Therapeutic drug use during pregnancy:A comparison in four European countries

A drug utilization study was performed using data of the OECM study on Occupational Exposures and Congenital Malformations, which was conducted in six European Registries of Congenital Anomalies (two in France, two in Italy, one in Great Britain, and one in The Netherlands): the mothers were interviewed after delivery for exposures during pregnancy, including use of therapeutic drugs. The analysis of drug use considered only the 1134 control mothers of healthy newborns, and focused on the first trimester of pregnancy: 36.2% of the interviewed mothers used at least one drug (excluding vitamins and minerals) during the first trimester. This rate varied from 22.5% in Glasgow to 50.3% and 44.2% in the French centers. Anti-infectives were the most frequent drugs (12.3% of mothers), then antinauseants (10.6%), and treatments for threatened abortion (5.5%). Important variations between countries were observed, reflecting different medical attitudes towards drug use during pregnancy.</p

Safety of poly-L-lactic acid (New-Fill®) in the treatment of facial lipoatrophy: a large observational study among HIV-positive patients

Background Facial lipoatrophy is a frequently reported condition associated with use of antiretroviral (ARV) drugs. Poly-L-lactic acid (PLLA) acid has been used to correct facial lipoatrophy in people with HIV since 2004 both in Europe and the United States. The objective of this study was to establish, in real life conditions and in a large sample, the safety of PLLA (New Fill®, Valeant US, Sinclair Pharma Paris, France) to correct facial lipoatrophy among HIV-positive patients. Methods A longitudinal study was conducted between 2005 and 2008 in France. Data from 4,112 treatment courses (n = 4,112 patients) and 15,665 injections sessions (1 to 5 injection sessions per treatment course) were gathered by 200 physicians trained in the use of PLLA. Results The average age of patients (88.3% males) treated for lipoatrophy was 47.1 ± 8.1 years (Mean ± SD); 91.2% of patients had been receiving ARV treatment for 10.9 (±4.2) years; CD4 T-cell count was 535 ± 266 cells/mm3. The duration of facial lipoatrophy was 5 ± 2.8 years and the severity was such that 47.3% of patients required five injection sessions of PLLA and 81.9% of the sessions required two vials of the preparation. The final visit, scheduled two months after the last injection session, was attended by 66.0% of patients (n = 2,713). 48 treatment courses (2.8%) were discontinued due to adverse events (AEs). The overall incidence of AEs per course was 18.8%. Immediate AEs, bleeding (3.4%), bruising (2.3%), pain (2.0%), redness at injection site (1.6%), and swelling of the face (0.7%), occurred in 15.4% of courses and 7.0% of sessions (usually during the first session). Non-immediate AEs, mainly nodules (5.7%), inflammation (0.7%), granuloma (0.3%), discolouration (0.2%), and skin hypertrophy (0.1%), occurred in 6.7% of courses. Non-immediate AEs occurred within a time ranging from 21 days (inflammation) to 101 days (granuloma) and all but three of the 13 cases of granuloma resolved. Product efficacy was rated satisfactory by 95% of the patients and physicians. Conclusions This study demonstrated, in real-life conditions and on a large sample, that PLLA injections were feasible, efficient, and safe when performed by trained physicians

Adaptation of HIV-1 Envelope Glycoprotein gp120 to Humoral Immunity over the Course of the Epidemic

Since 2009, a large panel of broad and potent monoclonal neutralizing antibodies (MoNAbs) against HIV-1 have been isolated. These MoNAbs can protect from lllV-1 infection and suppress established infection in animal models. Because their efficacy should be evaluated in human clinical trials, it is of importance to define the sensitivity of the most contemporary transmitted variants to these MoNAbs. We, and others previously, reported that HIV-1 has become more resistant to neutralization over the course of the epidemic (Bunnik et al., Nature Med 2010, Bouvin-Pley et al., PloS Pathog 2013). Methods: Here we extended the analyses to the most potent MoNAbs described since then, either more recently isolated or improved by structure-based gene modifications. Results: We fully confirmed the first observations showing an increasing resistance of HIV-1 clade B over time to MoNAbs targeting the major gp l20 epitopes but not to MoNAbs targeting the gp41 MPER. Despite this evolution, some MoNAbs still were able to neutralize efficiently the most recently transmitted HIV-1 variants (2006-2010). The most potent MoNAbs were the bi-specific PG9- and PG16-iMab that alone were able to neutralize an variants at less than 0.4 mg/mL. The sensitivity to iMAb remained similar over time, suggesting that the trend of increasing resistance to PG9-/PG16-iMAb may be attributed only to die antigen binding domain of PG9/PG16. NIH45-46m2 (and -m7), 10-1074 and 10E8 were also highly potent and, if combined, reached the potency of PG9-/PG16-iMAb. We also observed that 3BNC 117 was almost as potent as the modified NIH45-46 antibodies, and that the lama-derived JM4IgG2b was the most potent Ab among those that do not target the major gp 120 neutralizing epitopes. Conclusions: These data clearly suggest a continuous drift of the env gene of HIV-1 elude B over the epidemic, and that not a single epitope is concerned but the entire gp120 as a whole. The consequences of this adaptation on the envelope functionality are being explored

Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients

BACKGROUND: Low-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200). METHODS: ESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with ≥ 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was ≥-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period. RESULTS: 211 patients were randomized, 158 to APV600/RTV and 53 to APV1200. At week 24, APV600/RTV was similar to or better than APV1200 (HIV-1 RNA <200 copies/mL in 62% [73/118] vs 53% [20/38] of patients; intent-to-treat: observed analysis). In the APV600/RTV arm, significantly more patients achieved HIV-1 RNA <50 copies/mL (48% [57/118] vs 29% [11/38] with APV1200, P = 0.04), and greater mean reduction from baseline in HIV-1 RNA was observed (-2.21 vs -1.59 log(10 )copies/mL, P = 0.028). The two treatment arms were similar with respect to mean overall change from baseline in CD4+ count, frequency of drug-related grade 1–4 adverse events, and frequency of discontinuing treatment due to adverse events (most commonly nausea, diarrhea, vomiting or fatigue; 7% vs 8%), although a lower proportion of patients in the APV600/RTV arm experienced drug-related oral/perioral paresthesia (2% vs 8%). Eleven (73%) of 15 patients who had HIV-1 RNA <200 copies/mL at week 24 and chose to continue study treatment maintained this level of virologic suppression at follow-up 24 weeks later. CONCLUSIONS: APV600 RTV BID was similar to or better than APV1200 BID in virologic response. Virologic results in a small number of patients who continued treatment for 24 weeks post-study suggest that virologic suppression with APV600 RTV BID is durable

CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies

BACKGROUND: A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH. METHODS: PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations. RESULTS: We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR] = 2.02 [95% confidence interval {CI } = 1.23-3.31]) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 [95% CI = 1.58-6.22]) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 [95% CI = 1.60-6.56] for KS; HR = 5.28 [95% CI = 2.17-12.83] for NHL). CONCLUSIONS: Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3

Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir

Effects of Recombinant Human Interleukin 7 on T-Cell Recovery and Thymic Output in HIV-Infected Patients Receiving Antiretroviral Therapy: Results of a Phase I/IIa Randomized, Placebo-Controlled, Multicenter Study

Interleukin 7 induces a well-tolerated, dose-dependent, and sustained increase of CD4 T cells in human immunodeficiency virus-infected individuals treated with antiretroviral therapy, through an expansion of peripheral T cells that do not express activation markers, and increases thymic output in some patients

Recent HIV-1 Infection Contributes to the Viral Diffusion over the French Territory with a Recent Increasing Frequency

To analyse the contribution of primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) to the French viral epidemic. sequences included 987 PHI from the French ANRS PRIMO cohort between 1999 and 2010 and were analysed using a population-based phylogenetic approach. Clinical features, risk factors, sexual behaviour and drug resistance for clustered and nonclustered transmission events were ascertained.Viruses from 125 (12.7%) of PHI cosegregated into 56 transmission chains, with increasing frequency during the last years (10.2% before 2006 versus 15.2% of clusters in 2006–2010, p = 0.02). The mean number of patients per cluster was 2.44. Compared to unique PHI, clusters involved more often men, infected through homosexual intercourse, of young age, with a high number of casual sexual partnerships and frequent previous HIV serological tests. Resistant strains were found in 16.0% and 11.1% of clusters and unique PHI, respectively (p = 0.11). Overall, 34% (n = 19) clusters included patients followed in French regions far apart, involving 13 clusters with at least one Parisian patient.PHIs are a significant source of onward transmission, especially in the MSM population. Recently infected people contribute to the spread of the viral epidemic throughout the French territory. Survey of transmitted drug resistance and behavioural characteristics of patients involved into clustered PHI may help to guide prevention and treatment interventions

Nelfinavir, an HIV-1 Protease Inhibitor, Induces Oxidative Stress–Mediated, Caspase-Independent Apoptosis in Leishmania Amastigotes

Visceral leishmaniasis is the most severe form of disease caused by the parasite Leishmania. It is a major concern in South America, Africa, India and the Middle East. Additionally, it has now emerged as an important opportunistic disease in patients coinfected with HIV-1. This is due, in part, to the increasing overlap between urban centers and rural areas endemic for Leishmania. Although more efficient combinatorial antiviral drug regimens for treating HIV-1 infection have been developed, the impact of such therapies on HIV-1/Leishmania coinfection is yet to be explored. In this study, we investigated the effect of nelfinavir, a well-characterized anti-HIV-1 drug, on Leishmania. Treating the parasite with nelfinavir activates events that are hallmarks of programmed cell death (also called apoptosis). Among these are oxidative stress, changes in DNA replication and fragmentation, and release of mitochondrial enzymes. Furthermore, these events occur without the participation of caspases, which are classically linked to apoptosis; however, this atypical apoptosis requires the translocation of endonuclease G from mitochondria to the cytoplasm. These findings provide insights for the design of new anti-parasitic therapies, particularly in the case of Leishmania/HIV-1 coinfections