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Most countries exclude human immunodeficiency virus (HIV)‐positive patients from organ donation because of concerns regarding donor‐derived HIVtransmission. The Swiss Federal Act on Transplantation has allowed organ transplantation between HIV‐positive donors and recipients since 2007. We report the successful liver transplantation from an HIV‐positive donor to an HIV‐positive recipient. Both donor and recipient had been treated for many years with antiretroviral therapy and harbored multidrug‐resistant viruses. Five months after transplantation, HIVviremia remains undetectable. This observation supports the inclusion of appropriate HIV‐positive donors for transplants specifically allocated to HIV‐positive recipients. The authors report the first liver transplant from an HIV‐positive donor to an HIV‐positive recipient with a successful outcome at 6 months, and argue that the medical and social advances represented by this case call for legal and political progress. See the editorial from Fishman and Feng on page 2252.

Background Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS).Methods In this retrospective study (2000–2011), pLLV was defined as a VL of 21–400 copies/ml on = three consecutive plasma samples with =8 weeks between first and last analyses, in patients undetectable for =24 weeks on cART. Control patients had = three consecutive undetectable VLs over =32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/ml.Results Among 9,972 patients, 179 had pLLV and 5,389 were controls. Compared to controls, pLLV patients were more often on unboosted protease inhibitor (PI)-based (adjusted odds ratio [aOR; 95% CI] 3.2 [1.8, 5.9]) and nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-only combinations (aOR 2.1 [1.1, 4.2]) than on non-nucleoside reverse transcriptase inhibitor and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8, 315]), unboosted PI-based (aOR 12.8 [1.7, 96]) or NRTI-only combinations (aOR 115 [6.8, 1,952]), and VLs>200 during pLLV (aOR 3.7 [1.1, 12]). No VF occurred in patients with persistent very LLV (21-49 copies/ml; n=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared with 19/74 (26%) without change (P<0.001).Conclusions Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL=200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV>200 copies/ml.

Background Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs).Methods We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs.Results Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2–1.5; P<0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11, 95% CI 1.04–1.18; P=0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97–1.17; P=0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate.Conclusions The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

Background A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort.Methods We compared treatment-naive patients or patients with treatment interruptions =12 months starting either a TDF-based combination antiretroviral therapy (cART) (n=363) or a TDF-sparing regime (n=715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model.Results Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58–0.72) and 0.80 (95% CI 0.76–0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR]=2.34 [95% CI 1.24–4.42]), higher baseline cGFR (HR=1.03 [95% CI 1.02–1.04] by 10 ml/min), TDF use (HR=1.84 [95% CI 1.35–2.51]) and boosted protease inhibitor use (HR=1.71 [95% CI 1.30–2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency.Conclusion There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Background CD4+T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART).Methods Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included (n=1,816 patients). We studied CD4+T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4+T-cell measurements was used to study the dependence of CD4+T-cell slopes on clinical covariates and drug classes.Results Median CD4+T-cell increases following VL suppression were 87, 52 and 19 cells/µl per year in the three periods. In the multiple regression model, median CD4+T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+T-cell <650 cells/µ l at start of the period and low CD4+T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+T-cell increases compared with stavudine.Conclusions In our observational study, long-term CD4+T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+T-cell levels.

Objective To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma.Methods The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival.Results During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+T-cell count (<100 cells/µl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53–5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01–5.67]), the international prognostic index score (HR 1.98–3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13–5.78]).Conclusions Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged as a predictor of death beyond the well-known international prognostic index score and CD4+T-cell count.

