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Background: CD4 cell count is a key measure of HIV disease progression, and the basis of successive international guidelines for treatment initiation. CD4 cell dynamics are used in mathematical and econometric models for evaluating public health need and interventions. Here, we estimate rates of CD4 decline, stratified by relevant covariates, in a form that is clinically transparent and can be directly used in such models., Methods: We analyse the AIDS Therapy Evaluation in the Netherlands cohort, including individuals with date of seroconversion estimated to be within 1 year and with intensive clinical follow-up prior to treatment initiation. Owing to the fact that CD4 cell counts are intrinsically noisy, we separate the analysis into long-term trends of smoothed CD4 cell counts and an observation model relating actual CD4 measurements to the underlying smoothed counts. We use a monotonic spline smoothing model to describe the decline of smoothed CD4 cell counts through categories CD4 above 500, 350-500, 200-350 and 200 cells/μl or less. We estimate the proportion of individuals starting in each category after seroconversion and the average time spent in each category. We examine individual-level cofactors which influence these parameters., Results: Among untreated individuals, the time spent in each compartment was 3.32, 2.70, 5.50 and 5.06 years. Only 76% started in the CD4 cell count above 500 cells/μl compartment after seroconversion. Set-point viral load (SPVL) was an important factor: individuals with at least 5 log10 copies/ml took 5.37 years to reach CD4 cell count less than 200 cells/μl compared with 15.76 years for SPVL less than 4 log10 copies/ml., Conclusion: Many individuals already have CD4 cell count below 500 cells/μl after seroconversion. SPVL strongly influences the rate of CD4 decline. Treatment guidelines should consider measuring SPVL, whereas mathematical models should incorporate SPVL stratification.

Background and Objective: HIV-associated Pneumocystis jirovecii pneumonia (PJP) remains one of the commonest opportunistic infections in Western countries. Although it has been suggested that racial differences in PJP incidence exist, early studies report conflicting results. This study aimed to investigate differences in PJP incidence in a developed country among patients originating from sub-Saharan Africa compared with other regions of origin., Design and Methods: A retrospective observational cohort study was performed among 13,844 HIV-infected patients from the Dutch ATHENA cohort. The main outcome measure was occurrence of PJP., Results: A total number of 1055 PJP infections were diagnosed. Patients originating from sub-Saharan Africa had a significantly lower risk of having PJP at the time of HIV diagnosis after adjustment of confounders compared with patients from Western origin [Western Europe, Australia and New Zealand; adjusted odds ratio (aOR) 0.21 (95% confidence interval (CI) 0.15-0.29)]. Other factors associated with higher PJP risk were increasing age [aOR 1.01 per year (95% CI 1.00-1.02)], a low CD4 count at HIV diagnosis [CD4 <50 versus >350 cells/μl aOR 123.3 (95% CI 77.8-195.5)] and a high plasma HIV-RNA (>100,000 copies/ml) at HIV diagnosis [aOR 1.41 (95% CI 1.19-1.66)]. Moreover, a clearly lower risk for PJP acquisition later during follow-up was observed among sub-Saharan Africans versus Western patients [adjusted hazard ratio 0.60 (95% CI 0.39-0.90)]., Conclusion: Among HIV-infected patients living in the Netherlands, PJP occurrence is substantially lower in patients originating from sub-Saharan Africa, as compared to Western patients. Differences in genetic susceptibility may partially explain the lower PJP incidence in these patients.

Objective: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART)., Design: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml)., Methods: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/μl (group A), 200-350 cells/μl (group B), 351-500 cells/μl (group C) or more than 500 cells/μl (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs)., Results: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33-0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14-0.86)]., Conclusion: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

Objective: The potential for changing HIV-1 virulence has significant implications for the AIDS epidemic, including changing HIV transmission rates, rapidity of disease progression, and timing of ART. Published data to date have provided conflicting results., Design: We conducted a meta-analysis of changes in baseline CD4(+) T-cell counts and set point plasma viral RNA load over time in order to establish whether summary trends are consistent with changing HIV-1 virulence., Methods: We searched PubMed for studies of trends in HIV-1 prognostic markers of disease progression and supplemented findings with publications referenced in epidemiological or virulence studies. We identified 12 studies of trends in baseline CD4(+) T-cell counts (21, 052 total individuals), and eight studies of trends in set point viral loads (10 ,785 total individuals), spanning the years 1984-2010. Using random-effects meta-analysis, we estimated summary effect sizes for trends in HIV-1 plasma viral loads and CD4(+) T-cell counts., Results: Baseline CD4(+) T-cell counts showed a summary trend of decreasing cell counts [effect = -4.93  cells/μl per year, 95% confidence interval (CI) -6.53 to -3.3]. Set point viral loads showed a summary trend of increasing plasma viral RNA loads (effect = 0.013  log(10)  copies/ml per year, 95% CI -0.001 to 0.03). The trend rates decelerated in recent years for both prognostic markers., Conclusion: Our results are consistent with increased virulence of HIV-1 over the course of the epidemic. Extrapolating over the 30 years since the first description of AIDS, this represents a CD4(+) T cells loss of approximately 148  cells/μl and a gain of 0.39  log(10)  copies/ml of viral RNA measured during early infection. These effect sizes would predict increasing rates of disease progression, and need for ART as well as increasing transmission risk.

