Pre-hospital advanced airway management by anaesthetist and nurse anaesthetist critical care teams: a prospective observational study of 2028 pre-hospital tracheal intubations.

BACKGROUND: Pre-hospital tracheal intubation success and complication rates vary considerably among provider categories. The purpose of this study was to estimate the success and complication rates of pre-hospital tracheal intubation performed by physician anaesthetist or nurse anaesthetist pre-hospital critical care teams. METHODS: Data were prospectively collected from critical care teams staffed with a physician anaesthetist or a nurse anaesthetist according to the Utstein template for pre-hospital advanced airway management. The patients served by six ambulance helicopters and six rapid response vehicles in Denmark, Finland, Norway, and Sweden from May 2015 to November 2016 were included. RESULTS: The critical care teams attended to 32 007 patients; 2028 (6.3%) required pre-hospital tracheal intubation. The overall success rate of pre-hospital tracheal intubation was 98.7% with a median intubation time of 25 s and an on-scene time of 25 min. The majority (67.0%) of the patients' tracheas were intubated by providers who had performed >2500 tracheal intubations. The success rate of tracheal intubation on the first attempt was 84.5%, and 95.9% of intubations were completed after two attempts. Complications related to pre-hospital tracheal intubation were recorded in 10.9% of the patients. Intubations after rapid sequence induction had a higher success rate compared with intubations without rapid sequence induction (99.4% vs 98.1%; P=0.02). Physicians had a higher tracheal intubation success rate than nurses (99.0% vs 97.6%; P=0.03). CONCLUSIONS: When performed by experienced physician anaesthetists and nurse anaesthetists, pre-hospital tracheal intubation was completed rapidly with high success rates and a low incidence of complications. CLINICAL TRIAL NUMBER: NCT 02450071.

Motivations to participate in a Phase I/II HIV vaccine trial: A descriptive study from Dar es Salaam, Tanzania.

BACKGROUND: The search for an efficacious HIV vaccine is a global priority. To date only one HIV vaccine trial (RV144) has shown modest efficacy in a phase III trial. With existing different HIV-1 subtypes and frequent mutations, multiple trials are needed from different geographical sites particularly in sub-Saharan Africa where most HIV infections occur. Thus, motivations to participate in HIV vaccine trials among Tanzanians need to be assessed. This paper describes the motives of Police Officers who showed great interest to volunteer in HIVIS-03 in Dar es Salaam, Tanzania. METHODS: A descriptive cross-sectional study was conducted among Police Officers who showed interest to participate in the HIVIS-03, a phase I/II HIV vaccine trial in Dar es Salaam. Prior to detailed training sessions about HIV vaccine trials, the potential participants narrated their individual motives to participate in the trial on a piece of paper. Descriptive analysis using content approach and frequency distributions were performed. RESULTS: Of the 265 respondents, 242 (91.3%) provided their socio-demographic characteristics as well as reasons that would make them take part in the proposed trial. Majority, (39.7%), cited altruism as the main motive. Women were more likely to volunteer due to altruism compared to men (P < 0.01). Researchers' explanations about HIV/AIDS vaccine studies motivated 15.3%. More men (19.6%) than women (1.7%) were motivated to volunteer due to researchers' explanations (P < 0.001). Also, compared to other groups, those unmarried and educated up to secondary level of education were motivated to volunteer due to researchers' explanation (P < 0.05). Other reasons were: desire to become a role model (18.6%); to get knowledge for educating others (14.0%); to cooperate with researchers in developing an HIV vaccine (9.5%); to get protection against HIV infection (7.0%), and severity of the disease within families (6.2%). These results were supported by testimonies from both men and women. CONCLUSIONS: Participation in an HIV vaccine trial in a Tanzanian context is likely to be influenced by altruism and comprehensive education about the trial. Gender differences, marital status and education level need to be considered to enhance participation in future HIV vaccine trials.

Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience.

