Factors associated with time to achieve an undetectable HIV RNA viral load after start of antiretroviral treatment in HIV-1-infected pregnant women.

OBJECTIVE: To identify factors associated with the time to viral suppression in women starting antiretroviral treatment (ART) during pregnancy. Knowledge on duration of viral load (VL) decline could help deciding the timing of treatment initiation. METHODS: Highly active antiretroviral treatment (HAART)-naive pregnant women over 18 years of age who started treatment during pregnancy were included. The time to viral suppression was calculated and compared between subgroups. RESULTS: A total of 227 pregnancies matched our inclusion criteria. In 84.6% of these an undetectable VL was reached at the time of delivery. The median time to undetectable VL after initiation of treatment was 60 days (12-168 days). Only baseline VL <10,000 copies/mL showed an independent association with time to viral suppression in multivariate Cox regression analysis, with a mean time to reach a VL <50 HIV-1 copies/mL of 49 days (95% CI 44-53). No difference in time to undetectable VL was found between protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based regimens. Integrase inhibitors were not part of any treatment regimen. CONCLUSION: Our results suggest that in patients with baseline HIV RNA <10,000 copies/mL ART initiation might be postponed up to the twentieth week of pregnancy, thus minimising the risk of possible drug-related teratogenicity and toxicity.

Mode of delivery in HIV-infected pregnant women and prevention of mother-to-child transmission: changing practices in Western Europe.

OBJECTIVES: The aim of the study was to examine temporal and geographical patterns of mode of delivery in the European Collaborative Study (ECS), identify factors associated with elective caesarean section (CS) delivery in the highly active antiretroviral therapy (HAART) era and explore associations between mode of delivery and mother-to-child transmission (MTCT). METHODS: The ECS is a cohort study in which HIV-infected pregnant women are enrolled and their infants prospectively followed. Data on 5238 mother-child pairs (MCPs) enrolled in Western European ECS sites between 1985 and 2007 were analysed. RESULTS: The elective CS rate increased from 16% in 1985-1993 to 67% in 1999-2001, declining to 51% by 2005-2007. In 2002-2004, 10% of infants were delivered vaginally, increasing to 34% by 2005-2007. During the HAART era, women in Belgium, the United Kingdom and the Netherlands were less likely to deliver by elective CS than those in Italy and Spain [adjusted odds ratio (AOR) 0.07; 95% confidence interval (CI) 0.04-0.12]. The MTCT rate in 2005-2007 was 1%. Among MCPs with maternal HIV RNA<400 HIV-1 RNA copies/mL (n=960), elective CS was associated with 80% decreased MTCT risk (AOR 0.20; 95% CI 0.05-0.65) adjusting for HAART and prematurity. Two infants born to 559 women with viral loads <50 copies/mL were infected, one of whom was delivered by elective CS (MTCT rate 0.4%; 95% CI 0.04-1.29). CONCLUSIONS: Our findings suggest that elective CS prevents MTCT even at low maternal viral loads, but the study was insufficiently powered to enable a conclusion to be drawn as to whether this applies for viral loads <50 copies/mL. Diverging mode of delivery patterns in Europe reflect uncertainties regarding the risk-benefit balance of elective CS for women on successful HAART.

Steady-state nevirapine plasma concentrations are influenced by pregnancy.

OBJECTIVES: Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations. METHODS: We included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n=45) and non-pregnant (n=152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed. RESULTS: Steady-state NVP plasma concentrations were lower in pregnant women: 5.2 mg/L (interquartile range 3.9-6.8) vs. 5.8 mg/L (4.3-7.7) (P=0.08). After adjusting for confounders, both pregnancy (regression coefficient=-0.90 mg/L, P=0.046) and African descent (regression coefficient=+1.13 mg/L, P=0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8 mg/L during pregnancy and 5.8 mg/L outside pregnancy (paired t-test, P=0.073). CONCLUSIONS: Pregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.

