Natural history of advanced HIV disease in patients treated with zidovudine. The Zidovudine Epidemiology Study Group.

OBJECTIVE: To describe the natural history of advanced HIV disease in patients treated with zidovudine. DESIGN: Longitudinal, observational study. SETTING: Twelve academic and community-based sites. PATIENTS, PARTICIPANTS: Eight hundred and sixty-three patients with AIDS or AIDS-related complex (ARC) with a CD4+ lymphocyte count less than 250 x 10(6)/l, who first received zidovudine between 15 April 1987 and 14 April 1988. MAIN OUTCOME MEASURES: Survival, progression to AIDS and first development of specific opportunistic illness. RESULTS: Median survival after initiation of zidovudine therapy ranged from greater than 900 days in patients with a baseline CD4+ lymphocyte count greater than or equal to 150 x 10(6)/l to 560 days in patients with a CD4+ lymphocyte count less than 50 x 10(6)/1. Other factors associated significantly with poorer survival were diagnosis of AIDS (versus ARC), baseline age greater than or equal to 40 years, hematocrit less than 35%, and diminished functional status. In patients with ARC at enrollment, median time of progression to AIDS ranged from 810 days in patients with a CD4+ lymphocyte count greater than or equal to 150 x 10(6)/l to 310 days in patients with a CD4+ lymphocyte count less than 50 x 10(6)/l. Rates of development of specific opportunistic infections or neoplasms and HIV encephalopathy were determined for different baseline CD4+ lymphocyte count ranges. Myelosuppression was significantly more common in patients with CD4+ lymphocyte counts greater than or equal to 100 x 10(6)/l. Sixty-five per cent of patients with a CD4+ lymphocyte count greater than or equal to 100 x 10(6)/l and 51% with a CD4+ lymphocyte count less than 100 x 10(6)/l continued to receive zidovudine 2 years after starting therapy. CONCLUSIONS: We describe the natural history of a cohort of patients treated with zidovudine for advanced HIV disease. These CD4+ lymphocyte count-stratified estimates of disease progression should provide prognostic information useful in the clinical management of advanced disease and the design of future studies.     

Impact of tuberculosis on the course of HIV-infected patients with a high initial CD4 lymphocyte count.

OBJECTIVE: To assess the influence of tuberculosis (TB) on the progression of human immunodeficiency virus (HIV) infection in patients without immunological impairment. MATERIAL AND METHODS: In an observational study of retrospective cohorts, the evolution of 28 HIV-infected patients with TB and a CD4 lymphocyte count >500 x 10(6) cells/l was compared with 56 HIV-infected patients without TB. Each case was paired with two controls by CD4 lymphocyte count (+/-50 x 10(6)/l) and date of starting follow-up (+/-6 months). The progression of HIV infection was evaluated as: 1) immunological progression: time to CD4 lymphocyte count <200 x 10(6)/l; 2) clinical progression: time to development of acquired immune-deficiency syndrome (AIDS), excluding TB; 3) survival; and 4) global disease progression: time to the first defined event in 1, 2 and/or 3. The times to these events were estimated using Kaplan Meier curves. RESULTS: There were no significant differences between the cohorts for age, sex and risk group. Faster immunological impairment (RR 2.94; 95%CI 1.46-8.6; P < 0.01), greater progression to AIDS (RR 4.01; 95%CI 1.66-9.69; P < 0.01), lower survival (RR 3.89; 95%CI 1.53-9.87; P < 0.05) and higher global disease progression (RR 2.82; 95%CI 1.57-5.09; P < 0.01) were found in the cohort of TB patients. These associations were still significant after adjustment for CD4 lymphocyte counts. CONCLUSION: The diagnosis of TB in HIV-infected patients with a high initial CD4 lymphocyte count (>500 x 10(6)/l) was related to greater progression to AIDS and shorter survival.     