OBJECTIVE: To evaluate various strategies aimed at improving adherence to antiretroviral therapy (ART). METHODS: Patients initiated on ART at Muhimbili National Hospital HIV clinic were randomly assigned to either regular adherence counseling, regular counseling plus a calendar, or regular counseling and a treatment assistant. Patients were seen monthly; during these meetings self-reported adherence to treatment was recorded. Disease progression was monitored clinically and immunologically. RESULTS: Of the 621 patients randomized, 312 received regular counseling only, 242 regular counseling and calendars, while 67 had treatment assistants in addition to regular counseling. The mean (SD) follow-up time was 14.5 (4.6) months. During follow-up 20 (3.2%) patients died, and 102 (16.4%) were lost to follow-up; this was similar in all groups. In 94.8% of all visits, patients reported to have adhered to treatment. In only 39 (0.7%) visits did patients report a < or = 95% adherence. There were no differences in adherence (P = 0.573) or differences in CD4 count and weight changes over time in the interventions. CONCLUSIONS: Good adherence to ART is possible in resource constrained countries. Persistent adherence counseling in clinic settings by itself may be effective in improving adherence to ART.

Impairment of short-term memory and Korsakoff syndrome are common in AIDS patients with cytomegalovirus encephalitis.

BACKGROUND AND PURPOSE: The diagnosis of cytomegalovirus encephalitis (CMV-E) in AIDS patients is challenging as other illnesses may obscure the symptoms. Here, we characterize the clinical symptoms of CMV-E and link them to post-mortem findings. Patients and methods In 254 homosexual men with AIDS, followed from HIV diagnosis to death before the antiretroviral combination therapy era, CMV-E was suspected in 93 cases. All were CMV-positive in blood. Neurological examination, including cognitive testing was performed in 34 of them within 6 months before death. CMV-E was diagnosed by CMV-PCR in cerebrospinal fluid (n = 24) or by post-mortem (n = 24). RESULTS: The majority complained of forgetfulness (91%), balance difficulties (85%) and impotence (85%). Impaired short-term memory was present in 29 patients. It was extreme in 17, justifying the diagnosis of Korsakoff's syndrome. This was often associated with infectious CMV in blood (P = 0.01). Brainstem symptoms were found in 19 patients. Post-mortem examination often revealed ventriculoencephalitis. CMV was found primarily around the ventricles and in other structures, described in Korsakoff's syndrome. CONCLUSION: The location of CMV in the brain corresponded well to the clinical findings, demonstrating the close relationship between the neurological symptoms and the neuroanatomical lesions.

Risky sexual practices among youth attending a sexually transmitted infection clinic in Dar es Salaam, Tanzania.

BACKGROUND: Youth have been reported to be at a higher risk of acquiring STIs with significant adverse health and social consequences. Knowledge on the prevailing risky practices is an essential tool to guide preventive strategies. METHODS: Youth aged between 18 and 25 years attending an STI clinic were recruited. Social, sexual and demographic characteristics were elicited using a structured standard questionnaire. Blood samples were tested for syphilis and HIV infections. Urethral, high vaginal and cervical swabs were screened for common STI agents. RESULTS: A total of 304 youth were studied with mean age of 21.5 and 20.3 years for males and females respectively. 63.5% of youth were seeking STI care. The mean age of coitache was 16.4 and 16.2 years for males and females respectively. The first sexual partner was significantly older in females compared to male youth (23.0 vs 16.8 years) (p < 0.01). 93.2% of male youth reported more than one sexual lifetime partner compared to 63.0% of the females. Only 50% of males compared to 43% of females had ever used a condom and fewer than 8.3% of female youth used other contraceptive methods. 27.1% of pregnancies were unplanned and 60% of abortions were induced. 42.0% of female youth had received gifts/money for sexual favours. The HIV prevalence was 15.3% and 7.5% for females and males respectively. The prevalence of other STIs was relatively low. Among male youth, use of alcohol or illicit drugs was associated with increased risk of HIV infection. However, the age of sexual initiation, number of sexual partners or the age of the first sexual partner were not associated with increased risk of being HIV infected. CONCLUSION: Most female youth seen at the STI clinic had their first sexual intercourse with older males. Youth were engaging in high risk unprotected sexual practices which were predisposing them to STIs and unplanned pregnancies. There is a great need to establish more youth-friendly reproductive health clinics, encourage consistent and correct use of condoms, delay in sexual debut and avoid older sexual partners in females.

HIVIS-DNA or HIVISopt-DNA priming followed by CMDR vaccinia-based boosts induce both humoral and cellular murine immune responses to HIV.

