Case report: Cure of chronic infection with hepatitis C virus after 6 weeks of peg-interferon and ribavirin in a patient co-infected with HIV.

The recommended treatment duration of chronic hepatitis C virus (HCV) in patients infected with human immunodeficiency virus (HIV) is 48 weeks. This report describes a patient co-infected with HCV genotype 2 and HIV who discontinued HCV therapy after 6 weeks because of adverse events and had a sustained virologic response.

Survival trends in critically ill HIV-infected patients in the highly active antiretroviral therapy era.

INTRODUCTION: The widespread use of highly active antiretroviral therapy (ART) has reduced HIV-related life-threatening infectious complications. Our objective was to assess whether highly active ART was associated with improved survival in critically ill HIV-infected patients. METHODS: A retrospective study from 1996 to 2005 was performed in a medical intensive care unit (ICU) in a university hospital specialized in the management of immunocompromised patients. A total of 284 critically ill HIV-infected patients were included. Differences were sought across four time periods. Risk factors for death were identified by multivariable logistic regression. RESULTS: Among the 233 (82%) patients with known HIV infection before ICU admission, 64% were on highly active ART. Annual admissions increased over time, with no differences in reasons for admission: proportions of patients with newly diagnosed HIV, previous opportunistic infection, CD4 counts, viral load, or acute disease severity. ICU and 90-day mortality rates decreased steadily: 25% and 37.5% in 1996 to 1997, 17.1% and 17.1% in 1998 to 2000, 13.2% and 13.2% in 2001 to 2003, and 8.6% in 2004 to 2005. Five factors were independently associated with increased ICU mortality: delayed ICU admission (odds ratio (OR), 3.04; 95% confidence interval (CI), 1.29 to 7.17), acute renal failure (OR, 4.21; 95% CI, 1.63 to 10.92), hepatic cirrhosis (OR, 3.78; 95% CI, 1.21 to 11.84), ICU admission for coma (OR, 2.73; 95% CI, 1.16 to 6.46), and severe sepsis (OR, 3.67; 95% CI, 1.53 to 8.80). Admission to the ICU in the most recent period was independently associated with increased survival: admission from 2001 to 2003 (OR, 0.28; 95% CI, 0.08 to 0.99), and between 2004 and 2005 (OR, 0.13; 95% CI, 0.03 to 0.53). CONCLUSIONS: ICU survival increased significantly in the highly active ART era, although disease severity remained unchanged. Co-morbidities and organ dysfunctions, but not HIV-related variables, were associated with death. Earlier ICU admission from the hospital ward might improve survival.

Clinical and resistance consequences of misquantification of plasma and cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) RNA in samples from an HIV-1 subtype G-infected patient.

Human immunodeficiency virus (HIV) load is the main marker used to monitor antiviral treatment efficacy and resistance. We report a case of underquantification of HIV type 1 (HIV-1) RNA in plasma and cerebrospinal fluid from an HIV-1 subtype G-infected woman, leading to delayed diagnosis of HIV encephalitis and to the emergence of drug resistance.

One or two enzyme-linked immunosorbent assay tests on the first serum sample for initial diagnosis of HIV-1 infection?

In France, the first sample for the initial diagnosis of HIV-1 infection must be tested with two antibody assays: one being an enzyme-linked immunosorbent assay. If one is positive, confirmation tests are performed. We evaluated the performance of initial diagnostic strategies based on the use of one versus two enzyme-linked immunosorbent assay tests, either an antigen-antibody test or a simple antibody assay. We found that a single antigen-antibody test was more efficient than a combination of the two tests.

Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen.

BACKGROUND: Ritonavir-boosted darunavir (DRV/r) has proven potent efficacy when used in heavily pretreated patients, harboring protease inhibitor-associated resistance mutations. Limited data are available on resistance pattern emerging in patients failing DRV/r and on subsequent remaining protease inhibitor options. METHODS: Analysis of baseline and failure resistance genotypes were performed in patients experiencing virologic failure (>200 copies/ml) after at least 3 months on a DRV/r (600/100 mg twice daily)-containing regimen. RESULTS: Twenty-five highly protease inhibitor-experienced patients were included. Baseline median human immunodeficiency virus type 1 RNA was 5 log10 copies/ml and number of total-protease inhibitor, major-protease inhibitor and DRV-associated-resistance mutations was 13, 4 and 3, respectively. Median viral replication duration on DRV/r selective pressure was 34 weeks. Emergence of DRV-associated-resistance mutations was observed in 72% (18/25) of patients, at codons L89I/M/V (32%), V32I (28%), V11I (20%), I47V/A (20%), I54L/M (20%), L33F/I (16%) and I50V (16%). A high risk of DRV resistance was observed in patients with 2 and 3 baseline DRV-associated-resistance mutations and in patients with more than 24 weeks of ongoing viral replication. According to 2007 ANRS algorithm, isolates classified as susceptible to ritonavir-boosted tipranavir decreased from baseline to failure from 76 to 60% and susceptible to DRV/r from 32 to 12%. CONCLUSION: Emerging mutations observed after DRV/r failure were those already described to impact the DRV efficacy. Our study provided recommendations to firstly, reconsider lowering the cutoff number of DRV mutations to two; secondly, avoid keeping patients on a DRV-failing regimen for more than 24 weeks and thirdly, to examine the efficacy of using tipranavir after DRV failure.

Type I interferon subtypes produced by human peripheral mononuclear cells from one normal donor stimulated by viral and non-viral inducing factors.