Virologic and immunologic values allowing safe deferral of antiretroviral therapy

OBJECTIVE: To determine how long highly active antiretroviral therapy can be deferred in HIV-1 infected persons. DESIGN: Observational cohort study of HIV-1 infected men at four academic centers in the USA. OUTCOME: Progression to clinical AIDS or to CD4 cell counts < 200 x 10(6)/l in the absence of antiretroviral therapy among HIV-1 infected men. RESULTS: No participant with a CD4 cell count between 201 x 10(6) and 350 x 10(6)/l and having < 20 000 copies/ml of HIV RNA progressed to clinical AIDS within 1 year. In men with > 350 x 10(6) CD4 cells/l and < 60 000 copies of HIV RNA/ml there were also no instances of progression to clinical AIDS within 1 year. No participant with < 10 000 copies HIV RNA/ml and between 201 x 10(6) and 350 x 10(6) CD4 cells/l had a decrease in CD4 cells to < 200 x 10(6)/l within 1 year. In men with baseline CD4 cell counts > 350 x 10(6)/l and HIV RNA < 30 000 copies/ml, only 3% had a decrease in CD4 cell count to < 200 x 10(6)/l within 1 year. CONCLUSION: This analysis supports recommendations to defer therapy in HIV-1 infected individuals with CD4 cell counts > 350 x 10(6)/l and HIV RNA < 60 000 copies/ml and in persons with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l and < 20 000 copies/ml HIV RNA. Up to 79% of persons with > 350 x 10(6) CD4 cells/l and 29% with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l may, with close monitoring, safely defer therapy.     

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

OBJECTIVE: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. DESIGN: Cohort study. PARTICIPANTS: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load 1000 copies/ml. MAIN OUTCOME MEASURE: CD4 count changes. RESULTS: Among patients who maintained plasma HIV RNA levels /= 350 x 10(6)/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 x 10(6)/l, 88% achieved a CD4 cell count of >/= 200 x 10(6)/l and 59% achieved a count of >/= 350 x 10(6)/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). CONCLUSIONS: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune system's capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.     

Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda

BACKGROUND: Retrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis. METHODS: In a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status. RESULTS: During the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07-1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 x 10(6) cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 x 10(6)/l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27-3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 x 10(6)/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91; P < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 x 10(6) cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24-2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62-5.63) for subjects with CD4 lymphocyte counts > 200 x 10(6)/l and 1.5 (95% CI, 0.99-2.40) for subjects with a CD4 lymphocyte count of 200 x 10(6)/l or fewer. CONCLUSION: The findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.     

Evaluation of the World Health Organization staging system for HIV infection and disease in Ethiopia: association between clinical stages and laboratory markers

OBJECTIVE: To study the association between the clinical axis of the World Health Organization (WHO) staging system of HIV infection and disease and laboratory markers in HIV-infected Ethiopians. DESIGN: Cross-sectional study. METHODS: Clinical manifestations and stage of HIV-positive individuals participating in a cohort study of HIV infection progression, and of HIV-positive patients hospitalized with suspicion of AIDS, were compared to CD4+ T-cell count and viral load. RESULTS: Of the 86 HIV-positive participants of the cohort study, 53 (62%), 16 (19%), 16 (19%), and one (1.2%) were in stage 1, 2, 3 and 4, respectively. Minor weight loss (n = 15) and pulmonary tuberculosis (n = 9) were the most commonly diagnosed conditions among the 38 (44%) symptomatic HIV-positive individuals. Although 23 (27%) HIV-positive participants had CD4+ T-cell counts less than 200 x 10(6)/l, only one was in clinical stage 4. Among 79 hospitalized HIV-positive patients, 15 (19%) and 64 (81%) were in stage 3 and 4, respectively. The majority (83.5%) had CD4+ T-cell counts < 200 x 10(6)/l. Individuals at stage 3 had lower CD4+ T-cell counts and higher viral loads when seen in hospital as compared to cohort participants (P = 0.06 and 0.008, respectively). When grouping the two study populations, the median CD4+ T-cell count decreased (337, 262, 225, 126, and 78 x 10(6)/l, P< 0.01), and the median viral load increased (4.08, 3.89, 4.47, 5.65, and 5.65 log10 copies/ml, P < 0.01), with increasing clinical stage of HIV infection (1, 2, 3 cohort, 3 hospital, and 4, respectively). Median CD4+ T-cell counts were remarkably low in HIV-negative participants (749 x 10(6)/l), and in HIV-positive participants at stage 1 and 2 (337 and 262 x 10(6)/l, respectively). CONCLUSIONS: There was a good correlation between WHO clinical stages and biological markers. CD4+ T-cell counts were low in Ethiopians, particularly during early stages of HIV-1 infection, and preliminary reference values at different stages of HIV-1 infection were determined. In HIV-infected Ethiopians, lymphocyte counts less than 1,000 x 10(6)/l in non-hospitalized individuals, and less than 2,000 x 10(6)/l in hospitalized patients, had high positive predictive value, but low sensitivity, in identifying subjects with low CD4+ T-cell counts (< 200 x 10(6)/l) who would benefit from chemoprophylaxis of opportunistic infections. The on-going longitudinal study will be useful to confirm the prognostic value of the WHO staging system.     

