Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype

Verhofstede, Chris; Wanzeele, Filip Van; Gucht, Beatrijs Van Der; Cabooter, Nancy De; Plum, Jean

doi:10.1097/00002030-199912240-00007

Cited by 141 publications

(66 citation statements)

References 6 publications

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“…Furthermore, phylogenetic analysis of the nucleotide sequences of intermediate viruses revealed that those with fewer resistance mutations were clearly more closely related to wild-type viral sequences, excluding the possibility of selective reversion of resistance mutations or recombination in these cases. The rapid emergence of fully wild-type virus detected by standard genotypic analysis in this and in prior studies (11,32) and the rapid virus rebound that follows the interruption of an apparently fully suppressive antiretroviral therapy (28) further supports the conclusion that treated patients can continue to harbor strains lacking the full complement of resistance mutations.…”

Section: Discussionsupporting

confidence: 75%

“…Correspondingly, it has been observed that in patients who undergo STI following the development of resistant virus, an apparent replacement of the resistant plasma quasi-species by wild-type genomes occurs in most cases (10,11,32). In this study, we have shown that in most patients undergoing STI, small proportions of residual resistant viruses are still detectable at times when conventional bulk-plasma virus genotyping detected only wild-type sequences.…”

Section: Discussionmentioning

confidence: 51%

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Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

Hance

Lemiale

Izopet

et al. 2001

J Virol

120

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Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease that confer resistance to antiretroviral agents are usually accompanied by a reduction in the viral replicative capacity under drug-free conditions. Consequently, when antiretroviral treatment is interrupted in HIV-1-infected patients harboring drug-resistant virus, resistant quasi-species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantification of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persist in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of therapy and for whom conventional genotyping had revealed an apparent total reconversion to wild-type virus, minority populations expressing these mutations, representing 0.1 to 21% of total virus, were still detectable in 9 cases. Kinetic studies demonstrated that viruses expressing resistance mutations could be detected for >5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutations present in the resistant viruses prior to treatment interruption and appeared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance. Thus, following the interruption of treatment, viral populations containing resistance mutations can persist for several months after the time when conventional genotyping techniques detect only wild-type virus. These populations include viral strains with only some of the resistance mutations initially present, strains that presumably express better fitness under drug-free conditions.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 51%

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

Hance

Lemiale

Izopet

et al. 2001

J Virol

120

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“…This is similar to how resistance is selected when an individual is receiving treatment (28). Rapid reversions of acquired TDF and FTC mutations have been observed in humans after stopping therapeutic treatment (29)(30)(31). Therefore, resistant viruses selected while on PrEP may also be rapidly outcompeted by the wild-type strains once the pressure of PrEP is removed.…”

Section: (Materials and Methods)mentioning

confidence: 68%

HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis

Supervie

Garcı́a-Lerma²,

Heneine³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

101

129

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The administration of antiretrovirals before HIV exposure to prevent infection (i.e., preexposure prophylaxis; PrEP) is under evaluation in clinical trials. Because PrEP is based on antiretrovirals, there is considerable concern that it could substantially increase transmitted resistance, particularly in resource-rich countries. Here we use a mathematical model to predict the effect of PrEP interventions on the HIV epidemic in the men-who-have-sex-with-men community in San Francisco. The model is calibrated using Monte Carlo filtering and analyzed by constructing nonlinear response hypersurfaces. We predict PrEP interventions could substantially reduce transmission but significantly increase the proportion of new infections caused by resistant strains. Two mechanisms can cause this increase. If risk compensation occurs, the proportion increases due to increasing transmission of resistant strains and decreasing transmission of wild-type strains. If risk behavior remains stable, the increase occurs because of reduced transmission of resistant strains coupled with an even greater reduction in transmission of wild-type strains. We define this as the paradox of PrEP (i.e., resistance appears to be increasing, but is actually decreasing). We determine this paradox is likely to occur if the efficacy of PrEP regimens against wild-type strains is greater than 30% and the relative efficacy against resistant strains is greater than 0.2 but less than the efficacy against wildtype. Our modeling shows, if risk behavior increases, that it is a valid concern that PrEP could significantly increase transmitted resistance. However, if risk behavior remains stable, we find the concern is unfounded and PrEP interventions are likely to decrease transmitted resistance.mathematical model | men who have sex with men | prevention | epidemics | antiretrovirals T he administration of antiretroviral drugs (ARVs) before HIV exposure to prevent infection (i.e., preexposure prophylaxis; PrEP) is currently under evaluation in clinical trials (1). The PrEP regimens under consideration are based on tenofovir (TDF) alone or in combination with emtricitabine (FTC). Results from phase III efficacy trials are expected in 2010 and several additional trials will begin soon (SI Appendix, Table S1) (2). The results from these trials are widely anticipated because, if PrEP is shown to be safe and effective, it will become an important biomedical intervention for controlling the HIV pandemic. A phase II study of TDF-based PrEP showed daily TDF in HIV-uninfected women to be safe (3). However, because PrEP is based on ARVs, there is concern that wide-scale usage could lead to a substantial increase in transmission of ARV-resistant strains (4). Such an increase would have significant clinical repercussions [as individuals infected with these strains would be limited in their future treatment options (5)], as well as exacerbate the difficulty of controlling the pandemic. In particular, increases in resistance in high-risk communities in resource-rich countries...

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“…When this selective pressure is removed, the emergence of drug-sensitive quasispecies may be expected, as they would be predicted to have a higher fitness in a drug-free environment (9,15,19,20,22,25,34,40,42,43). This rationale led to the many structured treatment interruption (STI) studies carried out on patients with treatment failure and multidrug-resistant viruses (10,12,16,26,45,59). In those cohorts, a rise in plasma viral load and a concomitant fall in CD4 ϩ cell count was observed after treatment interruption; in approximately half of the patients, drug susceptibility shifted from resistant to sensitive.…”

mentioning

confidence: 99%

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Kijak

Simon

Balfe

et al. 2002

J Virol

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The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

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Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype

Cited by 141 publications

References 6 publications

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

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