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Since the first reported case of HIV infection in 1981, many HIV-seropositive patients have died as a result of diarrhoea induced by opportunistic protozoal infections: pathogens that would normally cause only a transient illness in immunocompetent individuals. The introduction of highly active antiretroviral therapy (HAART) in 1996 has been associated with a significant decline in incidence and mortality arising from infections such as cryptosporidia and microsporidia. Previously, there were no chemotherapeutic agents known to be effective in eradicating these parasites, but since the availability of HAART, the memory of the emaciated terminally ill patient with advanced AIDS suffering from refractory diarrhoea will hopefully be a thing of the past. Significant advances in the knowledge of the pathogenesis of HIV disease, earlier detection and thus treatment of the virus, and availability of improved diagnostic techniques and HAART have transformed the way HIV-associated diarrhoea is managed. In this review, we look specifically at the management of protozoa-induced diarrhoea.

The aim of the study was to identify possible causes of pancreatic insufficiency in patients with HIV infection.A retrospective analysis of 233 HIV-positive patients for whom faecal elastase measurement was available was performed to investigate potential associations with core demographic data, HIV infection characteristics, degree of immunosuppresion, exposure to antiretroviral therapy (ART), alcohol misuse, diabetes, hepatitis C virus (HCV) infection, triglyceride and cholesterol levels and symptomatology. The response to pancreatic enzyme replacement for patients with evidence of insufficiency was also evaluated.Of 233 patients, 104 (45%) had evidence of pancreatic exocrine insufficiency (faecal elastase200 mcg/g). A positive association with exocrine pancreatic insufficiency was found for HCV infection (P = 0.007), previous or current HCV treatment (P = 0.003), alcohol misuse history (P = 0.006) and the presence of steatorrhoea (P = 0.03). There was no demonstrated association between exocrine pancreatic insufficiency and didanosine (ddI) exposure (P = 0.43) or stavudine (d4T) exposure (P = 0.62). Seventy-seven per cent of patients who were treated with pancreatic enzymatic supplementation reported a subjective improvement in symptoms.Faecal elastase sampling should form part of the routine work-up for HIV-positive patients with chronic diarrhoea even in the absence of 'traditional' risk factors such as ddI exposure. In particular, if the patient has steatorrhoea, a history of alcohol exposure or their HCV serology is positive, they should be considered for investigation. Treatment with pancreatic enzyme supplementation appears to be effective in the treatment of chronic diarrhoea caused by pancreatic insufficiency in the majority of patients.

We wanted to study the effect of sputum induction on forced expiratory volume in one second (FEV1) and on oxygen saturation in normal controls, asymptomatic human immunodeficiency virus (HIV)-seropositive individuals, and HIV-seropositive patients under investigation for suspected Pneumocystis carinii pneumonia (PCP). Over a five month period, sputum induction with ultrasonically nebulized 3% saline was performed on 110 HIV-seropositive patients with suspected PCP, 10 asymptomatic HIV-seropositive patients, and 15 normal controls. Oxygen saturation (peak, trough and change in oxygen saturation (delta O2)) was measured throughout the procedure using pulse oximetry, and these results compared with the chest radiograph and the final pulmonary diagnosis. In addition, the effect of sputum induction on FEV1 was measured in the 15 control subjects and 10 asymptomatic HIV-seropositive patients. Compared with bronchoalveolar lavage, sputum induction had a diagnostic sensitivity for PCP of 76%. Chest radiography was 79% sensitive, and had specificity of 83%. Patients with PCP had lower peak and trough oxygen saturation values compared with the non-PCP group (mean peak 95 vs 97%; mean trough 88 vs 91%), and greater falls in O2 saturation during the procedure (mean delta O2 7.6 vs 5.5%). One subject desaturated to 76%, requiring supplemental oxygen. Sputum induction caused significant but temporary falls in FEV1 both in control and HIV-seropositive groups (mean maximum fall in FEV1 10.4 vs 12.5%). We conclude that although sputum induction causes significant falls in oxygen saturation and FEV1, it remains sensitive and safe, and provides a useful alternative to bronchoscopy for the diagnosis of PCP.

