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Biomedical subjects

G Pialoux

Publications and source records attributed to G Pialoux.

At least 37 records · Page 2Linked to original sources
PubMed2000

Efficacy and safety of combination therapy with interferon-alpha2b and ribavirin for chronic hepatitis C in HIV-infected patients.

OBJECTIVES: To evaluate the efficacy and safety of a combination therapy of interferon-alpha2b (IFN) and ribavirin for the treatment of chronic hepatitis C in HIV-seropositive patients. DESIGN: Open prospective trial. METHODS: Twenty patients co-infected with hepatitis C virus (HCV) and HIV, with a mean CD4 cell count of 350 +/- 153 x 10(6)/l were treated with IFN (3 MU three times per week) in combination with ribavirin (500 mg or 600 mg twice a day) for 6 months. Tolerance and efficacy were monitored at weeks 12 (month 3) and 24 (month 6). The primary endpoint was a complete virological response, as defined by the lack of detectable HCV RNA in serum. RESULTS: Baseline values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 121 +/- 72 IU/l and 75 +/- 67 IU/l, respectively. The total Knodell score was 10.4 +/- 2.4, with nine patients showing histological evidence of active cirrhosis (45%). All patients exhibited circulating HCV RNA. The treatment was well tolerated, with no impact on the course of HIV infection. After 6 months of combination therapy with IFN and ribavirin, 10 patients (50%) exhibited no further detectable HCV RNA viraemia, seven of whom achieved undetectable viraemia at month 3. Levels of ALT and AST decreased after 6 months of treatment from a mean of 121 +/- 72 to 51 +/- 40 IU/l and from a mean of 129 +/- 58 IU/l to 68 +/- 61 IU/l, respectively (P < 0.0002 and P < 0.0001). CONCLUSION: Our results indicate that combination therapy with IFN and ribavirin is effective in 50% of cases in clearing serum HCV RNA and may thus provide effective means of therapy in HIV-HCV-coinfected patients as initial treatment or in patients who have previously failed IFN monotherapy.

Adult↗
PubMed2000

Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team).

CONTEXT: In the Trilège trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy. OBJECTIVE: To identify mechanisms of virologic failure in the 3 arms of the Trilège trial. DESIGN: Case-control study conducted from February to October 1998. SETTING: Three urban hospitals in Paris, France. PATIENTS: Fifty-eight case patients with virologic failure (HIV RNA rebound to >500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression. MAIN OUTCOME MEASURES: At virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods. RESULTS: Only 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms. CONCLUSIONS: During the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Anti-HIV Agents↗
PubMed2000

Multiepitopic B- and T-cell responses induced in humans by a human immunodeficiency virus type 1 lipopeptide vaccine.

We have attempted to develop an anti-human immunodeficiency virus (HIV) lipopeptide vaccine with several HIV-specific long peptides modified by C-terminal addition of a single palmitoyl chain. A mixture of six lipopeptides derived from regulatory or structural HIV-1 proteins (Nef, Gag, and Env) was prepared. A phase I study was conducted to evaluate immunogenicity and tolerance in lipopeptide vaccination of HIV-1-seronegative volunteers given three injections of either 100, 250, or 500 microg of each lipopeptide, with or without immunoadjuvant (QS21). This report analyzes in detail B- and T-cell responses induced by vaccination. The lipopeptide vaccine elicited strong and multiepitopic B- and T-cell responses. Vaccinated subjects produced specific immunoglobulin G antibodies that recognized the Nef and Gag proteins. After the third injection, helper CD4(+)-T-cell responses as well as specific cytotoxic CD8(+) T cells were also obtained. These CD8(+) T cells were able to recognize naturally processed viral proteins. Finally, specific gamma interferon-secreting CD8(+) T cells were also detected ex vivo.

AIDS Vaccines↗
PubMed2000

Safety and efficacy of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects: an early report.

