How does loss to follow-up influence cohort findings on HIV infection? A joint analysis of the French hospital database on HIV, Mortalité 2000 survey and death certificates.

OBJECTIVE: We aimed to retrieve the vital status of patients lost to follow-up (LFU), with no further visits for at least 12 months, for the 34,835 patients in the Agence Nationale de Recherche sur le SIDA CO4 French Hospital Database on HIV (ANRS CO4 FHDH) seen in 1999 and to examine how loss to follow-up might influence estimates of survival and the impact of delayed access to care (DAC) on survival. METHODS: The status of LFU patients was established by using the mid-2006 update of the FHDH in which their status 12 months after loss to follow-up was added when available and by matching with the Mortalité 2000-Epidemiological Centre for Medical Causes of Death (CépiDc) database, which included HIV-infected patients dying in 2000. We compared Kaplan-Meier and hazard ratio (HR) estimates before and after correction for the status of LFU patients. RESULTS: In the mid-2006 updated FHDH, of the patients seen in 1999, 7.5% were LFU: of these, 2.1% later returned for follow-up, with a median time without follow-up in an FHDH centre of 3.5 years, and 5.4% had no further FHDH visits whatsoever, of whom 29.8% died according to Mortalité 2000-CépiDc. After correction, the estimated 1-year survival rates following enrolment in 1999 differed between the original and updated analyses (97.1 vs. 95.9%, respectively; P=0.017); the estimates of mortality HRs associated with DAC did not differ during the first 6 months, but did differ for the 6-18-month period. CONCLUSIONS: Among LFU patients, 28.1% returned to follow-up after several years and at least 21.4% died, which led to a slight overestimation of both survival and the impact of DAC on survival.

Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 study in collaboration with the Mortalité 2005 survey, ANRS EN19).

BACKGROUND: More than 10 years after the introduction of combination antiretroviral therapy (cART), we examined the trend in the proportion of deaths caused by end-stage liver disease (ESLD) in HIV-infected adults in France between 1995 and 2005. DESIGN AND METHODS: In 2005, 34 departments prospectively recorded all deaths in HIV-infected patients who were followed in those departments (around 24 000). RESULTS: were compared with those of four previous cross-sectional surveys conducted since 1995 using the same methodology. Results Among 287 reported deaths in 2005, 100 (35%) were related to AIDS, and 48 (17%) to ESLD. Three out of four patients who died from ESLD-related causes had chronic hepatitis C. Excessive alcohol consumption was reported in approximately half of the patients (48%). At death, 62% of patients had undetectable HIV viral load and the median CD4 count was 237 cells/microL. From 1995 to 2005, the proportion of deaths caused by ESLD increased from 2 to 17% (P<0.001). The proportion of deaths caused by hepatocellular carcinoma increased from 5% in 1995 to 25% in 2005 (P=0.0337). CONCLUSIONS: Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients. ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients.

Pregnancy may be followed by an inflexion of the immune reconstitution in HIV-infected women who receive antiretroviral drugs before conception.

BACKGROUND: Whether pregnancy has an impact on the evolution of CD4 cell counts in women treated with highly potent antiretrovirals before conception remains largely unknown. METHODS: Among patients enrolled in the ANRS CO8 (APROCO/COPILOTE) cohort, we selected all women aged between 18 and 50 years at initiation of combination antiretroviral therapy (cART). Slopes of CD4 cell counts during follow-up were estimated using mixed longitudinal models with time-dependent indicators for pregnancy and delivery. RESULTS: Of the 260 selected HIV-infected women, a pregnancy occurred in 39 women in a median follow-up time of 66 months. Women who became pregnant had higher CD4 cell count at baseline but this difference progressively lessened during follow-up because they had a slower increase than women who did not become pregnant. The estimated slope of CD4 cell count decreased significantly from +2.3 cells/muL/month before pregnancy and in women who did not become pregnant to -0.04 cells/microL/month after delivery (P=0.0003). CONCLUSION: A significant increase in CD4 cell count may be preferable before pregnancy in women treated with cART, in order to overcome the evolution observed after pregnancy.

