Antiretroviral Treatment of Adult HIV Infection

Günthard, Huldrych F.; Aberg, Judith A.; Eron, Joseph J.; Hoy, Jennifer; Telenti, Amalio; Benson, Constance A.; Burger, David M.; Cahn, Pedro; Gallant, Joel E.; Glesby, Marshall J.; Reiss, Peter; Saag, Michael S.; Thomas, David L.; Jacobsen, Donna M.; Volberding, Paul A.

doi:10.1001/jama.2012.7961

Cited by 1,208 publications

(297 citation statements)

References 203 publications

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“…The randomized controlled Strategic Timing of AntiRetroviral Treatment (START) trial has recently investigated the optimal timing of cART initiation in order to improve morbidity and mortality outcomes in HIV‐positive individuals 4. Nevertheless, there have already been changes to national and international HIV treatment guidelines 5, 6, largely driven by the impact of cART on viral transmission 7 and a pragmatic approach to cART roll out programmes.…”

Section: Introductionmentioning

confidence: 99%

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

José¹,

Quinn

Dunn

et al. 2015

HIV Medicine

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ObjectivesNo randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development.MethodsIn a large cohort of HIV‐positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART.ResultsOf 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL.ConclusionsWe found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL.

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Section: Introductionmentioning

confidence: 99%

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

José¹,

Quinn

Dunn

et al. 2015

HIV Medicine

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“…he level of HIV-1 RNA in blood plasma (viral load) is arguably the most important surrogate marker in the treatment of HIV infection (1). For over a decade, the endpoint PCR-based Roche Cobas Amplicor HIV-1 Monitor test (versions 1 and 1.5) (Amplicor) (2) was a widely used viral load assay and was in use in both clinical trials and routine practice.…”

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confidence: 99%

Comparative Performances of HIV-1 RNA Load Assays at Low Viral Load Levels: Results of an International Collaboration

et al. 2014

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Low-level viremia during antiretroviral therapy and its accurate measurement are increasingly relevant. Here, we present an international collaboration of 4,221 paired blood plasma viral load (pVL) results from four commercial assays, emphasizing the data with low pVL. The assays compared were the Abbott RealTime assay, the Roche Amplicor assay, and the Roche TaqMan version 1 and version 2 assays. The correlation between the assays was 0.90 to 0.97. However, at a low pVL, the correlation fell to 0.45 to 0.85. The observed interassay concordance was higher when detectability was defined as 200 copies/ml than when it was defined as 50 copies/ml. A pVL of ϳ100 to 125 copies/ml by the TaqMan version 1 and version 2 assays corresponded best to a 50-copies/ml threshold with the Amplicor assay. Correlation and concordance between the viral load assays were lower at a low pVL. Clear guidelines are needed on the clinical significance of low-level viremia.

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“…he drugs used in highly active antiretroviral therapy for the treatment of HIV infection can be classified into six classes: nucleoside/nucleotide reverse transcriptase (RT) inhibitors, non-nucleoside RT inhibitors, protease inhibitors, CCR5 antagonists, fusion inhibitors, and integrase strand transfer inhibitors (INSTIs) (1).…”

mentioning

confidence: 99%

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Hassounah

Mésplède

Quashie

et al. 2014

J Virol

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Studies on the in vitro susceptibility of SIV to integrase strand transfer inhibitors (INSTIs) have been rare. In order to determine the susceptibility of SIVmac239 to INSTIs and characterize the genetic pathways that might lead to drug resistance, we inserted various integrase (IN) mutations that had been selected with HIV under drug pressure with raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) into the IN gene of SIV. We evaluated the effects of these mutations on SIV susceptibility to INSTIs and on viral infectivity. Sequence alignments of SIVmac239 IN with various HIV-1 isolates showed a high degree of homology and conservation of each of the catalytic triad and the key residues involved in drug resistance. Each of the G118R, Y143R, Q148R, R263K, and G140S/Q148R mutations, when introduced into SIV, impaired infectiousness and replication fitness compared to wild-type virus. Using TZM-bl cells, we demonstrated that the Q148R and N155H mutational pathways conferred resistance to EVG (36-and 62-fold, respectively), whereas R263K also displayed moderate resistance to EVG (12-fold). In contrast, Y143R, Q148R, and N155H all yielded low levels of resistance to RAL. The combination of G140S/Q148R conferred highlevel resistance to both RAL and EVG (>300-and 286-fold, respectively). DTG remained fully effective against all site-directed mutants except G118R and R263K. Thus, HIV INSTI mutations, when inserted into SIV, resulted in a similar phenotype. These findings suggest that SIV and HIV may share similar resistance pathways profiles and that SIVmac239 could be a useful nonhuman primate model for studies of HIV resistance to INSTIs. IMPORTANCEThe goal of our project was to establish whether drug resistance against integrase inhibitors in SIV are likely to be the same as those responsible for drug resistance in HIV. Our data answer this question in the affirmative and show that SIV can probably serve as a good animal model for studies of INSTIs and as an early indicator for possible emergent mutations that may cause treatment failure. An SIV-primate model remains an invaluable tool for investigating questions related to the potential role of INSTIs in HIV therapy, transmission, and pathogenesis, and the present study will facilitate each of the above.

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Antiretroviral Treatment of Adult HIV Infection

Cited by 1,208 publications

References 203 publications

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Comparative Performances of HIV-1 RNA Load Assays at Low Viral Load Levels: Results of an International Collaboration

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

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