To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.

Objective To determine the safety and efficacy of liposomal amphotericin B (AmBisome) in the primary treatment of AIDS-associated cryptococcosis. Design A Phase II, multicentre, European, non-comparative, open study to assess the use of AmBisome in 23 patients (26 enrolments) with cryptococcosis. Dose requirements, mycological response and toxicity were documented. Setting Hospital-based HIV units. Patients Twenty-three HIV-1-seropositive patients. Results Drug toxicity, assessed in 25 enrolments, was well-tolerated with little renal, hepatic or haematological toxicity. Eighteen out of 23 (78%) enrolments responded clinically. Nineteen enrolments had cryptococcal meningitis: sterilization of spinal fluid was achieved in 12 out of the 18 (67%) who were mycologically evaluable. Fourteen out of the 19 (74%) responded clinically. Conclusion AmBisome is well-tolerated and may be an effective formulation in the treatment of cryptococcosis.

AIM: To compare the results of DNA amplification by the polymerase chain reaction (PCR) with immunofluorescence staining for detecting Pneumocystis carinii in bronchoalveolar lavage specimens taken from symptomatic HIV seropositive patients with suspected P carinii pneumonia (PCP). METHODS: Bronchoalveolar lavage specimens were obtained from 28 symptomatic HIV seropositive patients. Specimens were examined for P carinii using immunofluorescence, and by DNA amplification with PCR to obtain results on gel electrophoresis (gel) and a more sensitive Southern hybridisation (blot) technique. Specimens positive by immunofluorescence and gel electrophoresis were serially diluted to a 10(-6) concentration and each dilution strength tested for P carinii using PCR to compare quantitatively immunofluorescence with PCR. RESULTS: Of the 28 specimens analysed, 18 were negative for P carinii by both immunofluorescence and PCR, two were positive only by the blot technique of PCR, four were equivocally positive and four unequivocally positive by immunofluorescence. Three of the four equivocally positive patients tested by immunofluorescence were negative for P carinii by PCR, although one was positive by PCR (blot) technique. This patient had clinically confirmed PCP. Of the four unequivocally positive patients tested by immunofluorescence, three were gel and blot positive by PCR and had PCP clinically, but one was negative by both gel and blot techniques, although the patient certainly had PCP on clinical grounds. This patient had received nine days of treatment with high dose co-trimoxazole before bronchoalveolar lavage specimens were obtained. The three specimens positive by gel and blot techniques remained gel positive down to dilutions of between 10(-4) and 10(-6). CONCLUSIONS: PCR results may become negative soon after starting treatment for PCP. Specimens should therefore be taken before, or soon after, starting treatment. PCR seems to be between 10(4) and 10(6) times more sensitive than immunofluorescence.

A series of 83 rectal biopsies was examined by electron microscopy (EM), 78 from HIV-seropositive patients (64 with diarrhoea, 9 with weight loss, and 5 asymptomatic) and 5 from controls without risk factors for HIV infection. Although EM identified the likely cause of the diarrhoea in only nine cases, the majority of symptomatic HIV-seropositive patients had abnormal biopsies including the presence of tubuloreticular structures, loss of microvilli, and oedema and disruption of autonomic nerves. Neuronal abnormalities were particularly common in patients with cryptosporidiosis, but no ultrastructural marker was specific to 'pathogen-negative' diarrhoea.

