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In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to darunavir and efavirenz through to 48 and 96 weeks. Here we report 192-week results from both studies.

Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection.

New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3.

Background We hypothesized that rates and reasons for treatment modifications have changed since the implementation of combination antiretroviral therapy (cART) due to improvements in therapy.Methods From a nationwide population-based cohort study we identified all HIV-1-infected adults who initiated cART in Denmark 1997–2009 and were followed =1 year. Incidence rate ratios (IRRs) and reasons for treatment modifications were estimated and compared between patients, who initiated treatment in 1997–1999, 2000–2004 and 2005–2009. Rates of discontinuation of individual antiretroviral drugs (ARVs) were evaluated.Results A total of 3,107 patients were followed for a median of 7.3 years (IQR 3.8–10.8). Rates of first treatment modification =1 year after cART initiation did not change (IRR 0.88 [95% CI 0.78, 1.01] and 1.03 [95% CI 0.90, 1.18] in 2000–2004 and 2005–2009, respectively, compared with 1997–1999). Rates of multiple modifications decreased markedly (2000–2004 IRR 0.60 [95% CI 0.53, 0.67] and 2005–2009 IRR 0.38 [95% CI 0.32, 0.46]). Rates of treatment modifications due to virological failure, toxicity and other/unknown reasons decreased (IRR 0.25 [95% CI 0.14, 0.45], 0.69 [95% CI 0.56, 0.83] and 0.45 [95% CI 0.36, 0.57], respectively, in 2005–2009 compared with 1997–1999), whereas the rate of modifications with the aim of simplification increased (IRR 1.85 [95% CI 1.52, 2.25]).Conclusions Rates of first treatment modification =1 year after cART initiation have not changed since the early cART era, whereas the risk of multiple modifications has decreased markedly. Modifications due to virological failure and toxicity have decreased substantially, whereas rates of switch to simpler and less toxic regimens have increased.

Antiretroviral therapy is standard treatment for HIV-infected patients. Such therapy has decreased mortality and morbidity, but treatment success is often jeopardized by the emergence of viral drug resistance. Moreover, in recent years there has been a reported rise in the incidence of transmitted drug resistance, highlighting the importance of pretreatment resistance screening. In this report, we describe the development and utility of a sensitive multiplex approach for detecting mutations conferring drug resistance to HIV-1 reverse transcriptase inhibitors. This protocol, termed HIVSNaPshot, utilizes a multiplex primer extension assay with capillary electrophoresis reporting altered nucleotides at nine important drug resistance mutation positions. Mutations were successfully detected to levels of 5 in viral quasispecies populations. Furthermore, although developed and optimised for HIV-1 subtype B, drug resistance mutations could also be detected in most non-B subtypes. Comparison of the HIV-SNaPshot with the commercial Viroseq genotyping system in 10 patients gave similar results, but importantly, additional resistance mutations were identified in several patients by the HIV-SNaPshot assay. Thus, the HIV-SNaPshot is a method capable to support standard genotyping for the determination of minority HIV-1 resistance mutations, with equivalent and perhaps greater sensitivity than Viroseq.

Objective To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations.Methods Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4–3. Reversion of single mutations was performed in a patient-derived recombinant clone.Results Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received >12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3–6-fold resistance to PFA, a 2–20-fold decrease in resistance to zidovudine compared to baseline, and 14–39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of =3 mutations (K70G+K219R+L228R±V75T) induced PFA resistance and decreased zidovudine resistance 3–13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G?R and K219R?E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance.Conclusions In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.

Background: The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. Methods: The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. Results: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. Conclusion: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337?45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.

