Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS.

BACKGROUND: In the era of highly active antiretroviral therapy (HAART) mortality has decreased substantially among human immunodeficiency virus (HIV)-infected people with access to HAART, but there are concerns regarding co-morbidities and adverse effects of HAART, which may impair vital prognosis. The Mortality 2000 study examined the causes of death in HIV-infected adults at a national level in France in the year 2000. METHODS: All French hospital wards known to be involved in the management of HIV infection were asked to notify prospectively the deaths that occurred in 2000 among HIV-infected adults. The causes of death were documented using a standardized questionnaire. RESULTS: The 185 participating wards notified 964 deaths. The main underlying causes of death were AIDS-related (47%, non-Hodgkin's lymphoma: 23%), viral hepatitis (11%, hepatitis C: 9%, hepatitis B: 2%), cancer not related to AIDS or hepatitis (11%), cardiovascular disease (7%), bacterial infections (6%), suicide (4%), and adverse effect of antiretroviral treatments (1%). Among AIDS-related deaths, HIV infection had been diagnosed recently in 20%. Smoking was recorded in 72% of cancer-related deaths and alcohol consumption in 54% of hepatitis-related deaths. Among non-HIV related deaths between 25 and 64 years, the proportion of infectious diseases (including HCV and HBV-related deaths) was higher in HIV-infected adults than in the general population. CONCLUSIONS: Improved strategies for detecting HIV infection before AIDS-defining complications occur are needed in the era of HAART. The prevention of non-AIDS related cancers, especially lung cancer, the management of non-Hodgkin's lymphoma, and of viral hepatitis are also important priorities.

In vivo comparative pharmacokinetics and pharmacodynamics of moxifloxacin and levofloxacin in human neutrophils.

OBJECTIVE: Most of the newer fluoroquinolones are active against bacteria such as Streptococcus pneumoniae and Staphylococcus aureus, which are able to multiply inside polymorphonuclear leukocytes (PMNs). The aim of this study was to determine moxifloxacin and levofloxacin intracellular behaviour with their usual dosage regimen. METHODS: We determined the pharmacokinetics of moxifloxacin and levofloxacin at steady state in the PMNs of ten healthy volunteers receiving moxifloxacin 400mg and levofloxacin 500mg as a once-daily dosing regimen for 3 days. RESULTS: Both antibacterials showed a high level of intracellular penetration exhibiting PMNs/plasma ratios of 17.34 +/- 8.29 for moxifloxacin versus 8.15 +/- 5.23 for levofloxacin for maximum concentrations (C(max)) and 14.72 +/- 8.29 for moxifloxacin versus 8.15 +/- 5.23 for levofloxacin for the area under the plasma concentration-time curve. Estimation of the most predictive pharmacodynamic surrogate markers for concentration-dependent bactericidal antibacterials in the intracellular milieu by taking into account the susceptibility of S. pneumoniae and methicillin-susceptible S. aureus demonstrated consistently higher values with moxifloxacin than with levofloxacin, even though with both drugs the levels obtained are well above the recommended targets values. Indeed, C(max)/MIC ratios calculated in PMNs for moxifloxacin were 287.3 and 718.2 for S. pneumoniae and S. aureus, respectively, and for levofloxacin were 25.6 and 205.1, respectively. CONCLUSION: Moxifloxacin and levofloxacin seem to be well adapted for the treatment of infections due to susceptible intracellular bacteria, and moxifloxacin provides a greater margin of safety than levofloxacin.

An enzyme immunoassay for the quantification of plasma and intracellular lopinavir in HIV-infected patients.

