Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis.

BACKGROUND: Bacterial meningitis continues to cause high mortality. Few studies address the possible association between this mortality and antibiotic administration delays. AIM: To determine whether delays in antibiotic administration are associated with mortality from bacterial meningitis, and to identify inappropriate diagnostic-treatment sequences leading to such delays. DESIGN: Retrospective case record study. METHODS: We reviewed 123 cases of adult acute bacterial meningitis in 119 patients aged >/=16 years admitted to hospital from January 1990 to March 2002, using multivariate regression analysis to assess the association between meningitis mortality and door-to-antibiotic time (the time elapsed between emergency room presentation and antibiotics administration). RESULTS: The case fatality rate was 13% (16/123). Adjusted odds ratios (OR) for mortality were: 8.4 (95%CI 1.7-40.9) for door-to-antibiotic time >6 h; 39.4 (95%CI 4.3-358.1) for afebrility at presentation; and 12.6 (95%CI 2.2-72.0) for severely impaired mental status at presentation. Factors associated with a door-to-antibiotic time of >6 h were: (i) failure to administer antibiotics prior to transfer from another institution (OR 21.8); (ii) the diagnostic-treatment sequence: head CT then lumbar puncture, then antibiotics (OR 5.6); and (iii) the absence of the classic meningitis triad (OR 4.9). DISCUSSION: There is an independent incremental association between delays in administrating antibiotics and mortality from adult acute bacterial meningitis. Inappropriate diagnostic-treatment sequences were significant predictors of such treatment delays.

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Pharmacology and clinical experience with saquinavir.

Saquinavir is a peptidomimetic inhibitor of HIV protease. Initially marketed as Invirasetrade mark, the effectiveness of saquinavir was greatly hindered by its nearly complete first pass metabolism by cytochrome P450 3A4. A new formulation, Fortovasetrade mark, appears to yield some six times the drug exposure and has been demonstrated to yield virological and immunological results similar to those of other protease inhibitors (PIs) when used in conjunction with two nucleoside reverse transcriptase inhibitors (nRTIs). Emerging data suggest it is safe to use twice daily. Co-administration of either formulation of saquinavir with nelfinavir and especially ritonavir yields greatly increased blood levels, with corresponding superior magnitude and durability of viral suppression in first line therapy, albeit with increased adverse effects. The combination of ritonavir and saquinavir has also yielded the most promising results published for second line therapy, after virological breakthrough on previous PI-containing therapy. In addition, preliminary data suggests the possibility of once daily dosing of ritonavir and saquinavir, which would be expected to increase compliance and allow for direct observed therapy.

Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression.

The degree of immune recovery achievable with anti-human immunodeficiency virus (HIV) therapy remains to be established. The effects of potent antiretroviral therapy, including ritonavir and saquinavir, on immune function were studied for a prolonged period in 41 patients. After 96 weeks, 88% of patients had plasma HIV RNA levels below the limit of quantitation. There were continuous increases in CD4 lymphocyte counts and in CD4:CD8 ratios over time. About half the patients developed lymphoproliferative responses to HIV p24 antigen, and nearly all developed responses to phytohemagglutinin. This occurred in parallel with increases in interleukin-12 production and expression of CD28 on CD8 lymphocytes, despite potential antiproliferative effects of protease inhibitors. Transient increases in virus load were temporally associated with loss of proliferative responses. The improved immune function, including HIV-specific immunity in many subjects, demonstrates the potential reversibility of HIV-induced immunodeficiency and does not identify a limit to immune recovery.

Treatment of CMV retinitis with intravitral ganciclovir in the HAART era.

