Risk of non-AIDS-defining events among HIV-infected patients not yet on antiretroviral therapy.

OBJECTIVES: Certain non-AIDS-related diseases have been associated with immunodeficiency and HIV RNA levels in HIV-infected patients on combination antiretroviral therapy (cART). We aimed to investigate these associations in patients not yet on cART, when potential antiretroviral-drug-related effects are absent and variation in RNA levels is greater. METHODS: Associations between, on the one hand, time-updated CD4 counts and plasma HIV RNA and, on the other hand, a composite non-AIDS-related endpoint, including major cardiovascular diseases, liver fibrosis/cirrhosis, and non-AIDS-related malignancies, were studied with multivariate Poisson regression models in 12 800 patients diagnosed with HIV infection from 1998 onwards while not yet treated with cART. RESULTS: During 18 646 person-years of follow-up, 203 non-AIDS-related events occurred. Compared with a CD4 count ≥ 500 cells/µL, adjusted relative risks (RRs) for the composite endpoint were 4.71 [95% confidence interval (CI) 2.98-7.45] for a CD4 count < 200 cells/µL, 2.06 (95% CI 1.38-3.06) for a CD4 count of 200-349 cells/µL, and 1.19 (95% CI 0.82-1.74) for a CD4 count of 350-499 cells/µL. There was no evidence for an independent association with HIV RNA. Other important covariates were age [RR 1.40 (95% CI 1.31-1.49) per 5 years older], hepatitis B virus coinfection [RR 5.66 (95% CI 3.87-8.28)] and hepatitis C virus coinfection [RR 9.26 (95% CI 6.04-14.2)]. CONCLUSIONS: In persons not yet receiving cART, a more severe degree of immunodeficiency rather than higher HIV RNA levels appears to be associated with an increased risk of our composite non-AIDS-related endpoint. Larger studies are needed to address these associations for individual non-AIDS-related events.

HCV-specific T-cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance.

In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-gamma Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-T-cell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.

BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naïve adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-to treat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. CONCLUSION: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.

Thyroid function 10-18 years after mantle field irradiation for Hodgkin's disease.

Thyroid function was measured in 81 patients who had been curatively irradiated on a mantle field for Hodgkin's disease 10-18 years ago. 47 patients (58%) had elevated levels of thyroid stimulating hormone, indicating hypofunction of the thyroid gland, compared with 4.6% of controls (hospital visitors) matched for age and sex. The mean free thyroxine index (FTI) was significantly lower in patients than in controls, but all FTI values were still normal. Age at the time of irradiation, sex, time since irradiation and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. A life-long awareness of the possibility of insidiously developing myxedema in these patients is strongly advocated.

Pulmonary morbidity 10-18 years after irradiation for Hodgkin's disease.

Pulmonary function tests were performed in 78 patients who had been curatively treated for Hodgkin's disease with mantle field irradiation 10-18 years ago. Mean values of the total lung capacity (95.2%), vital capacity (VC) (95.9%), forced expiratory volume in 1 s (FEV1) (90.6%), and carbon monoxide diffusing capacity per unit alveolar volume (82.7%) showed significant deviations from the predicted normal values, standardised for age, sex, race and height. In a multiple regression analysis the normalised total dose of irradiation, the field of irradiation, and the interval since irradiation had independent negative effects on the test results. Patients reported more coughing, wheezing and dyspnoea on exertion in comparison with hospital-visitors. Their smoking habits and reported pulmonary disease were not different. It is concluded that small, but significant impairment of pulmonary function exists after a follow-up of 14 (2) years [mean (S.D.)]. The clinical impact of these findings seems, however, minimal. Further avoidance of pulmonary toxicity requires a careful quantitative study of the effects of the radiation dose and irradiated volume.

Quality of life after operatively corrected high anorectal malformation: a long-term follow-up study of patients aged 18 years and older.

Fifty-eight patients (median age, 26.0 years; range, 18.1 to 56.9 years) with an operatively corrected high anorectal malformation were evaluated by questionnaire. No patient had normal continence for feces; however, 84% had a socially acceptable defecation pattern. The quality of life (QOL) and general and mental health perception of these patients were evaluated. For social functioning and health perception, items from the medical outcome study (MOS) were used. QOL and health perception were compared with those of the general population. Most aspects of QOL (corrected for age and gender) and mental health did not differ from those of the general population. However, the patient population had lower educational and general health levels (P < .01). Twelve percent felt restricted socially by their handicap, and 24% never had a lasting relationship. Of the patients who had a lasting relationship, 43% noted that the handicap had been disturbing in the relationship. Associated anomalies had no influence on QOL and health perception. QOL, education level, and relationships were affected by fecal incontinence. It is possible that more appropriate psychosocial support, eg, addressing the implications of the handicap on everyday life, would have a positive influence.

The 48-week efficacy of once-daily saquinavir/ritonavir in patients with undetectable viral load after 3 years of antiretroviral therapy.

