Patterns of Resistance Emerging in HIV-1 From
Patterns of Resistance Emerging in HIV-1 From
Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of -0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue-associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.
Nucleoside reverse transcriptase inhibitors (NRTIs) are important drugs in the treatment of HIV-1 infection and have reduced the mortality associated with this disease. When combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI), NRTIs can suppress HIV-1 replication to undetectable levels. Many patients achieve sustained suppression of viral replication but a significant fraction of patients experience failure of their antiretroviral therapy (ART). Reasons for failure include poor patient adherence, drug-associated toxicities, and the development of resistance mutations due to incomplete suppression of viral replication. Cross-resistance of HIV-1 to the agents within a class of antiretroviral drugs may limit therapeutic options for treatment-experienced patients. Therefore, an understanding of HIV-1 resistance development has become an integral part of HIV-1 treatment design.
Tenofovir is an acyclic nucleotide analogue that is analogous to the monophosphate form of the other NRTIs. Upon entering cells, tenofovir requires 2 phosphorylation steps to reach the active diphosphate form, whereas 3 phosphorylation steps are required by the other NRTIs. Tenofovir disoproxil fumarate (tenofovir DF, Viread; Gilead Sciences, Foster City, CA) is an oral prodrug of tenofovir that is rapidly converted to tenofovir upon absorption. Tenofovir has in vitro activity against HIV-1, HIV-2, and human hepatitis B virus. Tenofovir selects for the K65R mutation in HIV-1 RT in vitro, and this mutation results in approximately 3-fold decreased susceptibility to tenofovir. The K65R mutation has also been observed to be selected in patients on antiviral therapy with tenofovir DF. The K65R mutation can also be selected by abacavir both in vitro and in vivo, by didanosine in vivo, by stavudine in vitro, and by zalcitabine in vitro and in vivo. However, analysis of a large panel of clinically derived viral isolates has shown that K65R is infrequent among treatment-experienced patients. Recent reports have indicated that the incidence of K65R has increased from approximately 1% in 1998 to 4% in 2003, which may reflect increased use of abacavir and tenofovir DF.
A phase 2 treatment intensification study in 186 treatment-experienced patients (GS-98-902) demonstrated the potency and favorable safety profile of tenofovir DF 300 mg dosed once daily. In addition, there was a low rate of emergence (3%) of the K65R mutation through 96 weeks of tenofovir DF therapy. A phase 3 intensification trial in 552 treatment-experienced patients (GS-99-907) has confirmed the antiviral efficacy and safety of tenofovir DF 300 mg in this patient population. Here we describe the patterns of resistance mutations emerging after 48 weeks of tenofovir DF therapy in GS-99-907 and the results of the phenotypic resistance analyses. Treatment of these patients with partially suppressed disease with tenofovir DF therapy for 48 weeks was associated with a significant and durable antiviral response and reduced the incidence of new resistance mutations associated with all classes of antiretrovirals. Furthermore there was a low incidence of genotypic and phenotypic resistance to tenofovir arising during 48 weeks of tenofovir DF therapy. The K65R mutation emerged in only 3% of tenofovir DF-treated patients and was not associated with viral load rebound. The lack of viral load rebound associated with K65R may be due to the low-level phenotypic changes and reduced viral replication capacity that result from this mutation. The K65R mutation arose only in patients who had no evidence of TAMs at baseline. Thus, these 2 mutational patterns may be incompatible in HIV-1 from patients undergoing ART.
Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of -0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue-associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.
Nucleoside reverse transcriptase inhibitors (NRTIs) are important drugs in the treatment of HIV-1 infection and have reduced the mortality associated with this disease. When combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI), NRTIs can suppress HIV-1 replication to undetectable levels. Many patients achieve sustained suppression of viral replication but a significant fraction of patients experience failure of their antiretroviral therapy (ART). Reasons for failure include poor patient adherence, drug-associated toxicities, and the development of resistance mutations due to incomplete suppression of viral replication. Cross-resistance of HIV-1 to the agents within a class of antiretroviral drugs may limit therapeutic options for treatment-experienced patients. Therefore, an understanding of HIV-1 resistance development has become an integral part of HIV-1 treatment design.
Tenofovir is an acyclic nucleotide analogue that is analogous to the monophosphate form of the other NRTIs. Upon entering cells, tenofovir requires 2 phosphorylation steps to reach the active diphosphate form, whereas 3 phosphorylation steps are required by the other NRTIs. Tenofovir disoproxil fumarate (tenofovir DF, Viread; Gilead Sciences, Foster City, CA) is an oral prodrug of tenofovir that is rapidly converted to tenofovir upon absorption. Tenofovir has in vitro activity against HIV-1, HIV-2, and human hepatitis B virus. Tenofovir selects for the K65R mutation in HIV-1 RT in vitro, and this mutation results in approximately 3-fold decreased susceptibility to tenofovir. The K65R mutation has also been observed to be selected in patients on antiviral therapy with tenofovir DF. The K65R mutation can also be selected by abacavir both in vitro and in vivo, by didanosine in vivo, by stavudine in vitro, and by zalcitabine in vitro and in vivo. However, analysis of a large panel of clinically derived viral isolates has shown that K65R is infrequent among treatment-experienced patients. Recent reports have indicated that the incidence of K65R has increased from approximately 1% in 1998 to 4% in 2003, which may reflect increased use of abacavir and tenofovir DF.
A phase 2 treatment intensification study in 186 treatment-experienced patients (GS-98-902) demonstrated the potency and favorable safety profile of tenofovir DF 300 mg dosed once daily. In addition, there was a low rate of emergence (3%) of the K65R mutation through 96 weeks of tenofovir DF therapy. A phase 3 intensification trial in 552 treatment-experienced patients (GS-99-907) has confirmed the antiviral efficacy and safety of tenofovir DF 300 mg in this patient population. Here we describe the patterns of resistance mutations emerging after 48 weeks of tenofovir DF therapy in GS-99-907 and the results of the phenotypic resistance analyses. Treatment of these patients with partially suppressed disease with tenofovir DF therapy for 48 weeks was associated with a significant and durable antiviral response and reduced the incidence of new resistance mutations associated with all classes of antiretrovirals. Furthermore there was a low incidence of genotypic and phenotypic resistance to tenofovir arising during 48 weeks of tenofovir DF therapy. The K65R mutation emerged in only 3% of tenofovir DF-treated patients and was not associated with viral load rebound. The lack of viral load rebound associated with K65R may be due to the low-level phenotypic changes and reduced viral replication capacity that result from this mutation. The K65R mutation arose only in patients who had no evidence of TAMs at baseline. Thus, these 2 mutational patterns may be incompatible in HIV-1 from patients undergoing ART.
