Protease inhibitor treatment effect on aortic stiffness in normotensive patients with human immunodeficiency virus infection.

OBJECTIVES: Human immunodeficiency virus (HIV) infection and protease inhibitor (PI)-based antiretroviral treatment might increase large artery (aortic) stiffness compared with healthy untreated controls. To clarify the role of PI therapy in the progression of subclinical arteriosclerosis in patients with HIV, we investigated the impact of PI treatment on arterial stiffness. METHODS AND RESULTS: In our single-centre, cross-sectional study, normotensive male HIV patients free from overt cardiovascular disease received PI treatment (n=60) or no PI treatment (n=42). The PI group had a significantly higher pulse wave velocity (PWV) than the PI-free group (9.0 ± 1.4 vs. 8.1 ± 1.3m/s; P=0.016). There was a significant positive correlation between age and PWV in the PI-free group (R(2) 0.310; P<0.0001) and, to a lesser extent, in the PI group (R(2) 0.181; P<0.0001). PI treatment was associated with a significant increase in the adjusted slope of the curve relating age to PWV as compared with no PI treatment. CONCLUSIONS: In normotensive HIV patients, PI treatment significantly increases both aortic stiffness and the positive correlation between PWV and age. Aortic stiffness predicts cardiovascular mortality, thus these results provide new insight on the relationship between PI treatment, mechanical arteriosclerotic and cardiovascular risk.

Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score.

OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.

[Use of enfurvitide in pregnancy in HIV positive women in seven cases]. / Utilisation de l'enfuvirtide chez la femme enceinte séropositive VIH, à propos de sept cas.

OBJECTIVE: With a panel of more than 22 drugs, the treatment of HIV subjects is nowadays quite easier. But due to the number of multiparus women often harbouring a multidrug resistant virus, or seen late in pregnancy or inobservant, taking care of these pregnancies remains difficult. The use of enfuvirtide seems quite interesting for these situations. PATIENTS AND METHODS: In a retrospective study, we have focused our work on the consequences of enfuvirtide used in seven pregnancies, paying particular attention to efficacy, pharmacokinetics and tolerance. RESULTS: The use of enfuvirtide during 30 days in average seems safe and the tolerance was satisfactory in all seven cases. All infants are seronegative without abnormalities. The dosages in umbilical cord were negative. Five women experienced an elective caesarean, one had caesarean section in emergency, and one had a vaginal delivery. DISCUSSION AND CONCLUSION: The 23 cases published in the English literature indicate the interest of enfuvirtide use in these difficult situations. Indeed, enfuvirtide is injectable, favouring the adherence; it has a good tolerance, a quick efficacy and no placental transfer. Evidently, enfuvirtide is always prescribed in association.

Recovery of fat following a switch to nucleoside reverse transcriptase inhibitor-sparing therapy in patients with lipoatrophy: results from the 96-week randomized ANRS 108 NoNuke Trial.

OBJECTIVES: To evaluate the impact on peripheral fat tissue of a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen in lipoatrophic HIV-1 infected patients. METHODS: This 96-week prospective, randomized study compared lipoatrophic patients switched to an NRTI-sparing regimen with patients remaining on an NRTI-containing regimen. The primary endpoint was the change in thigh subcutaneous fat tissue volume between baseline and week 48, as assessed by computerized tomography. RESULTS: One hundred patients were included, 50 in each arm. At baseline, patients had been on highly active antiretroviral therapy (HAART) for a median time of 6.6 years (4.9-9.7); 71% of the patients had received thymidine analogues [stavudine (37%), zidovudine (34%)]. The mean change in fat volume between baseline and week 48 significantly favoured the NRTI-sparing arm over the NRTI-maintaining arm in the intent-to-treat analysis, with a last-observation-carried-forward approach [+34 cm(3); 95% confidence interval (CI) 5-63 cm(3); P=0.002]. This was confirmed in the intent-to-treat analysis of available data, with a mean difference of +109 cm(3) (95% CI 34-185 cm(3)) at week 96 (n=53; P=0.001). This corresponded to increases of 12 and 30% in fat volume at weeks 48 and 96, respectively, in the NRTI-sparing arm. CONCLUSIONS: Switching from an effective NRTI-containing regimen to an NRTI-sparing regimen preserves immunovirological status and increases subcutaneous fat volume at weeks 48 and 96.

Causes of the first AIDS-defining illness and subsequent survival before and after the advent of combined antiretroviral therapy.

