A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Central retinal vein occlusion as an uncommon complication of sarcoidosis.

A 23-year-old black women with acute blurred vision of the right eye was referred for ophthalmological examination. Fundus examination and fluorescence angiography showed a non-ischaemic central retinal vein occlusion (papillophlebitis). The diagnosis of sarcoidosis, suggested by the presence of bilateral hilar and mediastinal lymphadenopathy, was confirmed by transbronchial biopsy of the lymphadenopathy demonstrating noncaseating granulomas. The eye problems were successfully treated with systemic corticosteroids. Central retinal vein occlusion is a rare complication of sarcoidosis.

Tako Tsubo cardiomyopathy, presenting with cardiogenic shock in a 24-year-old patient with anorexia nervosa.

Tako Tsubo cardiomyopathy is a serious condition that is caused by heart failure due to inordinate stress. We here present a case of a young woman with this disorder in association with anorexia nervosa. We postulate a pathophysiological relationship and discuss the management of Tako Tsubo cardiomyopathy.

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.

[Scombroid poisoning after eating tuna fish]. / Scombroïde-intoxicatie na het eten van tonijn.

On two separate occasions, a total of eight subjects ate tuna fish. Three out of four persons in the first case (a father aged 54, a mother aged 51 and a daughter aged 24 years) and one out of four persons in the second case (a 28-year-old woman) experienced erythema, respiratory distress and diarrhoea shortly after eating the fish. These symptoms are indicative of scombrotoxic fish poisoning. Histamine is produced in the muscle tissue of scombroid fish, such as tuna or mackerel, if it is kept at a temperature which is too high. Since the concentration of histamine is not evenly distributed through the fish's flesh, not everyone who eats the same fish will become ill to the same extent, and some may not even become ill at all. Furthermore, since the complaints are often mild and of short duration, most patients do not seek medical help, and probably few cases are officially reported. Despite the fact that sometimes only one person from a group of people eating the same fish becomes ill, and that the clinical complaints resemble an IgE-mediated allergic reaction, the illness is a food-borne intoxication with exogenous histamine. Therefore, patients can safely eat the same type of fish again.

Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study.

OBJECTIVE: To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen. DESIGN: The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection. METHODS: HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected. RESULTS: Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time. CONCLUSIONS: The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.

Normal T-cell telomerase activity and upregulation in human immunodeficiency virus-1 infection.

In human immunodeficiency virus (HIV)-1 infection, decrease of telomere length is mainly found in CD8(+) T cells and not in CD4(+) T cells. Telomerase, a ribonucleoprotein enzyme that can synthesize telomeric sequence onto chromosomal ends, can compensate for telomere loss. Here, we investigated if telomerase activity could explain differential telomere loss of CD4(+) and CD8(+) T cells in HIV-1 infection. Telomerase activity was higher in CD8(+) than in CD4(+) T cells from HIV-infected patients, but still in the same range as in healthy controls, and upregulation after stimulation was comparable to normal. Telomerase activity in lymph node CD4(+) and CD8(+) T cells from HIV-infected patients was in the same range as that in CD4(+) and CD8(+) T cells from peripheral blood (PB) and was normal in unseparated bone marrow cells. Thus, our study did not provide evidence for compartmentalized elongation of telomeres in HIV infection. In patients treated with reverse transcriptase inhibitors, telomerase activity was inhibited, but this did not lead to accelerated loss of telomere length in vivo. Thus, differential telomere loss in CD4(+) and CD8(+) T cells in HIV-1 infection cannot be explained by telomerase activity.

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy.

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.

Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study.

