A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance,
as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The
sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure.
Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%.
The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance
(hazard ratio 2.27 [95% confidence interval], 1.15–4.49; P = .018). These results support resistance testing before starting antiretroviral therapy
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"Previous studies have demonstrated that preexisting drug-resistance mutations have an important role in the development of drug resistance in treated AIDS patients –. It has been suspected that preexisting drug-resistance mutations have a similar role in drug resistance in treated CHB patients , , , . "
[Show abstract][Hide abstract]ABSTRACT: The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy.
"Antiretroviral drug resistance testing is recommended in HIV-1 infected subjects before starting antiretroviral therapy to guide the selection of appropriate first line regimens (Hirsch et al., 2008). In a previous study, the presence of pre-existing NNRTIresistant mutants detected by population sequencing was associated with a 2.3 fold increased risk of virologic failure of first line efavirenz-based therapy (Kuritzkes et al., 2008). Other data showed that antiretroviral drug resistance testing is cost-effective and improves the virologic, immunologic and clinical outcomes of antiretroviral therapy (Gunthard et al., 1998). "
[Show abstract][Hide abstract]ABSTRACT: There are conflicting data on the impact of low frequency HIV-1 drug-resistant mutants on the response of first-line highly active antiretroviral therapy (HAART), more specifically containing a NNRTI. As population sequencing does not detect resistant viruses representing less than 15-25% of the viral population, more sensitive techniques have been developed but still need clinical validation. We evaluated ultra-deep sequencing (UDPS), recently more available and affordable, as a tool for the detection of HIV-1 minority species carrying drug resistant mutation (DRM) in a clinical setting. A retrospective analysis of the reverse transcriptase (RT) gene of plasma HIV-1 from 70 patients starting a NNRTI based regimen was performed. Minority populations were defined as representing > 1% and < 20% of the total viral population. Using UDPS, we could not confirm an association between the presence of low minority variants harbouring RT mutations at the start of therapy and primary or secondary therapeutic failure.
"The limited impact on viral replication allows NNRTI resistance mutations to persist in predominant circulating viral strains both in drug-naïve patients and in patients that interrupted antiretroviral regimen. Indeed, NNRTI resistance mutations are the most common resistance mutations detected in drug-naïve patients, and have been shown to hamper the achievement of virologial success of a first line NNRTI containing regimen (Kuritzkes et al., 2008). Similarly, it has been shown that NNRTI resistant mutations K103N, Y181C/I, and G190A persist (up to 7 years as reported for K103N) in two-thirds of patients who interrupted therapy with NNRTIs (Joly et al., 2004; Capetti et al., 2005; Gianotti et al., 2005). "
[Show abstract][Hide abstract]ABSTRACT: In recent years relevant progress has been made in the treatment of HIV-1 with a consequent decrease in mortality. The availability of potent antiretroviral drugs and the ability of viral load assays that accurately evaluate the true level of viral replication, have led to a better understanding of pathogenesis of the disease and how to obtain improved therapeutic profiles. The highly active antiretroviral therapy (HAART), based on a combination of three or more antiretroviral drugs, has radically changed the clinical outcome of HIV. In particular, reverse transcriptase non-nucleoside inhibitors (NNRTIs) play an essential role in most protocols and are often used in first line treatment. The high specificity of these inhibitors towards HIV-1 has increased the number of structural and molecular modeling studies of enzyme complexes and that have led to chemical syntheses of more selective second and third-generation NNRTIs. However, a considerable percentage of new HIV-1 infections are caused by the emergence of drug-resistant mutant viruses that complicate treatment strategies. In this review we discuss relevant clinical and structural aspects for the management of antiretroviral drug resistance, with detailed explanations of mechanisms and mutation patterns useful to better understand the relation between drug resistance and therapy failure.
Full-text · Article · Feb 2011 · Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy
Andrew M Gross, Philipp A Jaeger, Jason F Kreisberg, Katherine Licon, Kristen L Jepsen, Mahdieh Khosroheidari, Brenda M Morsey, Susan Swindells, Hui Shen, Cherie T Ng, Ken Flagg, Daniel Chen, Kang Zhang, Howard S Fox, Trey Ideker