Article

Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection

Harvard University, Cambridge, Massachusetts, United States
Clinical Infectious Diseases (Impact Factor: 9.42). 08/2005; 41(2):236-42. DOI: 10.1086/430709
Source: PubMed

ABSTRACT Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance.
Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection.
Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study.
In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

0 Followers
 · 
106 Views
  • Source
    • "lower in the lamivudine monotherapy-group [Castagna et al., 2006]. The possible explanations for this finding include reduced HIV-1 fitness and residual antiviral activity of lamivudine despite the presence of the 184V mutation [Campbell et al., 2005; Deeks et al., 2005]. The aim of this study was to investigate the mechanisms underlying the virological and immunological changes occurring in patients undergoing treatment interruption or lamivudine monotherapy after treatment failure in the presence of the 184V mutation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to investigate the mechanisms underlying the virological and immunological changes occurring in failing HIV-1 infected patients undergoing treatment interruption or lamivudine monotherapy (the E-184V Study). Associations were sought between the de-selection of individual reverse transcriptase and protease resistance mutations and replication capacity recovery, HIV-RNA changes, and immunological changes. The replication capacity recovery was defined as the ratio between the replication capacity at weeks 24 or 48, and that measured at baseline. The replication capacity recovery, which was evaluable in 21 patients at week 24 and in 18 at week 48, was significantly higher in the treatment interruption than in the lamivudine group at week 24 (P = 0.002). Forty-eight week replication capacity recovery was greater when the 184V (P = 0.023), the 41L (P = 0.02), or the 215Y mutation (P = 0.037) were deselected at week 12. A greater reduction in the CD4+/CD8+ ratio at week 48 (P = 0.038) was observed as the 184V mutation was deselected and the de-selection of the 184V mutation at week 12 was the only independent predictor of the change of the CD4+/CD8+ ratio at week 48 from baseline at multivariable analysis (F-value = 6.72, P = 0.021). In conclusion, among patients undergoing treatment interruption or lamivudine monotherapy, the recovery of HIV-1 replication capacity was associated with the de-selection of reverse transcriptase mutations. The de-selection of the 184V mutation predicts independently a reduction in the CD4+/CD8+ ratio.
    Journal of Medical Virology 02/2008; 80(2):201-8. DOI:10.1002/jmv.21085 · 2.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This doctoral thesis includes four projects. The first project explored the role of innate HIV genetic polymorphisms in drug-selected mutations. By means of drug selection experiments, we comparatively evaluated emergent mutations in protease and reverse transcriptase in HIV-1 and HIV-2 subtypes. Genotypic and phenotypic analyses were used to determine time to appearance of resistance mutations and the levels of drug resistance, respectively. Natural polymorphisms in HIV-2 seemed to facilitate selection of protease inhibitor (PI) resistance: The acquisition of the I54M, I84V, L90M and L99F mutations resulted in multi-PI-resistant viruses. Nucleoside reverse transcriptase inhibitor (NRTI) combinations preferentially selected for the K65R mutation in HIV-1 subtype C, while in HIV-1 subtype B, and HIV-2 cultures favored the development of M184I. The K65R mutation was not detected in HIV-2 selections. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and the role that innate polymorphisms may have in dictating antiretroviral resistance pathways. In the second project, we studied the relationship between mutations in the RNase H domain on viral susceptibility to nucleoside analogues. Our results showed that although some mutations were observed in the connection domain, the presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients with thymidine analog-associated mutations. The third project performed a near full-length genomic analysis of a novel HIV-1 recombinant involving subtypes A1 and C in Quebec. The fourth project evaluated the genetic diversity of an HIV-1 isolate that was referred to us as a suspected case of superinfection. We evaluated this isolate's sequences from different time points and determined that the sequence was a unique A1/C inter-subtype recombinant at baseline and not a case of superinfection. We concluded that discrepancies of online tools for subtype designation of HIV may lead to false designation of dual infection and/or superinfection. Cette thèse de doctorat comprend 4 projets. Le premier explore le rôle du polymorphisme génétique du VIH dans la sélection des mutations de résistance. Au cours des tests de sélection, nous avons évalué comparativement le délai dans lequel les mutations de résistance émergent dans la protéase et la transcriptase inverse des sous-types de VIH-1 et de VIH-2. Des analyses génotypiques et phénotypiques ont été utilisées pour déterminer le délai d'émergence et le niveau de résistance des mutations, respectivement. Le polymorphisme naturel du VIH-2 semble faciliter la sélection des mutations de résistance aux inhibiteurs de protéase (IPs). L'acquisition des mutations de résistance I54M, I84V, L90M et L99F entraine une résistance croisée à plusieurs IPs. Les combinaisons d'inhibiteurs nucléosidiques de la transcriptase inverse (INTI) sélectionnent préférentiellement la mutation K65R chez le VIH-1 de sous-type C alors que les cultures du sous-type B et le VIH-2 favorisent le développement de M184I. La mutation K65R n'a jamais été détectée dans les sélections de VIH-2. Ces résultats mettent en évidence des différences dans les mécanismes de résistance du VIH-1 et du VIH-2 et le rôle que certain polymorphisme jouent dans les voies génétiques de résistance. Dans le second projet, nous avons étudié la relation existante entre le polymorphisme dans la RNAse H et la sensibilité aux analogues nucléosidiques. Nos résultats montrent que bien que certaines mutations soient observées dans le domaine de connection, la présence des mutations L74V et M184V était le facteur déterminant de la résistance phénotypique à la ZDV chez les patients avec des mutations TAMs (Thymidine Analogues Mutations). Le troisième projet a permi de caractériser le génome d'un nouveau recombinant de VIH-1 impliquant les sous-types A1 et C au Quebec. Le quatrième projet a évalué la diversité génétique d'une souche de VIH-1 qui nous a été référé comme un cas de super-infection. L'analyse des séquences à différentes périodes nous a montré qu'il s'agit bien d'un recombinant unique A1/C et non d'une super infection. Nous avons conclu que les discordances entre les outils en ligne pour la détermination des sous-types peuvent être la cause d'une mauvaise désignation des sous-types et/ou des super-infections.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1.0 Summary 1.1 HIV Testing 1.2 Methodology 1.3 Adherence 1.4 Gender and ethnicity 1.5 When to start treatment 1.5.1 Primary HIV infection 1.5.2 Symptomatic HIV Infection 1.5.3 Asymptomatic HIV Infection 1.5.3.1 Individuals with CD4 counts o200 cells/mL 1.5.3.2 Individuals with CD4 counts 4350 cells/mL 1.5.3.3 Individuals with CD4 counts
    HIV Medicine 08/2005; 6 Suppl 2(8):1-61. DOI:10.1111/j.1468-1293.2005.0311b.x · 3.45 Impact Factor
Show more