Background Antiretroviral therapy (ART) is a risk factor for cardiovascular disease (CVD) and smoking the most important modifiable cardiovascular risk factor.Methods We prospectively evaluated a smoking cessation programme (SCP) in HIV-infected individuals (intervention: counselling and nicotine replacement therapy). Primary endpoint was the smoking cessation rate at 12 months; secondary endpoints were CVD morbidity and mortality. Controls were a not randomized control group of smokers not participating in the SCP.Results Four-hundred and seventeen of 680 (61%) patients were smokers, and 34 of these participated in the SCP. Of these 34 individuals, 82% were male, the median age was 43 years, prior AIDS was recorded in 29%, and depressive disorder was recorded in 18%. Twenty-five (74%) patients were receiving ART. Additional risk factors were dyslipidaemia (68%), a prior cardiovascular event (24%), hypertension (15%), and a family history of CVD in 2/34 (6%) individuals. According to the Framingham equation, the 10-year risk of CVD was higher in SCP participants than in controls (11.2% versus 8.5%, P=0.06). At termination of the SCP, 17/34 (50%) individuals had stopped smoking compared with 57/383 (15%) controls. Self-reported smoking abstinence for =12 months was 13/34 (38%) in the intervention group and 27/383 (7%) in the control group (odds ration 6.2, 95% confidence interval 2.8–14.3). During the follow-up, two SCP participants and 4 controls experienced a myocardial infarction. One patient in the control group died of CVD.Conclusions SCP in HIV-infected individuals is feasible and should be encouraged. The long-term impact of smoking cessation on CVD morbidity and mortality should be evaluated in comparative trials.

Objective To assess the impact of antiretroviral therapy optimized by genotypic antiretroviral resistance testing (GRT) on healthcare costs over a 2-year period in patients after antiretroviral treatment failure.Study design Non-randomized, prospective, tertiary care, clinic-based study.Patients One-hundred and forty-two HIV patients enrolled in the ‘ZIEL’ study and the Swiss HIV Cohort Study who experienced virological treatment failure.Methods For all patients GRT was used to optimize the antiretroviral treatment regimen. All healthcare costs during 2 years following GRT were assessed using micro-costing. Costs were separated into ART medication costs and healthcare costs other than ART medication (that is, non-ART medication costs, in-patient costs and ambulatory [out-patient] costs). These cost estimates were then split into four consecutive 6-month periods (period 1–4) and the accumulated cost for each period was calculated. Univariate and multivariate regression modelling techniques for repeated measurements were applied to assess the changes of healthcare costs over time and factors associated with healthcare costs following GRT.Results Overall healthcare costs after GRT decreased over time and were significantly higher in period 1 (32%; 95% confidence interval [CI]: 18–47) compared with period 4. ART medication costs significantly increased by 1,017 (95% CI: 22–2,014) Swiss francs (CHF) from period 1–4, whereas healthcare costs other than ART medication costs decreased substantially by a factor of 3.1 (95% CI: 2.6–3.7) from period 1 to period 4. Factors mostly influencing healthcare costs following GRT were AIDS status, costs being 15% (95% CI: 6–24) higher in patients with AIDS compared with patients without AIDS, and baseline viral load, costs being 12% (95% CI: 6–17) higher in patients with each log increase in plasma RNA.Conclusions Optimized antiretroviral treatment regimens following GRT lead to a reduction of healthcare costs in patients with treatment failure over 2 years. Patients in a worse health state (that is, a positive AIDS status and high baseline viral load) will experience higher overall costs.

