Performance of the marginal structural cox model for estimating individual and joined effects of treatments given in combination.

BACKGROUND: The Marginal Structural Cox Model (Cox-MSM), an alternative approach to handle time-dependent confounder, was introduced for survival analysis and applied to estimate the joint causal effect of two time-dependent nonrandomized treatments on survival among HIV-positive subjects. Nevertheless, Cox-MSM performance in the case of multiple treatments has not been fully explored under different degree of time-dependent confounding for treatments or in case of interaction between treatments. We aimed to evaluate and compare the performance of the marginal structural Cox model (Cox-MSM) to the standard Cox model in estimating the treatment effect in the case of multiple treatments under different scenarios of time-dependent confounding and when an interaction between treatment effects is present. METHODS: We specified a Cox-MSM with two treatments including an interaction term for situations where an adverse event might be caused by two treatments taken simultaneously but not by each treatment taken alone. We simulated longitudinal data with two treatments and a time-dependent confounder affected by one or the two treatments. To fit the Cox-MSM, we used the inverse probability weighting method. We illustrated the method to evaluate the specific effect of protease inhibitors combined (or not) to other antiretroviral medications on the anal cancer risk in HIV-infected individuals, with CD4 cell count as time-dependent confounder. RESULTS: Overall, Cox-MSM performed better than the standard Cox model. Furthermore, we showed that estimates were unbiased when an interaction term was included in the model. CONCLUSION: Cox-MSM may be used for accurately estimating causal individual and joined treatment effects from a combination therapy in presence of time-dependent confounding provided that an interaction term is estimated.

Loss of long-term non-progressor and HIV controller status over time in the French Hospital Database on HIV - ANRS CO4.

OBJECTIVES: We studied the frequency and risk factors for loss of long-term non-progressor (LTNP) and HIV controller (HIC) status among patients identified as such in 2005 in the French Hospital Database on HIV (FHDH-ANRS CO4). METHODS: We selected patients who were treatment-naïve and asymptomatic in 2005 (baseline). Those with ≥8 years of known HIV infection and a CD4 cell nadir ≥500/mm3 were classified as LTNP and those with ≥10 years of known HIV infection and 90% of plasma viral load (VL) values ≤500 copies/ml in the absence of cART as HIC. cART initiation without loss of status and death from non AIDS-defining causes were considered as competing events. RESULTS: After 5 years of follow-up, 33% (95%CI; 27-42) of 171 LTNP patients and 17% (95%CI; 10-30) of 72 HIC patients had lost their status. In multivariable analyses, loss of LTNP status was associated with lower baseline CD4 cell counts and CD4/CD8 ratios. Only VL was significantly associated with loss of HIC status after adjustment for the baseline CD4 cell count, the CD4/CD8 ratio, and concomitant LTNP status. The hazard ratio for loss of HIC status was 5.5 (95%CI, 1.5-20.1) for baseline VL 50-500 vs ≤50 cp/mL, after adjustment for the baseline CD4 cell count. CONCLUSIONS: One-third of LTNP and one-fifth of HIC patients lost their status after 5 years of follow-up, raising questions as to the possible benefits and timing of ART initiation in these populations.

Incidence of herpes zoster in HIV-infected adults in the combined antiretroviral therapy era: results from the FHDH-ANRS CO4 cohort.

BACKGROUND: Recent studies have shown a decrease in the incidence of herpes zoster (HZ) among human immunodeficiency virus (HIV)-infected patients since the combined antiretroviral therapy (cART) era, but more data are needed on a possible increase in the risk early after cART initiation. METHODS: We studied HZ incidence and risk factors among patients followed in the French Hospital Database on HIV (FHDH) between 1992 and 2011. Standardized incidence ratios (SIRs) were used for comparison with the general population between 2005 and 2008. The risk of HZ following cART initiation (0-5 and ≥6 months) was studied with Poisson regression models. RESULTS: A total of 7167 cases of incident HZ were diagnosed among 91 044 individuals (583 125 person-years [PY]). The incidence declined significantly, from 2955 per 100 000 PY in 1992-1996 to 628 per 100 000 PY in 2009-2011. This decline was mainly explained by cART (relative risk [RR], 0.60; 95% confidence interval {CI}, .57-.64). The risk of HZ was associated with low CD4 cell counts, high HIV RNA levels, low CD4/CD8 ratios, and prior AIDS. Compared to the general population, the risk of HZ was higher in HIV-infected patients (overall SIR, 2.7; 95% CI, 2.6-2.9), particularly those aged 15-44 years (SIR, 4-6). In ART-naive patients, a moderate increase in the HZ risk was observed during the first 6 months of cART, with a peak at 3 months (RR, 1.47; 95% CI, 1.26-1.73), a finding that disappeared after adjustment for the current CD4 cell count (RR, 1.03; 95% CI, .81-1.32). CONCLUSIONS: The risk of HZ has declined markedly among HIV-infected patients in the cART era, but remains 3 times higher than in the general population. The risk increases moderately during the first 6 months of cART.

