Claudin-1 gene variants and susceptibility to hepatitis C infection in HIV-1 infected intravenous drug users (an ANRS case-control study).

Hepatitis C virus (HCV) seroprevalence is highly diverse among human immunodeficiency virus-1 (HIV-1) infected patients, ranging between 10% of HIV-1 infected homo-bisexuel men, to >92% in patients infected with HIV-1 who acquired HIV-1 through intravenous drug use. Thus, being HCV-free while having acquired HIV-1 via intravenous drug use is a rare situation. Claudin-1 is a protein involved in intracellular tight-junctions and has been identified as a major cellular co-receptor for HCV infection. Our objective was to determine whether Claudin-1 gene (CLDN1) mutations might be involved in natural resistance to HCV infection. We conducted a case-control study. All recruited patients acquired HIV-1 infection via intravenous drug use route before 1995. The case study patients remained free from HCV infection (negative anti-HCV antibodies and HCV-RNA). The control study patients was co-infected with HCV (positive anti-HCV antibodies). Direct genomic sequencing of the CLDN1 gene coding region and adjacent intron/exons junctions was performed from peripheral blood mononuclear cells. A total of 138 Caucasian patients were enrolled. Twenty-two patients (cases) were free from HCV infection and 116 (controls) were co-infected with HCV. We found single nucleotide polymorphisms (SNPs) described previously with no significant differences in allele frequencies between cases and controls. In conclusion, despite being a major cellular co-receptor for HCV entry in vitro, we did not identify any specific substitution in CLDN1 gene coding region in our study patients highly exposed but resistant to HCV infection in vivo. Other cellular co-factors involved in HCV infection should be investigated in this highly-exposed intravenous drug users patients.

Glomerular lesions in patients with sickle cell disease.

Sickle cell disease (SCD) is an increasing cause of chronic kidney disease, but the spectrum of glomerular lesions and their underlying mechanisms remain poorly described. We reviewed 18 renal biopsies from patients with SCD and glomerular involvement and studied the expression of hypoxic markers in the biopsy specimens. Four histopathologic variants were distinguished: focal segmental glomerulosclerosis (FSGS) (39%), membranoproliferative glomerulonephritis (28%), thrombotic microangiopathy glomerulopathy (17%), and specific sickle cell disease glomerulopathy (17%). Chronic organ damage and history of acute chest syndrome were associated with the occurrence of SCD glomerulopathy. All patients exhibited macroalbuminuria but only 6 patients displayed impaired renal function. SCD was not associated with a specific FSGS histologic variant. Long-term follow-up analysis revealed that 50% of patients exhibited chronic kidney disease. Regardless of the histologic variants, immunohistochemistry did not reveal a specific induction of hypoxic markers (inducible nitric oxide synthase [iNOS], nitrotyrosine, hypoxia-inducible factor [HIF]-1 alpha) at the time of renal biopsy. This large study shows that a wide spectrum of glomerular lesions is associated with SCD. Whatever lesions are observed, the renal prognosis is poor, and early renoprotective treatment is necessary. Hypoxic state does not seem to play a key role in the progression of glomerular lesions, but its potential role at an early stage of glomerular injury requires further investigation.

Ritonavir-boosted protease inhibitor monotherapy for the treatment of HIV-1 infection.

Guidelines for the use of antiretrovirals for HIV-1 infection recommend combining at least three agents. Toxicities, cost, and the complexity of such regimens warrant the search for other options. Boosted protease inhibitor monotherapy is one of the appealing options being investigated. Herein we review uncontrolled and controlled clinical trials evaluating boosted protease inhibitor monotherapy in several clinical settings: maintenance therapy, induction-maintenance strategies, and first-line treatment. Boosted lopinavir monotherapy has been largely investigated in maintenance and induction-maintenance strategies, showing its ability to maintain viral suppression in the majority of participants. The major concern is the higher proportion of patients experiencing transient episodes of low-level viremia (HIV-RNA 50-500 copies/ml) when compared to classical triple regimens. No protease inhibitor-associated resistance mutation was detected in patients who failed on boosted lopinavir monotherapy. Three uncontrolled maintenance strategy studies with boosted atazanavir monotherapy showed conflicting results. Thus, the reassuring results obtained with lopinavir might not be extended to the whole protease inhibitor class, warranting further studies with new generation protease inhibitors such as darunavir. Finally, one controlled trial comparing first-line boosted lopinavir monotherapy to a standard triple combination showed that the latter outperformed the boosted protease inhibitor monotherapy in this clinical setting. In summary, a boosted protease inhibitor single-agent strategy can maintain continuous plasma HIV-RNA suppression in a large proportion of patients already suppressed on a standard triple combination. The more frequent occurrence of low-level viremia, however, does not allow the widespread use of such a strategy outside of clinical studies at this time.

Post-exposure prophylaxis with a maraviroc-containing regimen after occupational exposure to a multi-resistant HIV-infected source person.

We report the case of a health care worker who received a post-exposure prophylaxis including an investigational drug, maraviroc, after a needle stick percutaneous injury to an HIV-infected patient with late-stage disease and harboring a multi-drug resistant virus. Post-exposure prophylaxis including maraviroc was pursued for a total of 28 days, with a weekly clinical and biological evaluation. Post-exposure prophylaxis was well tolerated, with no increase in liver function tests. The health care worker remained HIV-negative after a 6-month follow-up.