OBJECTIVES: To evaluate the efficacy and safety of once-daily saquinavir-soft-gel-capsules/ritonavir (SQV-SGC/RTV) 1600 mg/100 mg plus dual nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-infected patients with plasma viral load (pVL) <50 HIV-1 RNA copies/mL following 3 years of antiretroviral therapy. METHODS: A total of 69 patients with pVL <50 copies/mL after 162 weeks of antiretroviral treatment started SQV-SGC/RTV 1600 mg/100 mg once-daily while continuing dual NRTIs. Previous treatment consisted of 66 weeks of treatment with a half/full dose of zidovudine (ZDV)/zalcitabine (ddC), followed by 2 years of SQV-SGC twice a day (bid) plus ZDV/lamivudine (3TC) or didanosine (ddI)/stavudine (d4T). Efficacy (pVL), safety and immunological changes (CD4 cell counts) were evaluated after 48 weeks in this open-label, single-arm prospective study. RESULTS: SQV-SGC/RTV once-daily was well tolerated. No patient changed regimens or was lost to follow-up. After 48 weeks, 63 of 69 patients (91%) had pVL <50 copies/mL (five of the six remaining patients had pVL <400 copies/mL, and one patient had an unexplained rise to 39 500 copies/mL, which decreased to <50 copies/mL 12 weeks later). Median CD4 count increased from 534 cells/muL at the start of the SQV-SGC/RTV once-daily treatment to 664 cells/muL (P<0.001). Compared to the preceding 48 weeks on bid SQV-SGC, the CD4 cell count improved significantly on once-daily SQV-SGC/RTV (P<0.001). CONCLUSIONS: These data support the use of SQV-SGC/RTV 1600 mg/100 mg once-daily with two NRTIs as a convenient, safe and cost-saving regimen to maintain viral suppression and CD4 counts for 48 weeks in this preselected cohort on highly active antiretroviral therapy (HAART) with pVL <50 copies/mL. The CD4 count rise may be a result of continued immune reconstitution in patients with well-controlled infection.

Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: postoperative nausea with vomiting and economic analysis.

BACKGROUND: To assess the incidence of postoperative nausea and vomiting after total intravenous anesthesia (TIVA) with propofol versus inhalational anesthesia with isoflurane-nitrous oxide, the authors performed a randomized trial in 2,010 unselected surgical patients in a Dutch academic institution. An economic evaluation was also performed. METHODS: Elective inpatients (1,447) and outpatients (563) were randomly assigned to inhalational anesthesia with isoflurane-nitrous oxide or TIVA with propofol-air. Cumulative incidence of postoperative nausea and vomiting was recorded for 72 h by blinded observers. Cost data of anesthetics, antiemetics, disposables, and equipment were collected. Cost differences caused by duration of postanesthesia care unit stay and hospitalization were analyzed. RESULTS: Total intravenous anesthesia reduced the absolute risk of postoperative nausea and vomiting up to 72 h by 15% among inpatients (from 61% to 46%, P < 0.001) and by 18% among outpatients (from 46% to 28%, P < 0.001). This effect was most pronounced in the early postoperative period. The cost of anesthesia was more than three times greater for propofol TIVA. Median duration of stay in the postanesthesia care unit was 135 min after isoflurane versus 115 min after TIVA for inpatients (P < 0.001) and 160 min after isoflurane versus 150 min after TIVA for outpatients (P = 0.039). Duration of hospitalization was equal in both arms. CONCLUSION: Propofol TIVA results in a clinically relevant reduction of postoperative nausea and vomiting compared with isoflurane-nitrous oxide anesthesia (number needed to treat = 6). Both anesthetic techniques were otherwise similar. Anesthesia costs were more than three times greater for propofol TIVA, without economic gains from shorter stay in the postanesthesia care unit

Are adults content or continent after repair for high anal atresia? A long-term follow-up study in patients 18 years of age and older.

OBJECTIVE: This study investigated the current state of fecal and urinary continence in an extensive group of adults after operative correction for high anorectal malformations and how they cope with their incontinence. SUMMARY BACKGROUND DATA: Normal fecal continence is hardly to be expected after correction for high anorectal malformation; despite this, it is commonly accepted that for most patients fecal continence improves with growing age and that most adult patients have no problems. Until now, however, few long-term follow-up studies in small groups of adults have been performed to assess continence after operative repair for high anorectal malformation. METHODS: Fifty-eight adult patients (median age, 26.0 years; range, 18.1 to 56.9 years) with an operatively corrected high anorectal malformation were evaluated by questionnaire with respect to their current state of fecal and urinary continence and mode of control of defecation. RESULTS: Seven patients have a permanent ileostoma or colostoma. Of the 51 patients with anal defecation, 61% control defecation by themselves, whereas 35% control defecation by using enemas or bowel irrigations, and 4% do not have any control at all. Besides medical therapy, 65% take dietary measures to influence defecation. According to existing scoring methods, 41% reached good and 49% fair control of defecation, whereas only 10% had poor control. Current control of defecation was reached from a median age of 15.0 years (range, 5 to 31 years). CONCLUSION: Conclusively, the authors can say that after correction for high anorectal malformation nobody reached normal fecal continence. Most patients with anal defecation reached good and fair control of defecation, however. Of all 58 patients, 84% are satisfied with their level of cleanliness.