Distinct functional subsets of natural killer cells potentially contribute to the pathology of inflammatory bowel disease (IBD).To report the phenotypic and functional characteristics of natural killer cells in blood and lamina propria of IBD patients, and the effect of azathioprine.Natural killer cells from blood and lamina propria of healthy controls or patients with Crohn's disease, or ulcerative colitis were studied by flow cytometry. Activation, cytokine production, proliferation and apoptosis of natural killer cell subsets were studied in vitro.CD16(+) natural killer cells are increased in frequency in the lamina propria comparing Crohn's disease or ulcerative colitis with healthy controls. Azathioprine therapy was associated with a reduction in total natural killer cells in blood and lamina propria, preferentially of the CD16(+) subset. Azathioprine therapy did not impair natural killer degranulation, but reduced natural and cytokine-activated cytotoxicity and interferon-gamma (IFN-γ) production. Culture of resting peripheral blood mononuclear cells with azathioprine resulted in loss of natural killer cells and inhibition of activation and IFN-γ production. Azathioprine preferentially inhibited proliferation of CD16(+) natural killer cells and induced apoptosis in resting but not in pre-activated natural killer cells.Natural killer cells with cytolytic potential are enriched in the colonic lamina propria of individuals with IBD. Azathioprine is associated with a reduction in these cells and a normalization of natural killer cell populations.

Potential multiple opportunistic infections in patients with the acquired immune deficiency syndrome (AIDS) cause the clinician considerable problems. Firstly there is the problem of the correct diagnosis of which organism is producing symptoms and there is the possibility of more than one organism being responsible. Secondly when multiple drug therapy is used in AIDS patients it is likely to result in a number of adverse effects. These may be expected as part of the toxic profile of the drug but also may result from unexpected interactions, or exacerbations of underlying problems in individuals infected with human immunodeficiency virus.

Octreotide has been used to treat HIV-associated diarrhea. We aimed to assess the effect of octreotide on small intestinal motility in a group of HIV infected individuals with chronic diarrhea. Small intestinal motility was measured continuously for 48 hr by ambulatory strain gauge manometry in 12 HIV seropositive subjects with chronic diarrhea. During the second 24-hr period, intravenous octreotide was administered (100 microg every 8 hr). Postprandial and nocturnal fasting motility data were compared before and during administration of octreotide. Octreotide was associated with increased numbers of migrating motor complexes (MMCs) (7.25 vs 4.92, P = 0.03), and a relative decrease in the duration of phase II (22% vs 49.8, P = 0.03) during nocturnal fasting activity. Postprandial activity was absent in half of the subjects and the duration significantly reduced in the remainder. In conclusion, octreotide has a significant effect on small intestinal motility in HIV-infected individuals with diarrhea, which may influence intestinal transit.

The medical records of all 420 patients attending an outpatient clinic between June 1990 and June 1991 were retrospectively reviewed for causes of weight loss. Of the 121 (29%) patients who had lost weight, the majority had a clear contributing cause; opportunistic infections ( n = 57), psychosocial factors ( n = 20), drug related problems ( n = 9). Unexplained weight loss ( n = 35) was more likely to have occurred in those patients with a better preserved immune system and most of these had symptoms suggestive of an unconfirmed infection or had local oral lesions associated with a loss of appetite. Unexplained weight loss associated with HIV infection is uncommon.

Combinations of two nucleoside analogue reverse transcriptase inhibitors plus a third agent represent the current standard for antiretroviral therapy. Stavudine is a nucleoside analogue that demonstrates in vitro activity against human immunodeficiency virus type 1 (HIV-1) and HIV-2 within an acceptable therapeutic index in a range of T lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a number of other antiretrovirals including protease inhibitors in two and three way combinations and is active against zidovudine-resistant virus. It exhibits excellent oral bioavailability, with CSF penetration. In clinical use, stavudine exhibits antiretroviral activity as a monotherapy similar to zidovudine, and is of proven clinical benefit in zidovudine-pretreated patients. In combination with didanosine and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Comparative trials in zidovudine-experienced patients suggest a similar frequency of adverse events to that observed with zidovudine. Peripheral neuropathy is the most common dose-limiting toxicity with haematological and hepatic function disturbance being infrequent. Reasons for stavudine failure are not established, with no consistent genotypic pattern being associated with changes in stavudine sensitivity in vitro or in vivo. The role of stavudine is as a component of triple therapy regimens both in initial therapy and in patients with prior zidovudine experience.

