Immunological and epidemiological factors affecting candidiasis in HIV patients beginning antiretroviral therapy in an Asian clinic.

OBJECTIVES: Oropharyngeal candidiasis (OPC) is common in HIV patients beginning antiretroviral therapy (ART). Here we address the response to ART, and the roles of poor oral hygiene and defects in local innate immunity with a focus on salivary ß-defensins, as they are implicated in control of candidiasis but have not been investigated in this context. DESIGN: ART naïve HIV-infected adults (n=82) with <200 CD4+ T-cells/mm3 attending clinics at Cipto Mangunkusumo Hospital, Jakarta, were examined at the commencement of ART, and 73 were re-examined after 3 months. OPC was detected by clinical examination, and Candida albicans and fungal burdens were determined following culture on CHROMagar and saboroud-dextrose agar (resp). Salivary ß-defensins (-2 and -3) were quantified by ELISA. Healthy control subjects (n=40) matched the patients by age and gender. RESULTS: OPC was evident in 47 patients before ART, and associated with greater fingal burdens. No OPC was detected in healthy controls and culture positivity was rare. ART decreased the prevalence of OPC to 8/73 HIV patients re-examined after 3 months, with reduced total fungal and C. albicans burdens. The incidence of OPC was independent of oral hygiene. Hyposalivation was more common in untreated HIV patients (16%) than after 3 months on ART and was rare in healthy controls. HIV patients were also more likely to have acidic saliva. Salivary ß-defensin-2 was elevated in the presence of C. albicans pseudohyphae and OPC after 3 months on ART, but ß-defensin-3 was not affected by OPC or ART. CONCLUSIONS: ART reduces the prevalence of OPC, and the total fungal and C. albicans burden. Levels of salivary ß-defensin-2 may associate with OPC in HIV patients responding to ART.

Naive and Memory CD4⁺ T Cells Are Differentially Affected in Indonesian HIV Patients Responding to ART.

While most HIV patients beginning antiretroviral therapy (ART) with advanced immunodeficiency recover CD4(+) T cell numbers, the profiles and functions of the newly acquired CD4(+) T cells have not been monitored in a resource-limiting setting. In this study, HIV patients (n = 31) from Jakarta, Indonesia, were studied 9 months after commencing ART with nadir CD4(+) T cell counts <200 cells/µL. All patients were hepatitis C virus (HCV) seropositive, but asymptomatic. Twelve healthy age-matched controls from the same community were included. CD4(+) T cell subsets, immune activation (HLA-DR), and expression of the interleukin (IL)-7 receptor α chain (CD127) were quantitated by flow cytometry. Proliferation (expression of Ki67) was measured following in vitro stimulation (5 days) with anti-CD3 antibody or IL-7. Fifty-two percent of patients recovered CD4(+) T cell counts >200 cells/µL over 12 months. At 9 months, patients had fewer naive and CD31(+)-naive CD4(+) T cells, more effector memory (EM) CD4(+) T cells, and higher HLA-DR expression on CD4(+) T cells than controls. CD127 expression was low on all CD4(+) T cell subsets except for naive cells, where it was similar to controls. Similarly, after anti-CD3 antibody or IL-7 stimulation, patients had lower Ki67 expression than controls in all subsets, except naive CD4(+) T cells where it was normal or elevated. Overall in the first year of ART, patients had fewer naive and more EM CD4(+) T cells. Ongoing immune activation and, antigen-driven stimulation and differentiation of naive T cells may reduce the naive T cell pool, while driving the maturation and accumulation of memory cells with proliferative defects.

Increased proportions of dendritic cells and recovery of IFNγ responses in HIV/HCV co-infected patients receiving ART.

Dendritic cell (DC) numbers and functions can be affected by HIV and HCV disease, but the effects of antiretroviral therapy (ART) on DC and the implications of these changes are unclear. We examined circulating DC in samples from Indonesian patients beginning ART with advanced HIV disease and documented mild/moderate HCV hepatitis. Frequencies of myeloid and plasmacytoid DC increased after 6 months on ART, but frequencies of DC producing IL-12 or IFNα following stimulation with TLR agonists (CL075, CpG) did not change. IFNγ responses to CL075, HCV and other antigens rose over this period. Hence increased IFNγ responses during ART may be associated with increased DC frequencies rather than changes in their functional capacity.

Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus recover genotype cross-reactive neutralising antibodies to HCV during antiretroviral therapy.

When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral therapy, it is important to know whether HCV-specific antibody responses recover and whether antibody profiles predict the occurrence of HCV-associated immune restoration disease (IRD). In 50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48 weeks of therapy. Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the first 12 weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a lack of an association between nAb responses and HCV viral loads. These results showed that increased HCV-specific antibody levels during therapy were associated with CD4(+) T-cell recovery. Whilst genotype cross-reactive antibody responses may identify co-infected patients at risk of developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV replication during therapy.

Periportal CD4+ cell infiltration increases in HIV/hepatitis C virus-coinfected patients commencing ART, whereas CD8+ cells clear from the liver.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common in Asia, but the effects of antiretroviral therapy (ART) are unclear. Histopathological changes in the liver are described in a prospective study of HCV-seropositive HIV-infected patients at Cipto Mangunkusomo Hospital (Jakarta, Indonesia). Liver biopsy specimens were collected at baseline (n = 48) and 48 weeks (n = 34). Ishak scores showed mild but detectable inflammation and/or fibrosis. Levels of portal inflammation declined during ART (P = .03), whereas fibrosis remained (P = .11). Portal infiltration of CD4(+) cells increased during ART (P < .0001), whereas infiltration of CD8(+) cells subsided. Numbers of CD4(+) cells in the liver at baseline correlated with circulating CD4(+) T-cell counts (P = .03-.05). Numbers of liver-infiltrating CD4(+) and CD8(+) cells at baseline were not associates with subsequent experience of an immune restoration disease, which is defined by a rise in alanine transaminase levels during ART.

Antibody and markers of T-cell activation illuminate the pathogenesis of HCV immune restoration disease in HIV/HCV co-infected patients commencing ART.

Some HIV/hepatitis C virus co-infected patients beginning ART experience Immune Restoration Disease (IRD) manifested as a rise in serum alanine transaminase. This was investigated in HIV/HCV co-infected individuals (n=50) commencing ART in Jakarta (Indonesia). Samples were collected at weeks 0, 4, 8, 12, 24 and at HCV IRD. Nine patients experienced HCV IRD (incidence=9.2 per 1000 person-weeks). These resolved without changing treatment. Markers of T-cell activation (sCD26, sCD30) and immune recruitment (CXCL10) increased in many HCV IRD cases, so T-cells may mediate HCV IRD. Total anti-HCV antibody (core, NS3, NS4) remained lower in HCV IRD cases, but levels of antibody to core were not lower in HCV IRD cases. Rises in HCV RNA on ART were independent of HCV IRD, but there was a negative correlation between baseline HCV RNA and total anti-HCV antibody. High levels of antibody may protect against HCV IRD, via lower HCV antigen loads.