BACKGROUND: In order to develop a more effective prophylactic HIV-1 vaccine it is important optimize the components, improve Envelope glycoprotein immunogenicity as well as to explore prime-boost immunization schedules. It is also valuable to include several HIV-1 subtype antigens representing the world-wide epidemic. METHODS: HIVIS-DNA plasmids which include Env genes of subtypes A, B and C together with Gag subtypes A and B and RTmut/Rev of subtype B were modified as follows: the Envelope sequences were shortened, codon optimized, provided with an FT4 sequence and an immunodominant region mutated. The reverse transcriptase (RT) gene was shortened to contain the most immunogenic N-terminal fragment and fused with an inactivated viral protease vPR gene. HIVISopt-DNA thus contains fewer plasmids but additional PR epitopes compared to the native HIVIS-DNA. DNA components were delivered intradermally to young Balb/c mice once, using a needle-free Biojector® immediately followed by dermal electroporation. Vaccinia-based MVA-CMDR boosts including Env gene E and Gag-RT genes A were delivered intramuscularly by needle, once or twice. RESULTS: Both HIVIS-DNA and HIVISopt-DNA primed humoral and cell mediated responses well. When boosted with heterologous MVA-CMDR (subtypes A and E) virus inhibitory neutralizing antibodies were obtained to HIV-1 subtypes A, B, C and AE. Both plasmid compositions boosted with MVA-CMDR generated HIV-1 specific cellular responses directed against HIV-1 Env, Gag and Pol, as measured by IFNγ ELISpot. It was shown that DNA priming augmented the vector MVA immunological boosting effects, the HIVISopt-DNA with a trend to improved (Env) neutralization, the HIVIS-DNA with a trend to better (Gag) cell mediated immune reponses. CONCLUSIONS: HIVIS-DNA was modified to obtain HIVISopt-DNA that had fewer plasmids, and additional epitopes. Even with one DNA prime followed by two MVA-CMDR boosts, humoral and cell-mediated immune responses were readily induced by priming with either DNA construct composition. Priming by HIV-DNA augmented neutralizing antibody responses revealed by boosting with the vaccinia-based heterologous sequences. Cellular and antibody responses covered selected strains representing HIV-1 subtypes A, B, C and CRF01_AE. We assume this is related to the inclusion of heterologous full genes in the vaccine schedule.

HTLV-III infection in homosexuals and hemophiliacs in Sweden.

Two hundred and three homosexual (HS) men and 114 hemophiliacs in Sweden were examined for serum antibodies to human T-lymphotropic virus type III (HTLV-III) and for alterations of T-lymphocyte subsets. Sera were screened for HTLV-III antibodies by an enzyme-linked immunosorbent assay and/or a dot immunobinding assay, and positive reactions were confirmed by Western blotting. HTLV-III antibodies were demonstrated in 13 of 13 (100%) HS men with acquired immune deficiency syndrome, in 63 of 67 (94%) HS men with persistent generalized lymphadenopathy, in 17 of 45 (38%) symptomatic HS men, and in 6 of 78 (8%) asymptomatic HS men but in none of 108 male blood donors. Seropositive HS men had significantly lower T4/T8 (helper/suppressor) cell ratios and T4 cell numbers than had seronegative HS men. Seronegative HS men had decreased T-cell ratios compared to controls but not decreased T4 cell numbers. Among hemophilia A patients, HTLV III antibodies were demonstrated in 40 of 48 (83%) cases treated with American factor VIII concentrate and in 17 of 29 (59%) cases treated with both American and Swedish concentrates but in none of 13 cases treated exclusively with Swedish factor VIII. Twenty-one hemophilia B patients treated with Swedish factor IX concentrates were all seronegative, whereas one of 3 hemophilia B cases treated with imported factor IX was seropositive. T4/T8 cell ratios were significantly lower in seropositive as compared to seronegative hemophilia A patients.

The rationale behind a vaccine based on multiple HIV antigens.

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 influence of MT-2 tropism on the prognostic implications of the delta32 deletion in the CCR-5 gene.

