The management of dyslipidaemias in antiretroviral-treated HIV infection: a systematic review.

OBJECTIVES: The aim of the study was to assess the currently available evidence concerning the management of dyslipidaemias in HIV-infected individuals treated with antiretroviral therapy. METHODS: Randomized trials, published within the 5 years preceding 5 October 2005, were identified in PubMed Medline, Embase, and The Cochrane Central Register of Controlled Trials. Studies were then included or excluded, dependent on their meeting inclusion/exclusion criteria. The evidence obtained in the studies that were included was assessed using methods employed by the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: Thirteen relevant trials were identified, concerning the use of statins, fibrates, antiretroviral drug switches and insulin-sensitizing drugs. Most contained small numbers of trial participants. CONCLUSIONS: Most studies suggested beneficial effects and satisfactory safety profiles for the interventions studied. However, the insulin-sensitizing drug rosiglitazone appeared to have some detrimental effects on lipid profiles. With the small numbers of participants in the majority of studies, these studies were likely to have been inadequately powered to assess the effects of the interventions examined. Larger trials are therefore necessary.

Hepatitis C and HIV co-infection.

HIV accelerates progression of hepatitis C virus (HCV)-related liver disease. There are conflicting data on the effect of HCV on the risk of HIV progression and CD4 response to highly active antiretroviral therapy (HAART). Long-term prospective cohort studies are clearly required to resolve these issues. The optimal management of the co-infected patient is also unclear. For the co-infected patient, the optimal HAART regimen for best immune CD4 recovery and least adverse reactions remains unclear. Unfortunately, current HCV treatment is associated with significant side effects and a considerable proportion of HIV co-infected patients are poor candidates for HCV treatment. Better and more effective treatment for HCV (preferably not based on interferon) is urgently required for this group of patients. Patients with good CD4 cell count and with HCV genotypes 2 and 3 are likely to have a reasonable response to treatment.

Perspectives on HAART: switch maintenance therapy.

Switch studies have been carried out to explore changes in side effects in adherence. Discontinuing the protease inhibitor (PI) component of highly active antiretroviral therapy (HAART) regimen is often associated with improved adherence and improved quality of life. Following switching from a PI to a non-nucleoside reverse transcriptase inhibitor or abacavir, there is however a clear trend toward an improved metabolic profile particularly in insulin resistance and triglyceride levels when patients discontinue their PI. Peripheral wasting is likely to be associated with nucleoside analogues and for individuals with isolated fat accumulation, modification of HAART is not recommended. Virological suppression can be maintained following switch if adequate suppression of the virus has been achieved for at least six months prior to switch and the patient has not been previously exposed to suboptimal HAART. Discontinuing the PI preserves this class of agents for future use. Switching however may be associated with other side effects; hypersensitivity, skin rashes, hepatic or neuropsychiatric events.

Effect of chemokine receptor mutations on heterosexual human immunodeficiency virus transmission.

To assess the effect of mutations at the CCR-2 and CCR-5 loci on heterosexual human immunodeficiency virus (HIV) transmission, 144 persons heterosexually exposed to HIV (infected and uninfected [EU]) and 57 HIV-positive index partners were genotyped. A significantly higher frequency of 64I heterozygotes at CCR-2 was observed in HIV-positive than in EU women (P=.02, relative risk=1.6). The allele frequency of 64I in women was 8% in HIV-positive contacts and 1% in EUs (P<.02). At CCR-5, no difference in the frequency of Delta32 was seen between groups, and the CCR-5 genotypes did not differ in accumulated "at-risk" exposure in EUs. Combining the analysis of the Delta32 and 64I mutations in index partners suggested an additive effect on transmission (P=.10). Thus heterozygosity for 64I at CCR-2 acts as a risk factor for HIV infection of women after heterosexual contact but heterozygosity for Delta32 at CCR-5 has no detectable effect.

Combination therapy for HIV: the effect on inpatient activity, morbidity and mortality of a cohort of patients.

We set out to quantify the changes in HIV-related morbidity and mortality associated with the clinical use of antiretroviral therapy via prospectively collected patient-related events (admissions, bed days, deaths, WHO stage 3 and 4 events and drug costs) on all HIV patients known to the Regional Infectious Disease Unit (RIDU) from 1 January 1987 to 31 December 1996. The introduction of zidovudine monotherapy in 1987 for those with AIDS was associated with a subsequent decline of inpatient activity for 2 years: in 1989 there was a 23% reduction in bed days but only a 6% reduction in admissions. A further dramatic decline of patient-related events in those with AIDS was noted during 1996 following the introduction of combination therapy, a 39% reduction in admissions, 44% reduction in bed days, 54% reduction in stage 4 events, 33% reduction in WHO stage 3 events and 40% reduction in the death rate. Reductions were also observed for patients without AIDS including a 42% reduction in the rate of patients developing AIDS. Similar reductions were noted when the patients were classified by immunological instead of clinical status although data for 1997 suggest an increase in patient-related activity for those with CD4 counts >200 cells/microl possibly as a result of low levels of anti-HIV therapy. The introduction of combination therapy for HIV has to date led to a minimum saving of one inpatient bed per 100 patient years which helped defray the cost of combination therapy. Although we cannot imply causality from an observational study, dramatic reductions in patient-related activity were associated with the introduction of combination therapy into clinical practice. The ultimate extent and duration of this effect cannot as yet be predicted and caution is required since similar reductions were noted with zidovudine therapy which were unfortunately time limited.

