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Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.

Objective We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals.Methods International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP =140 and/or diastolic BP =90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline.Results 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2–6) were recorded over a median follow-up of 2.3 years (IQR: 1.5–2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences =5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2–76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated =10 months and >10 months compared with no exposure; P=0.005).Conclusions Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.

Death during the first year after hip fracture may be influenced by the type of hospital in which patients are treated as well as the time spent awaiting surgery. We studied 57 315 hip fracture patients who were admitted to hospital in Ontario, Canada. Patients treated in teaching hospitals had a decreased risk of in-hospital mortality (odds ratio (OR) 0.89; 95% confidence interval (CI) 0.83 to 0.97) compared with those treated in urban community institutions. There was a trend toward increased mortality in rural rather than urban community hospitals. In-hospital mortality increased as the surgical delay increased (OR 1.13; 95% CI 1.10 to 1.16) for a one-day delay and higher (OR 1.60; 95% CI 1.42 to 1.80) for delays of more than two days. This relationship was strongest for patients younger than 70 years of age and with no comorbidities but was independent of hospital status. Similar relationships were seen at three months and one year after surgery. This suggests that any delay to surgery for non-medical reasons is detrimental to a patient’s outcome.

As part of the Medical Research Council prospective study of the neurological complications of HIV infection, neurophysiological tests of spinal cord and peripheral nerve function were recorded in a cohort of homosexual or bisexual men. The studies included motor and sensory nerve conduction studies, vibration perception thresholds, somatosensory evoked potentials and motor evoked potentials elicited by magnetic stimulation. The results were compared with markers of immune function. The findings from 114 volunteers were analysed in a cross-sectional study. Fifty-nine were HIV-seropositive but asymptomatic, 26 had progressed to the symptomatic stages of HIV disease and 29 were persistently HIV-seronegative. There was some evidence of a mild sensory axonopathy in the symptomatic HIV-seropositive group. No differences were detected between the asymptomatic HIV-seropositive group and the HIV-seronegative comparison group. There were no consistently significant correlations between the neurophysiological measurements and CD4 counts and ß2-microglobulin levels. On repeated testing, there was no evidence of a trend towards deterioration over a mean period of approximately 3 years in 36 HIV-seropositive subjects who remained asymptomatic compared with 22 HIV-seronegatives. These findings have failed to demonstrate neurophysiological evidence of spinal cord or peripheral nerve dysfunction in the asymptomatic stages of HIV infection.

The purpose of this study was to examine by proton spectroscopy for any difference in cerebral metabolites in patients taking part in the Concorde study (comparing the efficacy of immediate versus deferred treatment with zidovudine on asymptomatic HIV infected individuals). Forty seven HIV positive male patients [29 immediate, 18 deferred zidovudine] were examined in the last 9 months of the therapeutic trial. Magnetic resonance imaging and proton spectroscopy were performed at 1.5 Tesla using a single voxel placed in the parieto-occipital white matter. No significant difference was found in metabolite ratios comparing immediate versus deferred zidovudine (NA/NA+Cho+Cr 0.52 vs. 0.52). High quality spectra were acquired in relatively large numbers of patients and logistically spectroscopy may be applied to clinical therapeutic studies.

Thirteen patients with AIDS or ARC on continuous zidovudine therapy (800–1200 mg daily), who developed severe anaemia (median Hb 7.9g dl−1range 4.9–9.4) after 66 days of treatment (median, range 35–258) were then treated with an intermittent regimen in an open study. The regimen consisted of cycles of 4 weeks on treatment (600–100 mg daily) followed by 2 weeks off. Intermittent treatment was tolerated for a significantly longer period of time (median 257 days range 72–603) and a higher cumulative does (P< 0.001). Four patients discontinued intermittent therapy in the period of follow-up, three due to bone marrow suppression. Eight of 13 patients needed red cell transfusions on continuous therapy compared to only one on the intermittent regimen. On intermittent therapy median haemoglobin concentration and neutrophil counts remained stable (Hb median 11.9g dl−1range 9.1–14.8, neut. median 1.7 × 109I−1range 0.6–4.3). Ten patients had detectable levels of P24 antigen which decreased from a median of 128 pg ml−1(range 15–242) to 24 pg ml−1(range 0–53) on continuous therapy. Subsequently, in eight of these patients on the intermittent regimen, levels of P24 Ag remained below 50% of initial pretreatment values (median 28 pg ml−1range 0–178) or below 50 pg ml−1.

The epidemiological, immunological and early virological observations on the acquired immune deficiency syndrome (AIDS) suggested that an agent was involved which was sexually, parenterally and perinatally transmitted and perhaps tropic for T helper lymphocytes. A new subgroup of human T lymphotropic retroviruses have been identified and seroepidemiological studies suggest that they are aetiologically related to AIDS. The syndrome is characterised by the development of tumours: such as Kaposi's sarcoma and non-Hodgkins lymphoma. with an aggressive clinical course and infection by a wide spectrum of opportunistic organisms, Both the tumours and the infections commonly involve the gut.