BACKGROUND: Long-term non-progression in HIV-1-infected patients has been reported to be associated with a 32 base-pair deletion (delta32) in one CCR-5 allele. The normal gene product acts as a coreceptor for HIV cell entry and is essential for infection of cells by non-syncytium-inducing and MT-2-negative HIV-1 strains. METHODS: Forty individuals were studied, all of whom had been HIV-1-seropositive for a mean of 8 years. RESULTS: Eight (20%) were heterozygous for the CCR-5 allele delta32 deletion. Six of these eight patients harboured MT-2-negative HIV-1 strains. Of these six, three were long-term non-progressors with a positive CD4 cell slope, not receiving antiretroviral treatment, whereas the other three were progressors (mean CD4 cell decline, 3.8 x 10(6)/l per month) receiving antiretroviral combination therapy. Two of the eight patients with the delta32 deletion had MT-2-positive HIV-1 strains. Both had very rapid CD4 cell decline (6.7 and 7.6 x 10(6)/l per month, respectively), despite triple antiretroviral therapy including a protease inhibitor. One of the patients with an MT-2-positive virus strain has suffered from Pneumocystis carinii bronchitis and the other from cytomegalovirus colitis. CONCLUSIONS: Disease progression may also occur in individuals with the coreceptor deficiency, especially in association with MT-2-positive HIV-1 strains. It is suggested that MT-2-positive HIV-1 enters cells through the CXC chemokine receptor-4 fusin coreceptor, thus circumventing the defective CC chemokine receptor-5 coreceptor. Various levels of expression of the wild-type CCR-5 gene and the gene with the delta32 deletion might explain variations in the disease progression in heterozygous patients with MT-2-negative HIV-1 strains.

MT-2 tropism and CCR-5 genotype strongly influence disease progression in HIV-1-infected individuals.

BACKGROUND: The beta-chemokine receptor CCR-5 is the coreceptor for cellular entry by non-syncytium-inducing (NSI) HIV-1 strains that dominate early in infection. A 32 base-pair deletion (delta32) in the CCR-5 gene renders this coreceptor non-functional. Heterozygosity for this deletion [delta32/wild-type (wt)] is associated with slow disease progression. The purpose of this study was to document the combined impact on HIV-1 disease progression of the CCR-5 genotype and the biological phenotype of HIV-1. METHODS: In a cross-sectional study of 258 HIV-1-infected Swedish individuals, the CCR-5 genotype (wt/wt or delta32/wt) was determined by polymerase chain reaction and the biological phenotype [NSI or syncytium-inducing (SI)] of virus isolates was determined in the MT-2 cell assay. Clinical status, HIV-1 RNA levels in plasma, CD4+ lymphocyte counts, and rate of CD4+ lymphocyte decline, based on retrospective analysis of CD4+ lymphocyte counts, were also recorded. None of the individuals were treated with protease inhibitors. RESULTS: The prevalence of the delta32/wt genotype was 23%. Subjects with the delta32/wt CCR-5 genotype more often carried SI virus than subjects with the wt/wt genotype (49 versus 35%; P=0.067), but there were no differences between the two groups in prevalence of AIDS, viral load, CD4+ lymphocyte count or CD4+ slope. NSI virus isolates were found in 159 (62%) out of 258 individuals. Individuals with NSI had lower prevalence of AIDS (39 versus 19%; P < 0.01), higher CD4+ lymphocyte counts (289+/-188 x 10(6)/l versus 153+/-162 x 10(6)/l; P=0.001), lower viral loads (median, 4.45 log10 versus 4.91 log10 copies/ml; P < 0.01) and a lower prevalence of the delta32/wt genotype (19 versus 29%; P=0.067) compared with individuals with SI virus. When the material was further subdivided, subjects with the delta32/wt genotype and SI virus had the highest prevalence of AIDS (P < 0.001), lowest CD4+ lymphocyte count (P=0.0001) and highest viral load (P=0.023) whereas the opposite was true for subjects with the delta32/wt genotype and NSI virus. A significantly higher proportion of subjects with NSI virus with delta32/wt and wt/wt CCR-5 genotype had been immunized with recombinant gp160. CONCLUSION: In summary, the delta32/wt CCR-5 genotype has a protective effect against HIV-1 disease progression that appears to be limited to individuals carrying HIV-1 variants with NSI phenotype. Immunization with recombinant gp160 tended to reduce the frequency of SI phenotypes.

Absence of a clinical correlation for complement-mediated, infection-enhancing antibodies in plasma or sera from HIV-1-infected individuals. Multicenter AIDS Cohort Study Group.

Neutralizing and complement-mediated infection-enhancing antibodies to HIV-1 were measured in sera or plasma from 54 HIV-1-positive individuals at various stages of disease, and from an additional 36 HIV-1-positive individuals for whom no clinical data were available. Antibodies were measured in microtiter infection assays utilizing MT-2 cells and the IIIB strain of HIV-1. The frequency of detection of both types of antibodies was identical, being 77 out of 90 cases (86%). Neutralizing and infection-enhancing antibodies were not always found together, and in four cases both were undetectable. No correlation was found between titers of either type of antibody and stage of disease. Furthermore, titers of infection-enhancing antibodies at early stages of disease did not predict rate of disease progression.