[Lopinavir/ritonavir in HIV-infected patient with long-term virological failure: immunovirological response and tolerance in 121 patients of the ANRS CO8 Aproco-Copilote cohort]. / Lopinavir/ritonavir chez le patient infecté par le VIH en situation d'échec virologique prolongé: évolution immunovirologique et tolérance chez 121 patients de la cohorte ANRS CO8 Aproco-Copilote.

OBJECTIVE: This study was made to determine the immunovirological outcome and tolerance to lopinavir/ritonavir (LPV/r) in HIV-infected protease inhibitors-experienced patients with long-term virological failure. DESIGN: Prospective follow-up was implemented for the French cohort ANRS CO8 Aproco-Copilote of 121 patients starting an LPV/r-containing regimen after a median duration of virological failure of 30.6 months. At baseline the median HIV-RNA plasma level was 4.1 log(10) copies/ml and the median CD4 cell count was 273/mm(3). RESULTS: On initiation of LPV/r, these patients were heavily pre-treated: 62% had received at least 4 NRTI, 65% at least 1 NNRTI, and 33% at least 3 PI. On prescription of LPV/r, the associated antiretroviral regimen was: no drug to which patients were previously naïve in 49 cases (40%), at least one new drug in 72 cases: 1 NRTI (n=42), 2 NRTI (n=22), 1 NNRTI (n=10), at least one new PI (n=6), enfuvirtide (n=2). The median HIV-RNA level was 2 log(10) copies/ml at M4 and M12, 1.7 log(10) copies/ml at M24 with respectively 74, 71 and 85% of patients achieving plasma HIV-RNA below 2.7 log(10) copies/ml. The median CD4 cell count was 385 and 429/mm(3) at M12 and M24 respectively. Among patients with genotypic testing at the time of LPV/r initiation, Ninety-five percent had at the most 5 protease mutations known to reduce LPV/r susceptibility. Thirty serious adverse events were reported but only 6 were related to LPV/r. CONCLUSION: The use of LPV/r in HIV-infected patients failing multiple antiretroviral regimens provided a potent and durable immunovirological response.

[Causes and characteristics of death among HIV-1 infected patients with immunovirologic response to antiretroviral treatment]. / Causes et caractéristiques des décès des patients infectés par le VIH-1, en succès immuno-virologique sous traitement antirétroviral.

INTRODUCTION: To analyse the causes of death among HIV-infected adults in France in the year 2000. METHODS: Based on data from a national survey, our study describes and analyses the causes and characteristics of patients with immunological and virological response (CD4>200/mm3, ARN-HIV<500 copies/mL), who died during antiretroviral treatment. RESULTS: Among a total of 964 deaths registered, data on 864 cases were available for analysis. One hundred forty-nine patients (17%)were immunovirological responders. The underlying causes of death were non AIDS-defining malignancies for 36 (24%), mainly due to lung cancer (16 cases), hepatocarcinoma (7) and ano-rectal carcinoma (3), AIDS for 22 (15%), mainly due to Non Hodgkin Lymphoma (10 cases) and uterine cancer (3), cardiovascular diseases for 22 (15%), post hepatitis C hepatic failure for 16 (11%), suicide for 16 (11%), and bacterial infections for 14(9%). When comparing characteristics of death in the 149 responders versus the 715 other patients, the responders were significantly more frequently: co-infected by HCV+ (45 vs. 33%), injected drug addicts (40 vs. 27%),alcoholics (38 vs. 28 %), and dyslipidemics (19 vs. 11%). In 2000,around 20% of registered deaths of HIV patients in France had occurred among good immunovirological responders. CONCLUSION: To further reduce mortality among such efficiently treated patients, attention must be focused on treatable conditions such as hepatitis C, dyslipidemia and on the prevention of malignancies such as lung cancer and cervical or ano-rectal carcinoma.

[Causes of death among HIV infected adults in French Guyana and the French West Indies in the era of highly active antiretroviral therapy (HAART)]. / Causes de décès des adultes infectés par le VIH dans les départements français d'Amérique à l'ère des traitements antirétroviraux hautement actifs.

