Effects of drug resistance on viral load in patients failing antiretroviral therapy

Clinique Médicale L'Actuel, Montreal, Quebec, Canada.
Journal of Medical Virology (Impact Factor: 2.35). 05/2006; 78(5):608-13. DOI: 10.1002/jmv.20582
Source: PubMed


Previous studies on patients who develop drug resistant HIV-1 variants have shown that continued use of failing regimens might provide clinical benefit. However, the effect of long-term exposure to drug resistant variants may lead to emergence of compensatory mutations that may jeopardize this effect. In this study, we assess associations among type and number of drug resistant mutations, viral load and disease progression in patients with long-term follow up. Patients with genotypic testing performed at the time of treatment failure were enrolled. Comparison of viral load and CD4 cell count between different resistance groups was performed using analysis of variance. Multiple linear regression analysis was performed to assess the simultaneous effects of the presence of particular mutations and their accumulation on viral load. Data from 475 patients who were followed for a median of 43 months from October 1999 to July 2005 were studied. A "V shape" relationship was observed between the number of mutations and viral load. Specifically, in patients harboring up to five mutations, viral load was reduced by 0.8 log/copies when compared to wild-type variants. However, with more than six mutations viral load progressively increased. Certain reverse transcriptase mutations such as M184V/I, K70R, V108I, and protease mutations such as L33FIV, M84V, and M36I were associated with reduced viral load. Together, these findings suggest that long-term maintenance of a sub-optimal antiretroviral regimen may have deleterious consequences for the patient.