Gastric emptying may be delayed in HIV infection. We aimed to characterize the pattern of gastric emptying in HIV seropositive subjects and correlate the findings with symptoms, as well as to identify possible etiological factors. Solid gastric emptying was measured using scintigraphy in 54 HIV seropositive subjects and 12 HIV seronegative controls. Gastrointestinal symptoms were evaluated using a standardized numerical score, and autonomic function was assessed using spectral analysis of heart rate variability. Fasting and postprandial duodenojejunal activity was recorded using strain gauge manometry catheters. Gastric emptying rate, but not lag phase, was significantly delayed in HIV-infected subjects, particularly those with enteric infections and more advanced disease. Delayed gastric emptying did not correlate with symptoms, autonomic dysfunction, or small intestinal motility. In conclusion, abnormalities found in autonomic function and gastric emptying in HIV infection are multifactorial in nature. The contribution of upper gastrointestinal motor dysfunction to gastric symptoms in such individuals is unclear.

Zalcitabine (ddC) is a nucleoside analogue reverse transcriptase inhibitor with demonstrated clinical benefit in combination use. More widespread use of zalcitabine has been limited by a number of factors including peripheral neuropathy and three times daily dosing. However, screening for the risk factors for peripheral neuropathy may enable a reduction in the incidence of neuropathy to below 10%. Additionally, new data on the use of zalcitabine twice daily suggest, based on the long intracellular half-life of the active triphosphate, that this is feasible. Additionally, while limited data exist for zalcitabine in true HAART combinations, data from small trials suggest a similar proportion of responders to standard HAART regimens.

To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment.Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200-500 x 10(6)/l and12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks.Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment.Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11-1.77 log10 copies/ml and median CD4+ cell counts increased by 63-111 x 10(6)/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02-2.24 log10 copies/ml (abacavir monotherapy) and by 1.81-2.01 log10 copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79-195 x 10(6)/l (abacavir monotherapy) and by 93-142 x 10(6)/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects.In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

A total of 95 patients who presented in 1994 and 1995 with focal brain lesions at a London HIV centre were studied retrospectively. Patients were allocated to "definite" or "presumed" diagnostic categories of toxoplasma encephalitis (TE), primary CNS lymphoma (PCNSL) or progressive multifocal leukoencephalopathy (PML), based on strict criteria. The number in each category was: TE, 20; PCNSL, 9; PML, 7; presumed TE, 12; presumed PCNSL, 8 and presumed PML, 17. There were 20 patients in whom a diagnosis could not be made, and there were three non-HIV diagnoses. Demographic data, features at presentation and routine CSF analysis were not discriminatory in making a diagnosis. Toxoplasma titres were a median of 1:256 in those with TE compared to 1:16 in all other groups (p < 0.001) and those with TE were less likely to be on toxoplasma prophylaxis compared to those with PCNSL (p < 0.002). Survival with TE (median of 446 days) was significantly longer than survival in all other groups. Survival with either confirmed or presumed PML was similar. The problems of diagnosis of focal brain lesions in HIV patients are discussed and a management flow chart for mass lesions is proposed.

Large-scale clinical end point studies comparing antiretroviral therapy with zidovudine alone, didanosine alone, and zidovudine combined with didanosine indicate that both didanosine alone and zidovudine/didanosine provide a better clinical outcome than zidovudine alone in patients with human immunodeficiency virus (HIV) infection. The superiority of combination didanosine/zidovudine therapy over zidovudine monotherapy was most significant in treatment-naive patients, but benefit was also seen in patients who had previously received zidovudine and also in all stages of disease. Activity marker data from other studies suggest that double or triple combination therapies that include didanosine and nucleoside analogues other than zidovudine, non-nucleoside reverse transcriptase inhibitors or protease inhibitors result in powerful suppression of viral replication that will provide additional clinical benefits. Apart from mostly mild gastrointestinal disturbances, didanosine alone and in various combination therapies has been generally well tolerated. Thus, didanosine represents a potent, versatile nucleoside analogue with potential benefits in both current and future antiretroviral regimens for HIV infection.

