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Objective: To determine if a case of HIV-infection in a patient (GP) with common variable immunodeficiency, and with no known risk factors for HIV-infection, could be due to horizontal nosocomial transmission., Methods: For determination of time of transmission stored serum-samples from GP were analysed for HIV RNA content. Patient records were used to identify patients, who had received intravenous therapy on the same day as GP. Samples from GP and these possible source patients were identified and phylogenetic analyses of the env, gag and RT-encoding region of pol were performed. Furthermore, routines in conjunction with intravenous therapy were examined., Results: We identified a patient (FDL) harbouring virus almost indistinguishable from the virus isolated from GP. The pairwise nucleotide distance between the C2-V3-C3 region of the env and gag sequences from the two patients were 1.9 and 0.9% respectively. In addition, GP harboured HIV RNA with a foscarnet resistance mutation further lending support to virus from the foscarnet-treated FDL being the source of the infection. Interestingly, GP experienced increases in immunoglobulin production after contracting the HIV-infection, and decreases after antiretroviral-induced viral suppression. A clinical procedure which, under stressful conditions, could lead to breaches in infection control measures was identified. The source of the infection was most likely a contaminated multidose vial., Conclusion: Through epidemiological and phylogenetic analyses a case of horizontal nosocomial HIV-transmission was disclosed. Identification of multidose vials as possible vehicles for horizontal nosocomial transmission recently led to the recommendation of restriction of the use of multidose vials, a recommendation supported by the present study. The study underlies the importance of a constant survey of infection control precautions.

Objective: To investigate the clinical implications of impaired levels of the natural immunity mediated by natural killer (NK) cells and lymphokine activated killer (LAK) cells during infection with HIV-1., Design: Data used were from 172 individuals with an estimated measure of NK cell activity and 146 with an estimated measure of LAK cell activity. Patients had active HIV infection at the time of enrolment in the study and have been followed-up prospectively for a median of 3.0 years., Methods: The lytic activity of NK cells and LAK cells, the CD4 T lymphocyte count, and the concentration of CD16/CD56 NK cells were measured at enrolment. HIV RNA in plasma was measured retrospectively. Survival analysis was performed considering three main endpoints: CD4 cell counts below 100 x 10(6) cells/l, clinical AIDS, and death., Results: In unadjusted analysis and after adjustment for age, CD4 T lymphocyte count and plasma HIV RNA at enrolment, low LAK cell activity was significantly associated with higher risk of progression to a CD4 T lymphocyte count < 100 x 10(6) cells/l (crude P = 0.001; adjusted P = 0.04) and to death (crude P = 0.0002; adjusted P = 0.02). Patients with low NK cell responsiveness to interferon-alpha tended to be at higher risk of death (crude P = 0.04; adjusted P = 0.13) whereas unstimulated NK cell activity and the concentration of NK cells were of no prognostic value for patients in this cohort., Conclusions: The present study suggests that low LAK cell activity and low NK cell responsiveness to interferon-alpha may be important in the pathogenesis of HIV infection.

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.

Objectives: To analyse use of antiretroviral therapy within Europe between 1994 and 1997., Design: From September 1994, the EuroSIDA study (cohorts I-III) has prospectively followed unselected HIV-infected patients from 50 clinical centres in 17 European countries (total, 7230)., Methods: Patients under follow-up at half-year intervals from September 1994 (n=2871) to September 1997 (n=3682) were classified according to number of drugs currently used (none, one, two, three, four or more). Use of antiretroviral therapy was stratified by CD4 cell count (< 200 versus > or = 200 x 10(6)/l) and by region of Europe (south, central, or north). Frequency data were compared by chi2 test and logistic regression modelling., Results: The proportion of patients on antiretroviral monotherapy diminished over time (1994, 42%; 1997, 3%), as did the proportion of patients without therapy (from 37 to 9%). Over time, the proportion of patients on triple (from 2 to 55%) and quadruple (from 0 to 9%) therapy increased, whereas use of dual therapy peaked in 1996 and subsequently fell. In the three regions of Europe, changes in use of antiretroviral therapy differed substantially. However, as of September 1997, only minor differences persisted. The proportion of patients on dual, triple, and quadruple therapy were as follow: south, 33, 52 and 5%, respectively; central, 23, 55 and 14%, respectively; north, 16, 59 and 10%, respectively. In September 1997, odds for use of three or more drugs including at least one protease inhibitor did not differ significantly between regions., Conclusions: Use of antiretroviral therapy in Europe has changed dramatically towards combination treatment in the last few years. Regional differences in use of antiretroviral therapy have decreased, and by September 1997 only minor differences remained. Antiretroviral therapy with three or more drugs and use of protease inhibitors has become more common in all regions of Europe.

