Thalidomide is Associated With Increased T Cell Activation and Inflammation in Antiretroviral-naive HIV-infected Individuals in a Randomised Clinical Trial of Efficacy and Safety.

TRIAL DESIGN: Open-label, randomised, controlled, pilot proof-of-concept clinical trial. METHODS: Participants: Antiretroviral naïve adult males with CD4 count ≥350cells/mm3. INTERVENTIONS: Patients were randomised to receive thalidomide 200mg QD for 3weeks (Thalidomide group) or not (Control group) and followed for 48weeks. OBJECTIVE: We hypothesized that short-term Thalidomide use would reduce HIV related inflammation and HIV replication among antiretroviral naïve HIV infected individuals. OUTCOME: Viral loads, CD4/CD8 counts, ultra-sensitive C-reactive protein (US-CRP), cell activation markers, and plasma lipopolysaccharide (LPS) were analyzed. Randomisation: Unrestricted randomisation. Blinding: No blinding was used. RESULTS: Numbers randomised: Thirty recruited individuals were randomised to Thalidomide (16 patients) or Control (14 patients) groups. Recruitment: Patients were recruited from April 2011 to January 2013. OUTCOME: Viral loads remained stable in both groups. During thalidomide treatment, a decrease in CD4/CD8 ratio (p=0.04), a decrease in CD4 count (p=0.04), an increase in cell activation calculated by the percentage of CD38 +/HLA-DR+ CD8 cells (p<0.05) and an increase in US-CRP (p<0.01) were observed in the Thalidomide group, with all parameters returning to baseline levels after thalidomide interruption. We confirmed that thalidomide increased HIV replication in vitro of 6 of 7 samples from long-term antiretroviral suppressed individuals. HARMS: No class 3/4 adverse events occurred. CONCLUSIONS: Short-term use of thalidomide led to an intense transient increase in T cell activation and inflammation, with a decrease in the CD4+ cell count without changes to the CD8+ cell count. We confirmed that thalidomide acts in vitro as a latency reversal agent and speculate that the in vivo results obtained were due to an increase in HIV replication.

Prevalence of transmitted HIV-1 antiretroviral resistance among patients initiating antiretroviral therapy in Brazil: a surveillance study using dried blood spots.

INTRODUCTION: In Brazil, the use of antiretrovirals is widespread: more than 260,000 individuals are currently undergoing treatment. We conducted a survey targeting antiretroviral-naïve individuals who were initiating antiretroviral therapy (ART) according to local guidelines. This survey covered five Brazilian regions. METHODS: The HIV Threshold Survey methodology (HIV-THS) of the World Health Organization was utilized, and subjects were selected from seven highly populated cities representative of all Brazilian macro-regions. Dried blood spots (DBS) were collected on SS903 collection cards and were transported by regular mail at room temperature to a single central laboratory for genotyping. RESULTS: We analysed samples from 329 individuals initiating highly active antiretroviral therapy (HAART), 39 (11.8%) of whom were harbouring transmitted drug resistance (TDR). The mean CD4+ T cell count was 253 cells/µL, and the mean viral load was 142,044 copies/mL. The regional prevalence of resistance was 17.0% in the Northeast, 12.8% in the Southeast, 10.6% in the Central region, 8.5% in the North and 8.5% in the South. The inhibitor-specific TDR prevalence was 6.9% for nucleoside reverse transcriptase inhibitors, 4.9% for non-nucleoside reverse transcriptase inhibitors and 3.9% for protease inhibitors; 3.6% of individuals presented resistance to more than one class of inhibitors. Overall, there were trends towards higher prevalences of subtype C towards the South and subtype F towards the North. Of the DBS samples collected, 9.3% failed to provide reliable results. DISCUSSION: We identified variable TDR prevalence, ranging from intermediate to high levels, among individuals in whom HIV disease progressed, thus implying that resistance testing before initiating ART could be effective in Brazil. Our results also indicate that the use of DBS might be especially valuable for providing access to testing in resource-limited and remote settings.

HIV-1 resistance testing influences treatment decision-making.

OBJECTIVE: To investigates how the use of HIV-1 resistance tests influences physician decision-making. METHODS: Ten experienced reference physicians from the Brazilian Network for Drug Resistance each received ten patients' case histories. The selected patients had experienced at least two virological failures. First, reference physicians were asked to empirically select a new regimen for each patient. Second, after genotype report (ViroSeq 2.6) was provided, and physicians were again asked to select a new regimen considering this additional information. Finally, they were asked to select a regimen after receiving a virtual phenotype result (vircoTYPE 3.9.00). RESULTS: In 79% of the cases, physicians changed their empirical choice of regimen after receiving the genotype report, resulting in an increase in the mean number of active drugs from 1.8 to 2.2 (p = 0.0003), while the average number of drugs/regimen remained at 4.0. After receipt of the virtual phenotype report, additional changes were made in 75% of the patient cases, resulting in an increase in the number of active drugs to 2.8 (p < 0.0001), while the average number of drugs/regimen remained at 4.0. After receipt of the genotype report, 48% of the changes were in NRTIs, 29% were in NNRTIs and 60% were in PIs; after consideration of the virtual phenotype, 61%, 10% and 49% of the changes, respectively, were in these categories of drugs. Fourteen percent of the physicians rated the genotype report as "extremely useful", whereas 34% rated the subsequent virtual phenotype report as "extremely useful" (p = 0.0003). CONCLUSIONS: Resistance testing has a significant impact on physicians' choices of antiretroviral salvage therapies, and it promotes the selection of more active drugs.

Limited penetration of lopinavir and ritonavir in the genital tract of men infected with HIV-1 in Brazil.

The concentrations of lopinavir and ritonavir in seminal and blood plasma and the seminal human immunodeficiency virus (HIV) viral load were quantified by HPLC and the Nuclisens assay, respectively, in a cross-sectional study of 16 HIV-1-infected Brazilian men under stable treatment with a lopinavir/ritonavir containing antiretroviral regimen. Semen and blood samples were collected on 2 occasions: at 6 to 60 minutes before ("trough"), and 5 to 6 hours after ("peak") ingestion of regular doses of lopinavir/ritonavir. Median seminal lopinavir levels were 120.6 ng/mL (range, <20-1481.8 ng/mL) and 233.1 ng/mL (range, 48.4-1133.4 ng/mL) at trough and peak points, respectively. The corresponding values for ritonavir were 9.2 ng/mL (range, <5-47 ng/mL) and 17.1 ng/mL (range, 6.6-66.7 ng/mL). The median concentrations of lopinavir and ritonavir in semen were, respectively, 1.9% to 3% and 3.7% to 4.4% of those measured in blood plasma samples collected within 30 minutes. HIV-1 viral load was detectable in the semen of 2 and in the blood of 6 of 16 patients. These results may have implications for drug-resistant HIV-1 evolution and transmission.