Manfred Dietrich

Decline in the AIDS and death rates in the EuroSIDA study: an observational study

BACKGROUND Since the introduction of highly active antiretroviral therapy (HAART), little is known about whether changes in HIV-1 mortality and morbidity rates have been sustained. We aimed to assess possible changes in these rates across Europe. METHODS We analysed data for 9803 patients in 70 European HIV centres including ones in Israel and Argentina. Incidence rates of AIDS or death were calculated for overall and most recent CD4 count in 6-monthly periods and in three treatment eras (pre-HAART, 1994-1995; early-HAART, 1996-1997; and late-HAART, 1998-2002). FINDINGS The incidence of AIDS or death fell after September, 1998, by 8% per 6-month period (rate ratio 0.92, 95% CI 0.88-0.95, p<0.0001). When AIDS and death were analysed separately, the incidence of all deaths during the late-HAART era was significantly lower than that during the early-HAART era in patients whose latest CD4 count was 20 cells/microL or less (0.43, 0.35-0.53, p<0.0001), but at higher CD4 counts, did not differ between early-HAART and late-HAART. Incidence of AIDS was about 50% lower in late-HAART than in early-HAART, irrespective of latest CD4 count (p<0.0001). In multivariate Coxs models, with early-HAART as the reference, there was an increased risk of AIDS (relative hazard 1.39; 95% CI 1.16-1.67, p=0.0004) and all deaths (1.29; 1.08-1.56, p=0.0065) in the pre-HAART era, and a reduced risk of AIDS (0.62; 0.50-0.77, p<0.0001) and all deaths (0.66; 0.53-0.82, p=0.0002) in the late-HAART era. INTERPRETATION The initial drop in mortality and morbidity after the introduction of HAART has been sustained. Potential long-term adverse effects associated with HAART have not altered its effectiveness in treating AIDS.

Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria.

PURPOSE Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathology of experimental malaria. To establish its relevance to human malaria, we studied serum levels of two monocyte-derived cytokines, TNF-alpha and interleukin-6 (IL-6), as well as of the lymphocyte-derived mediator interferon gamma (IFN-gamma) in patients with malaria before and during antiparasitic treatment. PATIENTS AND METHODS One hundred twenty serum samples of 40 patients with malaria (Plasmodium falciparum [n = 32], Plasmodium vivax [n = 8]) were analyzed. IL-6 was measured by a highly sensitive and specific bioassay, TNF-alpha by immunoradiometric assay, and IFN-gamma by radioimmunoassay. RESULTS Elevated cytokine levels could be detected in the majority of patients with P. falciparum malaria before treatment (31 of 32, 21 of 32, and 21 of 32 for TNF-alpha, IL-6, and IFN-gamma, respectively), but only in some patients with P. vivax malaria (four of eight, one of eight, and zero of eight for TNF-alpha, IL-6, and IFN-gamma, respectively). Serum concentrations of the monokines TNF-alpha and IL-6 correlated significantly with parasitic density (p less than 0.001). No such correlation was obtained with the circulating IFN-gamma concentration. The levels of monokines TNF-alpha and IL-6 were markedly elevated in 18 P. falciparum-infected patients with complicated clinical courses (median values for TNF-alpha 172 pg/mL, for IL-6 16 U/mL, peak values: 896 pg/mL and 1,000 U/mL, respectively). The correlation between TNF-alpha and IL-6 concentrations in serum (n = 40, r = 0.56, p = 0.0002) suggests co-ordinate production of those mediators. CONCLUSION Organ impairment in human malaria was found to be correlated with the amount of circulating cytokine levels of TNF-alpha and IL-6. Thus, imbalances of the cytokine network in untreated P. falciparum infection serve as markers of severity of disease. Modulation of cytokine response could represent a novel approach to the treatment of severe organ dysfunctions in human malaria.

Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe

OBJECTIVES To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. PATIENTS The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. METHODS Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. RESULTS At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% CI 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% CI 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% CI 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% CI 1.15-1.63; P = 0.0005). CONCLUSIONS Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.

Inhibition of HIV progression by dithiocarb

60 patients with HIV-1 infection in Walter Reed stages 2-4 were randomised to treatment with intravenous or oral dithiocarb (diethyldithiocarbamate, DTC) or placebo for 24 weeks in a paired double-blind design. 55 patients were evaluable at the end of the study: no patient who had received DTC but 6 placebo patients had AIDS, a significant difference. Significantly delayed disease progression was observed in the intravenous DTC group compared with its matching placebo. The benefit in the oral DTC group was not statistically significant. During an 18-month follow-up 3 deaths occurred in the original placebo groups, whereas no patient who had initially received DTC died. A significant delay in progression to AIDS was observed in the DTC groups.

Reactivation of Hepatitis B Virus Replication Accompanied by Acute Hepatitis in Patients Receiving Highly Active Antiretroviral Therapy

We describe 2 patients who were initially positive for antibodies to hepatitis B surface antigen and who experienced a strong and sudden increase of hepatitis B virus (HBV) replication during highly active antiretroviral therapy (HAART). We found that reactivation of HBV replication during HAART can occur independently of lamivudine resistance or withdrawal of lamivudine, and in spite of increasing CD4(+) cell counts.

Virologic, immunologic, and clinical response to highly active antiretroviral therapy: the gender issue revisited

Background: Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis for patients with HIV. There is ongoing debate over a potential gender effect on patient outcome after HAART. Methods: Individuals were from the EuroSIDA cohort, naive to protease inhibitors and nonnucleoside reverse transcriptase inhibitors, and had at least one viral load and CD4 measurement prior to starting HAART. Endpoints were virologic (time to <500 copies/mL, time to rebound [first of two consecutive viral loads >500 copies/mL]), immunologic (time to a 100/mm cell rise in CD4 count) and clinical (time to new AIDS and death). Hazard ratios (HR), derived using Cox regression models, compared female to male rates of achieving endpoints. Results: Of 2547 patients, 20% (511) were female. Significantly more females than males were nonwhite (24% vs. 10%, p < .001). Males were older (median age 39 vs. 35 years, p < .0001), had lower CD4 counts (211 vs. 240/mm, p = .03), higher viral loads (4.6 vs. 4.4 log copies/mL, p < .0001), were more likely to have a history of AIDS (26% vs. 18%, p < .001) and were more likely to be treatment‐naive (34% vs. 29%, p = .03). Adjusted HR for association between gender (comparing females with males) and the outcomes studied were as follows: for reaching <500 copies/mL 0.91 (0.81‐1.03, p = .17), rebound 1.17 (0.95‐1.44, p = .15), for 100 cell CD4 count rise 1.02 (0.88‐1.14, p = .99), for progression to new AIDS 1.12 (0.73‐1.71, p = .59) and for time to death 1.15 (0.69‐1.92, p = .57). Conclusions: We found no significant evidence of a gender difference in virologic, immunologic, or clinical outcomes after starting HAART.

High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role in Plasmodium falciparum Malaria

ABSTRACT To date, there have been conflicting reports concerning the clinical significance of nitric oxide (NO) in Plasmodium falciparum malaria. Some authors have proposed that NO contributes to the development of severe and complicated malaria, while others have argued that NO has a protective role. To investigate these apparently contradictory reports, reverse transcription-coupled PCR was used to study inducible NO synthase (iNOS) in whole-blood RNA samples from patients with severe and complicated malaria or uncomplicated malaria and from healthy donors. This work produced three principal findings. First, samples of patients with severe and complicated malaria were variably positive, with weak to moderate intensity. Markedly higher iNOS RNA levels were observed in samples of patients with uncomplicated malaria than in patients with severe and complicated malaria. Samples of healthy donors were uniformly negative. Second, since we initially demonstrated iNOS expression in whole-blood RNA samples, we extended our investigations to individual blood cells such as monocytes, lymphocytes, neutrophils, and platelets to identify the cellular source of iNOS. We found that iNOS was expressed predominantly in monocytes. Third, retrospective statistical analysis of monocyte counts clearly demonstrated that patients with uncomplicated malaria had higher monocyte counts at the time of presentation than patients with severe and complicated malaria. Taken together, our findings give room to the interpretation that NO may have a beneficial rather than a deleterious role in falciparum malaria.

