Virological response to darunavir/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA study).

BACKGROUND: We assessed the association of baseline HIV-1 mutations, phenotypic sensitivity and pharmacokinetics with virological failure (VF) at week 12 (W12) after onset of a darunavir/ritonavir (DRV/r)-based regimen in a cohort of 67 antiretroviral-experienced HIV-patients failing on highly active antiretroviral therapy (HAART). METHODS: VF was defined as HIV RNA >2.3 log10copies/ml at W12. HIV reverse transcriptase and protease sequencing was performed at WO; mutations with a P-value <0.25 in univariable analyses were used for a backward selection to find the best mutation set for VF prediction. Genotypic and phenotypic sensitivity scores were calculated and virtual phenotype predicted fold change (FC) assessed. DRV Cmin, Cmax, AUC(0-->12 h) and genotypic inhibitory quotient (GIQ) were determined. RESULTS: Patients had a median of 15 previous treatments for 10 years. Median W0 values included a T-cell count of 129 cells/microl, 4.7 log10 HIV RNA copies/ml, four major protease and six nucleoside reverse transcriptase inhibitor resistance mutations. At W12, median HIV RNA decrease was -2.1 log10 copies/ml with a gain of +67 CD4+ T-cells/microl; 40% of patients failed. We determined the genotypic score I13V+V32I+L33F/I/V+E35D+ M361/L/V+I47V+F53L+I62V. According to <4, 4-5 and >5 mutations, failure occurred in 11%, 48% and 100% of patients. Failure was associated with CDC stage, baseline CD4+ T-cell count, number of major protease inhibitor resistance mutations, FC and DRV/r score. Pharmacokinetics were not associated with failure, but GIQ was. CONCLUSION: At W12, 60% of heavily pretreated patients responded on DRV/r-based HAART. Genotypic and phenotypic information constituted the main virological response determinant in patients with optimal drug concentrations.

CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients.

BACKGROUND: Treatment initiation at the time of primary human immunodeficiency virus (HIV) type 1 (HIV-1) infection has become less frequent in recent years. METHODS: In the French prospective PRIMO Cohort, in which patients are enrolled at the time of primary HIV-1 infection, 30% of the 552 patients recruited during 1996-2004 did not start receiving antiretroviral treatment during the first 3 months after diagnosis. We analyzed the patients' clinical and immunological outcomes and examined potential predictors of disease progression. Progression was defined as the occurrence of an acquired immunodeficiency syndrome (AIDS)-related clinical event or a CD4 cell count <350 cells/mm3. RESULTS: Fifty-six (34%) of the untreated patients experienced immunological progression during a median duration of follow-up of 24 months, and 1 of these patients had an AIDS-related event. The estimated risks of progression were 25%, 34%, and 42% at 1, 2, and 3 years after enrollment, respectively. Compared with patients who did not have progression, those with progression had significantly lower CD4 cell counts at diagnosis (455 vs. 738 cells/mm3), higher plasma HIV RNA levels (4.9 vs. 4.5 log10 copies/mL), and higher HIV DNA levels (3.3 vs. 3.0 log(10) copies/10(6) peripheral blood mononuclear cells [PBMCs]). All 3 parameters were significantly associated with progression in univariate analysis. In multivariate analysis, only the CD4 cell count and HIV DNA level were independently predictive of disease progression (relative hazard for CD4 cell count, 1.84 per decrease of 100 cells/mm3; relative hazard for HIV DNA level, 2.73 per increase of 1 log(10) copies/10(6) PBMCs). CONCLUSIONS: Both a low initial CD4 cell count and a high HIV DNA level are predictive of rapid progression of untreated primary HIV-1 infection. Affected patients may therefore benefit from close clinical and laboratory monitoring and/or early administration of treatment.

Spontaneous hepatic decompensation in patients coinfected with HIV and hepatitis C virus during interferon-ribavirin combination treatment.