Additional congenital defects in anorectal malformations.

UNLABELLED: From 1974 until 1995 a total of 264 (141 male, 123 female) patients born with an anorectal malformation (ARM) were referred to the University Hospital Nijmegen in the Netherlands. All additional congenital defects (ACDs) were registered. Special attention was paid to whether the ACDs take part in associations, syndromes, or sequences. One or more ACDs were observed in 67% of the patients. In decreasing order the defects concerned the uro-genital tract (43%), skeleton (38%), gastrointestinal tract (24%), circulation (21%), extremities (16%), face (16%), central nervous system (15%), respiratory tract (5%), and remaining defects (5%). Associations were observed in 49% of the patients mostly (in 44%) the Vertebral, Anorectal, Cardial, Tracheo-Esophageal, Renal and Limb association. In 5% of the patients syndromes were recognized. Sequences were seen in 2% of the patients. Remarkable is the combination of trisomy 21 and ARM without a fistula. The combination of ARM and the Zellweger syndrome has not been reported before. CONCLUSION: Almost all combinations of ARM and ACDs can be classified as an association, syndrome or sequence. ARM-causing agents affect males and females in equal numbers but lead to different expression in the sexes. The origin of the Omphalocele, Extrophia of the bladder, Imperforate anus, Sacral anomalies complex probably differs from that of other forms of ARM.

Adults born with high anorectal atresia--how do they manage?

PURPOSE: We are interested in the way patients, who underwent surgery for high anorectal atresia, control their defecation. Considering that some patients, despite newer operative techniques, always will suffer from minor or major soiling we attempted to find some guidelines for postoperative support for future patients. METHOD: Fifty-eight patients (median age, 26 (range, 18.1-56.9) years) were personally interviewed. RESULTS: Regulating defecation is done in five different modes: 16 patients have stools after urge, 15 control their stools mainly by going to the toilet at regular times, 18 perform bowel-irrigations or use enemas, 2 have loss of feces continuously, and 7 patients have an ileostomy or colostomy. More than one-half of patients influence their defecation by diet. Of the patients with anal defecation, 6 never soil, 39 sometimes soil small amounts, and 6 often soil seriously. Eighteen patients occasionally suffer from constipation. There is no mode of defecation regulation outstanding in preventing soiling or constipation. However, patients who do not regulate defecation somehow suffer from serious soiling. Most patients are content with their level of cleanliness. CONCLUSION: Irrespective of the mode of defecation regulation, many patients soil sometimes small amounts and a few often soil seriously. In view of the fact that most patients had to find the current control of defecation regulation by themselves rather late and lacked professional support, it is questionable whether the chosen mode of defecation regulation is the most optimal mode for each patient. We assume that a stepwise protocol under professional support, starting by the most natural mode of defecation, will improve defecation regulation in a more efficient way (earlier and better).

Parenting children with anorectal malformations: implications and experiences.

Parents play a crucial role in the life of a child suffering from an anorectal malformation (ARM), since their guidance contributes to the degree to which the child learns to cope with his or her disability. We investigated whether they experience stress in parenting such a child and also attempted to identify somatic or behavioral characteristics in the child that influence the stress of parenting. The parents of 109 children (69 males, 40 females; median age 5.9 years, range 1-18 years) with an ARM (58 low, 10 intermediate, 41 high) were studied. The Nijmegen Questionnaire on Child-rearing Situations (NQCS) was used to investigate the existing parenting situation. Behavioral characteristics of the children were studied by means of the Child Behaviour Checklist (CBCL) and the Teacher Report Form (TRF). In a semi-structured interview, we investigated how parents experienced the implications of the disability in everyday life with their child. Our study showed that as far as the perception of parenting stress is concerned, parents of children with an ARM do not differ from those with healthy primary-school children. Within the group of parents with ARM-afflicted children, the parents of older, incontinent children experienced relatively more stress, especially when the child concerned was male. With regard to the children's behavior, the parents and teachers under investigation did not report a higher than normal incidence of deviant behavior. However, when individual parents observed difficult behavior in their child, they found it harder to deal with than the incontinence for feces. Regarding the implications of the disorder for their everyday lives, parents were concerned and indicated a need for specific counselling. We conclude that having a child with a somatic affliction, in this case an ARM, does not automatically imply that the parents experience child-rearing problems. However, certain groups of parents are more at risk, i.e., parents with older, incontinent sons and parents with children exhibiting behavioral problems. In addition, our study shows that parents do have difficulties in coping with the implications of the disorder and express a need for support. We feel that patient care can be improved if aid is tailored to these specific problems.

Pharmacokinetics of stavudine and didanosine coadministered with nelfinavir in human immunodeficiency virus-exposed neonates.

We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m(2) once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC(0-12)s) were 1,866 and 1,603, ng x h/ml, respectively, and the median peak concentrations (C(max)s) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC(0-10)s were 1,573 and 1,562 h x ng/ml, respectively, and the median C(max)s were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear.