Biomedical subjects

J D Lundgren

Publications and source records attributed to J D Lundgren.

At least 55 records · Page 3Linked to original sources

PubMed2000

[Treatment of HIV infections with antiretroviral drugs and recombinant interleukin-2].

The clinical effect of combination antiretroviral therapy against HIV-infection is indisputable, but the current treatment does not produce complete immuno-restitution. Many HIV-positive patients change treatment, because of side effects and virological failure. Owing to the limited number of treatment combinations, supplementary treatment is greatly needed. Intermittent subcutaneous rIL-2 treatment plus antiretroviral combination therapy results in a selective and long-lasting induction of CD4+ cells in 70-80% of HIV-patients and lowers the amount of replication competent virus in blood and lymph nodes. The expanded cell population consists of both naive cells and memory cells with the ability to respond to antigenic stimulation. It is not known whether the rise in the number of CD4+ cells reflects a better clinical outcome. This question is currently under investigation in two global phase III trials, namely the SILCAAT and the ESPRIT studies.

Anti-HIV Agents↗

PubMed2000

The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection.

The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr), ritonavir (Rtv), or Rtv and saquinavir (Rtv/Sqv). Similar percentages of patients in the 3 study arms achieved reduced levels (</=20 copies/mL) of HIV RNA. In the area under the curve minus baseline analyses, a better response was found in the Rtv/Sqv arm than in the Rtv arm. No difference was found when comparing Rtv/Sqv with Idr and Rtv with Idr. Patients in the 3 arms had comparable increases in CD4 cell counts. At 72 weeks of follow-up, there was no statistical difference between arms for the primary study end point (</=20 HIV RNA copies/mL); however, some of the additional analyses indicated an advantage for the Rtv/Sqv arm, especially when compared with the Rtv arm.

Adolescent↗

PubMed2000

[Atovaquone/proguanil. Prophylaxis and treatment of malaria].

Malarone is a combination of the two drugs atovaquone and proguanil. Malarone is useful as prophylaxis and for the treatment of falciparum malaria. Monotherapy using atovaquone or proguanil results in treatment failure in 30% and 90% respectively, whereas treatment failure is rare when a combination of the drugs is used (< 2%). This reflects the synergistic effect of this drug combination. Used as a chemoprophylaticum against falciparum malaria Malarone has an effect of > 95%. The protective mechanism is likely to act via the mitochondrial cytochrome bc complex, thus a different mechanism from other malaria drugs. For this reason, cross-resistance with other malaria drugs is not expected. The documentation of effect and safety profile of Malarone in malaria prophylaxis makes it a suitable alternative to mefloquine and doxycycline in case of contraindications. Malarone is effective for the treatment of acute uncomplicated malaria, and may be used as an alternative to mefloquine.

Antimalarials↗

PubMed2000

AIDS across Europe, 1994-98: the EuroSIDA study.

BACKGROUND: The clinical presentation of HIV-1 related diseases could have changed after the introduction of highly active antiretroviral treatment (HAART). We aimed to assess changes over time in the incidence of ADIs overall and within CD4 lymphocyte count strata, the relationship with treatment and degree of immunodeficiency at diagnosis of ADIs. METHODS: We did a prospective observational multicentre study of over 7300 patients in 52 European HIV-1 outpatient clinics. Incidence rates per 100 patient-years of observation were calculated. FINDINGS: In total, we recorded 1667 new ADIs; the incidence of ADIs declined from 30.7 per 100 patient-years of observation during 1994 (95% CI 28.0-33.4) to 2.5 per 100 patient-years of observation during 1998 (95% CI 2.0-3.0, p<0.0001, test for trend). Median CD4 lymphocyte count at diagnosis of a new ADI increased from 28 cells/microL to 125 cells/microL between 1994 and 1998 (p<0.0001), yet a steep decline in the rate of ADIs was seen after stratification by latest CD4 lymphocyte count within each year (< or = 50, 51-200, and > 200 cells/microL). Patients on HAART had a lower rate of ADIs than patients not on this treatment within each CD4 lymphocyte count strata. The proportion of ADIs attributable to cytomegalovirus retinitis and Mycobacterium avium complex declined over time (p=0.0058 and 0.0022, respectively), whereas the proportion of diagnoses attributable to non-Hodgkin lymphoma has increased (p<0.0001). In 1994, less than 4% of ADIs were non-Hodgkin lymphoma, in 1998 the proportion was almost 16%. This condition has become one of the most common ADIs in patients on HAART. INTERPRETATION: Our findings lend support to the idea that treatment regimens can lower the incidence of ADIs. The immediate risk of an ADI for a given CD4 lymphocyte count has declined over time and is lower among patients on HAART. Long-term follow-up of patients on combination treatment is essential to monitor the incidence of new and emerging diagnoses.

AIDS-Related Opportunistic Infections↗

PubMed2000

Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study.

BACKGROUND: Predictors of virological response to highly active antiretroviral therapy (HAART) have never been systematically evaluated in a large continental multicenter cohort of unselected human immunodeficiency virus (HIV)-infected people. OBJECTIVE: To determine the factors related to achieving and maintaining undetectable plasma HIV-1 RNA levels among HIV-1-infected patients first starting protease inhibitor- or nonnucleoside retrotranscriptase inhibitor-containing HAART in Europe. DESIGN: Prospective multicenter cohort study. SETTING: Fifty-two clinical centers in 17 European countries included in the EuroSIDA Study Group, from August 1996 to April 1999. PATIENTS: A total of 1469 HIV-positive patients first starting HAART recruited from an unselected cohort of more than 7300 HIV-positive patients. MAIN OUTCOME MEASURE: Detection of factors related to virological success after first starting HAART (baseline) and ensuing failure by standard survival techniques, including Kaplan-Meier techniques and Cox proportional hazards models. All analyses were intention to treat. RESULTS: Most patients (80%) achieved plasma HIV-1 RNA levels of less than 500 copies/mL during follow-up (60.4% at 6 months from the onset of HAART). Patients with higher baseline HIV-1 RNA levels (relative hazard [RH], 0.76 per log higher; 95% confidence interval [CI], 0.69-0.84; P<.001) and those taking saquinavir mesylate hard gel as a single protease inhibitor (RH, 0.62; 95% CI, 0.47-0.82; P<.001) were less likely to reach undetectable HIV-1 RNA levels. Conversely, higher CD4+ lymphocyte counts (RH per 50% higher, 1.09; 95% CI, 1.02-1.16; P = .008) and the initiation of 3 or more new antiretroviral drugs (RH, 1.29; 95% CI, 1.03-1.61; P = .02) were independent predictors of higher success. Once success was achieved, HIV-1 RNA levels rebounded in more than one third of all patients during follow-up (24% at 6 months). Antiretroviral-naive patients (RH, 0.50; 95% CI, 0.29-0.87; P = .01), older patients (RH, 0.86 per year older; 95% CI, 0.75-0.99; P = .04), and those starting a protease inhibitor other than saquinavir hard gel (RH, 0.66; 95% CI, 0.44-0.98; P = .04) were at decreased hazard for virological failure. Higher baseline HIV-1 RNA level (RH, 1.18 per log higher; 95% CI, 0.99-1.40; P = .06) and a longer time to achieve virological success (RH per 12 months, 1.53; 95% CI, 0.99-2.38; P = .06) were marginally significant predictors of a decreased hazard of ensuing virological failure. CONCLUSIONS: HAART is associated with a favorable virological response if started when the baseline HIV-1 RNA level is low, if at least 2 new nucleoside retrotranscriptase inhibitors are added, and if standard doses of saquinavir hard gel capsule are avoided as a single protease inhibitor. Older patients are more likely to achieve virological success. Thereafter, the higher durability of virological response is predicted by an antiretroviral-naive status and by the use of specific regimens. Lower baseline HIV-1 RNA levels and rapid maximal viral suppression seem to be other important factors in the durability of virological response.

Anti-HIV Agents↗

PubMed2000

Regional differences in presentation of AIDS in Europe.

Data were collected on 6578 patients diagnosed with AIDS at 52 clinical centres in 17 European countries during an 1-year period from 1979 to 1989. The centres were divided into four regions, North, Central, Southeast, and Southwest. Differences in the incidence of most AIDS-defining opportunistic infections and malignancies were found. After adjusting for known possible confounders, statistically significant differences between regions remained. Pneumocystis carinii pneumonia (PCP) was more common in Northern Europe, Kaposi's sarcoma and toxoplasmosis in Central Europe, cytomegalovirus retinitis in South-eastern Europe, and extrapulmonary tuberculosis in South-western Europe. These differences we attribute primarily to different degrees of exposure to the respective underlying pathogens. The prevalence of these and other micro-organisms will determine the clinical course of HIV infections in parts of Eastern Europe and elsewhere where the virus now is spreading.

AIDS-Related Opportunistic Infections↗

PubMed2000

Treatment with a monocolonal antibody to IL-8 attenuates the pleocytosis in experimental pneumococcal meningitis in rabbits when given intravenously, but not intracisternally.

The role of interleukin (IL)-8 as mediator in the recruitment of leucocytes into the CSF was investigated during experimental pneumococcal meningitis. Rabbits were inoculated intracisternally with approximately 10(6) CFU Streptococcus pneumoniae, and treated (i) intravenously with 5 mg of a monoclonal antibody to IL-8 (n = 7) or 5 mg of an isotype control antibody (n = 6); (ii) intracisternally with anti-IL-8, 100 microg (n = 5), 10 microg (n = 4), 1 microg (n = 4), 0.1 microg (n = 2). Ten rabbits served as untreated control group. Intravenous treatment with anti-IL-8 attenuated the pleocytosis significantly compared to untreated rabbits (P < 0.04) or rabbits treated with an isotype control antibody (P < 0.02). In contrast, intracisternal treatment with anti-IL-8 failed to attenuate the pleocytosis (P > 0.05). These results show, that IL-8 plays an important role in the recruitment of leucocytes during experimental pneumococcal meningitis, and that the functional activity of IL-8 in this process appears to be on the bloodstream side of the microvascular endothelium of the brain.

Animals↗

PubMed2000

Inhibition of leukocyte entry into the brain by the selectin blocker fucoidin decreases interleukin-1 (IL-1) levels but increases IL-8 levels in cerebrospinal fluid during experimental pneumococcal meningitis in rabbits.

The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte recruitment into the cerebrospinal fluid (CSF) during experimental pneumococcal meningitis. In the present study, the effect of fucoidin treatment on the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8 into the CSF was investigated. Rabbits (n = 7) were treated intravenously with 10 mg of fucoidin/kg of body weight every second hour starting 4 h after intracisternal inoculation of approximately 10(6) CFU of Streptococcus pneumoniae type 3 (untreated control group, n = 7). CSF samples were obtained every second hour during a 16-h study period. Treatment with fucoidin caused a consistent and significant decrease in CSF IL-1 levels (in picograms per milliliter) between 12 and 16 h (0 versus 170, 0 versus 526, and 60 versus 1,467, respectively; P < 0.02). A less consistent decrease in CSF TNF-alpha levels was observed in the fucoidin-treated group, but with no significant difference between the two groups (P > 0.05). In contrast, there was no attenuation in CSF IL-8 levels. Indeed, there was a significant increase in CSF IL-8 levels (in picograms per milliliter) in the fucoidin-treated group at 10 and 12 h (921 versus 574 and 1,397 versus 569, respectively; P < 0.09). In conclusion, our results suggest that blood-derived leukocytes mainly are responsible for the release of IL-1 and to some degree TNF-alpha into the CSF during pneumococcal meningitis, whereas IL-8 may be produced by local cells within the brain.

Animals↗

PubMed2000

Virological failure among patients on HAART from across Europe: results from the EuroSIDA study.

OBJECTIVES: To monitor the response to highly active antiretroviral therapy (HAART) over time and the proportions of patients with poor virological control in order to help provide some insight into drug resistance. DESIGN: Analysis of data from the EuroSIDA study; an observational study initiated in 1994 of almost 8500 patients with HIV from across Europe. METHODS: Patients who initiated HAART, and had both a CD4 lymphocyte count and viral load measured in the 3 months prior to starting HAART, were included in analyses. The proportion of patients with a poor virological response (defined as a viral load of > 10,000 copies/ml, using either a single measure or two consecutive measures) at 16 and 48 weeks was determined. Multivariate logistical regression was used to determine the factors associated with a poor virological response at both time points. RESULTS: Median CD4 cell count at starting HAART was 218 cells/mm3 [interquartile range (IQR), 113-327 cells/mm3] and median viral load was 4.36 log10 copies/ml (IQR, 3.57-5.04 log10 copies/ml). At 16 weeks, 16% had a viral load of > 10,000 copies/ml based on a single viral load measure and 10% if the more stringent definition of two consecutive viral loads above this level was used. At 48 weeks these proportions were 19% and 13%, respectively. Compared with patients from Southern Europe, patients from both Central and Northern Europe had approximately half the chance of a poor virological response at 16 weeks (odds ratios 0.53 and 0.47, P = 0.0015 and P < 0.0001, respectively), while at 48 weeks both regions still had approximately a 25% reduced chance of a poor virological response, but this was no longer statistically significant (odds ratio 0.77 and 0.75, P = 0.17 and P = 0.13, respectively). CONCLUSIONS: There were marked difference in virological response to HAART across regions of Europe, which may be partly explained by regional differences in access to HAART and utilisation. If drug resistance is closely related to virological failure, these results may help to provide an early insight into the potential problem of drug resistance across Europe. Continued follow-up is essential to monitor patients with poor virological control.

Anti-HIV Agents↗

PubMed1999

A comparison of exposure groups in the EuroSIDA study: starting highly active antiretroviral therapy (HAART), response to HAART, and survival.

BACKGROUND: Concerns have been raised that intravenous drug users may be less likely to start highly active antiretroviral therapy (HAART) and that adherence to therapy may be poor among this group of patients. Given the decreased mortality and incidence of AIDS-defining illnesses among patients with HIV who start HAART, this may lead to a poorer prognosis among intravenous drug users. PURPOSE: To compare homosexual men, intravenous drug users, and heterosexuals in EuroSIDA, a prospective European cohort of 7331 patients with HIV in terms of starting a HAART treatment regimen, immunologic and virologic response to therapy, and survival. METHODS: 6645 patients were included in this analysis. Logistic regression and Cox proportional hazards models were used to investigate the factors associated with use of HAART regimens and survival following recruitment to the EuroSIDA study. RESULTS: In a multivariate logistic regression model, intravenous drug users were significantly less likely to be receiving HAART at recruitment to EuroSIDA (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.37-0.62; p<.0001) when compared with homosexual men. Similarly, during follow-up, intravenous drug users were at a 27% reduced risk of starting HAART, after adjustment for other factors related to starting HAART (relative hazard [RH], 0.73; 95% CI, 0.64-0.82; p<.0001). There were no differences between heterosexual and homosexual patients, and similar results were found within regions of Europe (South, Central and Northern). Among those patients who started HAART, there were no significant differences between exposure groups in CD4 lymphocyte count response to HAART or virologic response to HAART. After adjustment for factors related to survival, intravenous drug users were at a small, but nonsignificant increased risk of death compared with homosexuals (RH 1.16; 95% CI, 0.99-1.38; p = .074). CONCLUSIONS: Intravenous drug users were significantly less likely to start HAART, but among those who did, response to therapy was similar to that of other exposure groups. There were no differences in risk of death. If intravenous drug users continue to use HAART less commonly than other exposure groups, it may result in a poorer prognosis, a different spectrum of AIDS-defining illnesses, and differential long-term clinical needs.

Adult↗

PubMed1999

Regional survival differences across Europe in HIV-positive people: the EuroSIDA study.

OBJECTIVES: To analyse the survival differences between macro-regions of Europe (northern, central and southern Europe) between 1994 and early 1999, and their possible association with antiretroviral treatment differences. DESIGN: From September 1994 the EuroSIDA study has prospectively followed non-selected HIV-infected people from 50 clinical sites in 18 European countries (n = 7331). METHODS: Cox proportional hazards models were used to compare death rates between regions and to investigate the relationship between treatment usage and regional mortality rates. Kaplan-Meier curves were used to compare survival from the first CD4 lymphocyte count of < 200 x 10(6)/l or < 50 x 10(6)/l. RESULTS: At the time of analysis, the median follow-up was 21 months and there was a total of 1544 deaths. In people with a CD4+ cell count that fell below 200 or 50 x 10(6)/l those from central Europe had a better prognosis compared with those from the two other regions (P < 0.05). Patients from central Europe were more frequently exposed to reverse transcriptase inhibitors and protease inhibitors compared with patients from other regions (P < 0.001). There was a significant difference in risk of death between regions after adjustment for baseline differences in demography, presence of AIDS and level of immunodeficiency (risk of death in central Europe was 37% lower than that in southern Europe (P < 0.0001) and 33% lower than in northern Europe (P < 0.0001)). After adjustment for use of individual antiretroviral agents, intensity of treatment regimen, CD4 lymphocyte count, weight, haemoglobin and development of AIDS as time-dependent covariates, the differences became much smaller (risk in central Europe 13% lower than that in southern Europe (P = 0.071) and 15% lower than in northern Europe (P = 0.054). CONCLUSION: Antiretroviral therapy has been used more aggressively in Europe in recent years, resulting in improved prognosis. In this study we observed that the HIV mortality rate in central Europe was significantly lower than those in northern and southern Europe in the period 1994 to early 1999. This finding appears to be due to the effect on survival of different treatment policies and drug availability in the three regions of Europe during this time period, with central European countries, on average, having introduced more aggressive treatment strategies earlier.

Adult↗

PubMed1999

Use of observational databases to evaluate the effectiveness of antiretroviral therapy for HIV infection: comparison of cohort studies with randomized trials. EuroSIDA, the French Hospital Database on HIV and the Swiss HIV Cohort Study Groups.

OBJECTIVES: It is important to assess the extent of bias when comparing the clinical efficacy of antiretroviral regimens in observational databases because, with the current lack of planned large trials, such analyses may represent the only means of assessing the risk of serious clinical events associated with new regimens. We aimed to compare the results from observational databases with those from randomized trials. METHODS: Three treatment comparisons from randomized trials [Delta, AIDS Clinical Trials Group (ACTG) 175, Community Programs for Clinical Research on AIDS (CPCRA) 007 and ACTC 320] were mimicked in cohorts: (i) zidovudine monotherapy versus combination regimens of two nucleoside analogues; (ii) zidovudine combined with either didanosine or zalcitabine; and (iii) a dual combination versus a triple regimen including a protease inhibitor. Data for over 10 000 patients from the French Hospital Database on HIV, the EuroSIDA study and the Swiss HIV cohort study were analysed for each of the comparisons. Progression to AIDS disease or death was analysed in Cox models, adjusting for baseline differences, and results compared with randomized trials. RESULTS: For comparison (i) the adjusted relative risk estimates from cohorts were between 0.61 and 0.84, favouring combinations over monotherapy, compared with 0.57 to 0.63 for trials. For comparison (ii) relative risk estimates from cohorts ranged from 0.81 to 1.01 compared with 0.77 to 0.92 for trials. For comparison (iii), two of the cohorts showed similar results to the ACTG 320 trial but one indicated a higher risk of progression on triple therapy [relative risk 1.20, 95% confidence interval (CI) 1.01-1.441, in direct contrast to the trial result (relative risk 0.50, 95% CI 0.33-0.76). CONCLUSION: Serious biases can be present when comparing outcomes from the use of antiretroviral regimens in observational studies. However, such bias is not inevitable and careful interpretation of the results from several observational studies considered together is likely to be informative, guiding the design of new trials.

Anti-HIV Agents↗

PubMed1999

Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia.

BACKGROUND: Sulpha drugs are widely used for the treatment and long-term prophylaxis of Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals. Sulpha resistance in many microorganisms is caused by point mutations in dihydropteroate synthase (DHPS), an enzyme that is essential for folate biosynthesis. We assessed whether mutations in the DHPS gene of P. carinii were associated with exposure to sulpha drugs and influenced outcome from PCP. METHODS: We studied bronchoalveolar samples collected in 1989-99 from a prospective cohort of HIV-1-infected patients who had PCP. In 144 patients with 152 episodes of PCP, we analysed portions of DHPS using PCR and direct sequencing. The relation between survival, P. carinii DHPS mutations, and other predictors of treatment failure was assessed by Kaplan-Meier and multivariate Cox regression analysis. FINDINGS: P. carinii DHPS mutations were found in 31 (20.4%) of 152 PCP episodes. 3-month survival was significantly lower in patients infected with mutant P. carinii DHPS strains than in those with wild-type strains (p=0.002). After adjustment for other prognostic variables, presence of DHPS mutations remained the most important predictor of mortality (hazard ratio 3.1 [95% CI 1.2-8.1]). DHPS mutations were significantly more common in patients who had previous exposure to sulpha drugs (18 of 29 [62%]) than in those who had no exposure (13 of 123 [10.5%]; p<0.0001). A significant increase with time in the rate of DHPS mutations (p=0.01 for trend) was closely correlated with the rate of previous or current use of sulpha drugs as chemoprophylaxis. INTERPRETATION: Mutations in DHPS are associated with impaired prognosis in PCP, and may develop as a result of exposure to sulpha drugs.

AIDS-Related Opportunistic Infections↗

PubMed1999

Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy?

BACKGROUND: In the 'USPHS/IDSA Guidelines for Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus', the indications for chemoprophylaxis are based on nadir CD4 cell count. Many patients have, however, experienced an increase in CD4 cell count after the introduction of highly active antiretroviral therapy (HAART). OBJECTIVES: To assess incidences of opportunistic infections after discontinuation of chemoprophylaxis in HIV-infected patients, who have experienced a HAART-induced increase in CD4 cell count. METHODS: The Danish guidelines for chemoprophylaxis against opportunistic infections in HIV-infected patients were revised in late 1997, allowing discontinuation of chemoprophylaxis after initiation of HAART if the CD4 cell count remained above a specified limit for more than 6 months. Consecutive patients were followed, and incidences of opportunistic infections after discontinuation of chemoprophylaxis were assessed. RESULTS: A total of 219 patients discontinued Pneumocystis carinii pneumonia (PCP)-chemoprophylaxis (12% maintenance therapy). One case of PCP was diagnosed within 174 person-years (PY) of follow-up, resulting in an incidence of 0.6 cases/100 PY follow-up (95% confidence interval, 0.0-3.2). No cases of cerebral toxoplasmosis, cytomegalovirus chorioretinitis, or disseminated Mycobacterium avium infection were observed. Follow-up time for these was, however, limited. CONCLUSION: PCP-chemoprophylaxis can be safely discontinued after HAART-induced increase in CD4 cell count to more than 200 x 10(6) cells/l. Among consecutive patients who discontinue chemoprophylaxis according to well-defined guidelines, the observed incidence of PCP is below those reported earlier in patients with similar CD4 cell count.

AIDS-Related Opportunistic Infections↗

PubMed1999

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

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.

Adolescent↗

PubMed1999

Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group.

BACKGROUND: Highly active antiretroviral therapy (HAART) has improved rates of CD4-lymphocyte recovery and decreased the incidence of HIV-1-related morbidity and mortality. We assessed whether prophylaxis against Pneumocystis carinii pneumonia (PCP) can be safely discontinued after HAART is started. METHODS: We investigated 7333 HIV-1-infected patients already enrolled in EuroSIDA, a continuing prospective observational cohort study in 52 centres across Europe and Israel. We did a person-years analysis of the rate of discontinuation of PCP prophylaxis and of the incidence of PCP after the introduction of HAART into clinical practice from July, 1996. FINDINGS: The rate of discontinuation of primary and secondary PCP prophylaxis increased up to 21.9 discontinuations per 100 person-years of follow-up after March, 1998. 378 patients discontinued primary (319) or secondary (59) prophylaxis a median of 10 months after starting HAART. At discontinuation for primary and secondary prophylaxis, respectively, the median CD4-lymphocyte counts were 274 cells/microL and 270 cells/microL, the median plasma HIV-1 RNA load 500 copies/mL, and the median lowest recorded CD4-lymphocyte counts 123 cells/microL and 60 cells/microL. During 247 person-years of follow-up, no patient developed PCP (incidence density 0 [95% CI 0-1.5]). INTERPRETATION: The risk of PCP after stopping primary prophylaxis, especially in patients on HAART with a rise in CD4-lymphocyte count to more than 200 cells/microL, is sufficiently low to warrant discontinuation of primary PCP prophylaxis. Longer follow-up is needed to confirm a similarly low risk for stopping secondary PCP prophylaxis.

