Biomedical subjects
Publications and source records attributed to E Sandström.
The viral diversity of HIV-1 is likely to require a vaccine strategy that induces broad cellular and humoral anti-HIV-1 immunity. Our strategy is based on multiple HIV-1 DNA immunogens together with adjuvant recombinant granulocyte-macrophage stimulating factor. This article describes pre-clinical and clinical work preceding the initiation of clinical HIV-1 phase I/II trials.
The aim of this study was to evaluate the immunological responses induced by DNA plasmids containing HIV regulatory genes administered in combination in HIV-1-infected patients with pretreatment with highly active antiretroviral treatment (HAART). The study is a double-blind, randomized, and placebo-controlled study, including 15 asymptomatic HIV-1-infected patients on stable HAART for at least 6 months and with plasma HIV RNA levels below 50 copies/ml. Ten patients received a combination of rev, tat, and nef intramuscularly (im) at weeks 0, 4, and 16 at increasing doses giving totals of 300 (100 x 3), 900 (300 x 3), and 1800 (600 x 3) micrograms DNA. Five patients received saline in the same amounts im. Antigen-specific cytotoxic T lymphocyte (CTL) levels were preserved or increased and new T lymphocyte proliferative responses were induced in the group immunized with the HIV DNA genes. No increase in antibody levels was noted. Despite a 10-fold higher vaccine dose, patients on HAART did not respond better to vaccination compared to non-HAART patients included in a previous study where the genes were administered separately. Combining the regulatory genes rev, tat, and nef in increasing doses may reduce the anticipated augmentation of HIV-specific T cell proliferative and CTL responses. Viral suppression did not seem to further improve the initial vaccine responses of patients with comparable CD4 levels.
OBJECTIVE: To study the impact of effective highly active antiretroviral therapy (HAART) on the preservation of long-term CD4 memory cells induced by vaccines in HIV-1-infected patients. METHODS: Thirty HIV-1-positive patients on HAART with undetectable viral load were randomized into three groups: 10 received HIV-1 rgp160 vaccine, 10 received tetanus vaccine and 10 patients were not immunized. As controls, 10 HIV-negative volunteers were immunized with tetanus vaccine. The results were compared with an rgp160 vaccine study performed before the era of HAART on patients with comparable CD4 levels. All patients were monitored for 2 years for T-cell proliferative responses, T-cell subset levels, serum IgG and viral load. RESULTS: After 1 year all patients immunized with rgp160 had strong T-cell responses to the rgp160 antigen. After 2 years this response was preserved in the HAART-treated group, but not in the rgp160 immunized non-HAART group, despite comparable CD4 levels. Recall effects of the CD4-specific responses towards other antigens were seen in the rgp160-immunized HAART group. CONCLUSION: Immunization with rpg 160 leads to positive effects on HIV-specific T-cell proliferative responses in patients both with and without HAART. Immune responses after immunization is better preserved in HAART-treated patients who have low viral amounts than in individuals with high viral load and no HAART despite comparable CD4 levels during 2 years' follow-up. Interruption of HAART with return of a high viral load might thus have negative effects on T-cell functions in the long term, even if CD4 levels are kept at clinically acceptable levels.
The relationship between CD4 percent and CD4 count has been reported to be different in industrialized countries compared to sub-Saharan Africa, where often only the former is reliable. CD4 determinations from an open cohort of hotel workers in Dar es Salaam followed between 1990 and 1998 were evaluated. T-lymphocyte determinations were offered once a year to 190 HIV-1 seropositive, 80 seroconverters and 495 sex and age matched HIV-seronegative subjects. After log transformation of the CD4 percent and CD4 counts a good fit to a linear regression curve was found, R(2) 0.697. The CD4 percent corresponding to a CD4 count of 200 cells/mm(3) was found to be 9.8%. CD4 percent determination can be useful to estimate CD4 counts, but needs to be locally standardized. The CD4 percent in Africa corresponding to AIDS defining CD4 counts seems to be lower than in the industrialized world.
Clinical and experimental studies of HIV-1 subcomponents were made in order to increase their immunogenicity. HIV subtype envelopes A, B and C have been compared and a detailed analysis made by peptides of the coreceptor-ligand interactions. We identified a direct interaction between HIV-1 envelope and a cellular receptor at the amino acid level. Both the viral subtype and its tropism appeared to influence inhibition of infection. Genetic immunization induced new cytotoxic responses while proteins appeared to efficiently boost previous responses. One HIV-1 subtype B antigen was strongly immunogenic in a human immunotherapeutic trial and permitted better survival at 2 years of the study in patients with poor prognosis.