A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok

OBJECTIVES: To examine the impact of high-dose multiple micronutrient supplementation on survival and disease progression among HIV-infected individuals in Thailand. DESIGN: Randomized placebo-controlled trial. METHODS: Four-hundred and eighty-one HIV-infected men and women living in and around Bangkok with CD4 cell counts in the range 50 x 10(6)- 550 x 10(6)/l were randomized to receive micronutrients or placebo for a period of 48 weeks. Trial participants were examined clinically 12-weekly and tested for CD4 cell count 24-weekly. A subset were tested for HIV plasma viral load at 48 weeks. RESULTS: Seventy-nine (16%) trial participants were lost to follow-up and 23 (5%) died. The death rate was lower in the micronutrients arm with the mortality hazard ratios [95% confidence interval (CI)] of 0.53 (0.22-1.25; P = 0.1) overall and 0.37 (0.13-1.06; P = 0.052) and 0.26 (0.07-0.97; P = 0.03) among those with CD4 cell counts < 200 x 10(6)/l and < 100 x 10(6)/l respectively. There was no impact on CD4 cell count or plasma viral load. CONCLUSIONS: Multiple micronutrient supplementation may enhance the survival of HIV-infected individuals with CD4 cell counts < 200 x 10(6)/l. This could have important public health implications in the developing world where access to antiretrovirals remains poor. The clinical findings need to be reproduced in other settings and the mechanism, which appears to be independent of change in CD4 cell count, merits further investigation.     

Initiating co-trimoxazole prophylaxis in HIV-infected patients in Africa: an evaluation of the provisional WHO/UNAIDS recommendations.

OBJECTIVE: To evaluate the proposed WHO/UNAIDS criteria for initiating co-trimoxazole prophylaxis in adult HIV-infected patients in Africa [WHO clinical stages 2--4 or CD4 count < 500 x 10(6) /l or total lymphocyte count (TLC) equivalent]. DESIGN: Observational cohort study of 5-year follow-up. SETTING: Adult HIV clinics, University of Cape Town, South Africa. METHODS: Effect of prophylactic low dose co-trimoxazole (480 mg per day or 960 mg three times per week) on survival and morbidity was assessed in patients stratified by WHO clinical stage, CD4 T-lymphocyte count or TLC. Patients receiving antiretroviral therapy were excluded. RESULTS: Co-trimoxazole reduced mortality [adjusted hazard ratio (AHR), 0.56; 95% confidence interval (CI), 0.33--0.85; P > 0.001] and the incidence of severe HIV-related illnesses (AHR, 0.52; 95% CI, 0.38--0.68; P < 0.001) in patients with evidence of advanced immune suppression on clinical (WHO stages 3 and 4) or laboratory assessment (TLC < 1250 x 10(6)/l or CD4 count < 200 x 10(6)/l). No significant evidence of efficacy was found in patients with WHO stage 2 or CD4 count 200--500 x 10(6)/l/TLC 1250--2000 x 10(6)/l. If we had applied the WHO/UNAIDS recommendations 88.3% of our patients would have received co-trimoxazole prophylaxis at their initial clinic visit. CONCLUSION: Co-trimoxazole in HIV-infected adults from an area in which Pneumocystis carinii pneumonia is uncommon demonstrated a survival benefit consistent with previous randomized trials. Further studies are needed to assess the optimal time of commencement of prophylaxis, as widespread co-trimoxazole use will lead to increasing antimicrobial resistance to other major pathogens in Africa.     

Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. European Study Group on Natural History of HIV Infection in Women

OBJECTIVES: To assess the impact of HIV-related immunodeficiency and antiretroviral treatment on the occurrence and evolution of abnormal Papanicolaou tests. STUDY DESIGN: Cohort of 485 HIV-infected women with a known date of infection, enrolled during May 1993-April 1998 in 23 centres (gynaecology, infectious disease or STD clinics, or drug treatment centres) in 12 European countries; in 21 centres, follow-up was performed every 6 months (median follow-up: 2 years). METHODS: Human papillomavirus (HPV) was detected at inclusion by Southern blot and PCR. The prevalence of squamous intraepithelial lesions (SIL), the incidence of SIL and regression from low-grade SIL were studied according to CD4 count after controlling for HPV detection results. RESULTS: Compared with women with CD4 cell counts > 500 x 10(6)/l, women with CD4 cell counts < 200 x 10(6)/l had a twofold increase in both prevalence and incidence of SIL and in non-regression from untreated low-grade SIL; in addition, these women had a lower response rate to treatment of high-grade cervical intraepithelial neoplasia. The increase in SIL incidence associated with a low CD4 cell count was significant in women not receiving antiretroviral treatment (relative risk, CD4 cell count 200-499 x 10(6)/l, 1.9; CD4 cell count < 200 x 10(6)/l, 2.9; CD4 cell count > 500 x 10(6)/l, reference), whereas it was less marked and not statistically significant in treated women. CONCLUSIONS: Severe HIV-related immunodeficiency strongly increases the risk of occurrence of SIL; antiretroviral treatment may reduce this risk, probably by restoring or at least preserving immune function.     

HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy.

OBJECTIVE: To determine if HIV-1 RNA and CD4 lymphocyte thresholds for the initiation of highly active antiretroviral therapy (HAART) are associated with clinical response to therapy. DESIGN: Observational cohort study. SETTING: Johns Hopkins Hospital HIV Clinic. PATIENTS: HIV-infected adults. INTERVENTION: Patients initiating HAART (n = 530) were compared with concurrent patients who did not receive HAART (n = 484). MAIN OUTCOME MEASURE: Progression to a new AIDS-defining illness or death. RESULTS: The average duration of follow-up for the cohort was 22 months. HAART resulted in decreased disease progression among persons with fewer than, but not more than, 200 x 10(6) CD4 lymphocytes/l prior to treatment. Among persons receiving HAART, plasma HIV-1 RNA level prior to therapy was not associated with HIV disease progression within CD4 T-lymphocyte count strata. In a Cox multivariate proportional hazards model that adjusted for age, sex, race, prior opportunistic infection, and CD4 T lymphocytes, < or = 200 x 10(6) CD4 lymphocytes/l was the strongest predictor of disease progression. HIV-1 RNA level prior to starting HAART of < 5000 copies/ml, 5001-55 000 copies/ml, or > 55 000 copies/ml was not associated with disease progression on therapy, particularly among persons with > 200 x 10(6) CD4 lymphocytes/l. There was no sex difference in disease progression on treatment. CONCLUSIONS: Our data suggest that current guidelines for initiating HAART should place greater emphasis on CD4 lymphocyte than HIV-1 RNA level for both men and women. Further longitudinal follow-up will be needed to better ascertain whether HAART initiated at > 200 x 10(6) CD4 lymphocytes/l is effective in slowing disease progression.     

Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study

OBJECTIVE: To assess the safety of discontinuing or withholding primary prophylaxis against disseminated Mycobacterium avium infection (MAC) in HIV infected patients on successful antiretroviral combination therapy. SETTING: National prospective multicentre cohort study. DESIGN: HIV-infected patients were eligible for the analysis if: (i) they had a history of at least two CD4 cell counts < 50 x 10(6)/l; (ii) they had never had MAC; (iii) they had discontinued or never begun primary prophylaxis against MAC; (iv) they received antiretroviral therapy and demonstrated an increase in CD4 cell counts to > or = 100 x 10(6)/l that was sustained for at least 12 weeks. From this time point until last follow-up, incidence of disseminated MAC disease was measured, and 99% confidence intervals were calculated assuming a Poisson distribution of events. RESULTS: Two-hundred and fifty-three patients (22.5% female; median age, 37 years, 30% injecting drug users) were eligible for analysis. Sixty-six per cent were in Centers for Disease Control and Prevention (CDC) stage C, and 28% were in CDC stage B. Their median nadir CD4 cell count was 10 x 10(6)/l, the median duration of CD4 cell count < 50 x 10(6)/l was 12 months. During a total follow-up of 364.3 patient-years there was no case of disseminated MAC. The one-sided 99% confidence limit for incidence density of MAC was 1.3 per 100 person-years. CONCLUSION: Discontinuing or withholding primary prophylaxis against MAC is safe in patients who have a sustained increase in their CD4 cell count to > or = 100 x 10(6)/l.     

Factors associated with clinical progression in HIV-2 infected-patients: the French ANRS cohort

OBJECTIVES: To identify factors associated with clinical progression in HIV-2 infected patients. DESIGN: French prospective cohort initiated in 1994. METHODS: Follow-up data are collected twice a year; viral load is assessed once a year by cellular viraemia, quantitative proviral DNA and plasma RNA. A Cox proportional-hazards model was used for studying baseline factors associated with clinical progression. RESULTS: By December 2001, 217 patients had been enrolled. At inclusion, 80%, 6% and 14% were Centers for Disease Control and Prevention (CDC) group A, B and C, respectively. Median CD4 cell count was 436 x 10(6)/l. In the 48% of positive specimens, the median plasma RNA titre was 3.0 log10 copies/ml. Mean follow-up of the 179 patients seen at least twice was 34.4 months. Of these 13 died and nine progressed to group C. Ninety-three (52%) received antiretroviral therapy during a mean of 33 months, including a protease inhibitor in 48%. The probability of remaining AIDS-free was 97% and 95% at 1 and 3 years, respectively. Independent variables associated with clinical progression were age > or = 40 years [hazard ratio (HR), 11; 95% confidence interval (CI), 1.4-91.8; P = 0.03] and plasma RNA (HR, 2.5 per additional log10 copies/ml; 95% CI, 1.3-4.7, P < 0.01). Prior group B symptoms and CD4 cell count < 200 x 10(6)/l were associated with progression to AIDS. AIDS and plasma RNA were predictive of death. CONCLUSION: Considering the limited progression rate of HIV-2 infection, combined antiretroviral therapy should be discussed in patients with high plasma RNA titres, which threshold value remains to be defined. It is recommended in case of AIDS, CDC group B symptoms or CD4 cell count < 200 x 10(6)/l.     

HIV-seropositive thrombocytopenia: the action of zidovudine.

