Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection
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.
- SourceAvailable from: Jeffrey A Johnson
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- "The cohort of animals described here shares similarities with HIV-infected humans who, despite the presence of multi-drug resistant viral mutants, have low viremia associated with strong antiviral immune responses [60,61]. A difference, however, is that in the HIV-infected patients, interruption of nucleoside reverse transcriptase RT inhibitors led to an immediate and persistent increase in viremia and a reduction in CD4+ cell counts [62-64]. Potential reasons for this difference include (i) later initiation of ART, (ii) a much shorter duration of treatment, (iii) persistent detectable viremia (> 400–1000 copies/ml) while on ART (indicating less effective antiviral immune responses even prior to drug withdrawal), and (iv) regimens without tenofovir, which in addition to its antiviral activity has shown unique immunomodulatory properties in animal models [65,66]. "
ABSTRACT: We reported previously that while prolonged tenofovir monotherapy of macaques infected with virulent simian immunodeficiency virus (SIV) resulted invariably in the emergence of viral mutants with reduced in vitro drug susceptibility and a K65R mutation in reverse transcriptase, some animals controlled virus replication for years. Transient CD8+ cell depletion or short-term tenofovir interruption within 1 to 5 years of treatment demonstrated that a combination of CD8+ cell-mediated immune responses and continued tenofovir therapy was required for sustained suppression of viremia. We report here follow-up data on 5 such animals that received tenofovir for 8 to 14 years. Although one animal had a gradual increase in viremia from 3 years onwards, the other 4 tenofovir-treated animals maintained undetectable viremia with occasional viral blips (≤ 300 RNA copies/ml plasma). When tenofovir was withdrawn after 8 to 10 years from three animals with undetectable viremia, the pattern of occasional episodes of low viremia (≤ 3600 RNA/ml plasma) continued throughout the 10-month follow-up period. These animals had low virus levels in lymphoid tissues, and evidence of multiple SIV-specific immune responses. Under certain conditions (i.e., prolonged antiviral therapy initiated early after infection; viral mutants with reduced drug susceptibility) a virus-host balance characterized by strong immunologic control of virus replication can be achieved. Although further research is needed to translate these findings into clinical applications, these observations provide hope for a functional cure of HIV infection via immunotherapeutic strategies that boost antiviral immunity and reduce the need for continuous antiretroviral therapy.Retrovirology 07/2012; 9(1):57. DOI:10.1186/1742-4690-9-57 · 4.77 Impact Factor
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- "In addition to the negative impact of nonadherence on individual health, the financial burden of nonadherence is also substantial. As HIV-infected individuals fail ARV regimens, each subsequent medication regimen becomes not only more complex but also more costly because a greater number of medications are needed to suppress HIV viral load.18 The ARV medications currently available to treat HIV disease are used in a strategic order and in well-defined combinations to ensure efficacy.19 "
ABSTRACT: REMARKABLE ADVANCES IN THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE HAVE BEEN BLUNTED BY WIDESPREAD SUBOPTIMAL ADHERENCE (IE, NONADHERENCE), WHICH HAS EMERGED AS A MAJOR BARRIER TO ACHIEVING THE PRIMARY GOAL OF ANTIRETROVIRAL (ARV) THERAPY: suppression of HIV viral load. Nonsuppressed HIV viral load is associated with drug resistance, increased morbidity and mortality, and a higher risk of person-to-person HIV transmission. For HIV-infected individuals who are failing HIV treatment due to nonadherence, becoming adherent is a life-saving behavior change. However, overcoming nonadherence is one of the most daunting challenges in the successful management of HIV disease. The purpose of this paper is to provide clinicians with a better understanding of nonadherence to ARV treatment and to review the various factors that have been associated with either adherence or nonadherence. Strategies are presented that may help the nonadherent individual become ready to take HIV medications as prescribed.HIV/AIDS - Research and Palliative Care 05/2011; 3:45-51. DOI:10.2147/HIV.S8993
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- "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. "
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