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    • "This compound not only inhibits enhancement of HIV replication by Nef, but also reverses Nef-mediated downregulation of MHC-I, raising the exciting possibility that it may enhance recognition of HIV-infected cells by cytotoxic T-cells. The growing number of HIV strains resistant to conventional antiretroviral therapy [63,64] combined with the lack of an HIV vaccine underscore the need for new anti-HIV drugs. Work presented here shows that compounds targeting HIV-1 Nef may provide a new avenue for anti-HIV therapy, and demonstrates the potential of a yeast-based, phenotypic screen based on the complex of an HIV-1 accessory protein with a host cell kinase as a route to their discovery. "
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    ABSTRACT: HIV-1 Nef is a viral accessory protein critical for AIDS progression. Nef lacks intrinsic catalytic activity and binds multiple host cell signaling proteins, including Hck and other Src-family tyrosine kinases. Nef binding induces constitutive Hck activation that may contribute to HIV pathogenesis by promoting viral infectivity, replication and downregulation of cell-surface MHC-I molecules. In this study, we developed a yeast-based phenotypic screen to identify small molecules that inhibit the Nef-Hck complex. Nef-Hck interaction was faithfully reconstituted in yeast cells, resulting in kinase activation and growth arrest. Yeast cells expressing the Nef-Hck complex were used to screen a library of small heterocyclic compounds for their ability to rescue growth inhibition. The screen identified a dihydrobenzo-1,4-dioxin-substituted analog of 2-quinoxalinyl-3-aminobenzene-sulfonamide (DQBS) as a potent inhibitor of Nef-dependent HIV-1 replication and MHC-I downregulation in T-cells. Docking studies predicted direct binding of DQBS to Nef which was confirmed in differential scanning fluorimetry assays with recombinant purified Nef protein. DQBS also potently inhibited the replication of HIV-1 NL4-3 chimeras expressing Nef alleles representative of all M-group HIV-1 clades. Our findings demonstrate the utility of a yeast-based growth reversion assay for the identification of small molecule Nef antagonists. Inhibitors of Nef function discovered with this assay, such as DQBS, may complement the activity of current antiretroviral therapies by enabling immune recognition of HIV-infected cells through the rescue of cell surface MHC-I.
    Retrovirology 11/2013; 10(1):135. DOI:10.1186/1742-4690-10-135 · 4.19 Impact Factor
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    • "This is interesting, but there are two important caveats in the interpretation of results. First, the 184V mutation may result in lower levels of viral load than those associated with wild-type viruses (Machouf et al., 2006). Therefore, the diminished frequency of transmission of M184V viruses may be attributable to the fact that individuals with low viral loads are less infectious in general than are people with higher viral loads (Turner et al., 2004; Wensing et al., 2005). "
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    ABSTRACT: Antiviral drugs that act at specific sites within the HIV life cycle have important rationale for development as anti-HIV microbicides. However, to be effective, such drugs must act by directly interfering with viral enzymatic function and eliminate the ability of HIV to mediate infection. Compounds that are developed as microbicides must have high potency, and should ideally not be well absorbed from the vaginal cavity in order to minimize any potential problems of drug resistance. Such compounds should also be active over long periods of time and should be able to be combined with other active agents, in order to promote the concept of synergy, such as that which has been demonstrated in HIV therapeutic studies.
    Antiviral Research 10/2006; 71(2-3):343-50. DOI:10.1016/j.antiviral.2006.05.013 · 3.94 Impact Factor
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    ABSTRACT: Hintergrund: Während für die Initialtherapie der HIV-Infektion evidenzbasierte Empfehlungen für die Auswahl der antiretroviralen Kombinationstherapie (cART) bestehen, existieren zur Zweit-Therapie nach erstem virologischem Versagen keine vergleichenden Studien zur Langzeiteffektivität verschiedener Therapieregime. Ziel dieser Studie war die Analyse unterschiedlicher Strategien für die Zweit-Therapie nach virologischem Versagen eines initialen Protease-Inhibitor (PI) -basierten Regimes, spezifisch der Vergleich zwischen dem Wechsel zu einem anderen PI und dem Klassenwechsel auf einen Nicht-Nukleosidischen Reverse-Transkriptase-Inhibitor (NNRTI). Patienten und Methodik: Für diese Untersuchung wurden Patienten des Projektes Klinische Surveillance der HIV-Krankheit, ClinSurv, des Robert-Koch-Instituts in eine retrospektiv ausgewertete Kohortenstudie (1999 bis 2008) eingeschlossen. Von den 14377 Patienten der ClinSurv Kohorte war für 157 Patienten ein Therapiewechsel nach virologischem Versagen der Erst-Therapie über mindestens 3 Monate dokumentiert. 84 der 157 Patienten (54%) hatten eine PI-basierte Erst-Therapie, so dass diese in die statistische Analyse eingeschlossen wurden. 51 der 84 Patienten (61%) wechselten auf einen anderen PI und 33 (39%) auf einen NNRTI. Primäre Ziele waren die Zeit nach Therapiewechsel bis zur Viruslastsenkung unter die Nachweisgrenze, die Dauer des erfolgreichen Zweit-Regimes und die Wahrscheinlichkeit für virologisches Versagen im Zweit-Regime. Ergebnisse: Die mediane Zeit bis zum virologischen Erfolg war mit 88 d in Gruppe 1 und 57 d in Gruppe 2 nicht signifikant unterschiedlich (p=0,16). Nach >3000 d waren in Gruppe 2 mit Klassenwechsel auf NNRTI noch >50% der Patienten erfolgreich behandelt, das Risiko eines virologischen Versagens damit deutlich niedriger als in der Gruppe 1 mit Wechsel innerhalb der PI, wo die mediane Zweit-Therapie-Dauer lediglich 581 d betrug. In der multivariaten Cox-Regressionsanalyse war keine der untersuchten weiteren Kovariaten ein signifikanter Prädiktor der Dauer des Zweit-Regimes oder ein Störfaktor. Es ergab sich für die Gruppe 1, die innerhalb der PI wechselte, ein >2-faches Risiko, während der Beobachtungszeit virologisch zu versagen. (HR=2,3; 95%CI 1,1-4,9; p=0,03). Folgerung: Nach virologischem Versagen eines PI-basierten Erst-Regimes hat ein Klassenwechsel von PI auf NNRTI im Gegensatz zu einem Wechsel innerhalb der PI deutliche Vorteile bzgl. der Durabilität des Zweit-Regimes.
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