Background Blood lipid abnormalities in patients on highly active antiretroviral therapy (HAART) have been associated with exposure to protease inhibitors (PIs), particularly ritonavir. First therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) leads to relatively favourable lipid profiles. We report on medium-term lipid profiles (up to 5 years) for antiretroviral-naive patients starting NNRTI- and PI-based HAART in the Swiss HIV Cohort Study.Methods Since April 2000, blood samples taken at visits scheduled every 6 months have been analysed for cholesterol and triglyceride concentrations. For 1065 antiretroviral-naive patients starting HAART after April 2000, we estimated changes in concentration over time using multivariate linear regression with adjustment for baseline covariates, use of lipid-lowering drugs and whether the sample was taken in a fasting state.Results Non-high density lipoprotein (HDL) cholesterol levels increase with increasing exposure to either PI- or NNRTI-based therapy, HDL cholesterol levels increase and triglyceride levels decrease with increasing exposure to NNRTI-based therapy, whereas triglyceride levels increase with increasing exposure to PI-based therapy. Between NNRTI-based therapies, there is a slight difference in triglyceride levels, which tend to increase with increasing exposure to efavirenz and to decrease with increasing exposure to nevirapine. Of the three common PI-based therapies, nelfinavir appears to have a relatively favourable lipid profile, with little change with increasing exposure. Of the other two PI therapies, lopinavir with ritonavir has a more favourable profile than indinavir with ritonavir, with smaller increases in both non-HDL cholesterol and triglycerides and an increase in HDL cholesterol. Increasing exposure to abacavir is associated with a decrease in the level of triglycerides.Conclusion In general, NNRTI-based therapy is associated with a more favourable lipid profile than PI-based therapy, but different PI-based therapies are associated with very different lipid profiles. Nelfinavir appears to have a relatively favourable lipid profile. Of the two boosted PI therapies, lopinavir appears to have a more favourable lipid profile than indinavir.

Background Body fat changes are common in patients with HIV. For patients on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), these changes have been associated with increasing exposure to therapy in general and to stavudine in particular. Our objective is to show whether such associations are more or less likely for patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART.Methods We included all antiretroviral-naive patients in the Swiss HIV Cohort Study starting HAART after April 2000 who had had body weight, CD4 cell count and plasma HIV RNA measured between 6 months before and 3 months after starting HAART, and at least one assessment of body fat changes after starting HAART. At visits scheduled every 6 months, fat loss or fat gain is reported by agreement between patient and physician. We estimate the association between reported body fat changes and both time on therapy and time on stavudine, using conditional logistical regression.Results Body fat changes were reported for 85 (9%) out of 925 patients at their first assessment; a further 165 had only one assessment. Of the remaining 675 patients, body fat changes were reported for 156 patients at a rate of 13.2 changes per 100 patient-years. Body fat changes are more likely with increasing age [odds ratio (OR) 1.18 (1.00–1.38) per 10 years], with increasing BMI [OR 1.06 (1.01–1.11)] and in those with a lower baseline CD4 cell count [OR 0.91 (0.83–1.01) per 100 cells/µl]. There is only weak evidence that body fat changes are more likely with increasing time on HAART [OR 1.16 (0.93–1.46)]. After adjusting for time on HAART, fat loss is more likely with increasing stavudine use [OR 1.70 (1.34–2.15)]. There is no evidence of an association between reported fat changes and time on NNRTI therapy relative to PI therapy in those patients who used either one therapy or the other [OR 0.98 (0.56–1.63)].Conclusion Fat loss is more likely to be reported with increasing exposure to stavudine. We find no evidence of major differences between PI and NNRTI therapy in the risk of reported body fat changes.

Objectives and methods To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy (ART) initiation.Results At baseline, HIV-1 DNA was higher in children with higher TREC (P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses (P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1 DNA declines in children with higher baseline TREC (P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART (P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline (P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression.Conclusions Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.

Objective Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort.Design Retrospective analysis in an observational cohort.Methods 1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success (<400 copies/ml), low-level (LF: 400–5000 copies/ml) or high-level failure (HF: >5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses.Results 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes.Conclusion Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.