The action of zidovudine when administered to individuals with severe HIV thrombocytopenia was investigated. Four individuals with platelets less than 50 x 10(9)/l and CD4 cells greater than 200 x 10(6)/l were treated with 600 mg zidovudine per day for 6 weeks, no drug for 6 weeks, 1200 mg zidovudine per day for 6 weeks, then no drug for 6 weeks. Glycocalicin, a platelet protein which correlates inversely with platelet survival, was assayed before and after treatment. Glycocalicin indices were also measured in four additional individuals with HIV thrombocytopenia. Platelet counts rose 2.5-fold [95% confidence interval (Cl), 2.0-3.0)] for four subjects who received 600 mg zidovudine per day and 4.9-fold (95% Cl, 4.0-5.8) for three subjects receiving 1200 mg zidovudine per day. Platelet counts declined during drug-free intervals. Plasma glycocalicin indices were elevated in all with untreated HIV thrombocytopenia. Indices fell after zidovudine treatment in six of seven individuals, suggesting that zidovudine prolonged platelet survival. Analysis of 170 HIV-seropositive asymptomatic individuals [mean CD4 count 474 x x 10(6)/l, standard deviation (s.d.) 245 x 10(6)/l] revealed that 14 (8%) had less than 125 x 10(9)/l platelets but only 2 (1%) had less than 50 x 10(9)/l platelets. Platelet counts increased spontaneously in eight individuals with mild HIV thrombocytopenia among the 10 for whom repeat counts were available.     

The association of clinical conditions and serologic tests with CD4+ lymphocyte counts in HIV-infected subjects without AIDS.

Early intervention guidelines in HIV infection require knowledge of CD4+ lymphocyte count; however, CD4+ determinations require special laboratory procedures and may not be readily available in all situations. Using data from 207 HIV-seropositive homosexual men without AIDS, we evaluated the association of difference clinical conditions or serologic tests with CD4+ count. Men with conditions including seborrheic dermatitis, hairy leukoplakia, oral candidiasis and chronic diarrhea, and men with beta2-microglobulin levels greater than or equal to 4.0 mg/l had significantly lower CD4+ counts. However, the probability that a subject with such parameters had less than 200 x 10(6)/l CD4+ cells was limited (25-63%). Although the probability that a subject with such parameters had less than 500 x 10(6)/l CD4+ cells was better (76-88%), the probability that a person without these parameters had greater than or equal to 500 x 10(6)/l CD4+ cells was only 45-50%. Clinical and serologic parameters may provide important prognostic information, but cannot be used to reliably determine the level of CD4+ cells.     

Pre-mobilization therapy blood CD34+ cell count predicts the likelihood of successful hematopoietic stem cell mobilization

We examined pre-mobilization blood CD34+ cell count to predict ability to mobilize adequate peripheral blood progenitor cells (PBPC) in 106 cancer patients and 36 allogeneic donors. Mean pre-mobilization therapy blood CD34+ cell count was 3.1 cells x 10(6)/l (s.d. = 3.9, r = 0.3-37) and mean CD34+ cells collected were 5.3 x 10(6) cells/kg/leukapheresis procedure (s.d. = 7.0, r = 0.03-53). Yields correlated with pre-mobilization CD34+ cells x 10(6)/l (r = 0.37, P-value < 0.0001); correlation was stronger in allogeneic donors (r = 0.56, P-value = 0.0004) and males (r = 0.46, P-value < 0.0001). Based on classification and regression tree multivariate analysis, the predictive value of pre-mobilization blood CD34+ cell count was confounded by other variables, including age, gender, mobilization regimen and malignancy type. We generated an algorithm to predict a minimum PBPC yield of 1 x 10(6) CD34+ cells/kg/leukapheresis procedure after mobilization. A threshold pre-mobilization blood CD34+ cell count of 2.65 cells x 10(6)/l was the most important decision point in predicting successful mobilization. Only 2% of subjects with pre-mobilization blood CD34+ cell counts > 2.65 cells x 10(6)/l did not achieve the minimum per apheresis, whereas 24% with pre-mobilization values below threshold had inadequate mobilization. Prospectively identifying individuals at risk for mobilization failure would allow for improved treatment planning, resource utilization and time saving.     

Immunological reconstitution after cord blood transplantation for an adult patient.