Cohort Profile: French hospital database on HIV (FHDH-ANRS CO4).

The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120,000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/_fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee.

Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV.

PURPOSE: To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS: From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS: In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/µL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/µL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/µL. CONCLUSION: Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM.

Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV.

OBJECTIVE: To estimate the prevalence and characteristics of long-term nonprogressor (LTNP) and HIV controller patients in a very large French cohort of HIV1-infected patients. METHODS: In the French Hospital Database on HIV [FHDH, Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) CO4], we selected patients who had been seen in 2005, who had been infected for more than 8 years, who were treatment-naive, and who remained asymptomatic. Patients with these characteristics then categorized as follows: LTNP (> or =8 years of HIV infection and CD4 cell nadir > or =500/microl), elite LTNP (> or =8 years of HIV infection, CD4 cell nadir > or =600/microl, and a positive CD4 slope), HIV controllers (>10 years of HIV infection with 90% of plasma viral load values < or =500 copies/ml), and elite controllers (same as HIV controllers, but with last plasma viral load value < or =50 copies/ml in 2005). RESULTS: Among the 46 880 HIV1-infected patients followed in 2005 in the French Hospital Database on HIV, 0.4% (N = 202) were LTNP, 0.05% (N = 25) were elite LTNP, 0.22% (N = 101) were HIV controllers, and 0.15% (N = 69) were elite controllers. Ten elite LTNP patients (40%) were also HIV controllers, eight (32%) were elite controllers, and 60% had detectable plasma viral load (>50 copies/ml). Among the elite controllers, 32 (46%) were LTNP, eight (12%) were elite LTNP, and one-quarter had a last CD4 cell count less than 500/microl. CONCLUSION: LTNP, elite LTNP, HIV controller, and elite controller patients are rare phenotypes. Elite LTNP patients are less frequent than HIV controllers. There is little overlap among the four subgroups of patients.

Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy.

OBJECTIVE: To describe the cases of anal cancer that appeared in the French Hospital Database on HIV between 1992 and 2004 and to study risk factors of anal cancer. METHODS: We examined the incidence rates of anal cancer between 1992 and 2004 and the risk associated among 86,322 HIV-infected patients included in the French Hospital Database on HIV. RESULTS: We identified 132 cases of anal cancer, including 124 cases in men (94%), of whom 75% had sex with men. Median age at diagnosis was 42.8 years (interquartile range: 36.9-49.4). At diagnosis, 103 patients (78%) were receiving combination antiretroviral therapy for a median of 37.1 months (interquartile range: 4.5-59.8). Median survival after anal cancer diagnosis was 5 years. The respective overall incidence rates of anal cancer per 100,000 person-years between 1992 and March 1996, April 1996 to 1998 and between 1999 and 2004 were 11 (95% confidence interval, 4-17), 18 (95% confidence interval, 10-27) and 40 (95% confidence interval, 32-47). The risk of anal cancer was higher among men who have sex with men. After adjustment for age at inclusion in the study, as well as gender, the HIV transmission group, the nadir CD4 cell count and AIDS status, the incidence was higher in the years 1999-2004 than in between 1992 to March 1996 (hazard ratio, 2.5; 95% confidence interval, 1.2-5.3), with no change in the years 1999-2004. CONCLUSION: The incidence of anal cancer has increased among HIV-infected patients in France since 1996. Although an ascertainment bias cannot be excluded, data indicate that combination antiretroviral therapy does not prevent anal cancer in these patients. This supports the urgent need for developing anal cancer screening programs for HIV-infected men who have sex with men.

Dual nucleoside reverse transcriptase inhibitor therapy in the combination antiretroviral therapy era and predictors of discontinuation or switch to combination antiretroviral therapy.