Effect of isoprinosine on HIV antigenaemia.

OBJECTIVE: The objective of this study was to evaluate the effect of isoprinosine on HIV-antigen expression in HIV-positive patients without AIDS. DESIGN: Serum samples from anti-HIV-positive patients without AIDS participating in a double-blind, placebo-controlled trial of isoprinosine in the treatment of HIV infection were analysed for the presence of HIV antigen. SETTING: Data and samples were collected from the 21 medical centres who participated in the Scandinavian multicentre placebo-controlled isoprinosine study. PATIENTS, PARTICIPANTS: Samples were available from 19 of 21 participating centres. Of 866 patients who enrolled, baseline serum samples were available for 642 (74%; 308 isoprinosine- and 334 placebo-treated patients). INTERVENTIONS: Treatment was 1 g isoprinosine administered orally three times a day or matching placebo for 24 weeks. MAIN OUTCOME MEASURES: Comparison of HIV-antigen levels before and during treatment in both the isoprinosine-treated group and the placebo-treated group of patients. RESULTS: During the study, AIDS developed in 19 patients; 17 of whom were receiving placebo treatment and two isoprinosine. The proportion of HIV-antigen-positive patients developing AIDS during treatment was significantly different from the proportion of HIV-antigen-negative patients in whom AIDS developed (6 versus 2%; P = 0.02). No significant changes in HIV-antigen levels were observed between the isoprinosine- and the placebo-treated group of HIV-antigen-positive patients. Median HIV-antigen levels did not change significantly in either the isoprinosine- or the placebo-treated group. CONCLUSION: Our results suggest that isoprinosine does not have antiviral activity against HIV in vivo.

Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment.

BACKGROUND: The efficacy of highly active antiretroviral treatment (HAART) in HIV-1 disease may vary between nucleoside-naive and experienced patients as well as between patients with different viral phenotypes and in different stages of disease. OBJECTIVE: To investigate variables of importance for successful long-term viral suppression by analysing virological, clinical and immunological characteristics at initiation of protease inhibitor treatment on suppression of HIV RNA over 1 year. DESIGN: An open, non-randomized, observational clinical study. SETTING: Venhälsan, Department of Dermatovenereology, Söder Hospital, Stockholm, Sweden. PATIENTS: A total of 147 unselected advanced patients with known HIV-1 infection for a mean of 7 years, of whom 37% had AIDS and who started treatment with a protease inhibitor during 1996. INTERVENTIONS: All patients received HAART with at least two nucleoside analogues in combination with either indinavir (81%) or ritonavir (19%). The majority (77%) had been previously treated with nucleoside analogues for a mean of 39 months. MEASUREMENTS: CD4+ lymphocyte count, plasma HIV-1 RNA, viral phenotype and HIV-1 coreceptor CCR-5 genotype at baseline. Viral load and CD4+ lymphocyte count were determined every 3 months. RESULTS: Patients were analysed on an intention-to-treat basis. The mean CD4+ lymphocyte count at baseline was 170 x 10(6)/l and the median viral load was 68 600 copies/ml. Heterozygosity for the delta32 deletion of the CCR-5 gene (delta32/wt) was found in 27%. MT-2 positive virus (syncytium-inducing) was isolated in 46%. Logistic regression revealed that nucleoside analogue experience and baseline log10 HIV-1 RNA were the only factors independently related to plasma HIV-1 RNA levels below 500 copies/ml after 1 year of treatment, which was found in 69%. CONCLUSION: The virological outcome after 1 year of HAART was strongly correlated to prior treatment history and baseline viral load, whereas CD4+ lymphocyte count, CCR-5 genotype and viral biological phenotype had less influence. The long-term antiviral efficacy of HAART was lowest in individuals with previous nucleoside analogue treatment and a high baseline viral load. In these individuals an even more aggressive treatment should be considered.