OBJECTIVE: The use of heparin-coated surfaces in cardiopulmonary bypass has been shown to decrease the inflammatory response imposed by the contact between blood and artificial surfaces. One would expect this reaction to improve clinical outcome. However, this has been difficult to verify. This investigation is based on an aggregation of two randomized studies from our institution and highlights possible effects of heparin coating on a number of clinically oriented parameters. DESIGN: Departmental analysis of patients subjected to coronary artery bypass surgery using heparin-coated circuits. Cardiopulmonary bypass was employed using either the Carmeda or Duraflo heparin coatings compared with a control. The systemic heparin dose was reduced in the heparin-coated groups (ACT > 250 s) vs control group patients (ACT > 480 s). The effects of heparin coating related to clinical outcome were studied. RESULTS: The use of heparin-coated circuits reduced the mean length of stay in hospital from 7.8 +/- 2.5 to 7.3 +/- 1.8 days (p = 0.040) and postoperative ventilation time from 9.7 +/- 9.2 to 8.2 +/- 8.5 h (p = 0.018), blood loss 8 h post surgery from 676 +/- 385 to 540 +/- 245 ml (p = 0.001), individual perioperative change of haemoglobin loss (p = 0.001), leukocyte count (p = 0.000) and creatinine elevation (p = 0.000), proportion of patients exposed to allogenous blood transfusions 39.2 vs 23.9% (p = 0.001), postoperative coagulation disturbances 4.4 vs 0.4% (p = 0.006), postoperative deviations from the normal postoperative course 47.2 vs 36.7% (p = 0.035), neurological deviations 9.4 vs 3.9% (p = 0.021) and atrial fibrillation 26.4 vs 18.0% (p = 0.041). No effects were found with respect to perioperative platelet count, postoperative fever reaction and 5-year survival. CONCLUSION: Based on several indicators, the use of heparin coating in cardiopulmonary bypass is associated with improved clinical results.
The incidence of gonorrhoea, chlamydia, syphilis and HIV infection is increasing among homosexual men in Stockholm, Sweden. This indicates that the frequency of unsafe sex is on the increase while the use of condoms is decreasing.
Both naive and memory T lymphocyte responses are lost during advanced HIV infection. Treatment with highly active antiretroviral therapy (HAART) is associated with an increase in T lymphocytes and a reduction in viral load. However, the viral response to HAART in patients with low levels of helper T lymphocytes and a high viral load is often not satisfactory. We investigated the capacity of long-term HAART to reconstitute the immune system in severely ill patients. A nonselected longitudinal patient population with high baseline viral levels and CD4(+) cells below 100 x 10(6)/liter were monitored for 2 years during HAART. Markers to estimate the therapeutic effects included viral levels and cell surface markers representing naive and memory T lymphocytes as well as activation markers, B cells, NK cells, and clinical events. After 2 years of treatment, viral load was reduced to undetectable levels in 55% (viral responders, vRs) and less than 1 log (median value) from baseline in 45% (viral low responders, vLRs). Elevated numbers of memory and naive CD4(+) and CD8(+) cells as well as a decrease in activation markers were seen in both vRs and vLRs. However, the magnitude was greater in vRs. No differences in the clinical outcome were observed between vRs and vLRs. We conclude that most patients, even in advanced stages of HIV disease, benefited from HAART. The magnitude of the response was related to good viral reduction, but even patients with poor viral reduction had a recovery of naive and memory CD4(+) and CD8(+) cells. Even a small reduction in viral load is thus of importance for health and potentially also for years of survival.
OBJECTIVE: The clinical significance of heparin coating in cardiopulmonary bypass has previously been investigated. However, few studies have addressed the possible influence on brain function and memory disturbances. METHODS: Three hundred low-risk patients exposed to coronary bypass surgery were randomised into three groups according to type of heparin coating: Carmeda Bioactive Surface, Baxter Duraflo II and a control group. Outcome was determined from a number of clinically oriented parameters, including a detailed registry of postoperative deviations from the normal postoperative course. Brain damage was assessed through S100 release and memory tests, including a questionnaire follow-up. RESULTS: Clinical outcome was similar for all groups. Blood loss (Duraflo only), transfusion requirements and postoperative creatinine elevation were reduced in the heparin-coated groups. A lower incidence of atrial fibrillation was noted in the Duraflo group. Heparin coating did not uniformly attenuate the release of S100 or the degree of memory impairment. CONCLUSIONS: Cardiopulmonary bypass (CPB) with heparin coating and a reduced dose of heparin seems to be safe. Clinical outcome and neurological injury seem not to be associated with type of heparin coating used for CPB. However, blood loss and transfusion requirements may be reduced.