The causal agent of Kaposi's sarcoma is unknown. That the disorder is ten times more common in homosexual or bisexual men with the acquired immunodeficiency syndrome (AIDS) than in other human immunodeficiency virus (HIV) transmission groups suggests that a certain aspect of their behaviour exposes them to the agent or facilitates its spread. We therefore assessed social and demographic characteristics, including sexual behaviour, of 65 homosexual or bisexual men with AIDS from London. Sexual practices in which there was contact with partner's faeces before AIDS developed were the main determinants of Kaposi's sarcoma risk. Risk increased with frequency of insertive "rimming" (oral-anal contact): Kaposi's sarcoma developed in 18% of the men with AIDS who reported never having practised insertive rimming compared with 50% who practised it less than once a month, 73% between once a week and once a month, and 75% or more once a week (two-sided exact p-value for trend <0·001). 45 men had been interviewed about their sexual practices before AIDS developed, and 20 were interviewed at the time the syndrome developed. The findings were similar and statistically significant when each group was analysed separately. The men with Kaposi's sarcoma also tended to be more sexually active and were more likely to engage in other sexual activities that entailed contact with faeces than were the men who had other features of AIDS only. Other behaviours and exposures, including the use of "poppers" (nitrite inhalants), were not related to Kaposi's sarcoma risk, after taking into account whether the subjects had practised insertive rimming. The data suggest that faecal-oral contact is the main route of transmission of the agent of Kaposi's sarcoma in homosexual or bisexual men with AIDS.

Four patients with acquired immunodeficiency syndrome (AIDS) (CDC group IV) were investigated for biliary disease because of the presence of both severe upper abdominal pain and raised levels of serum alkaline phosphatase. None was clinically jaundiced. Upper abdominal ultrasound was abnormal in three. All had endoscopic retrograde cholangiographic evidence of both an intrahepatic sclerosing cholangitis suggestive of primary sclerosing cholangitis and an irregular suprapapillary common bile duct dilation suggestive of papillary stenosis. Three had evidence of gastrointestinal cryptosporidiosis and two of disseminated cytomegalovirus infection. Endoscopic sphincterotomy, performed in two patients, gave good pain relief. We propose the name 'AIDS sclerosing cholangitis' for this form of secondary cholangitis. The cause of this disorder remains unclear. Recent evidence is discussed which suggests that it is not due to HIV itself but to an opportunistic infection. Cryptosporidium appears to be the most likely candidate.

Atevirdine is a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). In this study we investigated the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3. Patients were randomized to receive 600 mg of atevirdine (n = 15) or a placebo (n = 15) three times a day for 12 weeks. There was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data do not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients.

Twenty five homosexual men from London, 14 of whom had persistent lymphadenopathy and 11 of whom did not, were tested for immunity to Epstein-Barr (EB) virus. All yielded positive results to serological tests for the viral capsid antibody, and 11 had antibodies to the early antigen. Thirteen out of 17 were excreting virus into the saliva; culture of peripheral blood mononuclear cells from two of these patients showed no detectable regression induced by T cells that was specific to EB virus. No differences were found between the patients with and without lymphadenopathy. Peripheral blood B cells from six patients with hypergammaglobulinaemia were double stained for cytoplasmic immunoglobulin and EB viral nuclear antigen, and in all cases the activated B cells producing immunoglobulin did not contain EB nuclear antigen. Similarly, lymph node biopsy specimens from five patients showed no cells with EB nuclear antigen. These results indicate that although homosexual men have a high incidence of reactivated infection with EB virus, this viral infection is not the cause of the polyclonal activation of B cells seen in peripheral blood and is not implicated in the aetiology of the lymphadenopathy found in these men. [ABSTRACT FROM PUBLISHER]