Objective A high level of adherence to antiretroviral therapy is required for complete suppression of HIV replication, immunological and clinical effectiveness. We investigated whether cognitive behaviour therapy can improve medication adherence.Design Prospective randomized 1-year trial.Setting Collaboration of HIV university outpatient clinic and psychotherapists in private practice.Participants 60 HIV-infected persons on stable anti-retroviral combination therapy and viral load below 50 copies/ml.Intervention Cognitive behaviour intervention in individual patients, in addition to standard of care.Main outcome measures Feasibility and acceptance of intervention; adherence to therapy assessed using medication event monitoring system (MEMS) and self-report questionnaire; virological failure; psychosocial measures.Results The median number of sessions for cognitive behaviour intervention per patient during the 1-year trial was 11 (range 2–25). At months 10–12, mean adherence to therapy as assessed using MEMS was 92.8% in the intervention and 88.9% in the control group (P=0.2); the proportion of patients with adherence =95% was 70 and 50.0% (P=0.014), respectively. While there was no significant deterioration of adherence during the study in the intervention arm, adherence decreased by 8.7% per year (P=0.006) in the control arm. No differences between the intervention group and standard of care group were found regarding virological outcome. Compared with the control group, participants in the intervention group perceived a significant improvement of their mental health during the study period.Conclusions Cognitive behavioural support in addition to standard of care of HIV-infected persons is feasible in routine practice, and can improve medication adherence and mental health.

Objective To determine whether genotypic resistance testing leads to selection of more potent drug regimens when compared to regimens based on treatment history only.Design Prospective, tertiary care centre-based study. Patients: One-hundred-and-forty-five HIV-infected adults on stable antiretroviral therapy (ART) for >6 months experiencing virological failure.Methods The physicians’ decision-making process when choosing a salvage regimen was prospectively documented: at time of virological failure, on ‘failing ART’, genotyping was performed and a hypothetical ‘clinical expert ART’ based upon patient's drug history was documented. Subsequently, data on resistance mutations, rating by a decision support software and drug history were used to define ‘genotyping ART’. After discussion with the patient, final treatment, ‘new personalized ART’ was chosen and prescribed. To compare the relative potency of the four ART regimens in a standardized manner, a resistance score ranging from 1 (best) to 8 (worst) based on drug ranking by decision support software was attributed to each ART regimen. Virological and immunological outcomes were analysed based on the magnitude of the resistance score.Results Median follow-up was 1.5 years. In all 145 patients, median resistance scores for the stepwise selected ART regimens were: ‘failing ART’: 4.5, ‘clinical expert ART’: 1.8, ‘genotyping ART’: 1.5 and ‘new personalized ART’: 2. The latter was 1.5 in patients who effectively switched to ‘new personalized ART’ (n=89). Lower resistance scores translated into significantly improved virological response after initiation of ‘new personalized ART’. In multivariable analysis, lower resistance scores, lower baseline HIV RNA levels and use of novel antiretroviral drugs were associated with the probability of reducing plasma viraemia to <50 copies/ml. Conclusions: This study suggests that treatment choices including genotype and decision support software were virologically superior to those based on drug history only.

Objectives The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir.Study design and methods The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment. Responders with subsequent treatment failure (HIV-RNA >1000 copies/ml, bordered by HIV-RNA >400 copies/ml) were selected for genotypic analysis.Results Initial treatment response, maintenance of response and subsequent virological failure were observed at a comparable frequency in 1143 nelfinavir and 1555 indinavir subjects. Of the treatment-naive patients, 13% who took nelfinavir and 16% who took indinavir had HIV-RNA >1000 copies/ml at least once. These values increased to 24 and 27%, respectively, for reverse transcriptase inhibitor-experienced subjects. Genotypic analysis in a subset of subjects with virological failure identified 30N as the only primary mutation in the nelfinavir subjects (8 out of 21, 38%) whereas isolated or combined 82A/T and 46I/L mutations were detected in the indinavir subjects (9 out of 20, 45%).Conclusions In this population of previously PI-naive subjects, the rate of virological failure and the frequency of resistance mutations at the time of virological failure were comparable in subjects receiving nelfinavir- or indinavir-containing HAART. In nelfinavir subjects, 30N was the only primary mutation whereas isolated or combined 82A/T and 46I/L mutations were detected in indinavir subjects.

