The paradox of improved antiretroviral therapy in HIV: potential for nutritional modulation?

Chronic infection with HIV type 1 is associated with alterations in macronutrient metabolism, specifically elevated plasma lipids, glucose and reduced insulin sensitivity. These alterations are most severe in patients at the later stages of AIDS, indicating a relationship with disease progression. Recently, a metabolic syndrome, termed lipodystrophy, has been described in successfully-treated HIV patients in whom the altered macronutrient metabolism of HIV infection appears to be amplified markedly, with concurrent alterations in adipose tissue patterning. This syndrome presents a paradox, as before the development of highly-active antiretroviral therapy (HAART) the most severe perturbations in metabolism were observed in the sickest patients. Now, the patients that respond well to therapy are showing metabolic perturbations much greater than those seen before. The implications of this syndrome are that, whilst life expectancy may be increased by reducing viral load, there are concomitant increases in the risk of cardiovascular disease, diabetes and pancreatitis within this patient population. The aetiology of the syndrome remains unclear. In a collaborative trial with the Chelsea and Westminster Hospital in London we have used stable-isotope-labelled fatty acids to examine the hypothesis that treatment with HAART causes a delayed clearance of dietary lipid from the circulation, resulting in the retention of lipid within plasma and the downstream changes in insulin and glucose homeostasis. This hypothesis would indicate a role for low-fat diets, exercise and drugs that reduce plasma lipid or insulin resistance, in modulating the response to antiretroviral therapy in HIV infection.

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Clinical response to ketoconazole of HIV-related oral candidosis is predicted by Odds' relative growth method of susceptibility testing.

In-vitro ketoconazole susceptibility was assessed by measuring an isolate's relative growth in medium containing a fixed concentration of ketoconazole as a percentage of growth in drug-free medium. One hundred specimens from HIV-positive patients with candidosis were tested. Each patient's response was assessed following one week's treatment with ketoconazole 400 mg/day. A relative growth in ketoconazole of >75% predicted clinical failure of ketoconazole with a specificity of 97% and sensitivity of 79%.

Itraconazole cyclodextrin solution: the role of in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidosis.

OBJECTIVES: This study assessed the ability of in vitro susceptibility testing of clinical Candida isolates to predict in vivo response to itraconazole cyclodextrin solution. METHODS: One hundred specimens were obtained from HIV-positive patients with oral thrush, of which 72 speciments were from patients who were clinically unresponsive to fluconazole at standard doses and had fluconazole-resistant isolates in vitro. Susceptibility to itraconazole was assessed by measuring the relative growth of an isolate in liquid medium containing a single concentration of itraconazole and then expressing growth in itraconazole as a percentage of growth in antifungal-free medium. RESULTS AND CONCLUSIONS: Where specimens yielded only one isolate, a cut-off relative growth in itraconazole of 68% discriminated between isolates from patients failing to respond clinically to itraconazole solution and those from patients successfully treated with the preparation (specificity 100%; sensitivity 88%). The presence of mixed infection reduced the predictive accuracy of the test. Only 30% of fluconazole-resistant isolates were cross-resistant to itraconazole. No isolates were resistant to itraconazole but susceptible to fluconazole. Non-response to itraconazole solution was attributed to resistant yeast infection in the majority of cases, and this susceptibility method accurately identified specimens from patients unlikely to respond to the drug.

The value of barium enema and colonoscopy in patients infected with HIV.

Double contrast barium enema (DCBE) and colonoscopy were prospectively compared with rigid sigmoidoscopy, rectal biopsy and microbiological examination in the analysis of stool specimens in 58 HIV-1-infected patients with diarrhoea (more than three liquid motions/day for greater than 1 month). In 26 patients no cause for the diarrhoea was found. In 17 patients the cause of diarrhoea was microbiological, and in 19 rectal histology provided a specific diagnosis. In all these patients sigmoidoscopic appearances were abnormal except in those with Cryptosporidium alone. Colonoscopy provided additional information in only one individual, with cytomegalovirus ulcers of the transverse colon. DCBE was abnormal in only seven cases (cytomegalovirus in three, Kaposi's sarcoma in two, Giardia lamblia in two) and in no case provided additional information. A combination of stool microbiology and rectal histology gave a sensitivity of 97% with a positive predictive value of 100%. The sensitivities of DCBE and colonoscopy with histology were low (16 and 62%, respectively) although the specificity for each test was high, with high positive predictive values. We conclude that neither barium enema nor colonoscopy add usefully to rigid sigmoidoscopic biopsy and stool microscopy in HIV-positive patients with diarrhoea.