BACKGROUND: More severe liver disease together with a poor response rate to alpha interferon argue for the use of more potent anti-hepatitis C virus (HCV) therapies in human immunodeficiency virus (HIV)-HCV coinfected patients, but the efficacy and safety of interferon-ribavirin combination therapy in HIV infected subjects are unknown. AIM: To retrospectively evaluate the efficacy and safety of anti-HCV combination therapy in 21 HCV-HIV coinfected patients receiving antiretroviral therapy, and to access the clinical relevance of in vitro inhibition of phosphorylation by ribavirin of potent inhibitors of HIV-that is, zidovudine, stavudine, and zalcitabine. PATIENTS: Twenty one patients were treated with combined antiretroviral therapy including zidovudine (n=8) or stavudine (n=13) (in association with protease inhibitors in 12). All received ribavirin (1000 or 1200 mg/day) and alpha interferon (3 MU three times/week) for chronic hepatitis C infection. All patients had not responded (n=20) or relapsed (n=1) after a previous six month course of alpha interferon therapy. METHODS: HIV viral load (Monitor test) and CD4 cells count were measured at the beginning and every three months during and after ribavirin plus alpha interferon therapy over a mean period of 11 (1) months. Clinical and biological adverse effects were recorded. RESULTS: There was no significant variation in HIV viral load or CD4 cell counts after three or six months of ribavirin therapy compared with baseline values. Of the 21 subjects, three (14%) had an increase in HIV viral load of more than 0.5 log leading to discontinuation of ribavirin in one. Eleven of 21 (52.4%) had initial negative HCV viraemia at three (n=10) or six (n=1) months but only six were polymerase chain reaction negative at the end of therapy, leading to rates for primary response and breakthrough of 23.8% and 28.5%, respectively. Six months after completion of therapy, three patients relapsed (14. 3%) and three (14.3%) had sustained virological response. Median haemoglobin concentration decreased significantly after three and six months of ribavirin therapy (p= 0.0002 and p=0.0003, respectively) leading to withdrawal of therapy in one patient. CONCLUSIONS: These preliminary results show that: (1) despite in vitro interactions between ribavirin, zidovudine, and stavudine, significant variation in HIV replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin and different antiretroviral regimens, including zidovudine and stavudine; (2) alpha interferon and ribavirin combination therapy induced primary and sustained virological responses in 28.5% and 14.3% of treated subjects (who were previous non-responders to interferon therapy), respectively; (3) anaemia is a frequent adverse event. Such results should be confirmed in larger prospective trials.

Adult↗
PubMed1998

A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team.

BACKGROUND: The long-term effectiveness of potent three-drug antiretroviral regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection is limited by problems related to compliance and tolerability. We investigated whether two-drug maintenance therapy would suppress viral replication after a three-month period of aggressive triple-drug induction therapy. METHODS: A total of 378 HIV-1-infected adults who had not received previous antiretroviral treatment received three months of induction therapy consisting of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 800 mg of indinavir every 8 hours. The 279 patients in whom the plasma HIV-1 RNA titer fell below 500 copies per milliliter after two months of triple-drug therapy, and who completed the induction phase, were randomly assigned at month 3 to one of the following three open-label maintenance regimens: zidovudine, lamivudine, and indinavir; zidovudine and lamivudine; or zidovudine and indinavir. The primary end point was an increase in HIV-1 RNA levels to 500 copies or more per milliliter during the maintenance phase. RESULTS: The proportion of patients who reached the primary end point was significantly higher among patients receiving zidovudine plus lamivudine (29 of 93 patients, P<0.001) or zidovudine plus indinavir (21 of 94, P=0.01) than among patients receiving continued triple-drug therapy (8 of 92). This higher failure rate in the groups treated with the two-drug maintenance regimens was also observed in the subgroup of patients with maximally suppressed HIV-1 RNA (below 50 copies per milliliter) at the time of randomization to maintenance therapy. CONCLUSIONS: In HIV-1-infected adults not previously treated with antiretroviral drugs whose plasma HIV-1 RNA levels fell below 500 copies per milliliter after three months of induction therapy with zidovudine, lamivudine, and indinavir, two-drug maintenance therapy was less effective in sustaining a reduced viral load than continued three-drug therapy.

Adult↗
PubMed1998

Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy.

The interleukin-2 (IL-2)/IL-2 receptor (IL-2R) system is the main regulatory determinant of T cell reactivity. Although it is well known that IL-2 secretion is impaired during HIV infection, up to now IL-2R expression has not been extensively studied in HIV-infected patients despite the use of IL-2 in clinical therapy trials. We show here that IL-2R expression in HIV patients with high viral load (group 1 in the study) is greatly enhanced on B lymphocytes, CD8 T lymphocytes, and monocytes, but not on CD4 T lymphocytes, compared with noninfected individuals. Paradoxically, this modified IL-2R expression does not lead to increased IL-2 responsiveness, except for B lymphocytes. In patients receiving triple combination therapy (TCT, two reverse transcriptase inhibitors and one protease inhibitor) that has triggered a drastic reduction in plasma viral load and an increase in CD4 counts (group 2 patients), IL-2R expression is significantly lower than in group 1 patients. Moreover, cells involved in cellular immunity and CD4 T lymphocytes have the capacity to respond to IL-2 after TCT. These results allow us to anticipate a beneficial role of IL-2 immunotherapy in combination with TCT.

B-Lymphocytes↗
PubMed1998

Rapidly evolving hepatitis C virus-related cirrhosis in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy.

Triple antiretroviral therapy combining reverse transcriptase and protease inhibitors modifies the prognosis of human immunodeficiency virus (HIV) infection, with dramatic improvement in immune status. The precise impact, if any, of anti-HIV triple therapy on hepatitis C virus (HCV) infection is unknown. We describe an unusual case of rapidly evolving HCV-related cirrhosis that paralleled restoration of immune status in an HIV-infected patient and discuss the possible link between such a severe course of hepatitis C and anti-HIV triple therapy.

Adult↗
PubMed1997

Restricted specificity of anti-V3 antibodies induced in humans by HIV candidate vaccines.

