Pierre de Truchis

Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of Hiv-positive patients

ObjectiveTo assess the efficacy of highly active antiretroviral treatment (HAART) on AIDS–Kaposis sarcoma (KS). DesignProspective cohort of patients followed for 24 months. SettingFour referral hospitals of the West Paris metropolitan area. Patients/interventionThirty-nine AIDS–KS patients, 42u2004±u20049 years old, who began HAART (HIV-protease inhibitor and two nucleoside analogues) between March and December 1996, were enrolled. One was lost to follow-up at month 12. Main outcome measuresKS response, using criteria of the AIDS clinical trials group (ACTG), CD4 cell counts, and plasma HIV-RNA, assessed every 6 months. ACTG TIS staging of KS. ResultsEighteen patients had T1 KS and 21 T0 KS. One patient died from KS at month 6. KS improved progressively, with complete and partial response rates of 46% and 28% at month 24, respectively. Only six patients were still receiving systemic KS therapy at month 24. Complete response was observed in 10 of the 19 patients without systemic KS therapy at inclusion. Patients with complete response at month 24 had higher CD4 cell counts than others (465u2004±u2004343 versus 185u2004±u2004167u2004×u2004106/l;Pu2004 <u20040.01), but the proportion of patients with HIV-1 RNA <u2004500 copies/ml was not significantly different. An increase in CD4 cell counts from inclusion to month 12 of >u2004150u2004×u2004106/l [odds ratio (OR), 13.4; 95% confidence interval (CI), 2–82] and T0 KS at inclusion: [OR, 7; 95% CI, 1.1–42] were predictive of complete response at month 24. ConclusionsHAART appears to have prolonged efficacy on AIDS–KS, even without specific KS therapy, and this effect appears to be linked to the restoration of immune function.

Modest Public Health Impact of Nontargeted Human Immunodeficiency Virus Screening in 29 Emergency Departments

BACKGROUNDnTo lower the number of undiagnosed infections and to improve early detection, international health agencies have promoted nontargeted human immunodeficiency virus (HIV) screening in health care settings, including emergency departments (EDs). This strategy remains controversial and has yet to be tested on a large scale. We assessed the public health impact of nontargeted HIV-rapid test (RT) screening among ED patients in the metropolitan area of Paris (11.7 million inhabitants), where half of Frances new HIV cases are diagnosed annually.nnnMETHODSnDuring a randomly assigned 6-week period for each of the 29 participating EDs, 18- to 64-year-old patients who were able to provide consent for HIV testing were offered a fingerstick whole-blood HIV RT. Main outcome measures were the number of patients tested for HIV and their characteristics vs those of the general metropolitan Paris population and the proportion of newly diagnosed HIV-positive patients among those tested and their characteristics vs those from the national HIV case surveillance.nnnRESULTSnAmong 138,691 visits, there were 78,411 eligible patients, 20,962 of whom (27.0%) were offered HIV RT; 13,229 (63.1%) accepted testing and 12,754 (16.3%) were tested. The ED patients characteristics reflected the general population distribution. Eighteen patients received new HIV diagnoses (0.14%; 95% confidence interval, 0.08%-0.22%). Like national HIV case surveillance patients, they belonged to a high-risk group (n = 17), were previously tested (n = 12), and were either symptomatic or had a CD4 lymphocyte count lower than 350/μL, suggesting late-stage infections (n = 8); 12 patients were linked to care.nnnCONCLUSIONSnNontargeted HIV testing in EDs was feasible but identified only a few new HIV diagnoses, often at late stages, and, unexpectedly, most patients belonged to a high-risk group. Our findings do not support the implementation of nontargeted screening of the general population in EDs.

HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term

ABSTRACT HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4+ T cells were characterized by a higher frequency of gamma interferon (IFN-γ) production, perforin+/CD107a+ expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer-positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-γ-producing CD4+ T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-γ production, supporting the notion of a persistent immune dysfunction in HIV-specific CD4+ T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions.

Zidovudine therapy and Hiv encephalitis: a 10-year neuropathological survey

Objective:To assess the effect of zidovudine on productive HIV infection of the brain. Design:To correlate the incidence of HIV-specific neuropathology with zidovudine therapy. Patients:We examined 192 AIDS cases neuropathologically; 97 had never been treated with zidovudine, 72 had received zidovudine for over 3 months and until death, 23 had their treatment terminated more than 1 month before death. Results:The incidence of HIV encephalitis/HIV leukoencephalopathy (HIVE/HIVL) and of multinucleated giant cells (MGC) was significantly lower in patients who had received zidovudine than in those who had never received zidovudine. The yearly incidence of HIVE/HIVL increased between 1982 and 1987 probably because of improved survival, and decreased between 1987 and 1990 although the percentage of patients treated with zidovudine increased. Since 1991 the incidence of HIVE/HIVL and of MCC increased slightly. The percentage of patients treated with zidovudine until death decreased and that of patients whose treatment was terminated increased concomitantly. In 1989 and 1990, most patients whose treatment was terminated had MGC and HIVE/HIVL. In 1991 and 1992 this incidence decreased markedly, coinciding with the introduction of dideoxyinosine therapy. Conclusion:Zidovudine treatment significantly reduces the occurence of productive HIV infection of the brain in AIDS. Discontinuing zidovudine therapy may favour the occurrence of HIV encephalitis. Substitution therapy with dideoxyinosine also appears to protect against HIV-specific brain pathology.