AIMS: To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. METHODS: The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in acquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. RESULTS: Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 ng/ml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). CONCLUSIONS: Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.

The time course and magnitude of foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium were investigated in 13 male HIV-positive patients who had no active cytomegalovirus-associated disease. The patients had a mean age of 36 years (range 25-49 years) and a mean CD4 cell count of 550 cells/mm3 (range 130-1280 cells/mm3). Peak (mean +/- SD) plasma concentrations of foscarnet (0.89+/-0.10 mmol/l) were seen at the end of the period of drug infusion (90 mg/kg of foscarnet was infused over 2 hours) and declined with a terminal half-life of 5.7+/-0.7 hours. Plasma concentrations of total calcium declined over an 8-hour period, with the lowest concentration occurring after 4 hours (baseline: 2.29+/-0.09 mmol/l; lowest: 2.18+/-0.07 mmol/l; P0.001). By contrast, the lowest plasma concentration of ionized calcium occurred after 2 hours (baseline: 1.25+/-0.04 mmol/l; lowest: 0.99+/-0.05 mmol/l; P0.001), before gradually recovering to baseline levels over the next 10 hours. The mean maximal decrease in total calcium was 0.11+/-0.06 mmol/l, compared with 0.26+/-0.04 mmol/l for ionized calcium (P0.001). Plasma concentrations of total magnesium declined from 0.79+/-0.06 mmol/l (baseline) to 0.74+/-0.04 mmol/l (P0.05) after 4 hours and remained at this level after 8 hours. However, plasma concentrations of ionized magnesium fell steeply from 0.56+/-0.03 mmol/l to 0.39+/-0.03 mmol/l at 2 hours (P0.001), followed by a gradual recovery over the next 10 hours. The mean maximal decrease in total magnesium was 0.05+/-0.08 mmol/l, compared with 0.18+/-0.03 mmol/l (P0.001) for ionized magnesium. In summary, we found that foscarnet-induced changes in the plasma concentrations of total calcium and magnesium were dissociated from the corresponding changes in ionized calcium and magnesium. The maximal decreases in the plasma concentrations of total calcium and magnesium were smaller in magnitude and occurred much later than did the changes in ionized calcium and magnesium. The relative changes in the plasma concentration of ionized magnesium were greater than those of ionized calcium, indicating that foscarnet binds preferentially to the magnesium ion.

Langerhans cells (LC) are antigen-presenting CD4+ dendritic cells in the skin which may become infected by the human immunodeficiency virus (HIV). Decreased LC function could account for the cutaneous manifestations seen in HIV disease. Previous studies of epidermal LC density in HIV-infected subjects have produced conflicting results. A definitive, prospective, case-control study was performed to determine whether there is an association between epidermal LC density and HIV clinical disease stage. Skin cryosections were stained with the CD1 monoclonal antibody using a three-step immunoperoxidase method. LC were counted by light microscopy and epidermal dimensions calculated with computer-assisted planimetry. The stage of the HIV clinical disease correlated with epidermal LC densities was quantified by three different methods: mean LC numbers per mm length of basement membrane, mean LC per mm2 of epidermal area, and mean LC population per mm of epidermal surface length. Seventy-one subjects, recruited from a large out-patient HIV clinic in London, comprised 56 HIV-positive men and 15 male HIV-negative controls. Contrary to previous smaller studies, there was no detectable association between epidermal LC density (quantified by any of the three methods) and the stage of the HIV clinical disease. Given that HIV infects large numbers of CD4+ cells, we propose possible hypotheses to account for the apparent preservation of static LC numbers in the skin. Further studies of LC kinetics and function are required to elucidate their role in the natural history of HIV infection.