OBJECTIVES: To analyse the impact of combined antiretroviral treatment (cART) on survival with AIDS, according to the nature of the first AIDS-defining clinical illness (ADI); to examine trends in AIDS-defining causes (ADC) and non-AIDS-defining causes (non-ADC) of death. METHODS: From the French Hospital Database on HIV, we studied trends in the nature of the first ADI and subsequent survival in France during three calendar periods: the pre-cART period (1993-1995; 8027 patients), the early cART period (1998-2000; 3504 patients) and the late cART period (2001-2003; 2936 patients). RESULTS: The three most frequent initial ADIs were Pneumocystis carinii (jirovecii) pneumonia (PCP) (15.6%), oesophageal candidiasis (14.3%) and Kaposi's sarcoma (13.9%) in the pre-cART period. In the late cART period, the most frequent ADIs were tuberculosis (22.7%), PCP (19.1%) and oesophageal candidiasis (16.2%). The risk of death after a first ADI fell significantly after the arrival of cART. Lower declines were observed for progressive multifocal leukoencephalopathy, lymphoma and Mycobacterium avium complex infection. After an ADI, the 3-year risk of death from an ADC fell fivefold between the pre-cART and late cART periods (39%vs. 8%), and fell twofold for non-ADCs (17%vs. 9%). CONCLUSIONS: The relative frequencies of initial ADI have changed since the advent of cART. Tuberculosis is now the most frequent initial ADI in France; this is probably the result of the increasing proportion of migrants from sub-Saharan Africa. After a first ADI, cART has a major impact on ADCs and a smaller impact on deaths from other causes. The risk of death from AIDS and from other causes is now similar.

Liver-related mortality in human-immunodeficiency-virus-infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003 Study).

The objective of the present study was to determine mortality because of end-stage liver disease (ESLD) in a nationwide population of HIV-infected patients, 7 years following the introduction of highly active antiretroviral therapy (HAART). All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2003. Fifty-nine departments, following a total of 20 940 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995, 1997 and 2001. Among 215 deaths observed during 2003, 101 (46.9%) were related to AIDS, 27 (12.6%) to ESLD and 87 (40.5%) to other causes. Mortality because of ESLD represented 23.7% of non-AIDS-related deaths. Patients dying from ESLD had chronic hepatitis because of hepatitis C virus (HCV) in 92.6% of cases and moderate (30-60 g) or high (>60 g) alcohol consumption (43.5% and 26.0%, respectively). In this population, deaths because of ESLD were 1.5% in 1995, 6.6% in 1997, 14.3% in 2001 and 12.6% in 2003. The prevalence of hepatocellular carcinoma as a cause of death remained high in 2003 but stable when compared with 2001 (25%vs 14.8%). Treatment of hepatitis C in patients who died from ESLD was more frequent in 2003 (44.4%) than in 2001 (26.3%). Seven years after the introduction of HAART, ESLD associated with HCV infections is a leading cause of mortality in HIV-infected patients, which did not increase between the years 2001 and 2003.

Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study.

BACKGROUND: To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. METHOD: 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA < 400 copies/mL or rebound of > or = 0.7 log10. RESULTS: 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA > 50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels < 4, 4-5, and > 5 log10 copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma Cmin for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (< 50 copies/mL; median follow-up 48 weeks). CONCLUSION: Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.

Treatment intensification with abacavir in HIV-infected patients with at least 12 weeks previous lamivudine/zidovudine treatment.

OBJECTIVES: To demonstrate that lamivudine and zidovudine, given separately (lamivudine/zidovudine) or as a single combination tablet (Combivir), had equivalent efficacy. To evaluate the safety and antiretroviral activity of intensification with abacavir in patients treated with lamivudine/zidovudine for > or = 12 weeks. DESIGN: A 12-week, equivalence study of lamivudine/ zidovudine versus Combivir. Patients who completed this study could enter a 48-week, intensification study of Combivir plus abacavir. METHODS: In the equivalence study, treatment-naive patients were assessed for HIV-1 RNA, CD4 cell count and genotype. The same assessments plus phenotype were made in the intensification study. Serious adverse events were recorded in the equivalence study and all adverse events in the intensification study. RESULTS: Lamivudine/zidovudine (n=40) and Combivir (n=35) gave equivalent reductions in plasma HIV-1 RNA levels at week 12. An identical proportion of patients (74%) in each treatment group harboured virus with the M184V mutation after 12 weeks. Fifty-two patients entered the intensification study and 44 completed 48 weeks of treatment. At the time of intensification with abacavir, all 35 patients with evaluable isolates harboured HIV-1 containing M184V. Addition of abacavir to Combivir led to further decreases in plasma HIV-1 RNA and increases in CD4 cell counts compared with the start of intensification (P<0.001 at week 48). After 48 weeks of triple therapy, multi-nucleoside resistance mutations at codons 69 and 151 were not detected in any patients. All treatment regimens were generally well tolerated. CONCLUSION: Lamivudine/zidovudine and Combivir have equivalent antiretroviral activity over 12 weeks. Adding abacavir to Combivir can be a safe and effective therapeutic option for patients, including those harbouring virus with the M184V mutation.

Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor.

OBJECTIVE: To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy. METHODS: From the French Hospital Database on HIV, 1402 protease inhibitor-naive patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes. RESULTS: During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naive patients. CONCLUSION: In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.

Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV.

OBJECTIVE: To estimate the change in survival of patients with AIDS-related progressive multifocal leukoencephalopathy (PML), in relation to the introduction of protease inhibitors (PI). DESIGN: The French Hospital Database on HIV (FHDH) is a prospective cohort of 70 224 HIV-infected subjects. This study included the patients diagnosed with PML between 1 July 1995 and 30 June 1997. PML diagnosis was both presumptive and confirmed. We compared the survival probability according to the diagnosis period (period 1 or 2, before or after introduction of PI in France on 1 April 1996). Cox's model was used to calculate the relative hazards of death according to the antiretroviral regimen. RESULTS: The study included 246 patients, 109 diagnosed during period 1 and 137 during period 2. In all, 131 patients received an antiretroviral combination that included PI. By 31 December 1997, a total of 131 deaths had been reported. The probability of survival at 6 months for patients from period 2 was nearly twice as high as for patients from period 1 (60.5 versus 34.5%). In comparison with patients receiving no treatment, the risk of death in patients on combination therapy not including PI was reduced by 38% [relative hazard (RH) 0.62, 95% confidence interval (CI) (0.41; 0.95), P = 0.026] and in patients on combination therapy with PI, by 63% [RH 0.37, 95% CI (0.22; 0.64), P = 0.0004]. CONCLUSION: This study of a large cohort of patients diagnosed with PML (n = 246), provides evidence that a combination antiretroviral regimen, especially one including PI, confers marked survival benefits.

[Evaluation of erythrocyte concentrate prescription in a university hospital center]. / Evaluation de la prescription des concentrés de globules rouges dans un centre hospitalo-universitaire.

This prospective study, based on declaratory data, evaluates the appropriateness of red blood cell transfusion prescriptions in a university hospital. Local recommendations written after data collection and the analysis of prescriptions using a blinded method limited the bias related to the declaratory data. The results show that the rate of unjustified prescriptions is 4.2% (95% CI: 2.2%; 6.2%). This rate is statistically (P = 0.032) lower in the department of surgery (1.3%) than in the department of medicine (5.7%). This rate tends to decrease according to the experience of the prescriber (P = 0.06) and varies significantly according to the hemoglobin levels (P = 0.03). The logistic regression, integrating these three parameters, confirms that only the hemoglobin level is significantly related (P < 0.003) to the appropriateness of RBC transfusions. This study also highlights problems not linked to prescriptions, and the hospital created a quality assurance program as a result.

Candidemia: a nosocomial complication in adults with late-stage AIDS.

We retrospectively analyzed 13 episodes of candidemia observed between July 1990 and July 1995 in human immunodeficiency virus (HIV)-infected adults. Candidemia was nosocomially acquired by 11 patients, among whom nine had a central venous catheter (CVC). Twelve cases were of stage C2/C3 according to the 1993 classification of the Centers for Disease Control and Prevention. The median CD4+ cell count was 10/mm3 (range, 3-400/mm3). Causative species were Candida albicans in nine episodes and Candida glabrata and Candida krusei in two episodes each. Eleven episodes occurred in 11 patients who had previously received fluconazole (mean total dose, 7.4 g), including the four episodes caused by non-albicans species. Outcome did not differ according to the administered antifungal therapy. CVCs were removed from seven patients (78%). The overall mortality was 38%. Candidemia is a potentially lethal nosocomial complication during late-stage AIDS and can be due to C. albicans and non-albicans strains.

Effects of aerosolized pentamidine on glucose homeostasis and insulin secretion in HIV-positive patients: a controlled study.