OBJECTIVE: The survey "Mortality 2000" had for aim to describe the distribution of causes of death in HIV-infected adults in France. METHOD: Hospital wards involved in the management of HIV infection prospectively reported deaths occurring in 2000. The causes of death were documented using a standardized questionnaire. RESULTS: In French Guyana and the French West Indies the five referent wards reported 81 deaths. The main underlying causes of death were AIDS-related (67%), non-AIDS and non-hepatitis related cancer (9%), cardiovascular disease (7%), bacterial infections (5%), and end stage liver disease (4%). Among AIDS-related deaths, the more frequent diseases were histoplasmosis and toxoplasmosis in Guyana and atypical mycobacterial infection, tuberculosis, and cytomegalovirus disease in the West Indies. Median age was 43 years, transmission of HIV infection was heterosexual in 79%; 56% lived in poor socio-economic conditions, and 30% were born abroad. One out of five had been recently diagnosed with HIV infection and one out of three had never received antiretroviral treatment. CONCLUSION: In 2000, two in three death cases in HIV-infected adults were AIDS-related in French Guyana and the French West Indies. Improved strategies for screening HIV infection before the occurrence of AIDS are still needed taking into consideration poor socio-economic and migrant conditions.

Tuberculosis in HIV programmes in lower-income countries: practices and risk factors.

BACKGROUND: Tuberculosis (TB) is a common diagnosis in human immunodeficiency virus (HIV) infected patients on antiretroviral treatment (ART). OBJECTIVE: To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART. METHODS: Programme characteristics were assessed using standardised electronic questionnaire. Patient data from 2003 to 2008 were analysed and incidence rate ratios (IRRs) calculated using Poisson regression models. RESULTS: Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in respectively 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes. Eight sites (53.3%) used directly observed treatment and five (33.3%) routinely administered isoniazid preventive treatment (IPT). A total of 19 413 patients aged ≥ 16 years contributed 13,227 person-years of follow-up; 1081 new TB events were diagnosed. Risk factors included CD4 cell count (>350 cells/µl vs. <25 cells/µl, adjusted IRR 0.46, 95%CI 0.33-0.64, P < 0.0001), sex (women vs. men, adjusted IRR 0.77, 95%CI 0.68-0.88, P = 0.0001) and use of IPT (IRR 0.24, 95%CI 0.19-0.31, P < 0.0001). CONCLUSIONS: Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB, but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.

Characteristics and response to antiretroviral therapy of HIV-1-infected patients born in Africa and living in France.

BACKGROUND: The world-wide AIDS epidemic is reflected in Western Europe in an increasing number of HIV-infected persons who originate from Africa. We describe the characteristics and response to antiretroviral therapy (ART) of HIV-infected patients born in Africa and living in France. METHODS: Analysis of data from the (Anti PROtéase COhorte APROCO) cohort study of HIV-infected patients initiating ART was carried out. Included in the study were 90 patients born in sub-Saharan Africa, 53 in North Africa and 771 in metropolitan France. RESULTS: At baseline, there was a higher proportion of women and of the heterosexual transmission route of infection among patients born in sub-Saharan Africa, a higher proportion of injecting drug users among patients born in North Africa and a higher frequency of unemployment and of unstable housing conditions among patients born in both sub-Saharan and North Africa as compared with patients born in France. The median CD4 cell count was lower in patients born in both sub-Saharan and North Africa (sub-Saharan Africa: 197 cells/microL; North Africa: 222 cells/microL) than in patients born in France (307 cells/microL). Median HIV-1 viral loads were similar. After a median follow-up time of 36 months (2506 patient-years), the Kaplan-Meier estimations of probability of survival without new AIDS-defining events were not different. After 36 months of ART, in multivariate analysis, median CD4 cell count, CD4/CD8 ratio and viral load were not statistically different according to birthplace, but the median CD4 percentage was lower in patients born in both sub-Saharan and North Africa. The adherence profiles were similar. CONCLUSIONS: Although clinical response and adherence to ART did not appear to differ in patients according to their birthplace, the reasons for the more advanced HIV infection observed at ART initiation among patients born in Africa should be further investigated.