This paper is a prospective study of patients with advanced human immunodeficiency virus infection and chronic diarrhoea for which no cause could be found after extensive investigations, including examination of multiple stool specimens for all known faecal pathogens and the histological examination of small and large bowel biopsy specimens. Of 39 such patients recruited from 155 prospectively investigated patients, eight had a possible cause of diarrhoea identified on follow up investigations, including small bowel neoplasms in three and cytomegalovirus in two. In 17 of the remaining 31 the diarrhoea resolved completely in a mean of seven months from its onset. Eleven had continuing mild or intermittent diarrhoea and three had more than 1 litre of diarrhoea daily for which no cause could be found. The median survival for patients with 'pathogen negative' diarrhoea was 48.7 months, which is similar to that of control patients with no diarrhoea and significantly longer than that of matched patients with a gastrointestinal pathogen (9.6 months).

To determine the efficacy of high-dose oral acyclovir in preventing cytomegalovirus (CMV) and other herpesvirus disease in patients with advanced HIV disease and to evaluate its effect on patient survival.Double-blind, placebo-controlled randomized trial of up to 1 year's therapy.Outpatient clinics in 16 hospitals in Europe and Australia.A total of 302 patients with Centers for Disease Control and Prevention stage IV HIV disease, seropositive for CMV and with CD4+ lymphocyte countsor = 150 x 10(6)/l.Oral acyclovir (800 mg, four times daily) or matching placebo for 48 weeks.Time to development of CMV and other herpesvirus disease. Following the results of another study, the protocol was amended to make survival a second major endpoint.Acyclovir failed to reduce the incidence of CMV disease: the probability of developing CMV disease at 1 year was 0.24 and 0.23 in the placebo and acyclovir groups, respectively (P = 0.53). However, acyclovir significantly reduced the probability of dying at 1 year of follow-up (from 0.39 to 0.23; P = 0.018). As expected, acyclovir significantly reduced the incidence and frequency of herpes simplex virus disease. There were no notable differences between treatment groups in clinically adverse experiences and no changes in haematological parameters to indicate clinically significant drug-induced toxicity.High-dose acyclovir failed to reduce the incidence of CMV disease, but significantly reduced the probability of dying at 1 year of follow-up.

Pneumocystis carinii colonization was studied in 90 men using the polymerase chain reaction. These comprised ten heterosexual controls; ten HIV-seronegative homosexual controls; 20 HIV-seropositive homosexuals with blood CD4 count400 x 10(6) l-1; 20 HIV-seropositive homosexuals with CD4400 x 10(6) l-1; ten HIV-seropositive homosexuals with CD460 x 10(6) l-1 receiving PCP chemoprophylaxis; and 20 HIV-seropositive homosexuals with respiratory symptoms but without PCP. Induced sputum was obtained from all but the last group, who had bronchoalveolar lavage, and all specimens were tested for P. carinii using the polymerase chain reaction. The first four groups received no pneumocystis chemoprophylaxis, and all but the last group were asymptomatic. P. carinii colonization did not occur in the two control groups. P. carinii colonization rates were significantly different in the CD4400, CD4400, and CD460 groups (10%, 20%, and 40% respectively) (P0.025). Two patients (one each from CD4400 and CD460) developed PCP 4-6 weeks after sputum induction, both had previously had high levels of P. carinii on sputum induction. Two patients from the CD4400 group had high levels of P. carinii but did not develop PCP. In the symptomatic group, two subjects had low levels of P. carinii, but did not develop PCP. We have demonstrated P. carinii colonization in HIV-seropositive homosexuals in association with a low peripheral CD4 count. The polymerase chain reaction may be a useful technique for determining the need and efficacy of anti-pneumocystis chemoprophylaxis.