Through the activation of Toll-like receptors (TLRs) or cytosolic RNA helicases, a large number of pathogenic or synthetic components can induce the transcription of genes coding for type I interferons (IFNs). This family of related cytokines includes notably, a single IFN-beta protein and 13 different IFN-alpha subtypes, whose biological activities are probably not the same. The aim of this study was to characterize the type I IFN subtypes produced in vitro by human peripheral blood mononuclear cells (PBMCs) in response to specific inducers. Thus, PBMCs obtained from a single donor, were exposed to various agents including Sendai virus, Herpes simplex virus-1 (HSV-1), poliovirus-IgG complexes and serum from a patient with systemic lupus erythematosus (SLE). Six hours later, mRNA was extracted and amplified by RT-PCR using primers which recognize IFN-B mRNA and the different IFN-A mRNA subtypes. IFN-A subtypes were identified by cloning and sequencing the amplification product. Antiviral activity was assayed in supernatant at 18 hours. Human PBMCs were found to express constitutively type I IFNs mRNA. Antiviral activity and expression of IFN-A and IFN-B mRNA increased with each inducing agent. Although almost all the IFN-A subtypes were detected, their relative abundance appeared to be dependent upon the inducing agent. Incubation of PBMCs with a neutralizing monoclonal antibody directed against the type I IFN receptor (IFNAR) did not affect the level of antiviral activity in the supernatant of induced PBMCs. Our results suggest that the level of IFN-alpha expressed by PBMCs cells is independent of IFNAR feedback signalling and that the nature of the inducing agent modifies the pattern of IFN-A subtypes preferentially expressed by these cells.

Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).

BACKGROUND: Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. METHODS: This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. RESULTS: After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. CONCLUSION: A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

Changes in the peripheral blood mtDNA levels in naive patients treated by different nucleoside reverse transcriptase inhibitor combinations and their association with subsequent lipodystrophy.

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

[Treatment interruption in 30 HIV-infected patients with successful viral suppression under highly active antiretroviral treatment]. / Interruptions du traitement antirétroviral chez 30 patients infectés par le VIH en succès virologique.

OBJECTIVE: To evaluate clinical and laboratory results in HIV-infected patients with complete viral suppression under HAART (highly active antiretroviral treatment) for whom treatment was interrupted and to identify risk factors associated with prolonged (i.e., successful) treatment interruption. METHODS: Retrospective study of patients who interrupted therapy while on HAART with a plasma HIV RNA <400 copies/mL. Multivariate regression analysis was performed to identify factors associated with a prolonged interruption (more than 6 months). RESULTS: 36 treatment interruptions in 30 patients were analyzed. Patients' mean age was 42 years, 83% were men, and 60% were infected through homosexual contact. Median CD4 cell count at initiation of HAART was 292/mm3 and median viral load 43,000 copies/mL. Reported reasons for HAART discontinuation included patient or clinician choice (n=21) or drug toxicity (n=15). Median CD4 cell count when treatment interruption began was 606/mm3, and its median duration was 14 months. During treatment interruption, adverse clinical events or laboratory findings occurred in 9 patients (30%), all of whom had a CD4 cell count nadir < 300/mm3. When HAART resumed, median CD4 cell count was 302/mm3, and median viral load 59,800 copies/mL. Plasma HIV RNA dropped to <400 copies/mL in all patients within 4 months of resuming treatment. In multivariate analysis, the factors associated with resuming HAART within 6 month of treatment interruption were: HAART including non-nucleoside analog (adjusted Hazard Ratio [aHR]: 3.6, 95% CI: 1.2-10.6, p = 0.02), a CD4 cell count nadir < 300 (adjusted Hazard Ratio [aHR]: 5.5, 95% CI: 2.0-26, p = 0.0057), undetectable plasma HIV RNA for longer than 21 months at the interruption (aHR: 7.2, 95% CI: 2-26, p = 0.002). This probability was 45.5% in patients with a CD4 cell count nadir < 300 and 14.3% in the others (p 0.10). CONCLUSION: Antiretroviral treatment should be interrupted only with caution in patients with a CD4 cell count nadir <300/mm3 because of the risk of adverse clinical events or laboratory findings.

Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients.

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

French national sentinel survey of antiretroviral drug resistance in patients with HIV-1 primary infection and in antiretroviral-naive chronically infected patients in 2001-2002.

OBJECTIVE: To survey the frequency of genotypic antiretroviral resistance and the spread of non-B subtypes in patients with primary HIV-1 infection (2001-2002) and in treatment-naive chronically HIV-1-infected patients (2001). METHODS: Plasma samples from 303 patients with acute HIV-1 infection (Primo study) and 363 treatment-naive patients with chronic HIV-1 infection (Odyssee study) were tested for genotypic resistance. Resistance mutations were identified from the International AIDS Society Resistance Testing-USA panel and resistant viruses were defined according to the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm. RESULTS: In the Primo study, 14% of the patients had viruses with resistance mutations and 12% of patients had viruses with mutations conferring resistance to least 1 antiretroviral drug. Thirty patients had viruses with mutations to at least 1 antiretroviral drug in a single pharmacologic class. Six patients were infected by viruses resistant to 2 or 3 classes of drugs. In the Odyssee study, the prevalence of reverse transcript (RT) associated and major protease inhibitor-associated mutations was 6.1% (95% CI: 3.6-8.6). Six patients had viruses resistant to at least 1 antiretroviral drug and 3 patients had viruses resistant to 2 classes of antiretroviral drugs. Twenty-four percent of acutely infected patients harbored non-B subtype strains (19% in 1999-2000) and 33.2% of chronically infected patients (10% in 1998; P < 0.0001). CONCLUSION: In France, the frequency of HIV-1 resistance in untreated patients was not significantly higher in 2001-2002 than in previous surveys while the prevalence of non-B subtypes is increasing.

Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial.

BACKGROUND: We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL. RESULTS: At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8). CONCLUSIONS: Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression.

Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.

OBJECTIVE: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. METHODS: HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. RESULTS: The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. CONCLUSION: In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.