We analyzed the fine specificity of anti-V3 antibodies elicited in three different species (human, guinea pig, and macaque) by various HIV candidate vaccines. Following immunization with recombinant canarypox virus expressing gp160MN or with recombinant gp160MN/LAI, this antibody response was shown to be directed against the NH2-terminal region of the V3 loop. Although this response was increased by a prime-boost regimen using immunization with canarypox expressing gp160 followed by an rgp160 boost, its specificity remained restricted mainly to the recognition of this region of the V3 loop. Pepscan analysis of sera confirmed the results obtained by ELISA and allowed the definition of an immunodominant common binding site for these sera located within the sequence NKRKRIHIGPGR. In contrast to these results, a boost with the V3 peptide was shown to broaden the antibody response and pepscan analysis showed that sera from individuals boosted with the V3 synthetic peptide recognize determinants all along the V3 loop. Similar fine specificity of anti-V3 antibodies was obtained in human, guinea pig, and macaque following immunization by a prime-boost regimen using canarypox recombinants expressing gp160 or gp120 and purified rgp160. In contrast, a V3 synthetic peptide boost stimulated the production of antibodies that recognize multiple epitopes within the V3 loop. Because the induction of antibodies that recognize multiple sites in the V3 loop could be of major importance to neutralize different HIV isolates, these results may have implications for the design and selection of HIV candidate vaccines.

AIDS Vaccines↗
PubMed1997

Oral transmission of Candida albicans between partners in HIV-infected couples could contribute to dissemination of fluconazole-resistant isolates.

BACKGROUND: Fluconazole resistance has emerged among Candida albicans isolates and has been associated with the prolonged or repeated use of the drug. This study was designed to discover whether transmission of oral isolates could occur between sexual partners and thereby explain fluconazole resistance in patients never treated with the drug. MATERIALS AND METHODS: The oral flora of 10 HIV-infected couples (five heterosexual and five homosexual) were studied. In vitro susceptibility testing and genotyping (restriction fragment length polymorphism with EcoRI and HinfI) were used to delineate strain relatedness for 230 clones (five clones per sample, one to four samples per patient). RESULTS: The genetic diversity of the clones with one DNA subtype was specific to a given patient or a given couple, except in one case in which unrelated patients shared clones of the same genotype. The persistence of clones between partners was stable over time in six out of 10 couples and only transient in one couple. Fluconazole resistance in isolates from patients who had never been treated with azoles was associated in three patients with the first episode of oropharyngeal candidiasis and treatment failure. CONCLUSION: The observation that couples tended to share genetically indistinguishable clones was highly suggestive of transmission between partners. This phenomenon may, in part, explain the pathogenesis of oropharyngeal candidiasis and the increased frequency of fluconazole resistance both in vitro and in vivo.

AIDS-Related Opportunistic Infections↗
PubMed1997

Peripheral neuropathy in human immunodeficiency virus-infected patients with the diffuse infiltrative lymphocytosis syndrome.

A subset of human immunodeficiency virus (HIV)-infected patients develop persistent CD8 hyperlymphocytosis and a Sjogren's syndrome-like syndrome associated with multivisceral CD8 T-cell infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV-infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV-infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA-DR5 and 1 was HLA-DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T-cell lymphoma was observed during follow-up, but 2 patients developed a primary B-cell lymphoma. We conclude that DILS neuropathy represents HIV-associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host-determined and antigen-driven response to HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Interleukin-2 receptor beta and gamma chain dysregulation during the inhibition of CD4 T cell activation by human immunodeficiency virus-1 gp120.

We have observed that CD4 T lymphocytes from human immunodeficiency virus (HIV)-infected patients marginally express interleukin-2 receptor (IL-2R) beta and IL-2R gamma chains which are essential for IL-2 signal transduction. To analyze this observation further, we studied the influence of gp120 on the cell surface expression of IL-2R beta and IL-2R gamma by purified CD4 lymphocytes in vitro. Cross-linking of the T cell receptors of these lymphocytes initiates entry into the cell cycle as measured by CD69 and CD71 cell surface expression and [3H]thymidine incorporation. It also induces the cell surface expression of IL-2R beta and IL-2R gamma. We have shown that treatment of the CD4 T lymphocytes with HIV-1 gp120 before anti-CD3 stimulation impedes cell cycle progression as measured by reduced CD71 expression and inhibition of [3H]thymidine incorporation. Furthermore, cell surface expression of IL-2R beta and IL-2R gamma subunits, which from the functional intermediate-affinity IL-2R, are significantly inhibited. More importantly, addition of exogenous IL-2 does not restore the proliferation of the CD4 T cells treated with gp120, suggesting that cells are anergic and/or that the remaining IL-2R are not functional. This is the first study of IL-2R beta and IL-2R gamma dysregulation in the context of HIV infection and shows that CD4 is also involved in IL-2R expression.

CD4-Positive T-Lymphocytes↗