Objective: Heterozygosity for a 32 base pair deletion in the CCR5 gene (CCR5wt/Δ32) and the minor alleles of a single-nucleotide polymorphism in the HCP5 gene (rs2395029) and in the HLA-C gene region (-35HLA-C; rs9264942) has been associated with a lower viral load set point. Recent studies have shown that over calendar time, viral load set point has significantly increased at a population level. Here we studied whether this increase coincides with a fading impact of above-mentioned host genetic markers on HIV-1 control., Methods: We compared the association between viral load set point and HCP5 rs2395029, -35HLA-C rs9264942, and the CCR5wt/Δ32 genotype in HIV-1-infected individuals in the Netherlands who had seroconverted between 1982 and 2002 (pre-2003 seroconverters, n = 459) or between 2003 and 2009 (post-2003 seroconverters, n = 231)., Results: Viral load set point in post-2003 seroconverters was significantly higher than in pre-2003 seroconverters (P = 4.5 × 10(-5)). The minor alleles for HCP5 rs2395029, -35HLA-C rs9264942 and CCR5wt/Δ32 had a similar prevalence in both groups and were all individually associated with a significantly lower viral load set point in pre-2003 seroconverters. In post-2003 seroconverters, this association was no longer observed for HCP5 rs2395029 and CCR5wt/Δ32. The association between viral load set point and HCP5 rs2395029 had significantly changed over time, whereas the change in impact of the CCR5wt/Δ32 genotype over calendar time was not independent from the other markers under study., Conclusion: The increased viral load set point at a population level coincides with a lost impact of certain host genetic factors on HIV-1 control., (2011 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Background: Early diagnosis of HIV-1 infection will probably beneficially impact onward transmission and life expectancy. We compared mortality rates and CD4 cell counts at start of combination antiretroviral therapy (cART) in patients with different frequencies of diagnostic testing for HIV., Methods: Patients infected with HIV-1 through sexual contact and in follow-up anytime from 2004 through 2008 were selected from the AIDS Therapy Evaluation in the Netherlands national observational HIV cohort and stratified into three groups: patients without a prior negative HIV antibody test (i.e., with a positive first-test result); patients with 1-2 years between the last negative and first positive test; and patients with less than 1 year between tests. Outcome measures were mortality from 2004 through 2008 and CD4 cell count at cART initiation., Results: Of 5494 patients, the mortality rate was highest among the 4067 patients with a positive first test (1.33/100 person-years) and the adjusted relative risk of mortality was 0.50 in 561 patients with tests 1-2 years apart (P = 0.04 compared to patients with a positive first test) and 0.49 (P = 0.02) when tests were less than 1 year apart (n = 866). In patients with a positive first test, 48% had CD4 cell counts less than 200 cells/μl at cART initiation; this proportion was 23-26% in the two groups of repeatedly tested patients (adjusted odds ratio compared to patients with a positive first test 0.43 and 0.37, respectively; both P < 0.0001)., Conclusion: Frequent repeated testing for HIV may improve the rate of timely diagnosis and treatment, thereby preventing disease progression.

Objective: To compare life expectancies between recently diagnosed HIV-infected patients and age and sex-matched uninfected individuals from the general population., Design: : National observational HIV cohort in the Netherlands., Methods: Four thousand, six hundred and twelve patients diagnosed with HIV between 1998 and 2007 and still antiretroviral therapy-naive as of 24 weeks after diagnosis were selected. Progression to death compared to the age and sex-matched general population was studied with a multivariate hazards model in 4174 (90.5%) patients without AIDS events at 24 weeks. Life expectancy and number of life years lost were calculated using the predicted survival distribution., Results: During 17 580 person-years of follow-up since 24 weeks after diagnosis [median follow-up 3.3 years, interquartile range (IQR) 1.6-5.8], 118 deaths occurred, yielding a mortality rate of 6.7 [95% confidence interval (CI) 5.5-8.0] per 1000 person-years. Median CD4 cell counts at 24 weeks were 480 cells/microl (IQR 360-650). According to the model, the median number of years lived from age 25 was 52.7 (IQR 44.2-59.3; general population 53.1) for men and 57.8 (49.2-63.7; 58.1) for women without CDC-B event. The number of life years lost varied between 0.4 if diagnosed with HIV at age 25 and 1.4 if diagnosed at age 55; for patients with a CDC-B event this range was 1.8-8.0 years., Conclusion: The life expectancy of asymptomatic HIV-infected patients who are still treatment-naive and have not experienced a CDC-B or C event at 24 weeks after diagnosis approaches that of non-infected individuals. However, follow-up time is short compared to the expected number of years lived.

Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse events. Combined use of lopinavir/ritonavir and rifampicin is challenging as it implies balancing between suboptimal efficacy and toxicity.

Objective: Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic., Design: We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs., Methods: We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses., Results: We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate., Conclusion: We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

For 95 protease inhibitor-experienced HIV-1-infected patients, the genotypic inhibitory quotient (GIQ; trough level/number of mutations) was calculated for lopinavir. Three different sets of mutations showed equal predictive value. However, the use of cumulative numbers of mutations for calculation of the GIQ showed significantly better association with the virological response. Furthermore, the predictive value of the GIQ was no different from that of the number of mutations alone.