The AmRo study: pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery.

OBJECTIVE: To explore pregnancy outcome in HIV-1-positive and HIV-negative women, and mother-to-child transmission (MTCT) according to mode of delivery under effective highly active antiretroviral therapy (HAART). DESIGN: Cohort of 143 pregnant HIV-1-infected women including a matched case-control study in a 2:1 ratio of controls to cases (n=98). SETTING: Academic Medical Center in Amsterdam and Erasmus Medical Center in Rotterdam, the Netherlands. POPULATION: Consecutive referred HIV-1 infected pregnant women treated with HAART and matched control not infected pregnant women. MAIN OUTCOME MEASURES: MTCT, preterm delivery, low birthweight, pre-eclampsia. RESULTS: MTCT was 0% (95% CI 0-2.1%). Seventy-eight percent of HIV-1-infected women commenced and 62% completed vaginal delivery. The calculated number of caesarean sections needed to prevent a single MTCT was 131 or more. Preterm delivery rates were 18% (95% CI 11-27) in women infected with HIV-1 and 9% (95% CI 5-13) in controls (P=0.03). HAART used at <13 weeks of gestation was associated with a 44% preterm delivery rate compared with 21% when HAART was started at or after 13 weeks and 14% in controls. (Very) low birthweight and incidence of pre-eclampsia were not different between HIV-1 and controls. CONCLUSIONS: We have not demonstrated any MTCT after vaginal delivery in women effectively treated by HAART. The HAART-associated increase in preterm delivery rate is mainly seen after first trimester HAART use.

Quantification of the response to miltefosine treatment for visceral leishmaniasis by QT-NASBA.

A male patient with psoriatic arthritis and visceral Leishmania infantum infection was treated with oral miltefosine 50 mg three times a day for 4 weeks at the Academic Medical Center, Amsterdam, The Netherlands. Miltefosine plasma concentrations were measured with liquid chromatography/mass spectrometry. The parasite load was followed by quantitative nucleic acid sequence-based amplification (QT-NASBA) assay in blood. Miltefosine elicited a prompt therapeutic effect. After an initial worsening of symptoms and an increase of QT-NASBA values during the first week, recovery was rapidly achieved. QT-NASBA values declined exponentially and were negative after 6 weeks. Miltefosine plasma concentrations continued to accumulate during the 4 weeks of treatment. The terminal elimination half-life was 14.8 days.

[Severe psychosis in an African woman due to the antiretroviral agent efavirenz]. / Ernstige psychose bij een afrikaanse vrouw door het antiretrovirale middel efavirenz.

A 34-year-old woman originally from Ghana was given efavirenz as antiretroviral therapy. One week later she was found to be in a psychotic state with paranoid hallucinations and anxiety; she then stabbed a nurse. The literature indicates that female patients of African origin appear to be more susceptible to the side effects of efavirenz due to genetically reduced clearance and therefore higher serum levels.

[Treatment of HIV-1 infected pregnant women]. / De behandeling van HIV-1-geïnfecteerde zwangeren.

Since 1 January 2004, pregnant women in the Netherlands have been universally screened for HIV infection. Three HIV-infected, pregnant women aged 28, 24 and 33 years respectively, illustrate some of the problems that may be encountered in this situation, as well as the treatment options available to prevent the transmission of HIV from mother to child. The first patient had a positive antibody test early in pregnancy for which she did not need treatment, the second had a positive antibody test late in pregnancy and the third was seropositive and on medication, but had the wish to become pregnant. A vaginal delivery is possible when highly active antiretroviral therapy (HAART) of the mother is started in good time and the plasma HIV-RNA is < 400 copies/ml at the time of delivery. In this situation the risk of transmission is reduced to around 1%. However, if HIV infection is diagnosed late in pregnancy or, despite HAART, the plasma HIV-RNA is not expected to be < 400 copies/ml, an elective caesarean section is scheduled at 38 weeks of pregnancy. In all instances the neonate is treated for 28 days with antiretrovirals, as post-exposure prophylaxis. If a woman with a known HIV infection wants to become pregnant, the choice of antiretroviral regimen and when this is started is determined by her treatment history and the potential toxic effects of the medication on the foetus.