Zidovudine twice daily in asymptomatic subjects with HIV infection and a high risk of progression to AIDS: a randomized, double-blind placebo-controlled study. The European-Australian Collaborative Group (Study 017)

OBJECTIVE: To evaluate the efficacy of zidovudine given twice daily in subjects with asymptomatic HIV-1 infection and a high risk of progression to AIDS. DESIGN: Randomized, double-blind placebo-controlled trial. SETTING: Multicentre study in five European countries and Australia. PATIENTS: Asymptomatic subjects (n = 329) with CD4 cell counts between 200 and 400 x 10(6)/l, or if > 400 x 10(6)/l, subjects with HIV p24 antigenaemia (> 10 pg/ml). INTERVENTION: Patients were randomly assigned to receive zidovudine 500 mg or placebo twice daily for 104 weeks, following a 250 mg four times daily dose regimen for the first 4 weeks. MAIN OUTCOME MEASURES: The primary end-point was the development of AIDS or severe AIDS-related complex (ARC). Before unblinding the study other end-points were defined: the development of Centers for Disease Control and Prevention (CDC) group IV disease (AIDS, severe ARC and other CDC stage IV disease) and the development of symptomatic HIV disease (AIDS, severe ARC, other CDC stage IV disease and minor HIV disease). Changes in CD4+ cell counts, p24 antigenaemia and toxicity were also reviewed. RESULTS: Median treatment duration was 57 weeks for the placebo and 60 weeks for the zidovudine group, respectively. Progression to AIDS or severe ARC occurred in 17 placebo and 12 zidovudine recipients (log-rank P = 0.26). However, in the first of the 2 study years the rate of progression to AIDS or severe ARC was significantly higher in the placebo than in the zidovudine group. Zidovudine delayed progression to symptomatic HIV disease (P = 0.01); a trend in a delay in progression to CDC stage IV disease was observed (P = 0.08). Zidovudine recipients maintained CD4+ cell counts at or above baseline levels for longer than placebo recipients (P = 0.04). HIV p24-antigen levels decreased in the zidovudine group and returned to pretreatment levels by week 36. Substantial toxicity was not observed. CONCLUSIONS: Zidovudine twice daily is effective in delaying progression to symptomatic HIV disease in high-risk, asymptomatic HIV-infected subjects. Modified definitions of clinical end-points may be useful for evaluating Phase III trials in comparable patient groups in the light of changes in the definition of AIDS and the increasing use of primary prophylaxis against opportunistic infections.

Induction of specific T-cell responses in HIV infection.

OBJECTIVES: To induce recovery of HIV-1-specific immune responses by combining immunization with antiviral chemotherapy. DESIGN: Forty HIV-infected patients entered a double-blind study with recombinant gp160 in combination with zidovudine or placebo. The pretreatment observation period was around 2 years and the treatment period 5 years. Eighty matched HIV-infected patients served as controls. METHODS: Immune status was monitored by proliferation assays with HIV-specific antigens, mitogens and recall antigens. Viral load, CD4 cell counts, apoptosis, T-cell clonal analysis and CC-chemokine receptor (CCR)-5 status were determined. RESULTS: All immunized patients showed a strong and HIV-specific T-cell proliferative response. This response was related to the immunizations, and was not enhanced by the zidovudine monochemotherapy given during the first 6 months of the immunizations. The treatments did not significantly alter viral load. Potent antiviral combination therapy given to non-immunized individuals reduced their viral load but did not influence HIV-specific immune responses. There was a trend for an increased frequency of non-progression in the immunized group compared with controls. These individuals had both wild-type and mutant CCR-5 genes. CONCLUSION: The results clearly show that restoration of HIV-specific T-cell immunity occurs after immunization with the HIV gp160 antigen and is not influenced by the addition of antiviral monochemotherapy. Even intensive chemotherapy alone did not restore HIV-specific immunity and immunization alone did not influence viral load. This suggests that combinations of intensive chemotherapy with specific HIV immunization would result both in viral load reduction and improved immune responses to HIV.

The prevalence and incidence of HIV-1 infection and syphilis in a cohort of police officers in Dar es Salaam, Tanzania: a potential population for HIV vaccine trials.

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.

Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus.