AIDS-Related Opportunistic Infections↗

PubMed1999

Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: results from the EuroSIDA study.

BACKGROUND: The effect of previous CD4 cell count nadir on clinical progression in patients with increases in CD4 cell counts has not been investigated. OBJECTIVE: To assess risk for progression of HIV disease in patients with CD4 counts of at least 200 cells/mm3 (stratified by the lowest previous CD4 count) and compare the rate of progression in patients with CD4 counts less than 50 cells/mm3 with that in patients whose CD4 counts rebounded from less than 50 cells/mm3 to at least 200 cells/mm3. DESIGN: Prospective, observational multicenter study. SETTING: 52 HIV outpatient clinics in Europe. PATIENTS: Two groups were identified: those with CD4 counts of at least 200 cells/mm3 (group A) and those with CD4 counts less than 50 cells/mm3 (group B). Group A was stratified according to the lowest previous CD4 count: at least 150 cells/mm3 (stratum 1), 100 to 149 cells/mm3 (stratum 2), 50 to 99 cells/mm3 (stratum 3), and 1 to 50 cells/mm3 (stratum 4). MEASUREMENTS: Patients were followed until a progression event occurred (first AIDS-defining event, new AIDS-defining event, or death) or until the CD4 count decreased to less than 200 cells/mm3 (group A) or increased to more than 50 cells/mm3 (group B). Incidence rates were based on a patient-years analysis and reported as events per 100 patient-years of follow-up; the relative hazards for progression were based on Cox proportional hazards models. RESULTS: The overall rate of disease progression in group A was 3.9 per 100 patient-years (95% CI, 3.5 to 4.3 per 100 patient-years), whereas in group B it was much higher (72.9 per 100 patient-years [CI, 69.0 to 76.8 per 100 patient-years]). In group A, the rate increased in patients with previous low CD4 cell count nadirs, resulting in a significant increase in the relative hazard for progression. The relative hazards for strata 2, 3, and 4 were 2.29 (CI, 1.30 to 4.03), 3.65 (CI, 1.94 to 6.85), and 2.94 (CI, 1.44 to 6.00), respectively. CONCLUSIONS: Increases in CD4 counts from very low levels to at least 200 cells/mm3 are associated with a much reduced rate of disease progression. However, a previously low CD4 cell count nadir remains associated with a moderately higher risk for disease progression among patients with CD4 counts of at least 200 cells/mm3.

Adult↗

PubMed1999

Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial.

OBJECTIVES: To compare the efficacy and safety of indinavir 800 mg three times a day, ritonavir 600 mg twice a day, and a combination of ritonavir 400 mg twice a day and saquinavir 400 mg twice a day, when administered with two nucleoside analogues. DESIGN: A randomized, open-labelled, controlled trial. Two hundred and eighty-four patients started randomized treatment. The primary end-point was the proportion of patients with HIV RNA of 200 copies/ml or less (Roche Amplicor) and HIV RNA of 20 copies/ml or less (Roche ultradirect assay) at 6 months. Analysis was performed as intent-to-treat, and missing values were accounted for as failures. RESULTS: As of 1 May 1998, 269 patients should have completed 24 weeks of treatment. The proportion of patients with HIV RNA of 200 copies/ml or less was 71% (indinavir), 67% (ritonavir), and 82% (ritonavir + saquinavir), P = 0.07. In antiretroviral drug-naive patients (n = 119), the corresponding figures were 63, 57, and 89% (P < 0.01), whereas among drug-experienced patients (n = 165) 77, 74, and 77% had HIV RNA of 200 copies/ml or less (P = 0.90). The same pattern was observed in the ultradirect analysis. All three regimens were generally safe, but significantly more patients in the ritonavir group (37%) stopped treatment because of adverse drug reactions compared with the indinavir group (8%) and the ritonavir plus saquinavir group (16%) (P < 0.001). CONCLUSIONS: Treatment with saquinavir plus ritonavir in combination with two nucleoside analogues is generally safe, and has superior short-term antiviral efficacy compared with indinavir and ritonavir also combined with two nucleoside analogues in antiretroviral drug-naive patients. Further follow-up is needed to determine the durability of the viral response.

Adult↗