Spontaneous hepatic decompensation was observed in 7 of 383 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving treatment with interferon and ribavirin. Multivariate analysis identified the following risk factors: didanosine use (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.2-102.3; P < .02), cirrhosis, (OR, 8.8; 95% CI, 1.2-104.2; P<.02), and elevated total bilirubin level (OR, 7.9; 95% CI, 1.08-93.3; P<.03). Didanosine should thus not be given to patients with cirrhosis, particularly when treatments for HCV and HIV infections have to be administered concomitantly.

Causes of death in HIV-infected women: persistent role of AIDS. The 'Mortalité 2000 & 2005' Surveys (ANRS EN19).

BACKGROUND: Little is known about the causes of death in human immunodeficiency virus (HIV)-infected women in the era of combination antiretroviral therapy (ART). METHODS: In the French nationwide Mortalité 2000 and 2005 surveys, physicians reported causes of deaths in HIV-infected adults in 2000 and 2005, using a standardized questionnaire. We used multivariate logistic regression models to study the association between gender and AIDS-defining causes of death, adjusting for other characteristics. RESULTS: Of the 1013 HIV-infected adults who died in 2005, 247 (24%) were women. Half of women were infected through heterosexual contacts, compared with 25% men. In 2005, the proportion of AIDS-defining causes of death was higher in women than in men (43 vs 34%; P = 0.01), whereas it had been the same in 2000 (47% in women and men). In 2005, women died less frequently than men from respiratory malignancies (lung, ear/nose/throat) and cardiovascular disease (9% of all causes of death in women compared with 16% in men; P = 0.004), and suicides or accidents (4 vs 9%; P = 0.02). Socio-economic precariousness, younger age, less alcohol and tobacco consumption and lack of prior ART explained the higher proportion of deaths from AIDS in women compared with men. CONCLUSIONS: The higher proportion of AIDS-related deaths in women is probably explained by two factors: (i) some HIV-infected women, especially migrants in poor socio-economic conditions, may not have access to optimal care; and (ii) a lower prevalence of risk factors for respiratory, cardiovascular and violent deaths means that the risk of dying from non-AIDS causes may be lower in women.

Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients.

OBJECTIVE: Autommune diseases could constitute one emerging cause of morbidity in patients infected with human immunodeficiency virus (HIV) due to the chronicity of the infection and to the high level of B cell stimulation induced by HIV. We conducted a cross-sectional study investigating the clinical and biological signs of autoimmunity in HIV infected patients. METHODS: We studied the following plasma immunological variables: antinuclear antibodies (ANA) and antibodies to extractable nuclear antigens, antiphospholipids, anticardiolipins (aCL), antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), cryoglobulinemia, total complement, and C4 factor. HIV-RNA, CD4+ cell count, and serological status for hepatitis B (HBV) and C virus (HCV) were also studied. Clinical signs of autoimmune diseases were noted. RESULTS: In total, 97 patients were investigated (men 74%). Median age was 38 years (range 20-64). Median CD4+ count and HIV-RNA were 333/mm3 and 1662 copies/ml, respectively. Coinfection by HBV and HCV was present in 7% and 64% of the patients. In patients with HIV only, we detected cryoglobulinemia in 17% of patients, a positive RF in 19%, ANA > 1/100 in 21%, aCL in 51%, and ANCA > 1/20 in 17% (most of them type C by ELISA). There was a trend for a higher level of cryoglobulinemia and aCL in patients having CD4 lymphocyte counts > 350/mm3 than in others (25% vs 11%, p = 0.26, and 63% vs 42%, p = 0.23, respectively). Patients coinfected with HCV had a higher prevalence of cryoglobulinemia than HCV-free patients (42% vs 17%; p = 0.01). Prevalence of other immunological abnormalities was not different between patients with HIV only and HCV coinfected patients. Thirty patients expressed at least one clinical sign compatible with autoimmune disease. Patients with cryoglobulinemia more often had coinfection with HCV (OR 6.64, 95% CI 1.87-23.57) and IgM > 1.9 g/l (OR 6.16, 95% CI 2.15-17.67). CONCLUSION: Humoral immunological abnormalities are frequent in patients with HIV, but are rarely associated with severe clinical signs.