Combination antiretroviral therapy without a nucleoside reverse transcriptase inhibitor: experience from 334 patients in three cohorts.

BACKGROUND: Toxicity and resistance may limit the use of HIV nucleoside reverse transcriptase inhibitors (NRTIs). We assessed the safety and activity of regimens that did not include an NRTI. METHOD AND PATIENTS: We analysed NRTI-sparing regimens using pooled data from three cohorts in Australia and France where HIV RNA viral load, CD4 lymphocyte count and metabolic parameters are assessed prospectively. The inclusion criterion was the commencement of any antiretroviral combination excluding NRTIs. RESULTS: A total of 334 (3.9%) of 8477 patients were included in the present study for a median follow-up time of 105 weeks. Therapeutic combinations were one nonnucleoside reverse transcriptase inhibitor (NNRTI) plus one protease inhibitor (PI) (58%), two PIs (26%), one PI (16%), and one NNRTI plus two PIs (8%). At baseline, the median CD4 lymphocyte count was 264 cells/muL (interquartile range 164-446 cells/muL) and 25% of patients had plasma HIV RNA below 500 HIV-1 RNA copies/mL. In intent-to-treat analysis, 64% of patients had HIV RNA <500 copies/mL at 6 months and 68% at 24 months. The mean CD4 lymphocyte count increase was 60 cells/microL (95% confidence interval 41-76 cells/microL) at 6 months and 111 cells/microL (95% confidence interval 82-140 cells/microL) at 24 months. Prognostic factors for having HIV RNA <500 copies/mL at 6 months included independently having undetectable HIV RNA at baseline and being naïve for NNRTIs. The proportion of patients with triglycerides >2.3 mmol/L increased from 32% to 63% at 6 months and to 62% at 24 months (P-trend=0.002), and those with total cholesterol >6.2 mmol/L increased from 18% to 38% at 6 months and to 44% at 24 months (P-trend <0.001), with an increased risk for patients treated with NNRTI+PIs. Forty-one per cent of patients discontinued their NRTI-sparing regimen. CONCLUSION: In these antiretroviral-experienced patients, NRTI-sparing therapy appeared to have satisfactory virological and immunological efficacy. However, hyperlipidaemia was frequent and requires monitoring of cardiovascular risk factors.

Number of deaths among HIV-infected adults in France in 2000, three-source capture-recapture estimation.

We estimated the number of deaths in France for the year 2000 in HIV-infected adults using three sources. The sources were (1) the 'Mortalité 2000' survey (M2000): 964 deaths were documented by 185 hospital wards involved in HIV management; (2) 1288 death certificates with a mention of HIV infection (INSERM-CepiDc) and (3) the French hospital database on HIV infection (FHDH) identified 654 deaths. The capture-recapture method was used with log-linear modelling. Overall 1559 deaths were observed. Estimation of the number of deaths in France was 1699 (95% CI 1671-1727). The completeness of M2000, CepiDc and FHDH were 55%, 76% and 38% respectively. Diversification of diseases and of causes of death in HIV-infected adults may explain: (1) the diversification of physicians involved in their management and incomplete coverage of M2000 and FHDH, and (2) why HIV infection was not mentioned in all death certificates.

Mortality in a cohort of HIV-infected adults started on a protease inhibitor-containing therapy: standardization to the general population.

Death rates in the APROCO cohort of 1,157 HIV-1 infected adults starting for the first time a protease inhibitor-containing therapy were standardized to the 1996 French general population mortality rates stratified by age and gender. Median follow-up was 23 months and mortality rate was 2.2% person-years (95% confidence interval [CI] = 1.6-2.9). Overall mortality was 7.8 times higher than in the general population (95% CI = 5.7-10.4), 4.7 in men and 19.5 in women. Among the 144 patients considered complete responders, the death rate was 1.2% person-years (95% CI = 0.2-3.5) and mortality remained 5.1 times higher (95% CI = 1.0-14.9) than in the general population. Failure of treatment, long-term adverse effects, or less favorable socio-demographic status could explain these trends.