Abstract: The purpose of the study was to determine the role of sequential therapy (ST) in new patients with myeloma presenting with renal dysfunction (RD): serum creatinine >140 µmol/L (1.6 mg/dL). Between April 1985 and June 1998, 251 patients, 59 (23%) with RD were entered into a ST program comprised of infusional chemotherapy (IC) with VAMP/C-VAMP (vincristine, doxorubicin, and methylprednisolone with/without cyclophosphamide) followed by autologous transplantation and interferon maintenance. The median overall survival (OS) of 251 patients from the start of IC was 4.2 yr with the RD group faring significantly poorer (median 2.5 yr) than those with no renal dysfunction (NRD; median 4.6 yr; p=0.0025). Mortality during the first 100 d of IC was significantly higher in patients with RD (11/59; p=0.01) compared to patients with NRD. In patients consolidated with high-dose therapy, the OS and event-free survival (EFS) were not significantly different between the two groups. Cox analysis of the variables at presentation failed to show RD as a factor influencing outcome, but it showed that patients with beta-2-microglobulin (β2M)≥3.7 (p<0.0001), age ≥52.5 yr (p=0.002), performance status (PS) ≥2 (p=0.005) and patients with light-chain myeloma (p=0.03) had a significantly shorter OS, β2M≥3.7, PS≥2, and light-chain myeloma were predictive of shorter EFS. The study shows that with modern intensive schedules of treatment, renal disease at presentation in isolation does not compromise outcome.

A boy with the pseudo-hydrocephalic progeroid syndrome (McKusic 26409) [7] is presented and compared to five previously reported children. The boy presented with major skeletal abnormalities, which receded during the first few months of life. Special investigations like studies on collagen, electron microscopy, and growth studies of fibroblasts did not contribute to our knowledge of the pathogenesis of this rare disease.

Between 1985 and 1988 the use of percutaneous venous catheters in the intensive care of newborn infants was evaluated. A total of 140 polyurethane catheters used in 91 patients were compared with 143 silicone catheters in 121 neonates. Patients of both series were comparable regarding sex, weight, gestational age and severity of disease. Insertion technique, puncture site care and infusions remained the same for both observation periods. Peripheral insertion of silicone catheters required more venous cutdowns but threading them to a central vein or the right atrium was more often successful. Fewer local complications (i.e. reddening or swelling along the peripheral venous access) resulted in a longer catheter duration and a less frequent need for an additional venous access in the silicone group. On the other hand, silicone catheters caused more technical problems (i.e. rupture or obstruction). Upon removal, more silicone than polyurethane catheter tips were colonized with bacteria. This was independent of catheter duration and was never followed by clinical signs of infection. The silicone catheter gave better results, especially in very small newborn infants of low gestational age, but was associated with more technical problems.

A nationwide study involving 286 children of human immunodeficiency virus (HIV)-infected mothers living in Switzerland has been performed with the participation of all paediatricians interested in HIV infection in the country. Of these children 201 could be followed up prospectively from birth up to a median age of 22 months. Prevalence of HIV infection in Swiss parturients was estimated at 0.1% and apparently remained stable from 1986 to 1989. Vertical transmission rate was estimated at 14%–20%. Variables of maternal or perinatal history were not associated with transmission rate. Transmission to pairs of siblings of the same mothers was discordant in 33% (6 of 18), with always the elder sibling being infected. Postneonatal mortality in infants of HIV-infected mothers followed up from birth was increased 15-fold over the general population with a very high incidence (2 in 100) of sudden infant death apparently unrelated to HIV infection.

Abstract

Wilms' tumour (WT) occurs bilaterally in approximately 5-7% of affected children. In some patients, complete surgical removal of the malignant tissue cannot be achieved without bilateral total nephrectomy. In Denys-Drash syndrome (DDS), bilateral nephrectomy is indicated both because of the associated nephropathy usually progressing rapidly to end-stage renal failure and because of the high risk of WT development in any residual renal tissue.