The protease inhibitor lopinavir (LPV; [1S-[1R*(R*), 3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)-acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl) pentyl] tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimide acetamide) is widely used in anti-human immunodeficiency virus (HIV) therapy. Knowledge of the plasma and intracellular concentrations of the drug would be useful for a better understanding of LPV action and for therapeutic monitoring. The aim of this study was to develop a sensitive and specific immunoassay for LPV in plasma and cells. Anti-LPV polyclonal antibodies were raised in rabbits using a synthetic LPV derivative coupled to keyhole limpet hemocyanin (KLH) as immunogen. The enzyme tracer was prepared by chemically coupling the LPV derivative with acetylcholinesterase. These reagents were used to develop a competitive enzyme immunoassay (EIA) performed in microtitration plates. The assay was performed on a minimum of 50 microl of plasma or 2 x 10(6) cells. It showed good precision and efficiency in as much as recovery from human plasma and cell extracts spiked with LPV ranged between 87% and 104%, with coefficients of variation of less than 10%. The limit of detection (LOD) was 100 pg/ml, i.e., a value at least 10 times lower than those currently achieved using previously described techniques. Cross-validation with high-performance liquid chromatography (HPLC) revealed a good correlation between methods (r2=0.96). Intracellular concentrations of LPV were measured in cultured human T lymphoblastoid cells (CEM). A pharmacokinetic analysis of plasma and intracellular LPV was performed on a healthy volunteer, and measurements were done in patients infected with HIV. The results obtained indicated a high intracellular/extracellular concentration ratio in cultured cells (19.3) but not in cells from HIV patients (1.3). In contrast, in peripheral blood mononuclear cells (PBMC) the accumulation of ritonavir (RTV) was six times higher than LPV. To date, this is the first reported immunoassay for LPV, and this method is sensitive enough for monitoring plasma and intracellular LPV levels in HIV-infected patients and for intracellular studies.

Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice.

Highly active antiretroviral therapy (HAART) of human immunodeficiency virus-infected patients is associated with adverse effects, such as lipodystrophy and hyperlipidemia. The lipodystrophic syndrome is characterized by a peripheral lipoatrophy and/or fat accumulation in the abdomen and neck. In order to get insights into the physiopathological mechanisms underlying this syndrome, we treated mice with protease inhibitors (PIs) over a long period of time. Although atazanavir-treated mice presented the same circulating triglyceride concentration as control mice, lopinavir-ritonavir-treated mice rapidly became hypertriglyceridemic, with triglyceride levels of 200 mg/dl, whereas control and atazanavir-treated animals had triglyceride levels of 80 mg/dl. These results obtained with mice reproduce the metabolic disorder observed in humans. White adipose tissue (WAT) was analyzed after 8 weeks of treatment. Compared to the control or atazanavir treatment, lopinavir-ritonavir treatment induced a significant 25% weight reduction in the peripheral inguinal WAT depot. By contrast, the profound epididymal WAT depot was not affected. This effect was associated with a 5.5-fold increase in SREBP-1c gene expression only in the inguinal depot. Our results demonstrate that the long-term treatment of mice with PIs constitutes an interesting experimental model with which some aspects of the lipoatrophy induced by HAART in humans may be studied.

Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial.

BACKGROUND: The antiviral efficacy of didanosine in patients experiencing virological failure is not well known. METHODS: A total of 168 patients (139 men and 29 women) receiving stable antiretroviral therapy with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL were randomly assigned to have didanosine (n=111) or placebo (n=57) added to their currently failing regimen for 4 weeks. The primary efficacy end point was the change in HIV-1 RNA level from baseline to week 4. RESULTS: At baseline, the median HIV-1 RNA level was 3.8 log(10) copies/mL, the median CD4 cell count was 378 cells/mm(3), and the median number of nucleoside reverse-transcriptase inhibitor-associated mutations (NAMs) was 4. At week 4, a significant decrease in the median HIV-1 RNA level was observed in the didanosine group, compared with that in the placebo group (-0.56 vs. +0.07 log(10) copies/mL, respectively) (P<.0001). A total of 33 patients (31%) in the didanosine group, compared with 3 (6%) in the placebo group, had HIV-1 RNA levels <400 copies/mL (P<.001). Significant antiviral activity of didanosine was observed in patients with up to 5 NAMs at baseline. Diarrhea occurred in 5 patients (5%) in the didanosine group and 2 patients (4%) in the placebo group. CONCLUSIONS: In HIV-1-infected patients experiencing failure of antiretroviral therapy, didanosine retains short-term antiviral activity.

