Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children

Background  

Antiretroviral treatment (ART) in children has special features and consequently, results obtained from clinical trials with antiretroviral drugs in adults may not be representative of children. Nelfinavir (NFV) is an HIV-1 Protease Inhibitor (PI) which has become as one of the first choices of PI for ART in children. We studied during a 3-year follow-up period the effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children.     

Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels

OBJECTIVE: To determine if there is an association between plasma HIV-1 RNA levels and severity of HIV-associated distal symmetrical polyneuropathy (DSP). DESIGN: Substudy of AIDS Clinical Trials Group Protocol 291, a double-blind, placebo-controlled study of recombinant human nerve growth factor for the treatment of painful DSP. METHODS: Two-hundred and thirty-six subjects had plasma HIV-1 RNA load assayed at baseline. Mean and maximum neuropathic pain was assessed once daily by the Gracely Pain Scale. Other measures included subjects' global pain assessment and quantitative sensory tests (QST). These values were correlated with baseline HIV-1 RNA levels. RESULTS: Among 168 subjects with detectable plasma HIV-1 RNA, there was a significant correlation between plasma HIV-1 RNA and the severity of maximum and global pain, and toe cooling thresholds. Maximum and global pain assessment correlated with plasma HIV-1 RNA in individuals with detectable viral load (r, 0.162 and 0.194; P = 0.04 and 0.01, respectively). CONCLUSIONS: There is an association between plasma HIV-1 RNA levels and the severity of pain and QST results in HIV-associated DSP. Further studies are needed to determine if aggressive use of antiretroviral drugs, including the use of dideoxynucleosides, may be of benefit to prevent or improve peripheral neuropathy.     

Low levels of HIV-1 plasma viral load in patients infected with HIV-1 subtype b and advanced immunosuppression

OBJECTIVES: Some HIV-1 infected patients show low levels of viraemia despite having advanced immunosuppression. Cases with falsely undetectable viraemia by conventional PCR have been reported when patients were infected with non-B subtypes. The aim of this study was to investigate whether this immunovirological discordance can be due to the presence of HIV-1 non-B subtypes, and whether a modified PCR procedure can yield different HIV viraemia values in these cases. METHODS: Fifteen HIV-infected patients either naive for antiretroviral drugs or under treatment, with HIV plasma viraemia below 1000 copies/mm(3)and CD4+ cell counts lesser than 500 or 300 cells/mm(3), respectively, were included. Serotyping, genotyping and HIV plasmatic viraemia determinations were performed in all individuals. RESULTS: In five out of six treatment-naive patients the virus was categorized as non-B subtype by serotyping, although only one case was confirmed by genotyping as HIV-2. Eight out of nine patients under antiretroviral therapy were subtype B carriers by serotyping and confirmed by genotyping. The remaining patient was determined as a subtype A carrier by both procedures. A modified PCR procedure (Amplicor HIV Monitor Test version 1.5) did not yield higher viral load levels than the former version. CONCLUSIONS: The presence of HIV-1 subtypes non-B can explain a minority of cases of this immunovirological discordance, but in most of them the reason is still unknown. Likewise, a PCR procedure adapted for detecting HIV-1 non-B subtypes fails to find higher plasma viraemia in patients with such a discordance.     

Terminal ileum resection is associated with higher plasma homocysteine levels in Crohn's disease

BACKGROUND: Elevated plasma total homocysteine (tHcy) is associated with a higher risk of thrombosis. Crohn's disease (CD) is associated with hypercoagulability of undefined etiology. We investigated tHcy in patients with CD and its relationship with vitamin status, disease activity, location, duration, and history of terminal ileum (TI) resection. STUDY: We examined fasting plasma tHcy, folate, serum vitamin B12 levels, and sedimentation rate in consecutive adult patients with CD. Harvey-Bradshaw index of CD activity and history of TI resection and thromboembolism were recorded. RESULTS: Median plasma tHcy was 10.2 micromol/L in 125 patients with CD. Men (n = 60) had higher plasma tHcy than women (n = 65) (11.2 vs. 9.1 micromol/L; p = 0.004). Patients with a history of TI resection showed lower serum B12 levels (293 vs. 503 pg/mL; p < 0.001) and higher plasma tHcy levels (11.0 vs. 9.35 micromol/L; p = 0.027) than patients without such history. Multivariate analysis showed history of TI resection, serum B12, and creatinine levels to be significant predictors of elevated plasma tHcy. Fourteen patients with CD with a history of thrombosis had an elevated median plasma tHcy of 11.6 micromol/L. CONCLUSIONS: Terminal ileum resection contributes to elevated plasma tHcy levels in CD cases. We recommend tHcy screening in patients with CD, especially in those with prior history of TI resection, and the initiation of vitamin supplementation when appropriate.     

