In 2008, the goal of antiretroviral therapy is the suppression of viral load to undetectable levels (<50 HIV-RNA copies/ml) even in heavily pretreated patients harboring multidrug-resistant viruses. ...This ambitious goal can be achieved by combining at least two fully active antiretroviral drugs with an optimized background regimen according to genotypic and phenotypic resistance testing. This favorable situation has been accomplished by the advent of new compounds in already known drug classes (e.g. second-generation protease inhibitors and nonnucleoside reverse transcriptase inhibitors) as well as thanks to the development of new drug classes with a different mode of action (e.g. fusion inhibitors, integrase inhibitors, and coreceptor antagonists). Moreover, new diagnostic tools have been developed to better predict virologic response and tolerability of a given regimen in the individual patient, such as weighted mutation scores, virtual phenotypes, viral tropism assays, pharmacogenetics and pharmacokinetic analyses. This new array of therapeutic and diagnostic tools requires a highly specialized training of the treating physician to achieve the ultimate goal of halting disease progression. The purpose of this review is to introduce the new drugs and drug classes, and discuss their safety and use in combination therapy of multidrug-resistant viruses, guided by new diagnostic tools.
To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma ...encephalitis (TE).
Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life.
61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group.
In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.
Recently, it has been shown that human ejaculate enhances human immunodeficiency virus 1 (HIV-1) infectivity. Enhancement of infectivity is conceived to be mediated by amyloid filaments from peptides ...that are proteolytically released from prostatic acid phosphatase (PAP), termed Semen-derived Enhancer of Virus Infection (SEVI). The aim of this study was to test the range of HIV-1 infectivity enhancing properties of a large number of individual semen samples (n = 47) in a TZM-bl reporter cell HIV infection system. We find that semen overall increased infectivity to 156% of the control experiment without semen, albeit with great inter- and intraindividual variability (range -53%-363%). Using transmission electron microscopy, we provide evidence for SEVI fibrils in fresh human semen for the first time. Moreover, we confirm that the infectivity enhancing property can be inhibited by the major green tea ingredient epigallocatechin-3-gallate (EGCG) at non-toxic concentrations. The median inhibition of infection by treatment with 0.4 mM EGCG was 70.6% (p < 0.0001) in our cohort. Yet, there were substantial variations of inhibition and in a minority of samples, infectivity enhancement was not inhibited by EGCG treatment at all. Thus, topical application of EGCG may be a feasible additional measure to prevent the sexual transmission of HIV. However, the reasons for the variability in the efficacy of the abrogation of semen-mediated enhancement of HIV-1 infectivity and EGCG efficacy have to be elucidated before therapeutic trials can be conducted.
Summary
Hodgkin's disease (HD) is the most common non‐acquired immunodeficiency syndrome (AIDS)‐defining malignancy in human immunodeficiency virus (HIV)‐infected patients. We analysed the outcome of ...patients with HIV‐associated HD (HIV‐HD) with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and other prognostic factors. To evaluate the effects of several variables on overall survival (OS), Kaplan–Meier statistics and extended Cox regression analysis were performed. Response to HAART was used as a time‐dependent variable and was defined as an increase of >0·1 × 109 CD4 cells/l and/or at least one viral load <500 copies/ml during the first 2 years following diagnosis of HIV‐HD. Fifty‐seven patients with HIV‐HD diagnosed between 1990 and 2002 were included in the study. In the Cox model, the only factors independently associated with OS were HAART response relative hazard (RH) 0·19; 95% confidence interval (CI) 0·06–0·60, complete remission (RH 0·30, 95% CI 0·13–0·72), and age 45 years (RH 0·23; 95% CI 0·09–0·60). Median survival time in patients without HAART response was 18·6 months, whereas the median survival time in patients with HAART response was not reached (89% OS at 24 months). In this cohort, a significant improvement in survival was found in patients with HIV‐HD who responded to HAART.
Introduction
Dolutegravir (DTG) 50 mg once daily was superior to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL ...(p=0.025) 1. We present data through Week 96.
Material and Methods
FLAMINGO is a multicentre, randomized, open‐label, Phase IIIb non‐inferiority study, in which HIV‐1‐positive ART‐naïve adults with HIV‐1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator‐selected backbone NRTIs (TDF/FTC or ABC/3TC). Participants were stratified by screening HIV‐1 RNA (≤100K c/mL) and NRTI backbone.
Results
A total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002). Secondary analyses supported primary results: per‐protocol (DTG 83% vs. DRV/r 70%), 95% CI 12.9 (5.3, 20.6) and treatment‐related discontinuation = failure (98% vs. 95%), 95% CI 3.2 (−0.3, 6.7). Overall virologic non‐response (DTG 8%; DRV/r 12%) and non‐response due to other reasons (DTG 12%; DRV/r 21%) occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96) and in the TDF/FTC stratum (79% vs. 64%); consistent responses were seen in the ABC/3TC stratum (82% vs. 75%). Six participants (DTG 2, none post‐Week 48; DRV/r 4, two post‐Week 48) experienced protocol‐defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24); none had treatment‐emergent resistance to study drugs. Most frequent drug‐related adverse events (AEs) were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24%) than DTG (10%). Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22%) vs. DTG (7%), p<0.001; mean changes in creatinine for DTG (~0.18 mg/dL) observed at Week 2 were stable through Week 96.
Conclusions
Once‐daily DTG was superior to once‐daily DRV/r in treatment‐naïve HIV‐1‐positive individuals, with no evidence of emergent resistance to DTG in virologic failure and relatively similar safety profiles for DTG and DRV/r through 96 Weeks.