BACKGROUND: Highly active antiretroviral therapy (HAART) has led to health benefits for patients infected with HIV-1. However, long-term use of multidrug regimens is difficult to sustain. Simplifying antiretroviral treatment regimens would increase patients' adherence and minimise toxicity. We investigated the feasibility of a strategy of induction therapy followed by maintenance therapy with HAART in a randomised open-label study. METHODS: From March, 1997, we enrolled patients infected with HIV-1 with at least 200 CD4 cells/microL, at least 1000 HIV-1 RNA copies/mL in plasma, and no previous exposure to antiretroviral drugs. After 26 weeks of induction therapy (stavudine, lamivudine, saquinavir, and nelfinavir) patients were randomly allocated maintenance therapy (either stavudine and nelfinavir or saquinivir and nelfinavir) or prolonged induction therapy (if the plasma HIV-1 RNA concentration at weeks 24 and 25 was <50 copies/mL). FINDINGS: In February, 1998, we discontinued randomisation after an interim analysis. 62 patients had been enrolled. 39 (91%) of the 43 patients who were followed up for at least 26 weeks had an undetectable plasma HIV-1 RNA concentration at week 16. At week 26, 31 patients were randomly allocated treatment. Of these patients 25 had a total follow-up of at least 36 weeks. At week 36, a higher proportion of patients on maintenance therapy (nine [64%] of 14) had a detectable HIV-1 RNA than patients on prolonged induction therapy (one [9%] of 11, p=0.01). The initial virion-clearance rate during induction therapy was higher in five patients on maintenance therapy with a sustained undetectable plasma HIV-1 RNA concentration than in nine patients with recurrence of a detectable plasma HIV-1 RNA concentration at week 36 (0.35 vs 0.19 per day, respectively; p=0.0008). INTERPRETATION: The induction regimen provided a rapid suppression of viral replication to below 50 copies/mL. However, suppression was not sustained in a considerable number of patients who went onto maintenance therapy. It is currently inadvisable to continue attempts at moving from induction to maintenance therapy in day-to-day practice.

17 alpha-Hydroxylase deficiency; a rare cause of chronic hypertension.

We demonstrate a case with 17 alpha-hydroxylase deficiency that presented in an unusual way. The steroid metabolism and diagnostic procedures are discussed.

The renal handling of pepsinogen A isozymogens in man.

Pepsinogen A (PGA) isozymogens are low molecular weight proteins that are present in serum and urine. The differences in the molecular structure of PGA-isozymogens involve only 2-4 amino acid substitutions. In a previous study, performed in 13 subjects only, a remarkable difference between the fractional renal clearances of the main PGA-isozymogens (PGA-3, PGA-4 and PGA-5) has been demonstrated. The aim of the present study was to further investigate these differences in fractional clearance between PGA-isozymogens and to determine whether these differences are caused by differences in glomerular sieving. For this purpose the fractional clearances of PGA-isozymogens were measured in 57 subjects. In accordance with the previous study, the median fractional clearance of PGA-5 (13%) was lower than the median fractional clearance of PGA-4 (17%; p < 0.02) and the median fractional clearance of PGA-4 was lower than the median fractional clearance of PGA-3 (26%; p < 0.001). The glomerular sieving coefficients of PGA-isozymogens were measured in 11 subjects during an elective heart catheterization by means of the fractional renal extraction method. No significant difference between the glomerular sieving coefficients of PGA-isozymogens could be demonstrated, being 0.81 for PGA-3, 0.96 for PGA-4 and 0.84 for PGA-5. It is concluded that the differences in renal handling between PGA-isozymogens must be explained by differences in tubular reabsorption. These differences in tubular reabsorption between PGA-isozymogens support the hypothesis that positively charged amino acid residues of proteins are involved in the tubular protein reabsorption.

Microtiter enzyme-linked immunosorbent assay using recombinant derived antigens versus western blot in the confirmation of presence of antibodies against the human immunodeficiency virus type 1.

A microtiter enzyme-linked immunosorbent assay using recombinant derived antigens was compared with the Western blot (Dupont) in the confirmation of the presence of antibodies against the human immunodeficiency virus type 1 (HIV-1). Of 104 sera (104 individuals) that were negative by a screening ELISA, 91 were also negative by both confirmation assays. In three sera only the microtiter assay was found to be indeterminate, and in nine other sera only Western blot. The only microtiter assay positive serum was from a male patient at risk for infection with HIV. 279 sera from 83 patients were found positive by screening. Of these, 223 sera were positive in both confirmation assays, and no serum was negative. Only one serum was indeterminate by the microtiter ELISA in contrast to 55 sera, including follow-up samples from 25 patients, most of whom had AIDS, by Western blot (Dupont criteria). However, the number of Western blot indeterminate sera decreased substantially applying less stringent criteria for interpretation. In conclusion, the microtiter ELISA performed well as a confirmation test for the presence of antibodies against HIV-1. In addition, the results demonstrate that in the microtiter assay the envelope peptide kp41 is highly discriminative in detecting anti-HIV-1 negative and anti-HIV-1 positive sera.

Renal handling of insulin and C-peptide in patients with non-insulin-dependent diabetes mellitus.