葡萄糖激酶基因启动子G/A变异与空腹高血糖相关

目的　研究葡萄糖激酶 (GCK)基因启动子 - 30G/A变异在中国南方地区汉族人群中的分布并比较其在正常糖耐量 (NGT)者及糖耐量低减 (IGT)者中的差别及其与糖代谢相关指标之间的关系。方法　研究对象为 4 4 4例无糖尿病及亲缘关系的中国南方地区汉族人 ,其中 2 2 2例为NGT ,2 2 2例为IGT。通过PCR RFLP检测GCK启动子 - 30位置的G→A变异所导致BsiHKAⅠ酶切位点的缺失。结果　在IGT及NGT的人群中含有A等位基因的频率分别为 18.2 %及 19.8%。与GG基因型的人群相比 ,带有A等位基因的人群空腹血糖显著增高〔(5 .35± 0 .5 9vs 5 .19± 0 .5 3)mmol/L ,P =0 .0 0 6〕 ,在IGT的人群中 ,带有A等位基因的人群空腹血糖仍显著增高〔(5 .5 4± 0 .5 8vs 5 .35± 0 .5 2 )mmol/L ,P =0 .0 2〕 ,而在NGT的人群中 ,不同GCK基因型者的空腹血糖差异无显著性。结论GCK基因启动子 - 30G/A变异与空腹高血糖水平相关 ,可能对中国人的IGT有一定的影响。     

快速和早期病毒学应答对慢性丙型肝炎患者持续病毒学应答的预测价值

目的 探讨快速病毒学应答(RVR)和早期病毒学应答(EVR)对慢性丙型肝炎患者持续病毒学应答(SVR)的预测价值.方法 应用酶免疫方法检测105例慢性丙型肝炎患者基因型.患者给予聚乙二醇干扰素α-2a联合利巴韦林治疗.在治疗第4、12、24周和随访24周时检测患者的HCVRNA,观察不同时期的病毒学应答率以及对SVR的影响.结果 105例患者中,HCV基因1型44例,占41.9%;2型46例,占43.8%;3型15例,占14.3%.基因1型患者的RVR为51.2%,明显低于基因2或3型患者的73.8%(χ2=5.460,P=0.019);基因1型患者的EVR为73.2%,明显低于基因2或3型患者的96.7%(χ2=12.220,P=0.000);基因1型患者的SVR为43.9%,明显低于基因2或3型患者的75.4%(χ2=10.413,P=0.001).获得RVR的患者SVR为80.3%,明显高于未获得RVR的30.6%(χ2=24.662,P=0.000).RVR的阳性预测值均高于EVR,RVR的阴性预测值均低于EVR,但两者相比差异无统计学意义(P＞0.05).结论 基因1型患者的RVR、EVR和SVR均明显低于基因2或3型患者,RVR、EVR和SVR与基因型相关;RVR对慢性丙型肝炎患者SVR预测价值与EVR类似.     

Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB1 3435 CT(rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB1 3435 CT polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB1 3435 CT polymorphisms,except for height(OR=0.902,95% CI:0.835-0.973)(P0.05).The minor allele frequency of ABCB1 3435 CT was0.446.The frequency of the heterozygous mutant ABCB1 3435 C/T was 53.02%(n=79),ABCB1 3435 T/T homozygous mutant was 18.12%(n=21) and the wild type ABCB1 3435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR:(1.46-4.12) mg/L].The plasma concentration of efavirenz was higher in cases with ABCB1 3435 T/T homozygous mutant [2.73 mg/L,IQR:(2.02-4.19) mg/L] and ABCB1 3435 C/T heterozygous mutant [2.29 mg/L,IQR:(1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435 C/C homozygous [2.1 mg/L,IQR:(1.37-3.53) mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P0.05).Objective: To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods: A single nucleotide polymorphism of ABCB1 3435 CT(rs1045642) in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment. Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration. The relationship between plasma efavirenz concentrations and ABCB1 3435 CT polymorphisms was analyzed. Results: Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age, gender, body weight, CD4 count and plasma HIV-1 RNA, blood biochemical parameters, antiretroviral duration or ABCB1 3435 CT polymorphisms, except for height(OR=0.902, 95% CI: 0.835-0.973)(P0.05). The minor allele frequency of ABCB1 3435 CT was 0.446. The frequency of the heterozygous mutant ABCB1 3435 C/T was 53.02%(n=79), ABCB1 3435 T/T homozygous mutant was 18.12%(n=27) and the wild type ABCB1 3435 C/C genotype was 28.86%(n=43). The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L [IQR:(1.46-4.12) mg/L]. The plasma concentration of efavirenz was higher in cases with ABCB1 3435 T/T homozygous mutant [2.73 mg/L, IQR:(2.02-4.19) mg/L] and ABCB1 3435 C/T heterozygous mutant [2.29 mg/L, IQR:(1.41-4.28) mg/L] genotypes compared to the wild type ABCB1 3435 C/C homozygous [2.1 mg/L, IQR:(1.37-3.53) mg/L]. However, there was no statistically significant difference in the efavirenz concentration between the different genotypes(P0.05).Conclusions: There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB1 3435 T/T and ABCB1 3435 C/T genotypes. No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.     

Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy

BACKGROUND: To determine the impact of HIV-1 drug resistance at baseline and antiretroviral drug levels (DL) during follow-up on virologic response to the next antiretroviral regimen. METHODS: Baseline genotypic and phenotypic susceptibility was obtained for plasma virus from patients failing a protease inhibitor-containing regimen. Untimed plasma antiretroviral DL were performed and the distribution of DL after 12 weeks of follow-up was classified as above (DLHigh) or below (DLLow) the median. Inhibitory quotients [IQ = (DL at week 12)/(fold change in IC50 to wild-type)] were determined for each drug in the regimen. Primary outcome was change in log10 plasma HIV-1 RNA viral load (DeltaVL) from baseline to 12 weeks. RESULTS: There were 137 patients who had baseline resistance data available for the antiretroviral drugs used in the salvage regimen, and DL at week 12. Each drug with DLHigh was associated with DeltaVL = -0.40 (P = 0.0002) while each drug with DLLow had DeltaVL = -0.16 (P = 0.11). In multivariate models DeltaVL associated with each active drug (defined by genotype) with DLHigh was -0.48 log10 (P < 0.0001), and with each active drug with DLLow was -0.22 (P = 0.03). The DeltaVL was -0.18 if no drugs in the regimen had an IQ > median, compared to -0.58 for one drug, -1.06 for two drugs, -0.86 for three drugs, and -1.44 for four or five drugs with IQ > median (P < 0.0001 for trend). CONCLUSIONS: In salvage therapy, both the number of active drugs and the DL for each drug in the new regimen determine the antiviral response.     

High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals.

OBJECTIVE: To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial. METHODS: The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine, zidovudine and didanosine in 51 antiretroviral-naive HIV-1-infected patients. The relationships between the value of k, the time to reach an undetectable HIV-1 RNA concentration in plasma (< 20 copies/ml) and the success of therapy after 52 weeks of treatment as dependent variables and the exposure to nevirapine, baseline HIV-1 RNA and baseline CD4 cell count as independent variables, were explored using linear regression analyses, proportional hazard models and logistic analyses, respectively. RESULTS: The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02). CONCLUSIONS: A high exposure to nevirapine (in a twice daily regimen) is significantly associated with improved virological response in the short as well as in the long term. These findings suggest that optimization of nevirapine concentration might be used as a tool to improve virological outcome in (antiretroviral-naive) patients treated with nevirapine.     

Angiographic coronary artery disease is associated with progressively higher levels of fasting plasma glucose

This study evaluated the association between progressively higher levels of fasting glycemia (G) and insulin resistance parameters with coronary artery disease (CAD) in patients referred for coronary angiography. All 145 patients (age 58.4+/-0.9 years, 51.7% men) underwent clinical and laboratory evaluation before coronary angiography and subjects were divided into four groups: normal (N, <88 mg/dl), high-normal (H-N, 89-99 mg/dl), impaired fasting glucose (IFG, 100-125 mg/dl) and diabetes (DM, >126 mg/dl or known diabetics). Arteriographic evidence of CAD was determined by two criteria: (1) a 30% or greater diameter stenosis in at least one major coronary artery; (2) a 70% or greater diameter stenosis in at least one major coronary artery. HOMA-IR increased progressively according to each group: N=1.74+/-0.2, H-N=3.14+/-0.3, IFG=4.67+/-0.6 and DM=8.00+/-2.9; p=0.001. The proportion of patients with CAD according to both criteria increased with each G level: CAD criteria 1: N=39.4%, H-N=50%, IFG=60% and DM=69.6%, p=0.006; CAD criteria 2: N=27.3%, H-N=30%, IFG=36% and DM=50%, p=0.03. We demonstrated a significant association between subtle disturbances of the glucose metabolism, assessed by subnormal levels of fasting glucose and insulin resistance parameters, and angiographically documented coronary artery disease.     

Hyperimmunoglobulinemia in HIV-1 infected individuals does not clearly correlate with plasma levels of IL-6.

