Factors predictive of successful darunavir/ritonavir-based therapy in highly antiretroviral-experienced HIV-1-infected patients (the DARWEST study).

BACKGROUND: Darunavir (DRV) is the latest protease inhibitor (PI) to be approved for antiretroviral-naive and -experienced HIV-infected patients. OBJECTIVES: We examined virologic and immunologic outcomes of highly antiretroviral-experienced patients with triple-class drug resistance receiving DRV/r-based regimens, and attempted to identify factors predictive of virologic success. STUDY DESIGN: We studied patients beginning a ritonavir-boosted DRV (DRV/r 600/100mg twice daily)-containing regimen. Virologic success was defined as plasma viral load (pVL)<50copies/ml at week 36. RESULTS: We studied 62 patients with very severe immunodeficiency (CDC stage C in 69% of cases; median CD4 cell nadir 12/mm(3)). They had previously received a median of four PI and had extensive PI resistance, with a median of three major PI and two DRV resistance mutations. The baseline median pVL and CD4 cell count values were 4.6log(10) and 150/mm(3). At week 36, pVL had fallen by 2.6log(10) and the CD4 cell count had risen by 123cells/mm(3). The virologic success rate was 55% overall, and was improved by concomitant first use of enfuvirtide (67%), raltegravir (69%) or etravirine (75%). Virologic success was independently associated with fewer major PI mutations, previous tipranavir exposure, and concomitant first use of enfuvirtide or raltegravir. CONCLUSIONS: In these highly antiretroviral-experienced patients with triple-class drug resistance, virologic success of DRV-containing regimens was mainly associated with the use of new drug classes and/or fully active drugs. Interestingly, previous tipranavir failure did not undermine the efficacy of DRV, confirming the low level of cross-resistance and, probably, distinct resistance profiles between DRV and tipranavir.

Neuropathology and neurodegeneration in human immunodeficiency virus infection. Pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments.

A variety of HIV-induced lesions of the central nervous system (CNS) have been described, including HIV encephalitis, HIV leukoencephalopathy, axonal damage, and diffuse poliodystrophy with neuronal loss of variable severity resulting, at least partly, from an apoptotic process. However, no correlation could be established between these changes and HIV dementia (HIVD). From our study of HIV infected patients, it appeared that neuronal apoptosis is probably not related to a single cause. Microglial and glial activation, directly or indirectly related to HIV infection, plays a major role in neuronal apoptosis possibly through the mediation of oxidative stress. In our patients with full-blown AIDS, this mechanism predominated in the basal ganglia and correlated well with HIVD. Axonal damage, either secondary to microglial activation, or to systemic factors also contributes to neuronal apoptosis. Although massive neuronal loss may be responsible for HIVD in occasional cases, we conclude that neuronal apoptosis is a late event and does not represent the main pathological substrate of HIVD. The dementia more likely reflects a specific neuronal dysfunction resulting from the combined effects of several mechanisms, some of which may be reversible. Introduction of highly active antiretroviral therapy dramatically improved patient survival, however, its impact on the incidence and course of HIVD remains debatable. In our series, the incidence of HIVE has dramatically decreased since the introduction of multitherapies, but a number of cases remain whose cognitive disorders persist, despite HAART. The poor CNS penetration of many antiretroviral agents is a possible explanation, but irreversible "burnt out" HIV-induced CNS changes may also be responsible.

Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex.

The aim of this work was to study the role of HIV replication and the role of endogenous secretion of interferon-alpha in the pathogenesis of AIDS Dementia Complex (ADC). To accurately establish the diagnosis of ADC, 39 consecutive HIV-positive patients who presented with immune and intellectual deficiency underwent an extensive neurological evaluation. This included magnetic resonance imaging, neuropsychological testing and a lumbar puncture. The levels of HIV-1 RNA were measured in the cerebrospinal fluid (CSF) and blood by HIV Monitor (Roche Diagnostics) and those of interferon-alpha by an in-house biological assay. The diagnosis of ADC was established in 22 cases, which included nine out of the ten patients who had a high CSF viral load (above 4 log HIV-1 RNA copy per ml). Patients receiving highly active antiretroviral therapy had low viral loads in blood and CSF. In all 22 ADC patients, viral load in the CSF correlated with the staging of ADC (r=0.46, P=0.03), the CSF level of interferon-alpha (r=0.42, P=0.05) and with the bicaudate ratio (r=0.43, P=0.06), a measure of cerebral atrophy in the region of the caudate nucleus. No correlation was observed between CSF and plasma HIV-1 RNA. These results show that HIV may play a role in the neurological impairment of ADC patients possibly in part through the deleterious effect of interferon-alpha on the central nervous system and that highly active combination therapy should reduce or prevent these complications.

Left ventricular diastolic function in asymptomatic and symptomatic human immunodeficiency virus carriers: an echocardiographic study.

Acquired immunodeficiency syndrome (AIDS) is a systemic illness affecting multiple organs, including the heart. Left ventricular (LV) diastolic dysfunction has been reported as the first echocardiographically detectable abnormality in several cardiovascular disorders. We tested the hypothesis that Human Immunodeficiency Virus (HIV) carriers have LV diastolic impairment when studied early in the clinical course of the infection. Doppler echocardiographic and computerized time-motion parameters of LV diastolic function were obtained in 51 HIV patients and in 25 age- and sex-matched healthy controls. The HIV population consisted of 28 totally asymptomatic subjects and 23 patients with incipient AIDS. As compared to controls, the HIV group had similar heart rate, blood pressure level, LV dimensions and fractional shortening, but increased isovolumetric relaxation time (P = 0.03), early filling duration (P < 0.001) and decreased early mitral flow peak velocity (E) (P = 0.02) and EF slope (P < 0.001). HIV patients also showed lower values for posterior wall thinning (PWT, P < 0.01) and peak lengthening velocity of the posterior wall (PVL, P < 0.05), and a trend to a decreased peak rate of LV enlargement in diastole (D+, P = 0.05). Doppler-derived parameters of diastolic function were significantly altered in the asymptomatic HIV group vs controls. The LV diastolic indices were similar in symptomatic and asymptomatic HIV patients except for PWT, which was lower in the symptomatic HIV group (P = 0.04). Since mild and focal wall motion abnormalities were detected in 11 HIV carriers (22%), comparison of LV diastolic indexes between HIV patients and controls was also performed in two subgroups; these included asymptomatic (n = 26) and symptomatic (n = 14) patients with normal contractile state. The two subgroups had abnormalities of diastolic function similar to those of the HIV group as a whole, but with somewhat lower levels of statistical significance. Our data strongly suggest that there is myocardial involvement at the early stage of HIV infection; however, its impact on the clinical course of the disease remains to be clarified.