We transplanted 4.1x10(7) unrelated umbilical cord blood cells into a 27-year-old patient suffering from transformed acute myelocytic leukemia. The thawing method was the same as described by Rubinstein et al (Proc. Natl. Acad. Sci. USA 1995; 92: 10119-10122). ANC reached over 500x10(9)/l on day 19, and the patient was free from RBC and platelet transfusion on days 26 and 38, respectively. Cytogenetic and molecular analysis after transplant revealed complete chimerism. The CD3+CD4+ lymphocyte count became greater than 100x10(9)/l at 5 weeks after transplantation. The CD3+CD8+ count became greater than 500x10(9)/l at 7 weeks and thereafter progressively increased in spite of administration of CYA. This immunological reconstitution pattern after umbilical cord blood transplantation was different from that after bone marrow transplantation, and resistance of CD3+CD8+ lymphocytes to CYA was the distinguishing characteristic. The rapid hematological recovery and immunological reconstitution may be attributed to the high dose of transfused nucleated cells and umbilical cord blood transplantation may become a promising method for treatment for such cases.     

北京市重症急性呼吸综合征患者的临床免疫学特点

目的探索北京市所有重症急性呼吸综合征(SARS)患者的临床免疫学特点及其规律.方法对2003年3～7月期间在北京非典型肺炎定点医院住院的所有SARS患者病历进行完整录入、数据处理、回顾性统计分析.结果 2003年3～7月期间资料完整的确诊SARS患者1291例,其白细胞总数、淋巴细胞、CD3、CD4、CD8淋巴细胞亚群绝对值均在发病早期同时下降,总阳性率分别为56.91%、88.26%、47.96%、45.56%及41.10%;其CD3、CD4、CD8在前3天中位数分别为425×106/L、223×106/L、170×106/L,达病程的最低值;第2周分别为536×106/L、267×106/L、224×106/L,至第4周恢复正常(P<0.05);其数值出现随病程发展逐渐升高的正相关趋势.将连续4周检测的同一组患者,分别与相邻时间段的同一组患者和所有非同组患者的各免疫学指标进行比较分析,3组中CD3、CD4、CD8表达仍然是第1～3天最低,除连续检测组第3周CD3的中位数(954×106/L)偏高外,其他3组间差异无显著性(P<0.05),各数据与病程呈平行升高趋势.C反应蛋白早期升高,血沉,补体C3、C4均在正常范围内.结论 SARS患者的发病早期白细胞、淋巴细胞、淋巴细胞亚群CD3、CD4、CD8均同时明显减少,淋巴细胞、淋巴细胞亚群CD3、CD4、CD8随病程发展呈上升恢复趋势.特别是第1周内,CD3、CD4、CD8同时减低,是SARS的免疫学特征之一,有助于早期诊断.     

When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from the ICONA study

OBJECTIVES: To compare the response to highly active antiretroviral therapy (HAART) in individuals starting HAART at different CD4 cell counts. DESIGN: The mean increase in CD4 cell count and rate of virological failure after commencing HAART were measured in antiretroviral-naive patients (1421) in a large, non-randomized multicentre, observational study in Italy (ICONA). Clinical endpoints were also evaluated in a subset of patients who started HAART with a very low CD4 cell count. RESULTS: After 96 weeks of therapy, the mean rise in CD4 cell count was 280, 281 and 186 x 10(6) cells/l in patients starting HAART with a CD4 cell count < 200, 201--350 and > 350 x 10(6) cells/l, respectively. Patients starting HAART with a CD4 cell count < 200 x 10(6) cells/l tended to have a higher risk of subsequent virological failure [relative hazard (RH), 1.15; 95% confidence interval (CI), 0.93--1.42] compared with patients starting with > 350 x 10(6) cells/l. There was no difference in risk between the 201--350 and the > 350 x 10(6) cells/l groups (RH, 1.0; 95% CI, 0.79--1.29). The incidence of new AIDS-defining diseases/death in patients who started HAART with a CD4 count < 50 was 0.03/person-year (95% CI, 0.10--0.33) during the time in which the patient's CD4 cell count had been raised to > 200 x 10(6) cells/l. CONCLUSIONS: There was no clear immunological or virological advantage in starting HAART at a CD4 cell count > 350 rather than at 200--350 x 10(6) cells/l. The increase in CD4 cells restored by HAART is meaningful in that they are associated with reduced risk of disease/death.