Increased regulatory T cell counts in HIV-infected nonresponders to hepatitis B virus vaccine.

Hepatitis B virus (HBV) coinfection is a main cause of liver-related mortality in human immunodeficiency virus (HIV)-infected subjects. Unfortunately, HIV-infected subjects show a low rate of response to standard HBV vaccination (23%-56%), in contrast to rates >90% found in the general population, and the underlying causes (particularly cellular and molecular causes) are still unknown. We hypothesized that an increased frequency of regulatory T (T(reg)) cells could be involved in the low rate of seroconversion in HIV-infected subjects. Forty HIV-infected subjects were enrolled in the Assistance Vaccination Program against HBV of the Infectious Diseases Service from the Virgen del Rocío University Hospital, Seville, Spain. Freshly isolated peripheral blood mononuclear cells from baseline were immunophenotyped for T(reg) cells, CD4, and CD8 T cells in both naive and memory subpopulations and activation degree, as well as recent thymic emigrants. Baseline T(reg) cell frequency was found independently associated with the final nonresponse to HBV vaccine in HIV-infected subjects. Furthermore, a negative correlation between baseline frequency of T(reg) cells and antibody titers in the final response was found. These findings suggest an active role played by T(reg) cells on the immunization antigen-specific T and/or B cell responses with the final consequence of a B cell anti-HBs lower production.

Discontinuation of antiretroviral therapy in patients with chronic HIV infection: clinical, virologic, and immunologic consequences.

To investigate the clinical, virologic and immunologic consequences of planned treatment interruptions in chronically HIV-infected patients. One hundred forty-one patients with undetectable viral load for at least 6 months and CD4+ T cells count greater than 500 per microliter were recruited. Their antiretroviral therapy was stopped and clinical, analytic, virologic, and immunologic data were recorded at baseline, during discontinuation, and after restarting treatment. Viral load rebound after discontinuation in 137 (97%) patients, and was similar to prehighly active antiretroviral therapy (HAART) levels. A rapid decrease in CD4+ T-cell count (median, 240 cells per microliter), was observed in the first 3 months in all patients, with pronounced differences between them. After a median follow-up of 36 months, 45.5% patients were still without therapy. Factors related to a more severe decline were a prior lower CD4+ T nadir (<200 cells per microliter) before starting HAART, a greater increase (>500 cells per microliter) with it, a higher CD4+ T-cell count before interruption (>800 cells per microliter) and a higher viral load rebound after it. The increase in CD4+ T-cell counts after reinitiation was slower than the decline and only 55% of patients have regained the preinterruption levels at 12 months of follow- up. Twelve infectious events were registered. Treatment failure related to drug resistance was observed in two patients. Planned treatment interruptions may be safe in selected patients with previous CD4+ T cell nadir greater than 200 cells per microliter and pre-HAART VL less than 55.000 copies per milliliter, but should be not recommended in patients with the prognostic factors related to a rapid decline described in this study. Furthermore, there is a considerable concern about the development of drug resistance and the possibility of an incomplete immune reconstitution after the treatment interruption in some patients.

Virological and immunological stability in HIV infected patients undergoing partial-treatment interruption.

BACKGROUND: Partial-treatment interruption in patients with drug-resistant viremia has been associated with stable HIV RNA levels suggesting that interruption of protease inhibitors may be an effective strategy for patients without other therapeutic options while waiting for the development of new drugs. OBJECTIVE: Our goal was to maintain virological and immunological stability in patients experiencing virologic failure with multiresistant HIV to allow access to newly developed antiretroviral drugs, and to characterize the impact of partial-treatment interruption on replication capacity and resistance profile. STUDY DESIGN: From 2003 to 2004, a group of 12 heavily treated patients was studied. Protease inhibitor treatment was interrupted and patients were treated with nucleoside analog retrotranscriptase inhibitors (Trizivir) and the fusion inhibitor Enfurvirtide to establish the therapeutic benefit and the virologic response. RESULTS: Both, CD4 T-cell counts and viral load remained stable for a period of time that enabled all the patients to access rescue treatments (median=13.5 months; IQR: 9-19). The replication capacity of the patient-derived viruses significantly decreased or remained stable during the partial-treatment interruption. The decrease in replication capacity was mainly attributable to the selection of viruses carrying at least two fewer minor mutations in the protease. As of December 2008 10 of 12 patients maintained undetectable HIV RNA levels. CONCLUSIONS: Study results indicate that a partial-treatment interruption regimen based on Trizivir with Enfurvirtide augmentation allows for a loss of protease inhibitor resistance mutations as well as for a decrease in the replication capacity of patient-derive HIV protease gene recombinants.

Molecular epidemiology of HIV type 1 in newly diagnosed patients in southern Spain.

The prevalence of different HIV-1 subtypes in Spain varies by geographic region. In the present study isolates were collected from 72 newly diagnosed individuals in western Andalucia from 2004 to 2006. Viral sequences were amplified and the subtype diversity and prevalence of resistance mutations in the reverse transcriptase and protease genes were determined. The results presented here demonstrate that subtype B virus predominates in this region (88.9%), with the non-B subtypes CRF02_AG (9.7%) and B/G (1.4%) also present. Only two isolates (2.9%) carried resistance mutations in the reverse transcriptase gene and none of the isolates had major resistance mutations in the protease gene. Minor mutations in the protease gene were more prevalent with 86.1% of isolates containing at least one minor mutation. These results elucidate the subtype diversity present in this region and suggest that the transmission of highly resistant virus variants does not occur at a high frequency in this population.