During a progressive HIV-1 infection, the gradual decrease in functional CD4+ Thelper cells leads to immunodeficiency and eventually death in the untreated patient. The virulence role of the lentiviral accessory gene nef was first reported from deletion studies in the macaque model, and research during the past decade has revealed a pluripotent protein capable of multiple points of interference with cellular mechanisms. Importantly, Nef has the capacity to modify the plasma membrane signalling by regulation of receptor / ligand endocytosis as well as to modulate cellular regulation such as apoptosis and lymphocyte activation. This effective defence against an apparent vigorous and specific immune response is crucial for the ability of HIV-1 to persist in the host. Here we review the multitude of functions exerted by Nef and discuss the functional domains of the protein in terms of cellular interaction partners and the effect of nef mutations in the course of AIDS disease progression.

A commercially available kit, Amplicor®, was compared with a locally developed nested reverse‐transcriptase (RT) PCR for qualitative detection of HCV‐RNA. Sixty‐one serum samples from sixty‐one patients with liver disease, and 60 samples from 60 hemophiliacs without symptoms, but known to have been heavily exposed to hepatitis C virus, were investigated. There was a high degree of concordance between the two diagnostic tests (97%), the Amplicor® kit being slightly more sensitive than the in‐house PCR, when evaluated using serial dilutions of samples showing discrepant results. The relationship between viremia and abnormal ALT levels was studied in the two groups of patients. Among those with chronic liver disease, 8.3% of patients with viremia had normal ALT levels, whereas transaminases were normal in 20% of hemophiliacs with viremia. This points to ALT as being a poor marker of ongoing viral replication.

The acute phase C-reactive protein (CRP) was measured in serum of HIV-infected patients suffering from Pneumocystis carinii pneumonia (PCP) (32 patients), bacterial pneumonia (10 patients), and in 19 immunocompetent patients with bacterial pneumonia. The HIV-infected patients with bacterial pneumonia had a significantly lower CRP level than the immunocompetent patients (50% versus 95% had an s-CRP level >80 mg/l). No significant difference was found in the CRP response to P. carinii or bacteria in HIV-infected patients with pneumonia due to these microorganisms (20% versus 50% had s-CRP >80 mg/l). In the group of PCP patients, a significantly lower CRP level was found in those with CD4 positive lymphocyte counts below 50 × 106/l. There was no correlation between the CRP response and the severity of the PCP as estimated by the degree of hypoxia. We conclude that the CRP level cannot be used to discriminate between PCP and bacterial pneumonia in HIV-infected patients.

Neutrophils from human immunodeficiency virus (HIV)-negative blood donors, asymptomatic HIV-positive patients, AIDS patients with previous Pneumocystis carinii pneumonia (PCP), and AIDS patients without previous PCP were compared for their ability to activate the respiratory burst, measured as luminol-amplified chemiluminescence. P. carinii, Staphylococcus aureus, phorbol-12-myristate-13-acetate, and FMLP were used to stimulate the neutrophils. When stimulated with P. carinii, neutrophils from PCP patients had a significantly lower response than the other groups, whereas no difference was found when S aureus was used. A somewhat but not significantly lower response to P. carinii was also seen in non-PCP patients compared with HIV-negative donors. Priming of the neutrophils with recombinant granulocyte colony-stimulating factor (G-CSF) or recombinant human granulocyte-macrophage (GM)-CSF corrected this defect. A similar effect of these cytokines was seen on phagocytosis, whereas the chemiluminescence in unprimed cells did not correlate with phagocytosis.

Phagocytosis and superoxide production of neutrophils stimulated with Pneumocystis carinii were studied using P. carinii obtained from rats and neutrophils and serum from healthy blood donors. Superoxide generation increased in a dose-related way to the number of pneumocysts added and was significantly higher when the parasites were opsonized. The use of heat-inactivated serum for opsonization reduced superoxide production somewhat, but not significantly. Preincubation ofneutrophils with recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) increased superoxide production in neutrophils stimulated with pneumocysts from 7.0 to 9.6 fmol/cell/20 min; however, the production in unstimulated cells increased by the same amount. Activation of the respiratory burst was paralleled by phagocytosis, and very few phagocytic vacuoles were found in neutrophils stimulated with unopsonized pneumocysts. By electron microscopy, various stages of cyst degradation were seen.