In this study we evaluated interleukin-6 (IL-6) plasma levels in 80 human immunodeficiency virus type 1 (HIV-1) seropositive (+) individuals and 51 HIV-1 seronegative (-) blood donors. Plasma IL-6, detectable only in a subset of HIV-1(+) individuals (45 of 80) and normal blood donors (28 of 51), was significantly (p less than 0.01) increased in HIV-1(+) subjects 187 +/- 20.5 vs. 86.3 +/- 14 pg/ml). Among HIV-1-infected individuals, ARC/AIDS patients showed the highest IL-6 values (243.3 +/- 43.3 pg/ml). HIV-1(+) subjects showed, at all the different stages of the disease, a significant increase in total gammaglobulins, particularly IgG (2071 +/- 101 vs 1265 +/- 34 of HIV-1 seronegative controls). Although among HIV-1-infected individuals, the group with detectable plasma levels of IL-6 shows the highest levels of IgG (2243 +/- 146 vs. 1790 +/- 105, p less than 0.05), no positive correlations were observed between plasma levels of IL-6 and total gamma globulins (r = 0.2) or IgG (0.17). IL-6 production was also examined in the endotoxin-free supernatants of peripheral blood cultured monocytes and CD4+ T lymphocytes, in the presence or absence of specific stimuli. The amount of IL-6 released in monocyte and CD4+ T-lymphocyte culture supernatants was similar in 40 HIV-1(+) individuals and 35 HIV-1(-) controls. Our data show that plasma levels of IL-6 are significantly increased in HIV-1-infected individuals, in particular in ARC/AIDS patients. However, such an increase does not strictly correlate with the degree of hypergammaglobulinemia in the same HIV-1-infected individuals.     

Response to treatment of chronic hepatitis C with interferon α in patients infected with HIV-1 is associated with higher CD4+ cell count

Summary The aim of this study was to assess the efficacy and tolerance of interferon α (IFN α) treatment of chronic hepatitis C in HIV-seropositive patients. Seventeen patients with actively replicating hepatitis C were consecutively enrolled and treated with IFN α 5 MIU three times a week and followed up for at least 6 months after cessation of treatment. Eight patients responded to IFN α therapy with a complete remission of signs of active hepatitis and viral replication (ALT, HCV-RNA) at the end of treatment with IFN α. A sustained complete remission (ALT, HCV-RNA) for at least 6 months after the end of treatment was achieved in five of these eight patients. Complete responders had higher CD4+ cell counts (median 525/μl) compared to non-responders (median 245/μl) (p<0.001). All patients but one completed at least 4 months of treatment. No severe toxicity (> WHO grade 2) due to IFN α treatment occurred. The results indicate that IFN α treatment of chronic hepatitis C in HIV-seropositive patients is successful in a considerable number of cases. Success of treatment with IFN α is related to higher CD4+ cell counts.     

Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children

OBJECTIVE: To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS. DESIGN: A prospective observational study. SETTING: Two pediatric HIV clinics. PARTICIPANTS: Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4 < or =6%). INTERVENTION: HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy. MAIN OUTCOME MEASURES: Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype. RESULTS: Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P = 0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657x10(6) cells/l (range, 30-2240x10(6) cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P = 0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients. CONCLUSIONS: HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of 'virologic failure'. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure.     

Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes

Change of HIV-1 coreceptor use has been connected to progression of disease in children infected with HIV-1, presumably subtype B. It has not been possible to discern whether the appearance of new viral phenotypes precedes disease development or comes as a consequence of it. We studied the evolution of coreceptor use in HIV-1 isolates from 24 vertically infected children. Their clinical, virological, and immunological status was recorded and the env V3 subtype was determined by DNA sequencing. Coreceptor use was tested on human cell lines, expressing CD4 together with CCR5, CXCR4, and other chemokine receptors. The children carried five different env subtypes (nine A, five B, four C, three D, and one G) and one circulating recombinant form, CRF01_AE (n = 2). Of the 143 isolates, 86 originated from peripheral blood mononuclear cells (PBMCs) and 57 originated from plasma, received at 90 time points. In 52 of 54 paired plasma and PBMC isolates the coreceptor use was concordant. All 74 isolates obtained at 41 time points during the first year of life used CCR5. A change from use of CCR5 to use of CXCR4 occurred in four children infected with subtype A, D, or CRF01_AE after they had reached 1.5 to 5.8 years of age. There was a significant association with decreased CD4+ cell levels and severity of disease but, interestingly, the coreceptor change appeared months or even years after the beginning of the immunological deterioration. Thus CXCR4-using virus may emerge as a possible consequence of immune deficiency. The results provide new insights into AIDS development in children.     

A polymorphism in PRF1 gene is associated with HIV-1 vertical transmission in Brazilian children

We investigated the possible association between PRF1 gene polymorphisms and HIV-1 vertical transmission in Brazilian children by analyzing PRF1 gene coding and untranslated regions in 173 perinatally infected children (HIV+), 51 exposed uninfected (HIV-), and 171 HIV-unexposed uninfected children. Seven single nucleotide polymorphisms were identified in our samples. The rs885822 C allele and CC genotype were significantly more frequent in HIV-negative than in HIV-positive patients and associated with a protective effect toward HIV vertical transmission.