The kidney is responsible for a considerable part of the clearance of insulin and C-peptide. Two routes are thought to be involved in the renal extraction of insulin and C-peptide from the circulation: (1) glomerular filtration, and (2) uptake by tubular cells from peritubular capillaries. The aim of the present study was to investigate these processes in non-insulin-dependent diabetes mellitus (NIDDM). For this purpose we measured the renal extraction of inulin, insulin, and C-peptide in 12 NIDDM patients and 16 control subjects during elective heart catheterization. In addition, a 24-h urine sample was obtained from all subjects to assess the fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceeded the amount that was extracted by filtration, confirming the supposition that both peptides are cleared by an additional mechanism, most probably peritubular uptake. The peritubular uptake of insulin in the NIDDM group was not significantly different from that in the control subjects, whereas the insulin extraction over the legs was significantly lower in NIDDM than in the controls. The peritubular uptake of C-peptide was significantly lower in NIDDM, while the fractional clearance of C-peptide was significantly higher. The latter indicates that the reabsorption of C-peptide from the luminal side of the tubular cell is impaired in diabetes mellitus. It is therefore concluded that urinary C-peptide excretion is not a reliable index for insulin production in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

[Dental treatment of HIV-infected and AIDS patients in the dental office in The Netherlands]. / Patiënten met AIDS in de tandheelkundige praktijk.

Every dentist should accept the responsibility of treating HIV-infected and AIDS' patients in his own office. By taking the appropriate hygienic measures, the risk of HIV-transmission in the dental office can be almost completely eliminated.

Tubular reabsorption of pepsinogen isozymogens in man studied by the inhibition of tubular protein reabsorption with dibasic amino acids.

1. The fractional clearances of pepsinogen A (PGA), pepsinogen C (PGC) and the main PGA isozymogens, i.e. PGA-3, PGA-4 and PGA-5, were measured in 13 healthy male volunteers before and during blockade of tubular protein reabsorption by intravenous infusion of either L-arginine hydrochloride (n = 8; 0.5 g h-1 kg-1 body weight) or an equimolar amount of L-lysine hydrochloride (n = 5; 0.44 g h-1 kg-1 body weight). Glomerular filtration rate was measured by a radioisotope method. 2. The fractional baseline clearance of PGC (1 +/- 1%) was lower than that of PGA (20 +/- 10%). In addition, the fractional clearance of the PGA isozymogens appeared to be different: the fractional clearance of PGA-5 (7 +/- 3%) was lower than that of PGA-4 (18 +/- 9%), and the fractional clearance of PGA-4 was lower than that of PGA-3 (30 +/- 10%). These differences in fractional clearance between PGA isozymogens decreased during infusion of both arginine and lysine. 3. Pepsinogens are freely filtered proteins. It can therefore be concluded that the differences in fractional clearance between PGA isozymogens imply differences in tubular reabsorption. This is remarkable as PGA isozymogens are proteins with an almost identical amino acid sequence and electric charge. The disappearance of the differences in tubular reabsorption during arginine and lysine infusion suggests that PGA isozymogens differ in affinity for negatively charged binding sites in the tubular cell membrane. In order to explain the low fractional clearance of PGC compared with that of PGA and the less marked effect of arginine or lysine infusion on the fractional clearance of PGC, an additional PGC-specific binding site has to be postulated.

The effect of acute and chronic protein loading on urinary pepsinogen A excretion.

In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.

Oral hairy leukoplakia in HIV infection: a diagnostic pitfall.

Twenty-nine human immunodeficiency virus (HIV)-infected patients with white, nonremovable lesions on the lateral border of the tongue, clinically suggestive of oral hairy leukoplakia (HL), were studied. In particular, the value of local antifungal therapy in establishing the diagnosis of HL was investigated. In 15 patients (52%) the lesions could be ultimately attributed to a candidal infection of the tongue. In 10 of the remaining 14 patients, a biopsy was obtained from lesions persisting after local antifungal treatment. In all biopsy specimens, the diagnosis of HL was confirmed by histopathologic examination and the demonstration of Epstein-Barr virus DNA by polymerase chain reaction, Southern blot hybridization, and DNA in situ hybridization. The present data confirm that the diagnosis of HL in HIV-infected patients cannot be reliably made on clinical criteria alone, but requires histopathologic confirmation including the demonstration of Epstein-Barr virus DNA, preferably by DNA in situ hybridization. However, with regard to the differential diagnosis of white, nonremovable lesions on the lateral border of the tongue in HIV-infected patients, the present study suggests that persistence of lesions after local antifungal therapy is highly suggestive of HL.