[Highly active antiretroviral therapy (HAART) in HIV-positive pregnant women in the Netherlands, 1997-2003: safe, effective and with few side effects]. / Krachtige antiretrovirale therapie (HAART) bij HIV-positieve zwangeren in Nederland, 1997-2003: veilig, effectief en met weinig bijwerkingen.

OBJECTIVE: To assess the side effects, safety and efficacy of highly active antiretroviral therapy (HAART) in a cohort of HIV-infected pregnant women in the Netherlands. DESIGN: Retrospective. METHOD: Data were collected from the medical records of HIV-infected pregnant women who received HAART during pregnancy in the period 1 January 1997-1 June 2003 at 14 HIV-specialized centres in the Netherlands. The inclusion criteria were at least a triple drug regimen and birth at 20 or more weeks of gestation. Information was collected about patient characteristics, HAART prescribed, side effects, viral load response, mode of delivery and HIV-status of the neonate. RESULTS: A total of 267/413 women satisfied the inclusion criteria. Most women (n = 199) had not previously received anti-retroviral therapy and started HAART between weeks 21 and 28 of the pregnancy. The two most frequently used regimens contained nelfinavir (57%) or nevirapine (31%). Gastrointestinal side effects were more frequently observed in the nelfinavir group, while rash and hepatotoxicity were more frequently reported in the nevirapine group. Efficacy and pregnancy outcome were similar in both groups. Two infants (0.7%) were HIV-infected. CONCLUSION: HAART regimens containing nelfinavir or nevirapine in HIV-infected pregnant women were safe, effective and well tolerated.

[Physical diagnosis--ascites]. / Fysische diagnostiek--ascites.

The diagnosis of ascites can be made very likely by a good clinical history and a well-directed physical examination, if the patient suffers from a disease which can cause ascites. The physician should ask about recent weight gain, change in abdominal girth and ankle oedema. With a positive history, the likelihood of the presence of ascites may increase 3 to 4-fold. When the findings at physical examination are also positive, the likelihood may increase 10 to 20-fold. A fluid wave is the most specific but less sensitive symptom. Shifting dullness, bulging flanks and flank dullness are less specific but much more sensitive parameters. The presence of ascites is very unlikely if the prior probability is low and both the patient's answers and the findings at physical examination are negative. Abdominal ultrasound, the gold standard, is not strictly indicated for diagnosing ascites: if based on the trial tried: pretest probability, clinical history and physical examination, the diagnosis is very likely or very unlikely. Ultrasonography is always indicated, however, when ascites is suspected and a positive finding is of clinical relevance.

[Physical diagnosis--percussion and palpation of the spleen]. / Fysische diagnostiek--percussie en palpatie van de milt.

The accuracy of physical examination of the spleen was investigated in the literature. Ultrasonography or scintigraphy was used to test the findings at physical examination. Physical examination has a low sensitivity, but a reasonably good specificity. The interobserver variability is rather high. In general, palpation is more sensitive and specific than percussion. The findings of percussion improve the accuracy of palpation and the combination has a high specificity, of approximately 90%. The two should therefore be used in conjunction. The sensitivity is much lower although it is greatly influenced by the degree of splenic enlargement and the leanness of the patient.

In vitro production of cytokines in whole blood versus plasma concentrations of cytokines in AIDS.

Reports on plasma concentrations of tumor necrosis factor alpha (TFN-alpha), interleukin 6 (IL-6), IL-10, and IFN-alpha in AIDS patients are contradictory. An alternative approach for the estimation of cytokine production is the measurement of lipopolysaccharide (LPS)-stimulated cytokine production in whole blood. We compared plasma concentrations of these cytokines, soluble TNF receptor (sTNFr) types I and II, and LPS-stimulated cytokine production in whole blood from clinically stable AIDS patients (n = 6) and healthy controls (n = 6). The plasma concentrations of TNF-alpha and sTNFr-II were higher in AIDS patients compared with controls (mean [95% CL]: TNF-alpha, 24 [17-31] and 8 [1-16] pg/ml, respectively, p < 0.01; sTNFr-II, 6.8 [4.6-9.0] and 3.2 [2.4-4.0] ng/ml, respectively, p < 0.01). The plasma concentrations of sTNFr-I and IL-10 were not different between AIDS patients and controls. Neither IL-6 nor IFN-alpha was detectable in any plasma sample. LPS-stimulated production in whole blood of TNF-alpha, IL-6, IL-10, and IFN-alpha was not different between AIDS patients and controls at any combination of LPS concentration (0, 0.1, 0.5, 1, 10, 100, and 1000 ng/ml) and duration of stimulation (0, 4, 8, and 24 hr). It is concluded that the plasma concentrations of TNF-alpha and sTNFr-II, but not of IL-6, IL-10, IFN-alpha, and sTNFr-I, are higher in AIDS patients compared with controls. The production of cytokines in LPS-stimulated whole blood does not provide information additional to the measurements of plasma concentrations.

Soluble tumor necrosis factor receptors as surrogate markers for the assessment of zidovudine treatment in asymptomatic HIV-1 infection.

In untreated, asymptomatic human immunodeficiency virus type 1 (HIV-1) infection, elevated serum concentrations of soluble receptors for tumor necrosis factor (sTNFR) types I and II are associated with progression to AIDS. To assess the utility of sTNFRs as markers for the assessment of antiretroviral treatment, sTNFRs were sequentially determined in 47 asymptomatic HIV-1-infected men, who participated in a double-blind, randomized, placebo-controlled study. Progression to AIDS or severe AIDS-related complex occurred in six zidovudine (ZDV)- and six placebo-treated subjects. During ZDV treatment (n = 28) both types of sTNFRs declined compared with baseline and placebo, whereas they increased during placebo treatment (n = 19). A sustained decline of sTNFRs occurred only in subjects who experienced no disease progression. During the first 3 months of ZDV treatment, the hazard ratio for disease progression when sTNFR type II rose above the baseline value plus 5% was significantly increased (hazard ratio: approximately 25; 95% confidence interval: approximately 1.5-400; p < 0.03). Simultaneously determined CD4+ counts and serum neopterin levels showed a similar pattern in progressors and nonprogressors. Thus, in contrast to CD4+ counts and neopterin levels, sTNFR concentrations, especially those of the type II STNFR, appear to be valuable surrogate markers for monitoring the efficacy of ZDV treatment in asymptomatic HIV-1 infection.

Soluble receptors for tumor necrosis factor are markers for clinical course but not for major metabolic changes in human immunodeficiency virus infection.

Tumor necrosis factor alpha (TNF) is a potential mediator of the metabolic changes in human immunodeficiency virus type 1 (HIV) infection. Soluble TNF receptor types I and II (sTNFR-I and -II) presumably reflect TNF activity. To examine the relationship between s TNFRs and host metabolism, resting energy expenditure (REE), body composition, and transferrin, albumin, triglyceride, retinol-binding protein, and sTNFR concentrations were measured in 12 asymptomatic and 18 symptomatic HIV-infected male subjects and 15 male control subjects. sTNFRs were increased in parallel with disease severity. REE was elevated approximately 8% in HIV-infected subjects (P = .005). REE correlated positively with fat free mass (FFM) and the presence of HIV infection, but not with sTNFRs. Inverse correlations existed between sTNFR-I or -II and albumin concentration (r = -.48, P = .007, and r = -.49, P = .006, respectively), between sTNFR-II and transferrin concentration (r = -.53, P = .003), and between In(sTNFR-II) and percent body fat (r = -.37, P < .05), but not between sTNFRs and triglyceride or retinol-binding protein. Thus, sTNFRs are markers for clinical course but not for major metabolic changes in HIV infection.