BACKGROUND: Contrary to current HIV/AIDS management guidelines, and despite the arrival of potent combination antiretroviral therapy (cART) many years ago, some patients are still treated with dual nucleoside reverse transcriptase inhibitor (NRTI) regimens. METHODS: We selected 5222 patients who received dual NRTI therapy for at least 6 months during 1998 to 2002, representing 9.9% of the 52,981 ARV-treated patients recorded in the French Hospital Database on HIV. Factors associated with switching to cART or with ARV discontinuation were identified by using Cox models. RESULTS: The 3-year probabilities of switching to cART and of antiretroviral (ARV) drug discontinuation were 55.2% (95% confidence interval [CI]: 53.8 to 56.7) and 10.9% (95% CI: 10.1 to 11.8), respectively, whereas 1591 patients (30.5%) kept the dual NRTI therapy during all the study period. Place of birth and region of care did not influence the choice of treatment strategy. After adjustment, the likelihood of switching to cART was lower among women, intravenous drug users, and patients with an undetectable plasma viral load (pVL) on at least 1 occasion during follow-up; in contrast, it was higher among patients with AIDS and those with a low CD4 cell count at enrollment or at the last follow-up visit. The likelihood of ARV discontinuation was higher among women and intravenous drug users and lower among patients with a low CD4 cell count at inclusion or at the last follow-up visit and among patients with an undetectable pVL on at least 1 occasion during follow-up. The likelihood of switching to cART or discontinuing ARV drugs was higher among patients receiving zidovudine/zalcitabine or didanosine/stavudine than among those receiving zidovudine/lamivudine. CONCLUSIONS: In France, until recent years, some patients (mainly women and intravenous drug users) were still receiving dual NRTI therapy despite free access to care and to highly effective ARV regimens. Dual NRTI therapy is gradually being replaced by cART, although some patients with satisfactory immunovirologic status are discontinuing all ARV drugs.

Does accounting for gene-environment (GxE) interaction increase the power to detect the effect of a gene in a multifactorial disease?

Despite tremendous efforts, few genes involved in the susceptibility for complex disorders have been identified. One explanation is that these disorders are a result of an interaction between genes and environment, and under such conditions, it may be difficult to measure the true genetic effect without accounting for the interaction. Umbach and Weinberg ([2000] Am. J. Hum. Genet. 66:251-261) proposed an association test which looks at the joint effects of genotype and environment, using case-parent trios. In this study, we explore under which conditions accounting for GxE interaction enhances one's ability to detect the role of genetic factors in complex diseases. Using asymptotic power calculations, we investigate the power to detect the gene effect over varying exposure frequencies and different scenarios of GxE interaction. We show that for a given sample size, interaction scenario, and allele frequency, the actual gain in power while accounting for the interaction depends on the magnitude of the exposure frequency: the largest gains are seen for relatively low exposure frequencies. Moreover, a loss of power can be observed when the exposure is frequent and/or the exposure effect is strong. If we consider a gene with a disease allele frequency of 0.2, with no effect in the absence of exposure, an exposure with a 10-fold increase risk and a GxE relative risk of 2, then when the exposure frequency is 0.1, accounting for GxE interaction increases the power to detect the gene effect in 200 trios by 10%; alternatively, when the exposure frequency is 0.9, it decreases the power by 15%.

[Percutaneous endoscopic gastrostomy in elderly patients. A prospective study in a geriatric hospital]. / Résultats de la gastrostomie percutanée endoscopique chez le sujet âgé

OBJECTIVES: The purpose of this work was to search for prognostic factors after percutaneous endoscopic gastrostomy (PEG) for enteral nutrition in geriatric patients by studying complications, nutritional benefits, and impact on quality of life. METHODS: In this prospective study, 59 elderly patients referred for PEG were followed for 1 year or until tube removal or death. Complications, tolerance to enteral nutrition, nutritional status, infection, bedsores and quality of life were assessed by a questionnaire at tube insertion, at 1 month and every 3 months. Multivariate analysis was performed to look for factors predictive of early mortality before one month. RESULTS: Insertion of the PEG tube was always successful. Pneumonia in the week before tube insertion was predictive of early mortality (odds-ratio: 8.77 [1.63-47.2], P=0.01). Thirty-day mortality was 25%, but was never related to PEG tube insertion. During follow up, no local complication was observed and enteral feeding was well tolerated. After 3 months, serum albumin and prealbumin levels increased (P<0.001). There were fewer infections (P<0.001) and bedsores remained unchanged. Quality-of-life scores were not modified. At one year, the PEG tube was removed in 16 patients who resumed normal oral nutrition, and 6 other patients were able to return to their home. CONCLUSION: In a cohort of aged institutionalized patients, PEG for enteral nutrition was well tolerated and not definitive in more than one-quarter of them. Active lung infection is a risk factor of early mortality.