Daniel Sereni

Tenofovir-Related Nephrotoxicity in Human Immunodeficiency Virus-Infected Patients: Three Cases of Renal Failure, Fanconi Syndrome, and Nephrogenic Diabetes Insipidus

We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients.

Objectives:To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV–tuberculosis (TB) coinfected patients. Design:Prospective, multicenter study of 19 consecutive untreated HIV–TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS− if no IRS occurred within 3 months after HAART initiation. Methods:Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-γ quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. Results:Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-γ-producing cells increased sharply during IRS (median, 2970 spot forming cells/106 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6− but no 85B-specific responses. IRS− patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-γ, IP10 and monokine-induced by IFN-γ] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. Conclusion:An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.

Early Levels of HIV-1 DNA in Peripheral Blood Mononuclear Cells Are Predictive of Disease Progression Independently of HIV-1 RNA Levels and CD4+ T Cell Counts

BACKGROUND The objective of this work was to assess the role of human immunodeficiency virus (HIV) reservoirs in the risk of disease progression, by studying the relationship between HIV DNA level in peripheral blood mononuclear cells (PBMCs) and progression toward acquired immunodeficiency syndrome (AIDS). METHODS HIV-1 DNA levels in PBMCs were determined by quantitative polymerase chain reaction for 383 patients enrolled in the SEROCO Cohort Study who had experienced seroconversion and had been followed up for >8 years. We compared the predictive values of HIV DNA level, HIV RNA level, and CD4+ cell count. RESULTS Between 6 and 24 months after seroconversion, HIV DNA level was a major predictor of progression to AIDS independently of HIV RNA level and CD4+ T cell count (adjusted relative risk [RR] for a 1-log(10) increase, 3.20 [95% confidence interval {CI}, 1.70-6.00]). HIV DNA level was also a major predictor of disease progression during the first 6 months after seroconversion (adjusted RR, 4.16 [95% CI, 1.70-10.21]), when HIV RNA level and CD4+ T cell count were less predictive. Thus, a combination of these 3 markers provides the best estimate of the risk of disease progression for each patient. CONCLUSIONS Our results suggest that HIV DNA level could be a useful additional marker in clinical practice and could aid in helping to define the best time to initiate treatment for each patient.

A phase II dose‐escalating trial of clevudine in patients with chronic hepatitis B

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti‐hepatitis B virus (HBV) activity in vitro. A multicenter dose‐escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 × 106 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty‐two patients were enrolled (5, 10, 10, and 7 patients in the 10‐, 50‐, 100‐, and 200‐mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 in the 10‐, 50‐, 100‐, and 200‐mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose‐limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100‐mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV‐infected patients and support further clinical study. (HEPATOLOGY 2004;40:140–148.)

Once-Daily Combination Therapy with Emtricitabine, Didanosine, and Efavirenz in Human Immunodeficiency Virus—Infected Patients

The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study.

Evolution of cytotoxic T lymphocyte responses to human immunodeficiency virus type 1 in patients with symptomatic primary infection receiving antiretroviral triple therapy.

The impact of highly active antiretroviral treatment (HAART) on anti-human immunodeficiency virus (HIV) cytotoxic T lymphocytes (CTL) was studied in 17 patients with recent symptomatic HIV-1 primary infection receiving triple combination therapy. Anti-HIV CTL were initially detected in 15 patients. In 6, CTL disappeared rapidly and persistently after initiation of therapy. Most of them had a rapid and sustained decrease in plasma HIV RNA to undetectable levels. Conversely, in 6 other patients, CTL remained detectable, which was associated with a less efficient control of viral replication. In 3 others, CTL disappeared only transiently, without clear correlation with the virologic profile. Altogether, despite individual variations, there was a positive correlation between viral replication and anti-HIV-1 cytotoxicity in most subjects, suggesting that the persistence of viral antigens is the main determinant for the maintenance of CTL activity. This raises the question of the potential benefit of anti-HIV CTL induction by immunotherapy in acute seroconverters treated by HAART.

Highly Active Antiretroviral Treatment Initiated Early in the Course of Symptomatic Primary HIV-1 Infection: Results of the ANRS 053 Trial

Highly active antiretroviral treatment (HAART) was given early to 64 patients with symptomatic primary human immunodeficiency virus (HIV)-1 infection. At the time of analysis, patients had been followed up for 9-21 months. No patient had died or developed an AIDS-defining event. Survival analysis showed that by month 21 the proportion of patients with plasma HIV-1 RNA <50 copies/mL was 72% (95% confidence interval, 58%-95%) in intention-to-treat analysis. After 18 months of treatment, 50% of the patients with undetectable plasma HIV-1 RNA also had undetectable HIV-1 RNA in peripheral blood mononuclear cells (PBMC). Only 1 of 3 patients had undetectable HIV-1 RNA in lymphoid tissue, while all patients had quantifiable HIV-1 DNA both in PBMC and lymphoid tissue. The median CD4 lymphocyte increase from baseline was 230 cells/microL. These preliminary results support the use of HAART in patients with primary HIV-1 infection.