Soluble receptors for tumor necrosis factor as predictors of progression to AIDS in asymptomatic human immunodeficiency virus type 1 infection.

Serum concentrations of soluble receptors for tumor necrosis factor-alpha (sTNF alpha R) types I and II, beta 2-microglobulin, and CD4 cell counts were determined at entry and 3-5 months before AIDS diagnosis in 20 untreated, asymptomatic human immunodeficiency virus type 1 (HIV-1)-seropositive subjects, who progressed to AIDS within 5.5 years of study entry, and in an equal number of HIV-seronegative and untreated seropositive controls, who remained asymptomatic. At entry, concentrations of sTNF alpha R type II and beta 2-microglobulin were elevated and increased further in progressors. The odds ratio (OR) for sTNF alpha R type II concentrations > or = 6.5 ng/mL was 18.4 and for beta 2-microglobulin concentrations > or = 3 mg/L was 6.6; CD4 cell counts were not predictive. Five months before diagnosis, the OR was 102.0 for sTNF alpha R type II concentrations > or = 7.5 ng/mL, 13.5 for beta 2-microglobulin concentrations > or = 4 mg/L, and 6.9 for CD4 cell counts < 250/mm3 (counts < 500/mm3 were not predictive). Of the three variables, sTNF alpha R type II was proved by bivariate analysis to be the strongest and earliest predictor of disease progression.

Metabolic effects of hypoglycemic counterregulation during sustained mild hyperinsulinemia and constant glucose availability in healthy men.

Posthypoglycemic metabolic changes have been studied predominantly during waning of insulin action. We evaluated the effects of hypoglycemic counterregulation on glucose and lipid metabolism during continuous insulin infusion. Glucose was infused at a constant rate throughout the study (4 mg.kg-1.min-1). During the second part of the study, plasma glucose levels were clamped at approximately 4 mM by variable insulin infusion. In six subjects, but not in five control subjects, short-term hypoglycemia (nadir plasma glucose 2.80 +/- 0.05 mM) was induced by an additional bolus injection of insulin before starting insulin infusion. Substrate oxidation rates and plasma substrate fluxes were determined by indirect calorimetry and primed continuous infusions of [3-3H]glucose and [14C]palmitate. After hypoglycemia, higher insulin infusion rates than in the control group were required to clamp plasma glucose concentrations at similar levels (p < 0.05). Additionally, insulin levels were increased compared with those in control subjects (p < 0.01). There were no differences in substrate oxidation rates, hepatic glucose production, or lipolysis after hypoglycemia. In conclusion, the counterregulatory hormonal response after short-lasting mild hypoglycemia with sustained modest hyperinsulinemia and constant glucose availability induces insulin resistance with respect to glucose uptake but is unable to stimulate hepatic glucose production or lipolysis.

Low levels of specific T cell activation marker CD27 accompanied by elevated levels of markers for non-specific immune activation in the cerebrospinal fluid of patients with AIDS dementia complex.

Concentrations of soluble receptors for tumor necrosis factor (sTNFR-p55 and sTNFR-p75) and soluble T cell antigens CD25 and CD27 (sCD25 and sCD27) were measured in paired serum/cerebrospinal fluid (CSF) samples of 15 patients with AIDS dementia complex (ADC) and 15 HIV-infected control subjects (11 with other central nervous system (CNS) infections and four without CNS infection). In this study levels of sTNFR-p55, sTNFR-p75 and sCD25 were elevated in the CSF of ADC patients and of the 11 patients with other CNS infections, whereas CSF-levels of the specific T cell marker sCD27 were lower in patients with ADC as compared to the control subjects with and without other CNS infections. This pattern suggests a relative failure of eliciting a T cell-mediated immune response intrathecally in patients with ADC.