OBJECTIVE: To describe the course and outcome of cytomegalovirus (CMV) retinitis among AIDS patients treated with intravitreal ganciclovir and systemic highly active antiretroviral therapy (HAART). The secondary objective was to compare the course of CMV retinitis between patients receiving HAART and those not receiving this treatment. DESIGN: A retrospective cohort design consisting of 21 eyes from 16 patients with AIDS and CMV retinitis consecutively enrolled between January 1996 and August 1999. All patients received intravitreal ganciclovir therapy, and half of the patients began HAART as well. Duration of intravitreal therapy and ensuing disease quiescence, as well as CD4+ T cell counts at diagnosis and at cessation of ganciclovir, were calculated. Secondly, instantaneous hazards for outcomes such as CMV retinitis progression, ocular complications and mortality were compared. SETTING: Tertiary care centre in Ottawa, Ontario. RESULTS: Five of eight patients receiving HAART discontinued intravitreal ganciclovir after a mean treatment period of 428 days. During this period, their mean CD4+ count rose from 7.5 to 190microL. Subsequently, none of these patients experienced retinitis progression during follow-up periods lasting up to 820 days (mean of 617 days). Progression of CMV retinitis was 11.4 times more likely among those not receiving HAART (P=0.049). CONCLUSIONS: On initiating HAART, patients with CMV retinitis may enjoy significant recovery in CD4+ counts and sustained retinitis quiescence without specific anti-CMV therapy. Intravitreal ganciclovir injections seem well suited to offer effective CMV control during temporary periods of decreased CD4+ counts while awaiting HAART-mediated immune system reconstitution.

Decreased HIV-associated T cell apoptosis by HIV protease inhibitors.

Antiretroviral treatment of patients infected with HIV results in improvements in CD4+ T cell number. Emerging evidence suggests that some of the improvements in CD4+ T cell number that occur in response to protease inhibitor (PI) therapy may not be accounted for solely by enhanced viral suppression, implying that PI may directly affect T cell survival. Since HIV T cell depletion is associated with enhanced apoptosis, we analyzed the effect of PIs on T cell apoptosis. In vitro treatment of peripheral blood lymphocytes (PBLs) from HIV-infected but untreated patients with reverse transcriptase inhibitors (RTIs) does not alter apoptosis, whereas PI treatment rapidly reduces CD4+ and CD8+ T cell apoptosis. In contrast, PI treatment does not alter apoptosis in PBL blasts from HIV-negative patients, or in Jurkat T cells. Consistent with this observation, 8 days of PI therapy in HIV-infected patients does not significantly alter plasma viremia, yet results in significant inhibition of CD4+ and CD8+ T cell apoptosis. The inhibitory effects of PI on apoptosis have implications concerning the treatment of HIV and its pathogenesis.

Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus.

AIM: Our aim was to evaluate the effect of ketoconazole on ritonavir and saquinavir plasma and cerebrospinal fluid (CSF) concentrations. METHODS: Twelve patients who were human immunodeficiency virus-seropositive and who were receiving 400 mg of ritonavir and 400 mg of saquinavir twice daily completed a nonfasted, two-period, two-group, longitudinal pharmacokinetic study. Blood samples were collected over the daytime 12-hour dosing interval of the protease inhibitors at baseline (period 1, day 0) and after 10 days of coadministration of 200 mg (n = 6) or 400 mg (n = 6) of ketoconazole once daily (period 2, day 10). One set of paired CSF and blood samples was collected between 4 and 5 hours after the dose on both days. RESULTS: Ketoconazole significantly increased area under the plasma concentration-time curve, plasma concentration at 12 hours after the dose, and half-life of ritonavir by 29% (95% confidence interval (CI), 13%-46%), 62% (95% CI, 37%-92%), and 31% (95% CI, 13%-51%), respectively. Similar increases of 37% (95% CI, 4%-81%), 94% (95% CI, 41%-167%), and 38% (95% CI, 15%-66%), respectively, were observed for these parameters for saquinavir. Ketoconazole significantly elevated ritonavir CSF concentration by 178% (95% CI, 59%-385%), from 2.4 to 6.6 ng/mL, with no change in paired unbound plasma level (26 ng/mL); this led to a commensurate 181% increase (95% CI, 47%-437%) in CSF/plasma unbound ratio. All pharmacokinetic changes were unrelated to ketoconazole dose or plasma exposures. Corresponding changes for saquinavir CSF pharmacokinetics were insignificant (P > .06); saquinavir CSF levels were unmeasurable in 7 patients (<0.2 ng/mL). CONCLUSIONS: The disproportionate increase in CSF compared with plasma concentrations of ritonavir is consistent with ketoconazole inhibiting both drug efflux from CSF and systemic clearance.

HIV lipodystrophy: a review.

The dramatic clinical benefit of highly active antiretroviral therapy has been offset, to an extent, by the development of unforeseen long-term toxicities. Of these, the HIV lipodystrophy syndrome is most prominent. The array of related but possibly separate manifestations includes fat deposition and atrophy and metabolic complications such as hyperlipidemias and diabetes mellitus. These have been attributed to the use of protease inhibitors, but other factors may be involved, particularly the use of nucleoside reverse transcriptase inhibitors, especially stavudine. The pathogenesis of any of the manifestations of the syndrome remains to be explained. The metabolic complications may respond to standard treatments, but most therapies directed at fat changes have been unsuccessful. This review will summarize the state of knowledge in the field.

Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir.

UNLABELLED: Combination antiretroviral therapy with ritonavir and saquinavir has established potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain barrier. Penetration of these protease inhibitors into the cerebrospinal fluid (CSF) and CSF HIV RNA levels on such therapy has not been well described. DESIGN/METHODS: In a cross-sectional study, 28 HIV1-infected study subjects were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels. RESULTS: Across the treatment groups, a strong correlation was found between plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subject with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the limit of quantitation. Low levels of saquinavir (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF:plasma drug concentration ratio of < or = 0.005 (0.5%) in all study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13,97), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001). CONCLUSIONS: CSF ritonavir and saquinavir levels are consistent with the estimated known fraction of unbound drug in plasma (<2%). Across these treatment response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibrium between CSF and plasma, or it may represent CNS anti-HIV activity of protease inhibitors. The low drug levels and inverted ratio of HIV RNA in the CSF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection.

T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P<0.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBL's from HIV negative patients, and apoptosis sensitive PBL's from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

Effect of antiretroviral therapy and viral load on the perceived risk of HIV transmission and the need for safer sexual practices.

BACKGROUND: Dramatic reductions in plasma HIV RNA levels are possible with current antiretroviral regimens; the effect of potent therapies and "undetectable" viral load on the perceived risk of HIV transmission and need for safer practices remains unknown. METHODS: A questionnaire was developed to examine perceptions of HIV transmission risk and need for safer practices with unprotected anal, vaginal, and oral sex and intravenous drug use with needle sharing for HIV-discordant couples in which the HIV-infected partner was receiving no therapy, was receiving reverse transcriptase inhibitor therapy, and protease inhibitor (PI)-based therapy with viral load "undetectable". This was applied anonymously to 147 unselected HIV-infected individuals attending a university-based HIV clinic. RESULTS: Almost all respondents believed that all sexual activities except oral sex were "very risky" and that safer practices were "extremely important" for those not receiving antiretroviral agents. Significantly fewer considered that anal or vaginal sex was "very risky" for those receiving PI therapy (90.9% and 86.0%, respectively), and fewer thought that safer practices for anal or vaginal sex were "very important" for those receiving PI therapy (93.0% and 91.6%, respectively). In total, 20.4% thought the risk of HIV transmission for at least one activity was reduced for those receiving PI therapy, and 19.0% believed that the need for safer practices was reduced by PI therapy. CONCLUSION: A small but significant proportion of HIV-infected people perceive the need for safer practices to be reduced during antiretroviral therapy, particularly those containing PIs. Even if the risk is truly reduced, the importance of safer practices should be conveyed consistently and terms such as "undetectable" to describe HIV RNA responses should be avoided.

Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors.

Eight patients with infection due to human immunodeficiency virus type 1 developed fat pads at the bases of their necks a median of 22 weeks (range, 4-61 weeks) after initiation of protease inhibitor therapy. This finding was seen in association with the use of each of the available protease inhibitors. The patients had no other cushingoid features or histories of corticosteroid use, and all had normal 24-hour urine cortisol levels. The computed tomography scans of five patients showed large, nonencapsulated accumulations of subcutaneous adipose tissue. Histological examination of tissue from one patient confirmed a nonlipomatous subcutaneous fat deposition. Although the pathogenesis of this unique clinical finding is unclear, the temporal relationship between the use of protease inhibitors and the development of cervical fat pads is suggestive of a complication of therapy.

Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group.

