madrid. Results One hundred twelve infected patients were transferred to adult units between 1997 and 2011. They were mainly perinatally infected (93.7%), with a mean nadir CD4+-T-cells count of 10% and presented moderate or severe clinical symptoms (75%). By the time of transfer, the mean age was 18.9 years, the mean CD4+T-cells count was 627.5 cells/ml, 64.2% presented more than 350 CD4+T-cells/ml and 47.3% had ≤200 RNA-copies/ml. Most (97.3%) were ART experienced receiving Highly Active ART (HAART) (84.8%). Resistance prevalence among pretreated was 50.9%, 76.9% and 36.5% for Protease Inhibitors (PI), Nucleoside Reverse Transcriptase Inhibitors (NRTI) and Non-NRTI (NNRTI), respectively. Resistance mutations were significantly higher among transferred patients compared to non-transferred for the PI+NRTI combination (19% vs. 8.4%). Triple resistance was similar to non-transferred pediatric patients (17.3% vs. 17.6%). Conclusion Despite a good immunological and virological control before transfer, we found high levels of resistance to PI, NRTI and triple drug resistance in HIV-1 infected adolescents transferred to adult units.

Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents.

Background: There are pediatric patients receiving many highly active antiretroviral therapy (HAART) regimens entailing drug resistance mutations that complicate HAART effective therapies. Methods: This was a multicenter retrospective study of 19 multidrug-resistant children and adolescents enrolled from July 2007 to October 2009. Patients were nonresponders because no reduction in HIV type 1 (HIV-1) RNA to undetectable levels was observed during their previous antiretroviral treatment history. The long-term effectiveness of raltegravir (RAL)-based salvage therapy was assessed through a longitudinal analysis of immunologic, virologic, and clinical status of the patients. Results: Median age was 16.0 (15.0–18.0) years. At baseline, median HIV-1 RNA was 10,000 (4.0 log10 copies/mL) (interquartile range [IQR]: 4300–83,000), and median CD4+T-cell count was 329 (18.2% cells/&mgr;L) (IQR: 175–452). The backbone regimen included at least 1 fully active drug in 17/19 (89%) patients. Median follow-up with HAART including RAL was 80.1 weeks (IQR: 49.4–96.4): 16/19 (84%) exposed for >120 weeks and 6/19 (32%) >100 weeks. After RAL-based therapy, 4/19 (21%) patients achieved HIV-1 RNA <400 copies and 13/17 (68%) reached HIV-1 RNA <50 copies: 6 (32%) within the first month and 7 (37%) within the first 4 months. CD4+T-cell recovery (70% to 90% of the baseline values) was observed in 17/19 (89%) patients. No deaths, AIDS-defining illnesses, or symptoms of severe intolerance were recorded. Only 2 patients experienced mild-moderate short-term skin rash. Two (11%) patients had sustained and optimum adherence to HAART. No patients showed resistance mutations to RAL after follow-up. Conclusions: We observed a sustained antiviral response and improved immunologic indices in multidrug-resistant pediatric patients, most of whom had received RAL as part of salvage regimens with at least 1 fully active drugs.

Impact of Highly Active Antiretroviral Therapy (HAART) on AIDS and Death in a Cohort of Vertically HIV Type 1-Infected Children: 1980–2006

We evaluated the population effectiveness of highly active antiretroviral therapy (HAART) on the risk of AIDS and death in a multicenter cohort of 346 HIV-1 vertically infected children born between 1980 and 2006 in the Comunidad Autónoma de Madrid (CAM), Spain. Risks of AIDS and death in patients with the same duration of HIV infection were compared in different calendar periods [CP1: 1980-1989, CP2: 1990-1993 (reference), CP3: 1994-1996, CP4: 1997-1998, CP5: 1999-2006] through cumulative incidence curves and Cox proportional hazards models, allowing for late entry, that included the calendar period as the time-dependent covariate and adjusting for gender and mothers transmission category. The median follow-up was 11.8 years [interquartile range (IQR), 6.3-15.9]. Median CD4+ T cell percentage increased up to 26.5 in CP5 (IQR, 19.5-36.7) while the viral load decreased (median log(10) copies/ml in CP5, 3.66; IQR, 3.07-4.22). Multivariate analysis showed significant reduction in the risk of death since 1997 onward [CP4: adjusted hazard ratios (AHR), 0.29; 95% confidence interval (CI), 0.12-0.69; CP5: AHR, 0.06; 95% CI, 0.03-0.15]. Reduction in progression to AIDS reached borderline significance in CP4 (AHR, 0.49; 95% CI, 0.23-1.05) and was more marked in the last period (CP5: AHR, 0.30; 95% CI, 0.16-0.59). The reductions in the incidence of AIDS and death observed since 1996 were largely attributable to HAART.

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients

We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV‐1.

Trends in drug resistance prevalence in HIV-1-infected children in Madrid: 1993 to 2010 analysis.