Abstract Background and objectives Minority drug-resistant HIV-1 variants, undetected by conventional genotyping, may impair the outcome of antiretroviral therapy (ART). Thus, we retrospectively ...analyzed the prevalence of minority drug-resistant HIV-1 variants before ART in chronically HIV-1 infected patients initiating first-line therapy and assessed the impact on clinical outcome in the prospective German Truvada cohort. Study design Samples from 146 antiretroviral treatment-naïve patients were collected between April 2005 and August 2006. K65R, K103N, and M184V variants at low frequencies were detected by allele-specific real-time PCR. Results Minority drug-resistant HIV-1 variants were detected in 20/146 patients (13.7%): the M184V mutation in 12/146 patients (8.2%), the K103N mutation in 8/146 patients (5.5%), and the K65R mutation in 4/146 patients (2.7%). Four patients with the M184V mutation also harbored the K65R or the K103N mutation. The 12- and 24 months virological efficacy data revealed that the rate of treatment failure was not increased in the group of patients harboring minority drug-resistant HIV-1 variants prior to ART. Conclusions Minority drug-resistant HIV-1 variants can be frequently detected in treatment-naïve, chronically HIV-1 infected patients. Despite the presence of those mutations as minority variants before initiating ART, most of the patients were successfully treated.
BACKGROUND/AIM OF THE STUDY: The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART, ...-regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios.
Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study centres have been investigated since 1996. Biannual data cART-initiation, cART-changes, surrogate markers, clinical events and the Centre of Disease Control- (CDC)-stage of HIV disease are reported. Treatment duration was calculated on a daily basis via the documented dates for the beginning and end of each antiretroviral drug treatment. Prices were calculated for each individual regimen based on actual office sales prices of the branded pharmaceuticals distributed by the license holder including German taxes.
During the 13-year follow-up period, 21,387,427 treatment days were covered. Cumulative direct costs for antiretroviral drugs of €812,877,356 were determined according to an average of €42.08 per day (€7.52 to € 217.70). Since cART is widely used in Germany, the costs for an entire regimen increased by 13.5%. Regimens are more expensive in the advanced stages of HIV disease. The potential for cost savings was calculated using non-nucleotide-reverse-transcriptase-inhibitor, NNRTI, more frequently instead of ritonavir-boosted protease inhibitor, PI/r, in first line therapy. This calculation revealed cumulative savings of 10.9% to 19.8% of daily treatment costs (50% and 90% substitution of PI/r, respectively). Substituting certain branded drugs by generic drugs showed potential cost savings of between 1.6% and 31.8%.
Analysis of the data of this nationwide study reflects disease-specific health services research and will give insights into the cost impacts of antiretroviral therapy, and might allow a more rational allocation of resources within the German health care system.
HIV-1 bound extracellularly to follicular dendritic cells (FDC) in germinal centers (GC) of lymphoid tissues (LT) represents the largest viral reservoir in HIV-infected individuals; however there is ...no direct evidence as to whether HIV trapped in human GC remains infectious. In the GC, complement receptors and Fc gamma receptors have been suggested to participate in trapping of HIV; therefore, the relative contribution of complement- and Fc gamma receptors in binding HIV on LT was investigated and the infectivity of this virus was tested.
As it is difficult to isolate FDC without contaminations of productively infected cells, HIV was detached from LT of HIV positive individuals using antibodies blocking complement- and Fc gamma receptors. Isolated virus was tested in an infectivity assay.
HIV detached from LT was quantified by HIV p24 ELISA, PCR and in an in vitro infectivity assay. Presence and accessibility of viral envelope proteins, complement factors and immunoglobulins on the surface of detached viral particles were evaluated through viral capture by respective antibodies.
Although both C3d-fragments and IgG molecules were identified on the surface of HIV detached from LT, trapping of HIV was mediated solely by CR2-C3d interactions, whereas contribution of Fc gamma receptors was not detectable. Infectivity assays with HIV stripped from LT of HIV positive individuals revealed that in four out of ten patients HIV particles were infectious.
These findings indicate that in the GC infectious virus is trapped on CR2-expressing FDC (or B cells). Reduction of this pool of HIV could be a therapeutic goal.
HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during ...HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production.
HIV-HCV co-infection is associated with accelerated progression to hepatic fibrosis, cirrhosis and hepatocellular carcinoma than HCV mono-infection. The contribution of innate immunity during HIV-HCV ...co-infection has been a relatively under-investigated area. Natural killer (NK) cells are pivotal sentinels of innate immunity against viruses and tumour cells. In this study we evaluated the effect of HIV-HCV co-infection on peripheral blood NK cell subsets with emphasis on the phenotype of CD56.sup.bright NK cells. Sixty patients were included in the study; HIV mono-infected (n = 12), HCV mono-infected (n = 15), HCV-HIV co-infected (n = 21) and healthy controls (n = 16). PBMCs were isolated and immunophenotyping of NK cells was performed by flowcytometry. We observed an expansion of CD56.sup.bright NK cell subset in HIV-HCV co-infection as compared to healthy controls and HIV mono-infected group. All the infected groups had an upregulated expression of the activating receptor NKG2D on CD56.sup.bright NK cells in comparison to healthy controls while not differing amongst themselves. Thus, HIV-HCV co-infection is able to modulate the phenotype of CD56.sup.bright NK cell subset in a unique way such that NKp46 and CXCR3 expressions are distinct for co-infection while both mono-infections have an additive effect on CD56.sup.bright, CD69 with CD95 expressions. HCV mono-infection has a dominant effect on NKp30 expression while NKG2D and CD127 expressions remained same in all the groups.
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