BACKGROUND: Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. We undertook an international, multicentre, randomised, double-blind, placebo-controlled trial of ritonavir in patients with HIV-1 infection and CD4-lymphocyte counts of 100 cells/microL or less, who had previously been treated with antiretroviral drugs. METHODS: 1090 patients were randomly assigned twice-daily liquid oral ritonavir 600 mg (n = 543) or placebo (n = 547) while continuing treatment with up to two licensed nucleoside agents. The primary study outcome was any first new, or specified recurrent, AIDS-defining event or death. Open-label ritonavir was provided after 16 weeks in the study to any patient who had an AIDS defining event. FINDINGS: The baseline median CD4-lymphocyte count was 18 (IQR 10-43)/microL in the ritonavir group and 22 (10-47)/microL in the placebo group. Study medication was discontinued in 114 (21.1%) ritonavir-group patients and 45 (8.3%) placebo-group patients mainly because of initial adverse symptoms. Outcomes of AIDS-defining illness or death occurred in 119 (21.9%) ritonavir-group patients and 205 (37.5%) placebo-group patients (hazard ratio 0.53 [95% CI 0.42-0.66]; log-rank p < 0.0001) during median follow-up of 28.9 weeks, with loss to follow-up of 15 (1.4%) patients. Ritonavir was then offered to all patients; at median follow-up of 51 weeks, 87 (16%) ritonavir-group patients had died of any cause versus 126 (23%) placebo-group patients (hazard ratio 0.69 [95% CI 0.52-0.91], log-rank p = 0.0072). INTERPRETATION: Although earlier intervention with combination therapy may provide much more effective treatment, ritonavir in patients with advanced disease and extensive previous antiretroviral use is safe and effective, lowers the risk of AIDS complications, and prolongs survival.

Causes of death of HIV-infected persons in Ottawa, Ontario, 1984-1995.

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) has become a leading cause of death of young men in the United States. With the introduction of prophylaxes and antiretrovirals for opportunistic infection, there have been significant changes in the clinical history of human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine the cause of death of the patients followed up by our clinic from 1984 to 1995. METHODS: A critical chart review was performed on the records of all patients affiliated with the Ottawa General Hospital HIV/AIDS Clinic, Ottawa, Ontario, who died between 1984 and July 15, 1995. Data regarding the cause of death, last CD4 T-lymphocyte cell count before death, medication use at time of death, and location and year of death were collected. Data were analyzed for 1984 through 1988, 1989 through 1991, and 1992 through 1995, corresponding to the evolution of HIV-related medical care. RESULTS: The median CD4 T-lymphocyte cell count at death had declined. Pneumocystis carinii pneumonia has decreased significantly as cause of death (28.6%-3.8%, P < .001). No other specific attributable terminal illness has decreased in frequency during 11 years. The wasting illnesses, particularly HIV wasting syndrome (3.6%-13.7%, P = .04), and untreatable illnesses have increased in frequency as causes of death. Patients are increasingly likely to die at home (0%-25%, P < .001) and less likely to die in hospital (54%-35%, P < .001). CONCLUSIONS: The HIV-infected persons are dying with more advanced HIV immunosuppression. Advances in P carinii pneumonia prophylaxis and treatment have had a dramatic effect on the cause of death of HIV-infected persons. Improved prophylaxis and treatment for non-P carinii pneumonia opportunistic infections and malignancies and HIV wasting syndrome are required.

Impact of Mycobacterium avium complex prophylaxis on the incidence of mycobacterial infections and transfusion-requiring anemia in an HIV-positive population.

Disseminated Mycobacterium avium complex (MAC) infection is common in persons with advanced HIV infection and can be prevented by prophylactic use of rifabutin; however, routine prophylaxis is costly and incompletely effective. Chronic anemia is a common manifestation of MAC infection. We conducted a retrospective population study of the annual incidence of MAC bacteremia and blood transfusion for anemia in a regional HIV-positive population before and after the introduction of rifabutin to determine the effect of MAC prophylaxis on the incidence of transfusion-requiring anemia. The HIV-infected patient populations in 1992 and 1993 were comparable in number, severity of immunodeficiency, and zidovudine (ZDV) use. The use of rifabutin for MAC prophylaxis for those with CD4 T-lymphocyte counts < 100/microl increased from 17.2% in 1992 to 33.7% in 1993 (p < 0.001), whereas diagnostic surveillance for MAC bacteremia was stable. In 1993, there was a decrease in the number of HIV-infected persons from whom MAC was isolated (10 vs. 26, p = 0.004), and a significant decrease in the number of patients transfused for anemia (15 vs. 35, p = 0.002), number of transfusion episodes, and numbers of units transfused, associated with significant cost and resource savings. Adoption of MAC prophylaxis was followed by a significant decrease in the number of diagnosed MAC infections and in transfusion requirements in an HIV-positive population with sustained surveillance and similar levels of immunodeficiency, which may represent a health and economic benefit of effective [correction of defective] MAC prophylaxis in a population at risk.