One hundred and fifty-one patients intolerant to zidovudine (AZT) received didanosine (ddI) to a maximum dose of 12.5 mg/kg/day. Patient response was assessed using changes in CD4+ lymphocyte subset count, HIV p24 antigen, weight, and quality of life. Seventy patients developed major opportunistic infections whilst on therapy; this was the first AIDS diagnosis in 17. Only minor changes in CD4+ lymphocyte subset count were observed in AIDS patients, although a more significant rise occurred in those with earlier stages of disease. Of those positive for p24 antigen at the commencement of the study 67% showed a positive response, and this was most likely in those with CD4+ lymphocyte subset counts above 100 mm3. A positive weight response was seen in 16% of patients. Most patients showed improvement in individual parameters and global score of quality of life. Adverse reactions possibly attributable to didanosine were common. The most common side-effect was diarrhoea, which resulted in cessation of therapy in 19 individuals. Peripheral neuropathy occurred in 12 patients and pancreatitis in six. Thirteen patients developed a raised serum amylase without abdominal pain. Seven patients developed glucose tolerance curves characteristic of diabetes but these were mild, did not require treatment and returned to normal on ceasing didanosine.

The incidence of cryptosporidiosis in our unit has increased over the last 6 years, being diagnosed in approximately 5 per cent of all patients with HIV infection and in 21 per cent of those with AIDS, but a marked seasonal variation occurs. We have studied the course of the infection in 128 patients and identified four clinical patterns of disease: transient (28.7 per cent), chronic (59.7 per cent), fulminant (7.8 per cent) and asymptomatic (3.9 per cent). Transient disease occurred in patients with a wide range of CD4 lymphocyte counts, but was more common in less immunosuppressed patients. Fulminant disease, defined by the passage of more than 2 l of stool/day from the time of presentation, only occurred in patients with a CD4 count less than 50/mm3. This group had lost more than 7 kg in weight at presentation and more commonly had other intercurrent gastrointestinal infections. They survived for a median of only 5 weeks, compared with 20 weeks for those with chronic diarrhoea and 36 weeks for those with transient infection. The survival was unaffected by any treatment other than zidovudine. Cryptosporidiosis in HIV-infected individuals is a heterogeneous disease.

To test the hypothesis that absorption of orally administered itraconazole may be reduced in patients with the Acquired Immunodeficiency Syndrome (AIDS), 8 patients with AIDS were given two 100 mg capsules of itraconazole for 15 days. Plasma levels were measured by HPLC hourly for the first 8 h following ingestion, then at 24, 48, 72 and 96 h on days 1, 8 and 15. Peak plasma levels occurred after approximately 4 h. Mean peak plasma concentrations were 446 ± 196 and 530 ± 214 ng mL−1 at days 8 and 15. The area under the curve over 24 h (AUC0–24) was 2105 ± 1241, 7679 ± 3838 and 8748 ± 4385 ng mL−1 h for days 1, 8 and 15, respectively. Steady-state was achieved after one week of dosing. There was no evidence of hepatotoxicity and one patient stopped itraconazole due to a rash. It may be concluded that the absorption of oral itraconazole capsules is reduced in AIDS patients, by a factor of approximately 50%, when compared with normal volunteers. AIDS patients may require higher doses of itraconazole than used in non-AIDS patients to achieve comparable plasma levels.