BACKGROUND: CD4 lymphocyte counts are used to monitor immune status in HIV disease. An understanding of the variability of CD4 counts which occurs in the absence of HIV infection is essential to their interpretation. The sources and degree of such variability have not been extensively studied. OBJECTIVES: To establish reference ranges for CD4 counts in HIV-seronegative women and heterosexual men attending a genitourinary medicine (GUM) clinic, and to identify possible differences according to gender and cigarette smoking and, in women, any effect of the menstrual cycle, oral contraceptive use and cigarette smoking. DESIGN: Female and heterosexual male patients attending a GUM clinic and requesting an HIV-antibody test were recruited prospectively. Results from an earlier study of CD4 counts in homosexual men were available for comparison. METHODS: Lymphocyte subpopulation analysis on whole blood by flow cytometry. RESULTS: The absolute CD4 count and percentage of CD4 cells (CD4%) were significantly higher in women (n = 195) than heterosexual men (n = 91) [difference between the means 111 x 106/1 (95% CI 41, 180) and 3.1% (1.30, 4.88)]. The absolute CD4 count and CD4% were also significantly higher in smokers (n = 143) than non-smokers (n = 140) [difference 143 (79, 207) and 2.1% (0.43, 3.81)]. Reference ranges for absolute CD4 counts (geometric mean +/- 2SD) were calculated on log transformed data as follows; female smokers 490-1610, female non-smokers 430-1350, heterosexual male smokers 380-1600, heterosexual male non-smokers 330-1280. Among other variables examined, combined oral contraceptive pill use was associated with a trend towards a lower absolute CD4 count. Changes were seen in CD4% with the menstrual cycle. CD4 counts and CD4% did not differ significantly between heterosexual men and homosexual men (n = 45). CONCLUSION: There is a significant gender and smoking effect on CD4 counts. The effects of oral contraceptive use and the menstrual cycle warrant further investigation. [ABSTRACT FROM PUBLISHER]

Progression rates from asymptomatic to symptomatic Human Immunodeficiency Virus (HIV) infection according to the CDC classification were prospectively studied in a cohort of 172 seropositive homosexual and bisexual men. The median follow-up time was 4 years. The progression from data of entry to the study to any group IV disease was 56% (SE 7%) at 5 years. However, the progression from an estimated date of seroconversion to any group IV disease was 36% (SE 4%) at 5 years. This was more than double the progression rate to AIDS-14% (SE 3%) at 5 years calculated in the same way. There were no differences in progression to AIDS from group IV A (systemic symptoms such as unexplained fever, weight loss or persistent diarrhoea) and group IV C-2 (oral candida or oral hairy leukoplakia). Progression rates to AIDS were significantly lower (p = 0.02) in patients who were under 25 years of age at entry than in those over 25. A review of progression rates to AIDS among homosexual cohorts shows that they tend to be higher than in cohorts of haemophiliac patients, in the early stage of infection. However, when Pneumocystis carinii pneumonia is the outcome measure, progression rates in all studies are remarkably similar. [ABSTRACT FROM PUBLISHER]

Thirty one homosexual men with antibody to human immunodeficiency virus (HIV) but without major neurological complaints were assessed in a cross sectional study of neurological and neuropsychological function. Eleven patients had AIDS, 10 had persistent generalised lymphadenopathy (PGL), and 10 had HIV infection without PGL (called "well"). Thirteen age matched homosexual men without antibody to HIV acted as controls. Significant abnormalities were found in six on clinical neurological examination, in eight on nerve conduction studies, in six on electroencephalography, in six on neuropsychological assessment, and in eight on computed tomography of the head. Eighteen patients (nine with AIDS, four with PGL, and five "well") performed abnormally in at least one section of the assessment. The study highlights the incidence of nervous system dysfunction in HIV infection even in people who do not have AIDS. Prospective evaluation using electrophysiological and imaging techniques is necessary to assess the natural history of such manifestations and the effect of antiviral treatment. [ABSTRACT FROM PUBLISHER]

Sixty women patients experiencing a first attack of genital herpes were randomly treated with either oral acyclovir for 42 days or oral acyclovir for five days followed by placebo for 37 days. The median time to the first recurrence in patients receiving acyclovir for 42 days was 66.5 days compared with 24 days in those who received acyclovir for only five days (p less than 0.0001). This significant difference, however, was only observed for the treatment period. The frequency of recurrences was also reduced during the period of treatment in those who received prolonged treatment. During the subsequent follow up period, however, patients in both groups had a similar frequency of recurrences. Patients with infections due to herpes simplex virus type I (HSV I) had a significantly longer time to the first recurrence (p less than 0.001) and fewer recurrences (p less than 0.001) than those infected with HSV II, irrespective of treatment. [ABSTRACT FROM PUBLISHER]

Lymph node biopsy was performed in 39 homosexual men with unexplained persistent generalized lymphadenopathy (PGL). Thirtyseven (95 per cent) of these patients had antibodies to human Tlymphotropic virus type III (HTLV-III), at the time of biopsy. Histology in all but one showed only follicular hyperplasia, the exception showed caseating granulomata typical of tuberculosis. Clinical differentiation between lymphadenopathy associated with HTLV-III and other causes of generalized lymphadenopathy is difficult; however, the presence of antibodies to HTLV-III probably identifies patients in whom surgical biopsy will only occasionally reveal a specific histological diagnosis. It is suggested that the presence of antibodies to HTLV-III in patients with PGLjustifies a more selective approach to lymph node biopsy.