Tuberculosis-Associated Immune Restoration Syndrome in HIV-1-Infected Patients Involves Tuberculin-Specific CD4 Th1 Cells and KIR-Negative γδ T Cells

Tuberculosis (TB)-associated immune restoration syndrome (IRS) is a frequent event (10 to 30%) in HIV-1-infected patients receiving antiretroviral treatment and is associated with an increased number of IFN-γ-producing tuberculin-specific cells. To further understand the immune mechanisms of TB-IRS and to identify predictive factors, we prospectively analyzed the Th1 and TCRγδ T cells known to be involved in mycobacterial defenses and dendritic cells at baseline and after antiretroviral and TB treatment in 24 HIV-1+ patients, 11 with and 13 without IRS. At baseline, these two groups differed by significantly lower proportions of TCRγδ and Vδ2+ T cells displaying the inhibitory receptors CD94/NKG2 and CD158ah,b in IRS patients. The two groups did not differ in the baseline characteristics of CD8 or CD4 T cells or TLR-2 expression on monocytes or myeloid/plasmacytoid dendritic cells. During IRS, the increase in tuberculin-specific IFN-γ-producing cells involved only highly activated effector memory multifunctional (IFN-γ+TNF-α+IL-2−) CD4 T cells, whereas activated HLA-DR+ CD4+ T cells also increased during IRS. In contrast, dendritic cells decreased significantly during IRS and there were no changes in TLR-2 expression. Finally, the Vδ2+ T cells, mostly killer Ig-related receptor (KIR) (CD94/NKG2− and CD158−), significantly peaked during IRS but not in non-IRS patients. In conclusion, IRS is associated with an increase in the number of activated tuberculin-specific effector memory CD4 T cells and of KIR−Vδ2+ TCRγδ+ T cells. Higher proportions of Vδ2+TCRγδ+ T cells lacking KIR expression are present as baseline and distinguish patients who will develop IRS from those who will not.

Natural history of HIV-associated pulmonary arterial hypertension: trends in the HAART era.

Pulmonary arterial hypertension (PAH) is an infrequent but nevertheless serious life-threatening severe complication of HIV infection. As a result of its non-specific presentation, PAH tends to be recognized at a late stage of the disease, and patients have generally been in New York Heart Association functional class III or IV by the time of diagnosis. The widespread use of HAART has improved overall survival in HIV-infected individuals, but its effect on the incidence and severity of PAH in particular has been controversial. Data on the long-term impact of HAART on the course of PAH and patient survival in this context have been lacking. This article presents key data from two recent major European studies (the Swiss HIV Cohort Study and a prospective French national study) investigating the prevalence of PAH in the HIV-infected population and the effect of HAART on the long-term course of the disease. Data from these large studies do not suggest that HAART has a major effect on the course of PAH or on survival in these patients. Although there is evidence that new cases of PAH are declining, the overall prevalence is currently similar to the pre-HAART era, and there is still a significant number of HIV-infected individuals who have or are at risk of PAH. Given recent improvements in the treatment of PAH, the early recognition of these individuals is essential.

Qualitative and quantitative analysis of human cytotoxic T-lymphocyte responses to HIV-1 proteins.

ObjectiveTo study the degree of immunogenicity of each HIV-1 protein. DesignIn most viral systems, antiviral cytotoxic T-lymphocytes (CTL) from a given donor preferentially recognize only one or a small number of viral proteins. MethodsAnti-HIV CTL were generated by in vitro stimulation of peripheral blood mononuclear cells from seropositive donors and tested against multiple HIV-1 proteins or groups of proteins encoded by seven genes (env, gag, pol, nef, rev, tat and vif). Using autologous target cells infected with recombinant vaccinia viruses expressing one of the HIV-1 LA1 proteins, we compared the cytolytic activities obtained from bulk culture with those found in limiting dilution analysis (LDA). ResultsOur results were noteworthy for the following reasons. (1) Each responding donor reacted simultaneously to multiple proteins; this is very unusual in other viral systems. Anti-Gag CTL were detected in most, and anti-Pol in approximately three-quarters, of the patients, together with very high amounts of the corresponding CTL precursors in LDA. CTL against Env and Nef were found in two-thirds of the patients, while Vif- and Rev-specific CTL were less frequent. Finally, Tat was seldom recognized by CTL, but its antigenicity was revealed in LDA. (2) All responding cells revealed in bulk cultures as well as in LDA were CD8+ T-cells, and their in vitro differentiation did not require the help of CD4+ T-cells. (3) Proteins from the HIV-1LA1 isolate were recognized with high frequency by CTL from seropositive donors, most certainly being infected by other isolates, which suggests that relatively conserved epitopes are predominant targets of CTL. ConclusionTaken together, these results are encouraging for vaccine purposes, since anti-HIV-1 CTL stimulation is thought to be a requirement for such a vaccine.