OBJECTIVE: Intravenous pentamidine induces hypo- and hyperglycaemia (dose-dependent toxicity on islet beta cells), pancreatitis and nephrotoxicity. Conversely, aerosolized pentamidine (AP) is usually devoid of systemic side-effects: few reports of hypo- or hyperglycaemia have been published. Our study aimed to assess the influence on glucose homeostasis and insulin secretion of long-term exposure to AP used for prophylaxis of Pneumocystis carinii pneumonia in HIV-positive patients, and to compare the impact on insulin secretion of AP, whether administered for the first time or after prolonged monthly exposure. DESIGN: Retrospective cross-sectional controlled study (main objective) and non-randomized prospective controlled study. PATIENTS: We compared glucose homeostasis and C peptide response to 1 mg intravenous glucagon in patients who had previously inhaled > or = 10 prophylactic aerosols (group 1, n = 21) and in HIV-positive controls (groups 2 and 3, n = 28) who had received none. Both groups were comparable for age and body-mass index, but CD4 T-lymphocyte counts and Karnofsky scores were both significantly higher in the control group. RESULTS: Fasting (T0) blood glucose, fructosamine and response to the first glucagon test were similar in both groups, but postprandial glucose, glycated haemoglobin and fasting C peptide were significantly higher (P < 0.05) in the pentamidine group. A second glucagon test was performed on the same day, 3 h (T3) after AP inhalation in 35 patients (in 21 after > or = 10 aerosols, group 1; in 14 after the first, group 2) and in 14 HIV-positive controls (group 3). The only significant difference between the three groups in C peptide response to this second test was a lower peak T3/peak T0 ratio in group 1. Plasma amylase and creatinine were not altered by the aerosol. CONCLUSION: Long-term prophylactic exposure to AP had minor but significant effects on glucose homeostasis and insulin secretion but did not modify pancreatic and renal function. The detrimental effects induced by long-term exposure to AP found in our study are probably not clinically relevant, but a more prolonged exposure to AP might conceivably induce more severe alterations.

[Microangiopathic hemolytic anemia associated with cancers. Symptomatic treatment by plasma exchange]. / Anémies hémolytiques micro-angiopathiques associées aux cancers. Traitement symptomatique par échanges plasmatiques.

OBJECTIVE: To determine the interest of plasmapheresis in the management of cancer-associated microangiopathic haemolytic anaemia (MHA) not due to cancer treatment. MATERIAL AND METHODS: [corrected] National retrospective study using the file of the French Hemapheresis Society. RESULTS: We isolated 6 patients (5 men and a woman aged 32 to 69-year-old) who had prostatic (4 cases) or breast carcinomas or Hodgkin's disease. Diagnosis of cancer preceeded MHA in 3 patients (from 2 to 4 years). Bone or bone marrow metastases were demonstrated in 5 patients. The clinical presentation included anuria (4 cases), bleeding (4 cases), and laboratory findings were consistent with microangiopathic haemolysis and thrombopenia in all cases and intravascular coagulation (2 cases) and/or renal failure (4 cases). MHA symptomatic treatment included 4 to 10 courses of plasmapheresis, extra-renal epuration (4 patients), anticoagulation (4 patients) and/or antiagregant (3 cases), haemodialysis (4 cases) and vincristine (2 cases). Cancer treatment consisted of antitumoural chemotherapy (2 cases) and/or hormonotherapy (5 cases). In all cases, haemolysis, thrombopenia and intravascular coagulation were controlled within 30 days. MHA treatment was effective alone in 3 patients. No relapse were observed in 3 patients whereas the course of cancer continued in 2 patients. Two patients relapsed and died from MHA after 4 and 36 months. Two patients relapsed and died from MHA within a few months and 1 was lost to follow-up. CONCLUSION: Symptomatic treatment of cancer-associated MHA including plasmapheresis may be useful while waiting for an aetiologic management of the tumour.

Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction.

The authors report 6 cases of fulminant hepatitis in patients treated with isoniazid and rifampin. In 4 of these patients, the treatment had been started within 3 days after a general anesthesia. The course of the disease was remarkably similar in all 6 patients: (1) the time interval from the beginning of the isoniazid-rifampin administration to the onset of jaundice was 6 to 10 days; (2) disorders of consciousness appeared less than 3 days after the onset of jaundice; (3) serum transaminases were 26 to 80 times the upper limit of normal; (4) the main liver lesion was centrilobular necrosis; (5) hypersensitivity manifestations were absent; (6) all 6 patients recovered. Fulminant hepatitis might be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be increased as a consequence of the enzyme-inducing effect of rifampin and, possibly, other drugs administered for general anesthesia.