Clinical predictors of azole resistance, outcome and survival from oesophageal candidiasis in AIDS patients.

A retrospective review of AIDS-related oesophageal candidiasis was undertaken to identify clinical features helpful in predicting response to azole therapy and patient survival. Patients who had received daily azole prophylaxis against candidiasis were significantly less likely to respond to azole therapy than those who had not (P < 0.001). Patients who had lost > 5% of their body weight in the 2 months before oesophageal candidiasis were less likely to respond to azoles than the others (P < 0.001). Amongst those who had not received daily azoles, patients with a CD4+ cell count < 25/mm3 were less likely to respond to azole treatment (P = 0.05). The median survival beyond oesophageal candidiasis was 18 months. Survival from oesophageal candidiasis was significantly poorer for patients who did not respond to azole therapy but AIDS survival did not differ between azole responders and non-responders. Non-responders who had been taking daily azole prophylaxis had the poorest survival (median = 4 months).

Central venous catheters in patients with AIDS.

Central venous catheters (CVCs) for patients with AIDS are at risk of a number of complications including bacterial infections. A 6-year retrospective review was undertaken of the records of the 33 patients (42% infected by injection drug use (IDU)) who received intravenous therapy both in hospital and at home via CVCs. Twenty-eight per cent of 53 insertions suffered a complication, the commonest of which was a pneumothorax (8%). The post insertion complication rate was 0.98/100 catheter days (cd). Thrombotic occlusion (0.15/100 cd) was the commonest non septic event while sepsis was overall the commonest event (0.69/ 100 cd) of which half were considered serious (0.33/100 cd). The most frequently isolated organisms were Staphylococci spp. (71%). The median time to an exit site infection was 59 days and to serious catheter sepsis 86 days. Infection did not differ significantly with age, gender, transmission risk activity or catheter type although Portacaths had the lowest rate of infection (0.33/100 cd). The median survival of the 53 CVCs was 88 days although if the temporary catheters were excluded it was 118 days. Kaplan-Meier estimates of survival analysis revealed 55%, 32% and 19% of all the CVCs surviving 3, 6 and 12 months respectively. Our experience suggests that home intravenous therapy and previous IDU does not preclude the use of CVCs although further research is needed on reducing the infection-related complications of such therapy.

Antimicrobial treatment of fish tank granuloma.

Three patients with fish tank granuloma of the hand and forearm are reported. Each patient was treated with antimicrobial regimes which have rarely or never been previously used in this condition. Two patients responded well to treatment, one who received ciprofloxacin plus clarithromycin and another who was given clarithromycin plus ethambutol. The third patient received six different antimicrobial regimes before responding to a combination of rifabutin and ciprofloxacin. Our experience suggests that there now exist a number of effective alternatives to antimicrobials which have been traditionally used in the treatment of cutaneous Mycobacterium marinum infection.

Pre-AIDS deaths in HIV infection related to intravenous drug use.

We prospectively collected data on deaths in the Edinburgh City Hospital HIV cohort of patients (60-70% acquired via injection drug use) from October 1986 to September 1994. Sixty-four patients (25% of all HIV deaths or 2.5/100 person-years) had died without an AIDS diagnosis, and 42 (66%) of these had autopsy data available. Some pre-AIDS deaths (20% or 0.5/100 person-years) were the expected consequence of underlying medical conditions diagnosed during life: the remainder (80% or 1.98/100 person-years) were sudden or unexpected. Examining the underlying conditions, drug overdoses accounted for 45% or 1.1/100 person-years; bacterial sepsis, 25% or 0.6/100 person-years; liver disease, 26% or 0.6/100 person-years; and an undiagnosed AIDS condition, 9% or 0.2/100 person-years. Drug overdoses were the commonest cause of pre-AIDS death in this cohort of patients predominantly infected via IDU, but many of the sudden deaths had significant underlying pathology, which may have increased their susceptibility to an overdose of drugs. In future, death before an AIDS diagnosis should be classified into Medical or Expected Non-AIDS (MNA or ENA) and Sudden Non-AIDS (SNA).

Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients.