Background: Drug resistance mutations compromise antiretroviral treatment (ART) effectiveness in HIV-1–infected children. Trends in drug resistance prevalence have not been previously evaluated in HIV-infected children in Spain. Methods: HIV-1 variants, drug resistance prevalence dynamics and drug susceptibility were analyzed from 1993 to 2010 in HIV-infected children with available pol sequence, sample or drug resistance profile. HIV-1 variants were characterized by phylogenetic analysis. Resistance mutations in pretreated and naive patients were identified according to International AIDS Society-2010 and the World Health Organization list, respectively. Results: In 232 patients, genotypic resistance profiles (n = 11) or pol sequences (n = 128) were recovered or newly generated from infected samples (n = 93). Patients were mainly in care at pediatric units (63%), were mostly Europeans (84%), with moderate AIDS symptoms (65%), on ART (91%) and infected by HIV-1 subtype B (89%). Transmitted major drug resistance mutations were selected in 6 (13.6%) of the 44 ART-naive children: 4.8%, 9.3% and 11.6%, for protease inhibitors, nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. Overall resistance prevalence was higher (71.8%) among ART-exposed children: 39.9%, 66.5% and 35.3% for protease inhibitors, nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. Resistance prevalence among ART-exposed children was higher in 2009 to 2010 relative to 1993 to1999 for nonnucleoside reverse transcriptase inhibitors (42% versus 6%; P = 0.006), protease inhibitors (39% versus 13%; P = 0.004) and nucleoside reverse transcriptase inhibitors (63% versus 44%; P = NS). Susceptibility to each drug in resistant viruses was predicted. The rate of non-B infections increased in the last years, mainly caused by recombinant viruses. Conclusions: The increasing resistance prevalence among the HIV-infected pediatric population in Spain highlights the importance of specific drug resistance and drug susceptibility surveillance in long-term pretreated children to optimize treatment regimens.

Interferon-γ release assay for the diagnosis of tuberculosis in children

Aims To compare the QuantiFERON-TB GOLD In Tube test (QTF) and the tuberculin skin test (TST) in children. Methods A prospective study was carried out in nine hospitals in Madrid, Spain. TST and QTF were performed in immigrants, tuberculosis (TB) contacts and patients with TB disease (TBD). Results 459 children were included. Disagreement between the tests was more frequently observed among latent tuberculosis infection (LTBI) cases (54%; 38/70) than in non-infected or TBD cases (0.8%; 3/369) (p<0.01). There were more BCG-vaccinated children among LTBI cases with negative QTF (76%) than among LTBI cases with positive QTF (40%) (p<0.001). Agreement between tests in BCG-vaccinated children was lower than in non-vaccinated cases (p<0.05). Tests in TB exposed patients showed better agreement than in non-exposed children (p<0.05). Conclusions Agreement of both tests was excellent in TBD cases, non-vaccinated children and non-infected patients. A significant number of QTF negative results were observed among LTBI cases, especially in BCG-vaccinated children. Agreement was better in exposed children.

Spatial pattern of HIV-1 mother-to-child-transmission in Madrid (Spain) from 1980 till now: demographic and socioeconomic factors.

Objective:To evaluate any possible association between indicators of social inequalities and the geographical distribution of HIV-1 mother-to-child transmission (MTCT) cases in Madrid. Methods:We carried out an observational survey of 224 HIV-1 vertically infected children born in 1980–2006 living in Madrid. We elaborated maps representing the prevalence of HIV-1 MTCT cases. We assessed the association between indicators of social inequalities and the spatial distribution of MTCT cases. Poisson univariate and multivariate analysis of risk factors for MTCT were performed. Results:We identified core areas of transmission mainly in southern Madrid until 2006. The prevalence of MTCT cases was significantly correlated to the percentage of immigrants, illiterates, unemployed women and the income in 1996 and 2000/2001. The risk of MTCT increased in the periods up to 1996 compared with the calendar period 1980–1989, whereas the risk decreased in 1999–2006 [relative risk, 0.08; 95% confidence interval (CI), 0.03–0.18; P < 0.001]. The risk was especially high in the districts of Usera (absolute relative risk, 11.4; 95% CI, 2.6–49.5; P = 0.001), Puente de Vallecas (absolute relative risk, 14.0; 95% CI, 3.4–57.9; P < 0.001) and San Blas (absolute relative risk, 12.5; 95% CI, 2.9–53.6; P = 0.001). The percentage of illiterates was the indicator that explained the risk of MTCT (absolute relative risk, 1.07; 95% CI, 1.05–1.10; P = 0.001). Conclusion:We observed a geographic heterogeneity of the HIV-1 vertical transmission with the highest prevalence in disadvantaged districts. What is described in the present review is the HIV-1 vertical transmission within a social context; this approach could be relevant in analysing the pattern of HIV-1 transmission in other Western cities or highlighting the distribution of other infectious diseases.

Cardiovascular biomarkers in vertically HIV-infected children without metabolic abnormalities

Early cardiovascular disease is a major concern for ART-suppressed vertically HIV-infected children; however, evidence is lacking regarding specific preventive measures. In this study, a complete panel of biomarkers was determined together with carotid intima-media thickness (IMT), in a cohort of 64 HIV-infected children and 30 controls. Mean age of participants was 14.1±5 years. HIV-infected patients showed normal lipid profile, with only slightly higher triglycerides, and no differences between groups were found regarding IMT. HIV-infected patients displayed higher levels of soluble CD14 (sCD14) and soluble vascular cell adhesion molecule-1 (sVCAM) (all p<0.05). However, levels of C-reactive protein, interleukin-6, myeloperoxidase, monocyte chemoattractant protein-1, P-selectin and tissue plasminogen activator were similar between groups. Vertically HIV-infected subjects on ART with no significant metabolic disturbances displayed increased sCD14 and sVCAM but not up-regulation of proinflammatory pathways. Larger studies are warranted to assess the impact of a strict metabolic control on cardiovascular risk and to define specific cardiovascular disease preventive strategies in this population.