OBJECTIVES: To investigate sex specific sexual behaviour in youths visiting a youth clinic for sexual and reproductive health in Dar es Saalam. METHODS: A questionnaire was administered to a random sample of youths between 10 and 24 years of age attending the youth health clinic in Dar es Saalam. The clinical investigation included testing for syphilis and HIV-1 antibodies RESULTS: 1423 youths attended the clinic between September 1997 and August 1998. The study population comprised 213 (53.5%) males and 185 (46.5%) females. 97 (24.4%) were below 20 years. The mean age at coitarche was 16.5 and 17.0 years of age for males and females, respectively. The coitarche was involuntary in 15 females (8.6%). 49.5% males reported more than five lifetime partners compared with 14.1% for females (p<0.0001). Males reported recent partners to be 2.5 years younger, while females reported them to be 5.0 years older. No contraceptive use was reported by 29.7% of the males and 40.3% of females. 52.7% females had been pregnant and 26 (14.1%) reported induced abortions. Genital discharge was found in 69.5% and 73.9% and GUD in 36.6% and 27.1% of males and females respectively. 12 males (5.9%) and 43 females (24.6%) were found to be HIV-1 infected. 13.8% of the females with only one lifetime partner were HIV-1 infected compared with 40.9% with more than five partners (p = 0.028). CONCLUSIONS: Many youths in Dar es Salaam engage in sexual behaviours that put them at risk of unwanted pregnancies and STIs including HIV infection. Female youths were more likely to contract HIV infection than males. In African urban areas youth oriented clinics can have a pivotal role in HIV/STI prevention and control
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OBJECTIVES: To assess the suitability of a cohort of police officers in Dar es Salaam for HIV vaccine trials by determining the prevalence and incidence of HIV-1 infection, active syphilis and their associated factors. DESIGN AND SETTING: An open cohort study of police officers in Dar es Salaam, Tanzania. METHODS: Recruitment of police officers began in 1994. A standardized questionnaire was completed at enrolment and subsequent visits. HIV antibodies were determined using two consecutive enzyme-linked immunosorbent assays. Samples repeatedly discordant on the two tests were tested by a Western blot assay. Treponema pallidum antibodies were first determined by Venereal Disease Research Laboratory (VDRL) test and reactive sera were confirmed by Treponema pallidum hemagglutination test. RESULTS: At the end of 1996 a total of 2850 police officers had been recruited of whom 2733 (96%) consented to be tested for HIV. The overall HIV-1 seroprevalence at recruitment was 13.8% (378 of 2733). Females had a significantly higher HIV-1 seroprevalence, 18.0% (55 of 306), as compared to males, 13.3% (323 of 2427), P< 0.05. From a total of 2215 married police officers, 585 (26.4%) responded to a question on extramarital sex within the previous 3 months of whom 36.2% (212 of 585) admitted to have had at least one extramarital sexual intercourse. Condoms were not used during these encounters by 178 of 212 (84.0%). As of 31st December 1998, among the 1524 males observed for 2553 person-years (PYAR), 50 had seroconverted and among 200 females observed for 357 PYAR, eight had seroconverted. The overall crude HIV-1 incidence was thus 19.9/1000 PYAR; 19.6 and 22.4/1000 PYAR for males and females, respectively. The overall prevalence and incidence of active syphilis were 3.1% (88 of 2850) and 8.6/1000 PYAR (26 of 3149), respectively. Males had a higher prevalence of active syphilis, 84 of 2525 (3.3%) than females, five of 325 (1.5%), P = 0.09. CONCLUSIONS: There was high risk sexual practice including low condom use in this cohort of police officers. The incidence and prevalence of HIV infection were high. Police officers in Dar es Salaam are therefore a potential population group for HIV vaccine evaluation.
