Abstract
Background
Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less ...likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy.
Methods
We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons.
Results and conclusions
We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir’s companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir’s companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.
Summary Background Results of cohort studies and mathematical models have suggested that increased coverage with highly active antiretroviral therapy (HAART) could reduce HIV transmission. We aimed ...to estimate the association between plasma HIV-1 viral load, HAART coverage, and number of new cases of HIV in the population of a Canadian province. Methods We undertook a population-based study of HAART coverage and HIV transmission in British Columbia, Canada. Data for number of HIV tests done and new HIV diagnoses were obtained from the British Columbia Centre for Disease Control. Data for viral load, CD4 cell count, and HAART use were extracted from the British Columbia Centre for Excellence in HIV/AIDS population-based registries. We modelled trends of new HIV-positive tests and number of individuals on HAART using generalised additive models. Poisson log-linear regression models were used to estimate the association between new HIV diagnoses and viral load, year, and number of individuals on HAART. Findings Between 1996 and 2009, the number of individuals actively receiving HAART increased from 837 to 5413 (547% increase; p=0·002), and the number of new HIV diagnoses fell from 702 to 338 per year (52% decrease; p=0·001). The overall correlation between number of individuals on HAART and number of individuals newly testing positive for HIV per year was −0·89 (p<0·0001). For every 100 additional individuals on HAART, the number of new HIV cases decreased by a factor of 0·97 (95% CI 0·96–0·98), and per 1 log10 decrease in viral load, the number of new HIV cases decreased by a factor of 0·86 (0·75–0·98). Interpretation We have shown a strong population-level association between increasing HAART coverage, decreased viral load, and decreased number of new HIV diagnoses per year. Our results support the proposed secondary benefit of HAART used within existing medical guidelines to reduce HIV transmission. Funding Ministry of Health Services and Ministry of Healthy Living and Sport, Province of British Columbia; US National Institute on Drug Abuse; US National Institutes of Health; Canadian Institutes of Health Research.
There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level ...sustainability of this strategy has not been characterized.
We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals.
HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%.
Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.
A goal of HIV therapy is to sustain suppression of the plasma viral load below the detection limits of clinical assays. However, widely followed treatment guidelines diverge in their interpretation ...and recommended management of persistent viremia of low magnitude, reflecting the limited evidence base for this common clinical finding. Here, we review the incidence, risk factors, and potential consequences of low-level HIV viremia (LLV; defined in this review as a viremia level of 50 to 500 copies/ml) and very-low-level viremia (VLLV; defined as a viremia level of <50 copies/ml detected by clinical assays that have quantification cutoffs of <50 copies/ml). Using this framework, we discuss practical issues related to the diagnosis and management of patients experiencing persistent LLV and VLLV. Compared to viral suppression at <50 or 40 copies/ml, persistent LLV is associated with increased risk of antiretroviral drug resistance and overt virologic failure. Higher immune activation and HIV transmission may be additional undesirable consequences in this population. It is uncertain whether LLV of <200 copies/ml confers independent risks, as this level of viremia may reflect assay-dependent artifacts or biologically meaningful events during suppression. Resistance genotyping should be considered in patients with persistent LLV when feasible, and treatment should be modified if resistance is detected. There is a dearth of clinical evidence to guide management when genotyping is not feasible. Increased availability of genotypic assays for samples with viral loads of <400 copies/ml is needed.
•We looked for genetic differences at RPV resistance codons among HIV-1 subtypes.•E138A was found to occur more frequently in subtype C than B HIV-1 sequences.•E138A could impact RPV therapy in ...resource limited settings.
The nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV) has been co-formulated with emtricitabine and tenofovir disoproxil fumarate for initial therapy of HIV-1-infected individuals. RPV, formulated as a long-acting nanosuspension, will also be assessed for its ability to prevent HIV-1 infection in resource limited settings. In this study, we determined whether any pre-existing genetic differences occurred among different HIV-1 subtypes at residues in RT associated with decreased virologic response to RPV. We found that the E138A substitution occurs more frequently in subtype C (range: 5.9–7.5%) than B (range: 0–2.3%) sequences from both treatment-naïve and -experienced individuals (p<0.01) in 4 independent genotype databases. In one of the databases (Stanford University), E138K and E138Q were also more common in RTI-experienced subtype C sequences (1.0% and 1.1%, respectively) than in subtype B sequences (0.3% and 0.6%, respectively). E138A/K/Q in subtype C decreased RPV susceptibility 2.9-, 5.8-, and 5.4-fold, respectively. Taken together, these data suggest that E138A could impact treatment or prevention strategies that include RPV in geographic areas where subtype C infection is prevalent.
Introduction
Entry inhibitors are a relatively new class of antiretroviral therapy and are typically indicated in heavily treatment experienced individuals living with HIV. Despite this, there is no ...formal definition of ‘heavily treatment experienced’. Interpretation of this term generally includes acknowledgement of multidrug resistance and reflects the fact that patients in need of further treatment options may have experienced multiple lines of therapy. However, it fails to recognize treatment limiting factors including contraindications, age‐associated comorbidities, and difficulty adhering to regimens.
Methods
This manuscript follows a roundtable discussion and aims to identify the unmet needs of those living with HIV who are in need of further treatment options, to broaden the definition of heavily treatment experienced and to clarify the use of newer agents, with an emphasis on the potential role of entry inhibitors, in this population.
Results/Conclusions
Within the entry inhibitor class, mechanisms of action differ between agents; resistance to one subclass does not confer resistance to others. Combinations of entry inhibitors should be considered in the same regimen, and if lack of response is seen to one entry inhibitor another can be tried. When selecting an entry inhibitor, physicians should account for patient preferences and needs as well as agent‐specific clinical characteristics. Absence of documented multidrug resistance should not exclude an individual from treatment with an entry inhibitor; entry inhibitors are a valuable treatment option for all individuals who are treatment limited or treatment exhausted. We should advocate for additional clinical trials that help define the role of entry inhibitors in people with exhausted/limited ART options other than drug resistance.
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction ...between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.
Most individuals chronically infected with hepatitis C virus (HCV) are asymptomatic during the initial stages of infection and therefore the precise timing of infection is often unknown. ...Retrospective estimation of infection duration would improve existing surveillance data and help guide treatment. While intra-host viral diversity quantifications such as Shannon entropy have previously been utilized for estimating duration of infection, these studies characterize the viral population from only a relatively short segment of the HCV genome. In this study intra-host diversities were examined across the HCV genome in order to identify the region most reflective of time and the degree to which these estimates are influenced by high-risk activities including those associated with HCV acquisition. Shannon diversities were calculated for all regions of HCV from 78 longitudinally sampled individuals with known seroconversion timeframes. While the region of the HCV genome most accurately reflecting time resided within the NS3 gene, the gene region with the highest capacity to differentiate acute from chronic infections was identified within the NS5b region. Multivariate models predicting duration of infection from viral diversity significantly improved upon incorporation of variables associated with recent public, unsupervised drug use. These results could assist the development of strategic population treatment guidelines for high-risk individuals infected with HCV and offer insights into variables associated with a likelihood of transmission.
Summary Background Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients ...in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. Methods We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70–99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT 00576693. Findings During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (–0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 26% of 224 patients vs 42 19% of 227 patients; p=0·0468) and major haemorrhage (29 13%of 224 patients vs 10 4% of 227 patients; p=0·0009). Interpretation The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. Funding National Institute of Neurological Disorders and Stroke (NINDS) and others.
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