Opportunistic infections as causes of death in HIV-infected patients in the HAART era in France.

The objective of the study was to describe the underlying causes of death of HIV-infected patients in the HAART era and to focus on those related to opportunistic infection (OI), in a national multicentre study ('Mortalité 2000'). A total of 964 deaths were recorded and 924 cases were available for analysis. Underlying cause of death were AIDS-related (47%), viral hepatitis (11%), non-AIDS cancers (11%), cardiovascular diseases (7%) and others (11%). Among patients who died of AIDS events, 262 (27%) died of at least one OI. OIs reported at the time of death were Cytomegalovirus infection 67 times, Pneumocystis jiroveci pneumonia 56, disseminated Mycobacterium avium intracellulare infection 53 and cerebral toxoplasmosis 48. Compared to patients who died of other causes, patients who died of OIs were younger and more likely to be infected through heterosexual contact, in poor socioeconomic conditions, migrants, more recently diagnosed for HIV infection, and naive of antiretroviral therapy and OI prophylaxis. OIs are still a major cause of death in HIV-infected patient in the HAART era, especially among patients recently diagnosed for HIV infection and who do not have access to care, as well as in long term infected patients where prophylaxis should be revisited.

Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol.

BACKGROUND/AIMS: We analyzed the characteristics of HIV infected patients who died from liver disease, focusing on hepatitis virus co-infection. METHODS: One-hundred and eighty-five French hospital departments involved in HIV/AIDS management prospectively notified all deaths occurring in 2000. Patients whose hepatitis C (HCV) and hepatitis B (HBV) serostatus was known were classified as being infected by HCV alone, HBV alone (HBsAg positive), both HCV and HBV, or neither HCB nor HBV. RESULTS: Among 822 HIV infected patients, 29% were infected by HCV alone, 8% by HBV alone, and 4% by both HCV and HBV. The most frequent causes of death were liver disease (31% of cases) and AIDS (29%) among HIV-HCV co-infected patients, and AIDS (38%) and liver disease (22%) among HIV-HBV co-infected patients. Liver disease was a more frequent cause of death among patients co-infected by both HCV and HBV (44% of cases). Hepatocellular carcinoma was present in 15% of patients who died from liver disease, and was associated with HBV co-infection. Nearly half the patients who died from liver disease had more than 200 CD4/mm3. CONCLUSIONS: Liver disease is now a leading cause of death among HIV-HCV co-infected patients and is becoming an important cause of death among HIV-HBV co-infected patients. The risk of death from liver disease is highest in patients co-infected by both HCV and HBV.

Sensitive enzyme immunoassay for measuring plasma and intracellular nevirapine levels in human immunodeficiency virus-infected patients.

We have developed an enzyme immunoassay to measure nevirapine (NVP) in plasma and peripheral blood mononuclear cells. Anti-NVP polyclonal antibodies were raised in rabbits by using a synthetic NVP derivative coupled to keyhole limpet hemocyanin as the immunogen, and the enzyme tracer was prepared by chemically coupling the NVP derivative with acetylcholinesterase. These reagents were used to develop a sensitive competitive enzyme immunoassay performed in microtitration plates with a 100-pg ml(-1) limit of detection and thus approximately 100 times more sensitive than previously published techniques. The plasma assay was performed directly without extraction (in this case, a 500-pg ml(-1) limit of detection was observed) on a minimum of 30 micro l of plasma. This assay shows good precision and efficiency, since recovery from human plasma and cell extracts spiked with NVP ranged between 87 and 104%, with coefficients of variation of <10%. A pharmacokinetic analysis of plasma NVP was performed for seven patients infected with human immunodeficiency virus (HIV), and it gave results similar to published findings. Intracellular concentrations of NVP were measured in cultured human T-lymphoblastoid cells and peripheral blood mononuclear cells from HIV-infected patients. The results indicated a very low intracellular/extracellular concentration ratio (0.134), thus demonstrating the absence of intracellular drug accumulation. This is the first intracellular assay of a nonnucleoside reverse-transcriptase inhibitor, and this method could be useful in monitoring plasma and intracellular NVP levels in HIV-infected patients.

Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy.

BACKGROUND: Before the introduction of highly active antiretroviral therapy (HAART), malignancies accounted for less than 10% of all deaths among human immunodeficiency virus (HIV)-infected patients. This figure may have increased, and the observed types of malignant disease may have been modified, as a result of decreased occurrence of opportunistic infections, the chronicity of HIV infection, the possible oncogenic role of HIV itself, and the aging of the HIV-infected population. METHODS: All French hospital wards involved in the management of HIV infection were asked to prospectively document the deaths of HIV-infected patients in the year 2000. Underlying causes of death were defined using a standardized questionnaire. RESULTS: Of a total of 964 deaths, 269 (28%) were attributable to malignancies. Acquired immunodeficiency virus (AIDS)-related malignancies were the underlying cause of 149 deaths (15%); among these malignancies were non-Hodgkin lymphoma (n = 105 [11%]), noncerebral lymphoma (n = 78 [median CD4 count, 86 x 10(6) per liter; interquartile range [IQR], 35-231 x 10(6) per liter), and primary cerebral lymphoma (n = 27 [median CD4 count, 20 x 10(6) per liter; IQR, 4-109 x 10(6) per liter). Kaposi sarcoma was associated with 40 deaths (4%), and cervical carcinoma was associated with 5 (0.5%). Non-AIDS-related malignancies were the underlying cause of 120 deaths (13%); these non-AIDS-related malignancies included 103 solid tumors (50 respiratory tumors, 19 hepatocarcinomas, 9 digestive tumors, and 6 anal tumors; median CD4 count, 218 x 10(6) per liter; IQR, 108-380 x 10(6) per liter) and 17 hemopathies (12 Hodgkin lymphomas, 4 myeloid leukemias, and 1 myeloma; median CD4 count, 113 x 10(6) per liter; IQR, 56-286 x 10(6) per liter). Compared with patients who died of other causes, patients who died of solid tumors were more likely to be male, to smoke, to be older, and to have higher CD4 counts. CONCLUSIONS: Malignant disease has been a major cause of death among HIV-infected patients in industrialized nations since the introduction of HAART. Whereas lethal hemopathies and Kaposi sarcoma are associated with advanced immunosuppression, lethal solid tumors can occur in patients with controlled HIV infection.

[Causes of death in HIV-infected French drug users, 1995-2000]. / Causes de décès chez les usagers de drogues français infectés par le VIH, 1995-2000.

Since the decline in mortality among HIV-infected persons after introduction of highly active antiretroviral therapy, concerns related to co-morbidities have increased as they may impair vital prognosis, particularly in intravenous (IV) drug users. We describe firstly the changes in the distribution of the causes of death between 1995 and 2000 among IV drug users in the "Aquitaine Cohort" based on hospital information system, and secondly the distribution of the causes of death among IV drug users in the French national survey "Mortalité 2000" specifically set up in 2000 for optimal exhaustiveness. The total number of deaths declined between 1995 and 2000 and 1/3 were IV drug users. Deceased IV drug users were younger than other deceased patients, had longer median time from diagnosis of HIV infection and higher median CD4 cell count. Poor socio-economic conditions were notified in 55%. Among IV drug users, the proportion of AIDS-related deaths was above 75% in 1995 and below 30% in 2000. In 2000, 25% of deaths were HCV-related, 12% of deaths were due to accident, overdose or suicide, and 8% were due to non-AIDS non-HCV related cancer. Among IV drug users, improvement in vital prognosis requires to improve management of HCV infection and to take into account socio-economic conditions and other addictive behaviours like alcohol consumption and smoking.