Nineteen cases of cerebral toxoplasmosis (CTOX) are reported from a group of Edinburgh AIDS patients. All patients were severely immunodeficient at the time of presentation with CD4 count < 50 cells/mm3. Thirteen patients had suffered a previous AIDS-defining illness. In Edinburgh, CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3. It is estimated that at least half of the toxoplasma seropositive patients will develop CTOX if they survive for 21 months after reaching a time in their illness when the CD4 count = 50 cells/mm3. The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%. All patients showed improvement on treatment and there was no correlation between clinical or radiological features and patient survival. Those patients unable to tolerate first choice anti-toxoplasma therapy had a significantly shorter survival than the remainder but there was no single therapeutic regimen which conferred a survival advantage. Eighteen patients had died at the time of study and the median survival following diagnosis of cerebral toxoplasmosis was 10 months (range 3-38 months). Postmortem examination of the brain was available in 8, 4 of whom had concomitant cerebral lymphoma. The survival from AIDS or CD4 count = 50 cells/mm3 did not differ significantly between those with treated CTOX and a control group who had no toxoplasma infection, suggesting that treatment is reasonably effective. CTOX is a disease associated with severe HIV-related immunodeficiency and, in those with a CD4 count < 50 cells/mm3, occurs more than 35 times as frequently in toxoplasma-seropositive than toxoplasma-seronegative patients. Treatment is effective but the outcome of treated disease cannot be predicted from presenting clinical or radiological features. Concomitant space-occupying cerebral pathology is evident in 50% of post-mortem examinations.

Venous thrombosis in HIV infection.

Previous reports indicate that venous thrombosis is an infrequent problem in patients with HIV infection. Despite this, various HIV-related factors have been proposed as potentially thrombogenic and an HIV-related hypercoagulability has been suggested. At the present time, there exists no consensus of opinion regarding prophylaxis against venous thrombosis for hospitalized patients with HIV. This article aims to provide an overview of venous thrombosis in HIV infection with particular reference to published and personal evidence for possible risk factors and their implications for prophylaxis.

An audit of the clinical features and use of antimicrobials in adult diarrhoea.

We reviewed the case records of 128 adult patients hospitalized with diarrhoea. A relevant stool pathogen was isolated from 45, a diagnosis of culture-negative or non-specific gastroenteritis (NSGE) was made in 40 and the remaining 43 patients had no enteric infection. A history of fever or bloody stools was more common in those with culture-positive gastroenteritis than it was in those with NSGE or other diarrhoeal illness. The mean duration of diarrhoea prior to admission was significantly shorter in those with all forms of gastroenteritis than it was in the remainder. Epirical treatment with ciprofloxacin was commenced in 46% of all cases of gastroenteritis, of which 51% were found to have a relevant pathogen on stool culture. Patients with NSGE were just as likely to be treated with ciprofloxacin as those who were subsequently found to have culture-positive gastroenteritis. A history of abdominal tenderness or bloody stools did not discriminate for treatment with empirical ciprofloxacin in any patient group. Patients with positive stool cultures were more likely to be given ciprofloxacin if they were febrile but the same was not true for the other patients. In the patients reviewed, a significantly higher proportion of those with culture-positive diarrhoea presented with a history of fever or bloody stools. Despite this, the empirical use of ciprofloxacin in suspected infective gastroenteritis appeared to be only partially guided by the clinical features.

Haemophilus parainfluenzae: an unusual case of psoas abscess.

A case of Haemophilus parainfluenzae psoas abscess in a previously healthy 36-year-old man is reported here. The absence of any bowel pathology indicates that abscess formation occurred secondary to haematogenous spread of the organism.

Disseminated disease due to Mycobacterium avium complex in AIDS.

We retrospectively analysed 46 cases of disseminated infection with Mycobacterium avium complex (MAC) within a cohort of 702 HIV-infected patients in Edinburgh. Clinical features were compared with case-matched controls (AIDS cases without disseminated MAC), and survival and progression times were controlled for confounding variables that influence survival. Disseminated MAC was diagnosed antemortem in 18% of AIDS patients, and was the AIDS-defining diagnosis in 6% of all AIDS cases. Concomitant colonization of respiratory and gastrointestinal tracts was common (61% and 48%, respectively). In 58% of cases, CD4+ counts were < 10 cells/mm3 (median 6 cells/mm3). Weight loss, anaemia, leucopenia, and elevated liver transaminases and alkaline phosphatase were significantly more common among cases than controls. Therapy was given in 74%, and not tolerated in 32%. Following AIDS diagnosis, disseminated MAC incidence was 14% at one year, 25% at 2 years and 36% at 3 years. Median survival after disseminated MAC diagnosis was 6 months, with shorter survival in untreated cases. However, overall survival from AIDS diagnosis was not significantly different between patients who did or did not develop disseminated MAC. Disseminated MAC contributes significantly to AIDS morbidity, and its incidence increases with prolonged AIDS survival. Although survival following diagnosis is short, the development of disseminated MAC in AIDS probably does not affect overall survival. In cohorts with a low incidence, an alternative to prophylaxis might be surveillance and early diagnosis.

Why disease due to Mycobacterium tuberculosis is less common than expected in HIV-positive patients in Edinburgh.

By December 1993, only five cases of tuberculosis were observed in the 1030 HIV-positive patients in Edinburgh, U.K., although, on the basis of historical tuberculin skin test data, between four and eight new cases of tuberculosis were expected per year. Of 310 HIV-positive patients, none of the 19 (6.1%) who were tuberculin skin test positive had developed tuberculosis after 87 months (average) of follow-up. It is suggested that new or re-infection is a more common cause of tuberculosis in HIV-positive patients than reactivation. Restriction fragment length polymorphism typing of Mycobacterium tuberculosis strains could confirm this hypothesis and support currently suggested additional infection control procedures.