Bronchial narrowing is the major side effect of inhaled nebulised pentamidine isethionate, used for the prophylaxis and treatment of Pneumocystis carinii pneumonia. Several agents and delivery systems were assessed for prophylaxis of bronchial narrowing in HIV-positive males receiving regular nebulised pentamidine isethionate. In a previous study we found the mean maximum fall in FEV1 with nebulised pentamidine alone to be 21%. FEV1 was measured before and after inhaling nebulised pentamidine, preceded by one of the following bronchodilator/immunoregulatory agents: Terbutaline metered dose inhaler (500 micrograms), nebulised salbutamol (5 mg), nebulised ipratropium bromide (500 micrograms), nebulised sodium cromoglycate (20 mg), and nedocromil sodium metered dose inhaler (4 mg). Each agent was administered once only to ten different subjects. Nebulised salbutamol gave most effective prophylaxis against bronchial narrowing induced by nebulised pentamidine (mean maximum fall in FEV1 = 5% vs. 21%, P less than 0.001). Terbutaline given by metered dose inhaler was significantly less effective than high dose terbutaline (10 mg) given by nebuliser, demonstrated in the previous study (mean maximum fall in FEV1 = 14% vs. 6%, P less than 0.05). Mean maximum falls in FEV1 for ipratropium bromide, sodium cromoglycate and nedocromil sodium were 16, 17 and 16%, respectively. High dose beta 2-agonists administered by nebuliser give more effective prophylaxis against nebulised pentamidine-induced bronchial narrowing than either lower doses given by metered dose inhaler, anticholinergics or immunoregulatory drugs.

Foscarnet, administered via a central line, was used for the treatment of 18 episodes of cytomegalovirus (CMV) esophageal ulceration in 15 patients, and in the treatment of 27 episodes of CMV colitis in 22 patients. In 15 of the 18 episodes of the esophageal disease, there was complete loss of symptoms within 2 wk. Only three of the 15 patients responding to foscarnet therapy had a relapse of their esophageal disease. Two of these patients were successfully retreated with foscarnet. Of the 22 patients receiving foscarnet for CMV colitis, four died during foscarnet therapy. Of the 18 patients completing the course of treatment with foscarnet for first-episode CMV colitis, 11 remitted completely and six had a partial remission. All patients with partial remission had a second pathogen responsible for the continuation of their diarrhea. Only one patient completing a course of foscarnet failed to respond microscopically to treatment. Three patients experienced relapse of their CMV colitis, two of whom responded to further courses of foscarnet. Foscarnet is an effective therapy for CMV disease of the gastrointestinal tract, with rapid resolution of clinical symptoms, long-term remission of esophageal disease, and shorter disease-free periods for CMV colitis.

Nebulized pentamidine is increasingly used for the prevention of Pneumocystis carinii pneumonia in HIV antibody-positive patients. We report our experience of the efficacy and tolerance of a high dose regimen (300 mg every second week) in 173 HIV-positive patients over a 2 1/2-year period. Only seven episodes of P. carinii pneumonia occurred but 48 patients (28 per cent) died of other AIDS-related illnesses. Patients who had never had an episode of P. carinii infection were less likely to accept long-term prophylaxis (17 of 81), compared to those who had previously been treated for the condition (five of 92). Nebulized pentamidine is an effective form of prophylaxis against P. carinii pneumonia, but long-term mortality is still high in AIDS patients. Side-effects with this regimen were almost always local and confined to the period of nebulization.

The causes of abdominal pain in patients with AIDS are different from those of the general population, and there are no guidelines as to which investigations are optimal. We reviewed our experience of 63 patients who presented with abdominal pain as the main reason for admission to the AIDS unit at St Stephen's and Westminster Hospital between January 1988 and January 1990. All patients were assessed within the same structured diagnostic programme. Thirty-five had upper abdominal pain, predominantly in the right upper quadrant in 27; seven had lower abdominal pain, which was concentrated in the right iliac fossa in three; 21 had diffuse abdominal pain. The causes of pain were determined satisfactorily in the majority of patients using routine gastroenterological investigations. The predominant site of pain had considerable predictive value in the diagnosis. The commonest cause of right upper quadrant pain was sclerosing cholangitis (17 of 27); endoscopic retrograde cholangio-pancreatography was necessary for a confident diagnosis. Diarrhoea was frequently associated (15 of 21) with diffuse abdominal pain; the commonest cause (six of 21) was cytomegalovirus colitis. Neoplasia was the cause of abdominal pain in eight patients. The other causes of abdominal pain and the utility of various investigations are discussed. An investigatory route which may provide maximum information has been suggested.