Investigation of upper gastrointestinal symptoms in patients with AIDS.

Double contrast barium radiology and upper gastrointestinal endoscopy were compared prospectively on 45 occasions in patients infected with HIV who presented with upper gastrointestinal symptoms. In 40 cases, a definite pathological diagnosis was reached and in four cases no organic basis for symptoms could be found. A correct and complete diagnosis was made on visual endoscopic criteria in 43 cases (95.5%) but in only 14 cases (31.1%) from barium studies alone. Radiology showed no abnormality in 22 cases where pathological changes were documented (oesophageal candidiasis in 21 cases). Where pathological confirmation of diagnosis existed (40 cases), endoscopy (without pathological support) had a sensitivity of 97.5% and a specificity of 100% compared with the sensitivity and specificity of 25 and 100% for barium studies. The difference between the sensitivities of the two methods was highly significant (P less than 0.005). The combination of oral candidiasis and upper gastrointestinal symptoms without dysphagia or weight loss was so strongly associated with uncomplicated oesophageal candidiasis (negative predictive value 93%; P less than 0.025), that this is supported as a basis for therapy without the need for further investigation, although if upper gastrointestinal investigation is required, endoscopy should be the method of choice.

Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients.

Thirty of 81 consecutive HIV antibody positive patients referred with non-cryptosporidial diarrhoea had no potential infectious cause; most had AIDS related complex rather than the full blown syndrome. Opportunistic infections with cytomegalovirus (CMV), mycobacterium avium-intracellulare (MAI), and herpes simplex virus (HSV), which allowed a diagnosis of AIDS to be made, were found in 19 patients and were the presenting features of AIDS in five. Other potential pathogenic species included entamoeba, giardia, campylobacter, and salmonella (without septicaemia). Cytomegalovirus infection was often accompanied by abdominal pain. Severe weight loss (greater than 10 kg) at presentation was found in patients with CMV infection and MAI. Bloody diarrhoea was confined to the group with HSV procitis. Malignant causes of diarrhoea were rare. Two patients developed a squamous carcinoma of the anorectal margin and one a non-Hodgkin's lymphoma. In only two of 12 patients who had Kaposi's sarcoma was this considered as a cause of diarrhoea. Rigid sigmoidoscopy showed macroscopic abnormalities in over a third (32) of the 81 patients with non-cryptosporidial diarrhoea. Most commonly this was severe inflammation (17) or discrete ulceration (four) [three of whom had CMV colitis]. Kaposi's sarcoma was identified in 11 patients. Non-specific inflammation was seen histologically in 40 of the 60 patients with no sigmoidoscopic inflammatory changes. Barium enema only revealed an abnormality in a minority of the patients and a colonoscopy only revealed information additional to rigid sigmoidoscopy in two patients--one with CMV ulcers in the transverse colon and the other with evidence of Kaposi's sarcoma not seen in the rectum. Ten patients had a rectal biopsy examined by electron microscopy as no infective cause of diarrhoea was uncovered. In four of these microtubular structures which are commonly seen in viral infections were found and two had prelymphomatous changes and in one of these frank lymphoma has developed. We recommend multiple stool analysis, sigmoidoscopy and rectal biopsy as the initial investigations in these patients reserving tests of malabsorption, colonoscopy, and barium enema for the small number of more difficult cases.

Weight loss caused by a thalamic astrocytoma.

We describe a case presenting as weight loss without neurological signs, caused by a thalamic astrocytoma.