A practical guide to applying the intention-to-treat principle to clinical trials in HIV infection

It is recommended that randomized controlled trials be analyzed on an intention-to-treat (ITT) basis whereby patients are analyzed in the group to which they were originally assigned, irrespective of the treatment actually received. However, in trials of antiretroviral therapy, it is quite common for patients to withdraw from the trial, and information on virological or immunological endpoints may not be available. The way in which this missing information is dealt with in the analysis can have a large effect on the results of a trial and, therefore, the principle of ITT may be adhered to more closely in some studies than in others. This article describes some simple approaches commonly taken to impute missing data values and discusses the possible effects of these approaches on the results of a trial.     

Mixed results

A discordant response indicates an increase in T-cells despite an increase in viral load, or vice versa. Researchers studying the use of either Ziagen (abacavir) or Crixivan with Combivir noted that the best predictor of discordant response was a high T-cell count when starting therapy. In 85 percent of 562 people in the study, there was a decrease in viral load and an increase in T-cells, while 13 percent experienced discordant responses with a decrease in viral load and a decrease in T-cell count.     

Communicating prostate biopsy results

Prostate biopsy data are critical for patient management. Guidelines focus of detailed criteria to ensure that these are precisely and reproducibly reported. However, conflicting recommendations by different expert groups have led to significant reporting variation that could negatively impact patient care. We describe a different approach focusing on optimising communication of histopathological parameters such as tumour extent and grade to the clinical team. Communication is crucial because clinicians usually do not view histological material and are dependent on the information included in the histopathology report. Precision could become less critical if the biopsy findings are effectively conveyed by the pathologist and correctly interpreted by the clinician. Strategies to effectively communicate the message in contentious scenarios such when a prostate needle biopsy set contains prostate cancer that is discontinuous, of borderline grade, of disparate grades or associated with intraductal carcinoma of the prostate are outlined.     

Recent results with Megace

HIV-related weight loss can be broken into four categories: 1) episodic weight loss accompanying acute infections or malignancies; 2) intermittent anorexia; 3) the late, accelerated weight loss phase associated with a 10 -20 percent loss of body weight; and 4) the terminal phase of HIV disease in which weight loss has resulted in cachexia and weakness. Several studies using megestrol acetate to treat advanced breast cancer, HIV-associated cachexia, and AIDS wasting, have demonstrated its association with weight gain. These led to the establishment of two multicenter, randomized, double- blind trials. In the first study patients received either 800 mg/day of Megace (a liquid suspension of megestrol acetate) or placebo; and in the second they received one of three daily doses of Megace (100 mg, 400 mg, or 800 mg) or placebo. Most patients were in the fourth phase of weight loss. Over 50 percent of the enrollees dropped out of the first study. Increased calorie consumption, fat mass and overall weight was observed in the remaining 65 enrollees in the treatment group. The second study, enrolling 271 patients, showed a dose-dependent, step-wise relationship between megestrol acetate administration and weight gain. Overall, megestrol acetate was well tolerated. Patients receiving treatment experienced greater caloric and protein intake, weight gain and subjective sense of well-being. Therefore, a starting dose of 400 mg/day is recommended, to be adjusted after four weeks of therapy. Drug treatment in the earlier stages of weight loss should be considered.     

Linkage results in schizophrenia

We described four offspring of a consanguineous couple with arterial tortuosity “syndrome” (ATS). The affected children had extensive arterial involvement although the clinical presentations were quite variable. Clinical manifestations included cutis laxa or soft/thin skin, joint laxity or contractures, and arachnodactyly. Aortic tortuosity and pulmonary artery aneurysms with or without peripheral stenoses were demonstrated in all four sibs. All three males had inguinal hernias. Inconsistent facial anomalies were downslanting palpebral tissues, beaked nose, micrognathia, and high-arched palate. Results of collagen type I and type III biosynthesis studies were normal on skin fibroblasts. Histologic findings on autopsy of one affected child showed arterial changes with disruption of elastic fibers of the media and fragmentation of the internal elastic membrane as well as mucosal and transmural necrosis of the stomach, small bowel, colon, and extensive necrosis of the liver. Coronary artery involvement was also seen in this child as well as biventricular hypertrophy. We conclude that ATS is an autosomal recessive connective tissue condition associated with diffuse arterial changes and involvement of the skin, joints, and other organs. © 1996 Wiley-Liss, Inc.     

Misuse of computer-generated results

The number of statistical tests performed has increased by several orders of magnitude through the use of computers and ready-made statistical packages. The vast majority of these tests neither physically can be, nor ever are, published. Only tests which show a strong statistical correlation between some variables seem to be sorted out for publication. This practice, which can be found in applied sciences such as the social and medical sciences, is investigated and shown in many cases to lead to a considerable increase in the percentage of published false results. A new function to be performed by statistical packages is then proposed which will reduce this percentage.     

Air-exposed urine dipsticks give false-positive results for glucose and false-negative results for blood

Urine dipstick jars often are left uncapped, which led the authors to wonder what effect prolonged air exposure might have on dipstick accuracy. Unexpired Ames Multistixs (Miles Inc., Elkhart, IN) were exposed to ambient air for intervals of up to eight weeks and were used to test urine for the presence or absence of blood, protein, and glucose. Multistixs were read by a blinded participant. A urine sample reading negative for glucose with unexposed (control) Multistixs tested trace positive with three of three Multistixs exposed for 7 days, and 1+ (three of six) or trace positive (three of six) (P less than 0.05) with Multistixs exposed for 28 days. A urine sample reading 1+ for blood with controls tested negative with five of six (P less than 0.05) and six of six (P less than 0.05) Multistixs exposed for 28 and 56 days, respectively. Protein detection was accurate up to 56 days. The authors conclude that urine dipstick jars should be recapped to avoid prompting needless evaluations of glucosuria or delaying detection of important causes of microscopic hematuria.     

False-negative HIV antibody test results

Ideally HIV antibody tests have to be both extremely sensitive and able to recognize all known HIV subtypes. Three patients whose sera failed to react with a synthetic oligopeptide-based HIV antibody test are described in this report. The patients were a Pakistani male infected recently, an Australian male infected for several years, and a Ugandan woman with AIDS. The presence of anti-HIV antibodies was confirmed by means of a standard algorithm with different assay formats. All three sera failed to react in one antiglobulin enzyme-linked immunosorbent assay (ELISA) (Bioelisa HIV-1+2, Biokit SA). No single underlying reason could be identified for the assay failure in the three cases. The first patient, probably infected recently when first tested, was strongly positive by the same assay a year later, confirming the relative insensitivity of oligopeptide assays reported previously for detecting the early antibody response. The other two patients appear to have been infected for several years. Although unlikely to have been infected with a non-clade B virus, the sample from patient 2 lacked detectable antibody to the transmembrane glycoprotein (gp41), the site of the synthetic oligopeptides. Patient 3, of Ugandan origin, was found to be infected with a non-clade B virus. Although her serum reacted strongly to subtype B gp41 in Western blot, it failed to react in the antiglobulin ELISA. Since there appears to be no single common explanation for these three failures there is little opportunity to identify prospectively those situations where testing using assays employing synthetic oligopeptides on the solid phase is likely to fail.