Stronger host response per parasitized erythrocyte in Plasmodium vivax or ovale than in Plasmodium falciparum malaria

Objective and methods  Fever tends to start at a lower level of parasitemia in Plasmodium vivax or ovale than in P. falciparum malaria, but hyperparasitemia and complications are more likely to occur in P. falciparum malaria. Therefore, we compared the relationship between parasitemia and host response parameters before therapy in 97 patients with P. faciparum malaria (18 with complications), and 28 with P. vivax or ovale malaria.

Activation of the host response in human plasmodium falciparum malaria: Relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels☆

PURPOSE Hemostatic alterations and elevated tumor necrosis factor/cachectin (TNF alpha) serum levels may contribute to the pathogenesis of organ complications in human Plasmodium falciparum malaria. Therefore, we examined whether altered protein C (PC) and thrombin-antithrombin III (TAT) plasma levels correlated with TNF alpha serum concentrations, parasitemia, and the clinical course of human P. falciparum malaria. PATIENTS AND METHODS Forty-seven patients with P. falciparum malaria were evaluated prospectively before and during antiparasitic therapy. TNF alpha serum levels were determined by immunoradiometric assay, PC and TAT plasma antigen by enzyme-linked immunosorbent assay, and PC and PC inhibitor-1 (PCI-1) activity levels by functional tests. Cultured endothelial cells were incubated with serum from four patients with malaria and from healthy control subjects and then assayed for procoagulant activity. Northern blot hybridization was used to detect tissue factor mRNA. RESULTS In vivo, TNF alpha serum concentrations were elevated (median: 38.6 pg/mL; n = 47) while plasma levels of PC (antigen 55.4%; activity 39.0%; n = 47) and PCI-1 (0.56 U/L) were decreased in almost all patients before antiparasitic treatment. At the same time, TAT concentrations were high. These alterations correlated significantly (p less than 0.01) both with the severity of the disease (as defined by organ impairment) and with the number of circulating parasitized erythrocytes. Low PCI-1 activity correlated with low PC activity (p less than 0.001) and antigen (p less than 0.05) levels. The plasma level of coagulation factor IX, another vitamin K-dependent protein, was not significantly changed. In vitro, incubation of endothelial cells with patient serum (severe P. falciparum malaria) increased both endothelial cell procoagulant activity and cytoplasmic tissue factor mRNA levels. CONCLUSION Elevated levels of TNF alpha and TAT, decreased plasma levels of anticoagulant PC, and the induction of procoagulant activity in endothelial cells by patient serum indicate a shift in the balance of hemostatic activity towards a procoagulant state in P. falciparum malaria. The alterations in TNF alpha, TAT, and PC levels may be a response to infection, since they correlate with parasitemia and are reversed during antiparasitic treatment.

Procalcitonin as a Parameter of Disease Severity and Risk of Mortality in Patients with Plasmodium falciparum Malaria

The serum levels of procalcitonin (PCT) in Plasmodium falciparum malaria were evaluated for clinical significance in 66 nonimmune and semi-immune patients. Of the 66 patients, 36 had uncomplicated malaria, 24 had severe and complicated malaria, and 6 had fatal malaria (5 from previous studies). Pretreatment PCT concentrations were closely correlated with parasitemia. Concentrations were lowest in semi-immune patients with uncomplicated malaria, compared with those in nonimmune patients (geometric mean concentrations [GMCs], 1.07 and 2.37 ng/mL, respectively), and were highest in severe and complicated cases (GMC, 10.67 ng/mL; P<.001 among all subgroups). Six of 7 patients with PCT concentrations >25 ng/mL died. PCT concentrations decreased on day 2 of treatment in survivors but not in patients with fatal outcome. Thus, repeated PCT measurements may provide useful prognostic information, especially in medical centers that are not experienced in parasite density determination.