Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. To examine postulated associations of genetic alleles with HIV-1 disease progression. Meta-analysis of individual-patient data. 19 prospective cohort studies and case–control studies from the United States, Europe, and Australia. Patients with HIV-1 infection who were of European or African descent. Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. Both the CCR5-Δ 32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, −0.18 log₁₀ copies/mL and −0.14 log₁₀ copies/mL; P < 0.05 for both). Having the CCR5-Δ32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3′A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). The CCR5-Δ 32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3′A homozygosity carried no such protection.

AN APPROPRIATE comprehension of the factors that affect the virological response to antiretroviral treatments is warranted to improve the clinical treatment of human immunodeficiency virus (HIV)–infected patients. It is important, as well, to expand the rational basis for the accurate design of effective therapies and to reduce the duration and complexity of clinical trials. Formerly, the natural history of HIV infection was invariably unidirectional, progressively leading to acquired immunodeficiency syndrome (AIDS) and death, and the efficacy of therapy was determined by its ability to delay this fatal progression. Therefore, predictors of clinical progression have been extensively studied and precisely determined in HIV-infected patients.^1-8 Today, the clinical prognosis of HIV infection has radically changed because of the widespread use of highly active antiretroviral therapy (HAART), including protease inhibitors (PIs).^9-11 Partly because these studies link plasma HIV-1 RNA levels with risk of clinical progression, the positivist goal of antiretroviral therapy is now to reduce and maintain HIV-1 RNA levels below the lowest detectable.¹²

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. 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. 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. 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.

To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting. Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates. Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with -2.22% points per year (95% CI -3.21 to -1.23), Burkholderia cepacia complex -1.95% (95% CI -2.51 to -1.39), Achromobacterxylosoxidans -1.55% (95% CI -2.21 to -0.90), and Pseudomonas aeruginosa -0.95% (95% CI -1.24 to -0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope. In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function.

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

Nontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described. In this retrospective observational study we identified all Scandinavian CF patients with a positive NTM culture from airway secretions from 2000 to the end of 2012 and used national CF databases to describe microbiological and clinical characteristics. During the 13-year period 157 (11%) CF patients were culture positive for NTM at least once. Mycobacterium abscessus complex (MABSC) (45%) and Mycobacterium avium complex (MAC) (32%) were the predominant species with geographical differences in distribution. Younger patients were more prone to MABSC (p<0.01). Despite treatment, less than one-third of MABSC patients with repeated positive cultures cleared their infection and a quarter had a lung transplant or died. NTM are significant CF pathogens and are becoming more prevalent in Scandinavia. MABSC and MAC appear to target distinct patient groups. Having multiple positive cultures despite treatment conveys a poor outcome.