Emergence of HIV Drug Resistance During First- and Second-Line Antiretroviral Therapy in Resource-Limited Settings

Hosseinipour, Mina C.; Rk, Gupta; Zyl, Gert van; Eron, Joseph J.; Nachega, Jean B.

doi:10.1093/infdis/jit107

Cited by 123 publications

(100 citation statements)

References 55 publications

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“…Between these widely spaced visits, a small fraction of patients usually stop cART (Ͻ2% of patients/year), leading to rebounds in viral loads and loss of CD4 ϩ T-cell counts. Thus, patients with "typical" treatment failures, which occur at a rate of approximately 10% per year (9,53,54), are mixed with patients with defined cessations of cART. Both groups would have the laboratory parameters to trigger a request for HIV-1 drug resistance testing.…”

Section: Antiretroviral Treatment Outcomes Following Sanger Sequencinmentioning

confidence: 99%

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Kyeyune

Gibson

Nankya

et al. 2016

Antimicrob Agents Chemother

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Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified lowfrequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drugresistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

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Section: Antiretroviral Treatment Outcomes Following Sanger Sequencinmentioning

confidence: 99%

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Kyeyune

Gibson

Nankya

et al. 2016

Antimicrob Agents Chemother

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“…However, cART is not curative and thus must be administered for the lifetime of the infected patient. This long-term therapy is associated with issues of toxicity and compliance, and resistance to currently available antiretroviral drugs may become a significant problem for many patients (23)(24)(25)(26). Understanding the basis for drug resistance is thus key to the sustained success of antiretroviral therapy.…”

mentioning

confidence: 99%

Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

Martins

Waheed

Ablan

et al. 2016

J Virol

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HIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-AlaPro (PTAP), located in the p6 region of Gag (p6 Gag ), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6Gag significantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6Gag confers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy. IMPORTANCEResistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients.

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“…The clinical management of HIV-TB patients presents significant challenges, especially in resource-limited settings (2,4), where virological failure or intolerance to first-line antiretroviral therapy requires the use of HIV protease inhibitors (PIs) (5). PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6).…”

mentioning

confidence: 99%

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Roberts

Khoo

Owen

et al. 2017

Antimicrob Agents Chemother

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Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentrationdependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where ␤ was equal to Ϫ234 (95% confidence interval [CI] ϭ Ϫ275 to Ϫ193; P Ͻ 0.0001) and Ϫ73 (95% CI ϭ Ϫ89 to Ϫ57; P Ͻ 0.0001), respectively. RTV was more effective in lowering 10 M RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] ϭ 0.025 M) than COBI (IC 50 ϭ 0.223 M). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis. KEYWORDS antiretroviral agents, cobicistat, darunavir, drug-drug interaction, human immunodeficiency virus, in vitro, rifampin, ritonavirA pproximately 25% of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients worldwide are coinfected with Mycobacterium tuberculosis (1, 2) (referred to here as HIV-tuberculosis [TB] patients), with such coinfections accounting for 390,000 deaths in 2014 (3). The clinical management of HIV-TB patients presents significant challenges, especially in resource-limited settings (2, 4), where virological failure or intolerance to first-line antiretroviral therapy requires the use of HIV protease inhibitors (PIs) (5). PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6). Consequently, PIs are commonly administered in combination with pharmacokinetic (PK) boosters, such as ritonavir (RTV) or cobicistat (COBI), which act by inhibiting CYP3A4-mediated PI metabolism and P-GP-mediated PI efflux, thereby improving the PK profile of PIs by prolonging PI half-life and increasing PI bioavailability (7-9).Rifampin (RIF) is an essential component of short-course anti-TB treatment regimens (2, 10); however, RIF is also a potent...

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Emergence of HIV Drug Resistance During First- and Second-Line Antiretroviral Therapy in Resource-Limited Settings

Cited by 123 publications

References 55 publications

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

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