The purposes of the present study are (1) to assess the health-related quality of life (HRQOL) and the subjective health status in a sample of human immunodeficiency virus (HIV)-infected persons (2) to relate the results to different population groups and (3) to investigate the relationship of medical and demographic variables with HRQOL. A total of 72 HIV-infected men were included. They answered the Swedish health-related quality of life questionnaire and the health index. Demographic and medical data were obtained from the medical records. The data collection took place before entering a therapeutic HIV vaccine trial. The results showed a more negative impact on the HRQOL and subjective health status in the HIV-positive subjects, compared with male population groups. The dimensions of emotional well-being were most affected. When comparisons were made according to the medical and demographic variables for different subgroups within the HIV sample, differences in the physical-dimension scales were most prominent. Symptomatic HIV infection or acquired immunodeficiency syndrome (AIDS), anti-retroviral treatment, sick leave or disability pension, low income and basic education were associated with worse HRQOL and health status. In conclusion, it is of utmost importance to take into account, aspects of the patients' emotional well-being in nursing, as well as in medical care and interventions. Moreover, individualized caring programs are needed because the disruptions in HRQOL fluctuated within the HIV sample.
Immunization with a recombinant glycoprotein 160 envelope immunogen derived from a virus of genetic subtype B induced strong specific T-helper cell responses in asymptomatic human immunodeficiency virus (HIV) carriers infected with subtypes B to G. This indicates that the HIV-specific T-helper immunity, which is the basis for development of antibodies and cytotoxic T lymphocytes, can be improved by both homologous and heterologous antigens. It also suggests that a particular immunogen can be effective against many different HIV strains.
The long-term effects of fat metabolism, storage and utilization in HIV-1 infected patients on highly active antiretroviral therapy (HAART) including a protease inhibitor are profound and cause increasing concern. The main importance of these lipid/metabolic disorders lies in their assumed contribution to an increased risk of coronary heart disease (CHD). In the general population increased levels of lipoprotein(a) [Lp(a)] constitute an independent risk factor for CHD by itself as well as in combination with increased levels of cholesterol and low density lipoprotein (LDL)-cholesterol, respectively. Two hundred and fifty-six patients with 27 +/- 7 months HAART and 84 treatment-naive HIV-1 positive patients were screened for cardiovascular risk factors. The subjective perception of fat wasting and/or accumulation in different sites of the body, which was possible to evaluate in 235 patients on HAART and 73 treatment-naive patients, the levels of plasma triglycerides (TG), cholesterol, LDL and high-density lipoproteins (HDL)-cholesterol, LDL/HDL ratio and Lp(a) were measured. Of the patients on HAART, 42% (98/235) reported abnormal fat distribution as compared with 4% (3/73) of the treatment-naive patients (P<0.0001). The levels of TG, cholesterol and LDL-cholesterol, but not HDL-cholesterol or Lp(a) were higher (P<0.0001) in the HAART group as compared with the naive group. Very high Lp(a) levels (> 700 mg/l) were more common among HAART patients as compared with naive, 14% (36/256) vs 2% (2/83); P=0.0022. The Lp(a) levels correlated to the levels of LDL-cholesterol, but not to total cholesterol, HDL-cholesterol or TG, and did not differ between patients with and without subjective perception of abnormal fat distribution. A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD. The elevation of Lp(a) did not relate to any other clinical or laboratory parameter than to LDL-cholesterol.
OBJECTIVE: To determine the acceptability, compliance and side effects of isoniazid (INH) prophylaxis against tuberculosis among HIV infected police officers (PO) in Dar es Salaam. DESIGN: A nested study from a prospective follow up of a cohort of police officers. SETTING: Dar es Salaam, Tanzania. SUBJECTS: One hundred and forty three HIV-1 infected police officers. MAIN OUTCOME MEASURES: Acceptance and compliance to INH prophylaxis. RESULTS: Of the 400 HIV-1 infected officers, 143 (35.7%) came forward for post-test counselling and HIV test results. Sixty per cent (87/143) of them accepted to be on INH prophylaxis. However only 42.5% (37/87) came forward for evaluation regarding their suitability for INH prophylaxis. During the evaluation, eight (21.6%) of 37 otherwise asymptomatic PO were found to have active pulmonary tuberculosis (TB). Eventually only 29 PO were actually started on INH, and only 16 (55.2%) of them completed the six months course. No serious side effects were observed. One PO developed TB two months after loss to follow up before completing the six months. CONCLUSIONS: There was low acceptability of and poor compliance with INH prophylaxis among the HIV-1 infected PO despite being educated on the benefits of prophylaxis. The prevalence of PTB among asymptomatic HIV-1 infected PO was high, and therefore persons with HIV infection should be examined for TB even in the absence of symptoms.
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