The rearrangement of Ig genes is known to be regulated by the production of H and kappa L chains. To determine whether lambda L chains have a similar effect, transgenic mice were produced with a lambda 2 gene. It was necessary to include the H chain enhancer, since a lambda gene without the added enhancer did not result in transgene expression. The lambda 2 transgene with the H enhancer was expressed in lymphoid cells only. The majority of the B cells of newborn transgenic mice produced lambda, whereas kappa + cells were reduced. Concomitantly, serum levels of kappa and kappa mRNA were diminished. By 2 wk after birth the proportion of kappa-expressing cells was dramatically increased. Adults had reduced proportions of B cells that produced lambda only, but the levels of lambda were still higher than in normal littermates. Also, kappa + cells were still lower than in normal mice. Analysis of hybridomas revealed that reduction of kappa gene rearrangement was the basis for the decreased frequency of kappa + cells. Furthermore, many cells also contained an unrearranged H chain allele. It was concluded that feedback inhibition by the lambda 2 together with endogenous H protein may have inhibited recombinase activity in early pre-B cells, leading to inhibition of both H chain and kappa gene rearrangement. Thus, lambda 2 can replace kappa in a feedback complex. The levels of serum lambda 1 and, to a lesser degree, of spleen lambda 1 mRNA were reduced in the lambda 2 transgenic mice. However, the proportion of hybridomas with endogenous lambda gene rearrangement was at least as high as in normal mice. It was therefore concluded that the suppression of functional lambda 1 may be a consequence of decreased selection of endogenous lambda-producing cells because of the excess of transgenic lambda. The escape of kappa-producing cells from feedback inhibition may be the result of several mechanisms that operate to varying degrees, among them: (a) kappa rearrangement during a period in which the recombinase is still active after appearance of a lambda 2/mu stop signal; (b) a B cell lineage that is not feedback inhibited at the pre-B cell stage; (c) subthreshold levels of transgenic lambda 2 in some pre-B cells; and (d) loss of the lambda 2 transgenes in rare pre-B cells.

Two highly homologous enhancers associated with the two murine immunoglobulin lambda constant-region clusters were recently identified. In order to better understand the molecular basis for the developmental stage- and cell-type-restricted expression of lambda genes, we have undertaken an analysis of the putative regulatory domains of these enhancers. By using a combination of DNase I footprinting, electrophoretic mobility shift assay, and site-specific mutations, four candidate protein binding sites have been identified at analogous positions in both enhancers. A mutation of any of these sites decreases enhancer activity. Two of the sites, lambda A and lambda B, are essential for enhancer function, and both of these sites appear to bind both B-cell-specific and general factors. Nevertheless, isolated lambda A and lambda B sites show no evidence of inherent transactivating potential, alone or together, even when present in up to three copies. We suggest that the generation of transactivating signals from these enhancers may require the complex interaction of multiple B-cell-specific and nonspecific DNA-binding factors.

The efficacy of a polymerase chain reaction (PCR) method for early detection of human immunodeficiency virus (HIV) in infants at risk for HIV infection was assessed. The PCR method was added to the routine laboratory test programme in these patients in 1988. PCR was performed in a total of 26 children at risk (age range 2 days to 58 months), including 17 infants born to HIV-infected mothers, who were followed up clinically from the time of birth for a mean period of 23 months (range 6 to 54) in a prospective study. Twelve children were PCR-positive. Eight had AIDS, ARC or symptoms suggestive of HIV infection. All these patients had at least one culture positive for HIV (6/8) and/or one positive serum p24-antigen test (5/8). One child was repeatedly PCR positive, but asymptomatic as well as virus- and antigennegative. Three asymptomatic children with a single positive PCR result were PCR negative in subsequent tests. Fourteen children with negative PCR did not show clinical or immunological signs suggestive of HIV infection. Their cultures for HIV and antigen-p24 assays were negative. It is concluded that in addition to clinical and immunological parameters PCR is a useful technique for diagnosis of HIV infection in infants born to HIV-infected mothers. However, in case of negative HIV cultures and/or serum p24-antigen tests, single positive PCR results in asymptomatic patients must be interpreted with caution and should be confirmed by repeated tests.