Objective: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count., Design: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54)., Setting: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark., Participants: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA., Main Outcome Measure: Survival time., Results: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level)., Conclusions: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

The objectives of this study were to evaluate the prognostic value of a single serum HIV-RNA measurement 6-24 months after HIV seroconversion, and to investigate whether any differences in outcome related to the clinical course of primary infection could be explained by presumed steady-state HIV-RNA levels at 6-24 months after seroconversion. Disease progression was analyzed by life tables and Cox proportional hazard models. A total of 93 HIV seroconverters followed for a median of 76 months (range, 19-143 months) were included in the study. The main outcome measures were development of AIDS stratified by age, the year of seroconversion, serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The proportion of patients who developed AIDS was 36% (95% confidence interval, 22%-50%) at 8 years and 50% (26%-75%) at 10 years. In the unadjusted analyses, clinical progression was significantly associated with serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The adjusted analyses indicated that HIV-RNA was the strongest predictor. Patients with long-lasting symptoms associated with primary infection had significantly higher serum HIV-RNA levels than those with less severe presentations (median counts, 11,660 vs. 2880 copies/ml, p = 0.001). It is concluded that the serum HIV-RNA level in early HIV infection is a strong independent predictor of clinical progression. Patients with long-lasting primary illnesses reach a higher viral load in steady state after seroconversion, which is probably the main reason for the poorer prognosis observed in this group of patients.

The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.

Objective: Recently, it has been shown that a homozygous 32 base-pair deletion in the gene encoding CKR-5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1. We have investigated whether HIV-seropositive individuals who were heterozygous for the CKR-5 deletion had a different course of the disease., Design: Thirty-five high-risk HIV-seronegative and 99 HIV-seropositive Danish homosexual men followed form 1985 to 1996 and 37 blood donors were analysed for their CKR-5 genotype by polymerase chain reaction., Results: Two (6%) of the 35 HIV-seropositive subjects at high-risk of infection were homozygous and seven (20%) were heterozygous for the CKR-5 deletion. This was not significantly different from the distribution in normal donors. Twenty-two (22%) of the 99 HIV-seropositive subjects were heterozygous and none was homozygous. Two subgroups of patients who had an opposite course of the HIV disease were identified. Of nine long-term non-progressors, six (66%) were heterozygous for the deletion. This frequency is significantly higher than in nine rapid progressors of whom non was heterozygous. The frequency of heterozygotes in long-term non-progressors was also significantly higher than in the cohort as a whole. A Kaplan-Meier plot of the HIV-seropositive subjects, of whom 57 developed AIDS, showed a significantly better prognosis within the first 7 years of follow-up for those who were heterozygous for the deletion. Heterozygous individuals also had a significantly slower decrease in CD4 T-cell count per year., Conclusion: Individuals who are heterozygous for the 32-base-pair deletion in the CKR-5 gene have a slower decrease in their CD4 T-cell count and a longer AIDS-free survival than individuals with the wild-type gene for up to 11 years of follow-up.

Objective: To investigate the longitudinal changes in serum HIV RNA, and to clarify whether the viral load early in infection has a predictive value for the clinical outcome; also, to correlate viral phenotype at seroconversion and changes in CD4 cell counts with viral burden., Design: Twenty seroconverters with HIV isolates available at seroconversion had HIV RNA quantified by polymerase chain reaction (PCR) at seroconversion and thereafter every 6 months. Mean follow-up time was 65 months. Patients were classified according to viral phenotype at seroconversion, time to AIDS progression, serum viral load within the first year (less or more than 1.5 x 10(4) copies/ml)., Results: High viral load at seroconversion was followed by a significant decline within the first months (P < 0.0005). Decline to < 1.5 x 10(4) copies/ml was correlated with slower progression to AIDS (P < 0.05). A correlation between the rate of CD4 decline and the median viral load during the ensuing viral load plateau phase was also shown (P < 0.05). Subsequent to this phase the viral burden increased. Rapid progressors had higher viral load than slow- or non-progressors; this was particularly pronounced late in infection. Harbouring syncytium-inducing (SI) virus at seroconversion was associated with faster progression to AIDS than non-SI (NSI; P < 0.005). The increased in vitro replication rate of SI over NSI was not translated into significantly higher serum HIV RNA., Conclusion: Serum HIV RNA is high around the time of seroconversion. A significant decline within the first months hereafter is followed by a plateau phase, which in turn is followed by an increase in HIV RNA. HIV RNA early in infection has a predictive value for the clinical outcome. The increased virulence of SI over NSI virus did not translate into significantly higher HIV RNA values.