HIV infection perturbs interleukin-7 signaling at the step of STAT5 nuclear relocalization.

Objective:Interleukin-7 (IL-7) responses are impaired in CD4+ T cells from HIV-infected patients, which may play a significant role in the loss of CD4+ T-cell homeostasis. We set to investigate the nature of IL-7-dependent signaling defects in patients with progressive HIV-1 infection. Design and methods:IL-7 signaling was compared in CD4+ T cells from viremic patients with a viral load more than 10u200a000 copies of HIV RNA/ml (nu200a=u200a23) and from healthy blood donors (nu200a=u200a23). Phosphorylation of the transcription factor STAT5 on the regulatory serine S726 and the key tyrosine Y694 was monitored by intracellular flow cytometry. Phospho-STAT5 relocalization to the nucleus was analyzed by quantitative immunofluorescence imaging. Results:In control CD4+ T cells, S726 phosphorylation was mostly constitutive and inducible by IL-7 to a limited extent (1.3x, Pu200a<u200a0.05). In contrast, phosphorylation at Y694 was highly inducible by IL-7 (12.6x, Pu200a<u200a0.0001). Progressive HIV infection led to hyperphosphorylation of both S726 and Y694 in naive CD4+ T cells, with these changes correlating together (Ru200a=u200a0.66, Pu200a=u200a0.01). Quantitative image analysis revealed an impairment in the nuclear relocalization of both forms of phospho-STAT5 in patient cells (Pu200a<u200a0.005 for S726; Pu200a<u200a0.05 for Y694). The nuclear relocalization defect correlated with increased HLA-DR expression (Ru200a=u200a0.75, Pu200a<u200a0.01), suggesting a role for chronic immune activation in perturbed IL-7 signal transduction. Conclusion:HIV infection perturbs IL-7 signaling by impairing the access of STAT5 to the nuclear compartment. This defect may contribute to the loss of CD4+ T-cell populations in patients with chronically high immune activation.

Public T cell receptors confer high-avidity CD4 responses to HIV controllers

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.

Undiagnosed HIV prevalence based on nontargeted screening in emergency departments.

To estimate the 2009–2010 undiagnosed HIV prevalence in the Paris metropolitan region, where half of Frances new HIV cases are diagnosed annually, we used a direct method based on a large sample of emergency department patients unaware of their HIV status. The overall expected prevalence was 0.09% (95% confidence interval 0.04–0.13). Undiagnosed infections were exclusively found in high-risk groups. This prevalence is below the 0.1% threshold suggested by regulatory authorities for implementing universal screening.

Efficacy and safety of a quadruple combination Combivir + abacavir + efavirenz regimen in antiretroviral treatment-naive HIV-1-infected adults: La Francilienne.

Objective: To evaluate the safety and efficacy of a protease inhibitor sparing, quadruple therapy (Combivir + abacavir + efavirenz) in antiretroviral treatment‐naive HIV‐1‐infected adults. Design: Multicenter open‐label pilot study. Clinical and biological assessments were performed at baseline and at weeks 2, 4, 8, 16, 24, 32, 40, 48. Results: Thirty‐one subjects enrolled with a median baseline viral load (VL) of 4.69 log10 copies/mL and CD4 cell count of 322 cells/mm3. At week 48, 90% (intention‐to‐treat [ITT] switch included) and 77% (ITT switch = failure) patients had a VL <50 copies/mL. These results were similar in the population (n = 13) with a VL >100,000 copies/mL at baseline. Combivir + abacavir + efavirenz demonstrated an early antiretroviral response: 58% of patients had plasma HIV‐1 RNA <50 copies/mL at week 8. Using a modified assay, the percentage of patients with VL <5 copies/mL at week 48 was 55% (17/31) and 42% (13/31) using ITT (switch included) and ITT (switch = failure), respectively. Median VL decreased by ‐4.0 log10 copies/mL at week 48 (ITT). Median CD4+ cell count change from baseline at week 48 was +129 cells/mm3 (ITT). Most patients experienced at least one drug‐related adverse event that was not considered treatment‐limiting by the investigator. There were no cases of abacavir hypersensitivity reactions. Conclusions: Safety and efficacy results from this study demonstrated that the quadruple regimen Combivir/abacavir/efavirenz is generally safe and displays potent and durable antiretroviral activity in antiretroviral treatment‐naive HIV‐1‐infected patients, offering a promising therapeutic option in a PI‐sparing strategy.