Six patients with human immunodeficiency virus were given foscarnet in oral solution, 4000 mg every 6 hours for 3 days, followed by a washout period for 2 days and continuous intravenous infusion of 16,000 mg/24 hr over 72 hours. After oral foscarnet, plasma concentrations were less than 33 mumol/L in four patients; two had occasional concentrations of 35 to 50 mumol/L. The extent of absorption varied between 12% and 22%. During intravenous infusion, plasma concentrations ranged between 75 and 265 mumol/L. The disposition of foscarnet was triphasic, with mean half-lives of 0.45, 3.3, and 18 hours. Excretion data suggested elimination was by tubular secretion and glomerular filtration. Renal clearance was 176 ml/min 1.73 m2. The apparent nonrenal clearance, 40 ml/min 1.73 m2, probably reflects sequestration of foscarnet into bone. Ten percent to 28% of the cumulative dose may have been deposited in bone 2 days after infusion. A slight increase in serum calcium levels and changes in serum phosphate values may reflect the uptake of foscarnet in bone. Five patients had diarrhea (oral) and two had thrombophlebitis (intravenous).

CD4-mimicking antibodies in HIV-positive and normal human sera.

An earlier study showed that approximately 5% of HIV-seropositive human sera contain gp120 antibodies that mimic CD4, seen as anti-idiotypic to the CD4 monoclonal T4.2. The present study shows the existence of a second type of CD4-mimicking gp120 antibody, which specifically binds to the CD4 monoclonal, OKT4A. This anti-idiotypic antibody to OKT4A is less frequent than the antibody reacting with T4.2. In two patients studied, this OKT4A binding antibody seems to appear as early during infection as the anti-idiotypic antibody to T4.2; however, the concentration varies more with time. In order to evaluate the possible clinical relevance of these CD4-mimicking antibodies, sera from 208 HIV-seropositive and 204 healthy seronegative individuals were screened. There was a significantly higher frequency of anti-idiotypic antibodies to T4.2 among HIV-positive individuals compared to healthy controls (p = 0.05). However, no correlation was found between the presence of CD4-mimicking antibodies and clinical classification of HIV-infected individuals.

HIV-1 peptides induce a proliferative response in lymphocytes from infected persons.

In a comprehensive search for T-cell epitopes of HIV-1, several new regions were discovered. The analysis was performed with lymphocytes of HIV-1-infected persons in various stages of the infection. Peptides covering the entire group antigen (gag), and transmembrane (gp41) regions, and one-half of envelope (gp120) regions of HTLV-IIIB were studied. Both common and patient-unique responses were identified. Twelve common gag T-cell sites were discovered, as well as patient-unique activating peptides. The gag peptides elicited the most frequent cell responses and the responses remained in late stages of disease. Only 1 of the 12 T-cell activating gag peptides was reactive with specific anti-HIV IgG. Eighteen common env-representing peptides evoked T-cell responses. They could be grouped into four previously undescribed regions of gp120 and two known sites, the hypervariable stretch and part of the CD4 binding region. Cell responses to env peptides were common in early stages of disease and tended to decrease in ARC and AIDS. The gp41-representing peptides evoked a cellular response to a region close to the N-terminus of the hydrophobic transmembrane region. In addition to the T-cell activating peptides, peptides representing p15 and p19 as well as previously recognized regions of gp120 and gp41 appeared to be potent B-cell epitopes.

Effects of adjuvants and multiple antigen peptides on humoral and cellular immune responses to gp160 of HIV-1.

The capacity of five different adjuvants, AlPO4, a muramyldipeptide formulation (MDP.TSL), Freund's adjuvant, immunostimulating complex and its matrix components to elicit humoral and cellular responses in rabbits immunized with the human immunodeficiency virus type 1 (HIV-1) envelope protein rgp160IIIB was compared. The highest antibody titers against gp160 and gp41/gp120 epitopes were seen with rgp160 in MDP.TSL or Freund's adjuvant, whereas the broadest responses were seen in rabbits immunized with rgp160 in matrix or MDP.TSL. The broadest spectrum of high-avidity antibodies was also induced by rgp160 in MDP.TSL. Neutralizing titers against HIV-1IIIB, low titers to HIV-1MN, and the most efficient inhibition of viral cell-to-cell spread was seen with rgp160 in MDP.TSL. The strongest and most persisting cellular responses were induced by rgp160 in AlPO4 or MDP.TSL. Using MDP.TSL as the adjuvant, we also improved the immune response against gp120 epitopes by boosting rgp160-primed rabbits with rgp160, multiple antigenic peptides (MAPs), or unconjugated peptides. The MAPs induced high neutralizing titers and were superior to rgp160 alone in inducing both humoral and cellular reactivity. MAPs are therefore strong candidates for inclusion into future HIV-1 vaccines.