Library Volume 2, Issue 4: Resistance Reporter © XVII International AIDS Conference


Selections from the XVII International AIDS Conference (IAC); 3-8 August, 2008; Mexico City, Mexico


Section 1

Drug Resistance Surveillance of Transmitted HIV

TUAA02

Co-Chairs: Françoise Brun Vezinet, France, Osamah Hamouda, Germany


This session focused on the drug resistance surveillance of transmitted HIV, with the goal of addressing this complex and potentially very worrisome new aspect of the AIDS pandemic. As drug resistant HIV strains become more or less prevalent among the populations of transmitted viruses ("primary drug resistance"), the field focuses on monitoring this phenomenon in various geographical and socio-economic settings, increasing the performance (i.e., sensitivity and/or specificity) of the relevant assays, and incorporating this knowledge into clinical practice. In an interesting talk, Dr. Banks (Harare, Zimbabwe) explored the potential discordance when drug resistant strains are investigated at the level of plasma RNA versus cell-associated DNA. Drs. Hamouda and Archibald described two epidemiological studies (from Germany and Canada) a ~9% and ~14% incidence, respectively, of primary drug resistance, which in the Canadian study was more common among B subtype viruses. A similar trend towards lower incidence of primary drug resistance in non-subtype B was observed by Dr. Diaz in a cohort of South Brazilian HIV-infected individuals. Finally, Dr. Kato (Tokyo, Japan) described a new, very sensitive PCR/mass spectroscopy-based assay that would help quantify minor populations of drug-resistant viruses.


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Drug Resistance Surveillance in Treatment Experienced

TUAA03

Co-Chairs: Francoise Brun Vezinet, France, Luis Soto-Ramirez, Mexico


This session focused on current issues in drug resistance monitoring. Birgit Dau, from Stanford University, showed that mutations in the "connection domain" of RT are associated with diminished response to HAART. However, he noted that it is too early to conclude on a direct effect of these mutations, since they were also associated with classical primary resistance mutations. Daria Hazuda (Merck) reported that the integrase inhibitor raltegravir has comparable antiviral potency against B and non-B HIV subtypes. Primary resistance mutations in non-B subtypes included N155H and Y143R, which are also characteristic of raltegravir resistance in subtype B. A difference may lie in the pathway to resistance, which is preferentially initiated by the Q148H/R/K mutation in subtype B, and by the N155H mutation in non-B subtypes. L. Liao (China CDC, Beijing) presented a cross-sectional survey of drug resistance in 2689 treated patients from China. Drug resistance mutations were found in 17.6 % of patients, with a predominance of NNRTI targeting mutations. Jose-Henrique Pilotto (IPEC, Brasil) showed that women who received antiretroviral therapy to prevent mother to child HIV transmission (PMTCT) and who stopped therapy after delivery developed antiviral drug resistance mutations in 10% of the cases. The authors noted that thse two studies emphasized the need to implement HIV genotyping assays on a large scale. A. Maroszan (Progenics) explained how a maraviroc resistant virus could be generated in vitro by long-term culture in the presence of slowly escalating doses of the drug. He also noted that the maraviroc resistant virus remained susceptible to another CCR5 inhibitor, the monoclonal antibody Pro140. Thus, he posited that an alternative anti-CCR5 therapy could be considered in cases of maraviroc resistance without switch to X4 tropism.


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HIV Drug Resistance

TUSY02

Chairperson:Douglas Richman, United States


The ability of antiretroviral drugs to suppress virus replication relies on each drug's interaction with their specific HIV protein targets. Variations in HIV genetic sequence may alter these specific interactions, generating drug resistance and therefore a less effective control of viral replication. This session focused on major recent findings in the field of HIV drug resistance in a variety of settings. Dr. Pillay's talk described the main complication in assessing the presence of drug resistant HIV strains in resource-constrained countries where, in absence of virological monitoring, changes in antiretroviral therapy are driven only by signs of clinical failure. Dr. Kuritzkes provided an excellent overview on the resistance to the newer classes of antiretroviral drugs, i.e., CCR5 antagonists and integrase inhibitors. He noted that the main reason for virological failure of CCR5 antagonists are (1) the emergence of CXCR4-using HIV from pre-existing minority population, and (2) mutations in the V3 loop that allow the virus to bind the drug-bound form of CCR5. For integrase inhibitor drugs, specific mutations responsible for virological failure were identified, with resistant viruses showing reduced fitness.


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Resistance profile of patients failing first line ART in Malawi when using clinical and immunologic monitoring

TUAB0105

Hosseinipour M, van OosterhoutJJ, et al


In this study 94 samples of 96 patients failing a first line regimen (d4T or AZT-3TC-NVP) showed high rates of pan nucleoside resistance in Malawi. Mean (sd) CD4 count, HIVRNA, and duration on ART were: 121cells/ml (131), 135984 copies/ml (201278), and 38 months (20.4), respectively. Four samples did not amplify and 5 samples had no mutations identified. Seven samples had M184V plus NNRTI mutations only. NNRTI mutations 181C, 103N, 106M, 188L, 190 occurred with similar frequency. The most common mutation pattern was M184V plus NNRTI mutations with one or more TAM (most common = 215F/Y) which occurred in 55% of patients. The authors were surprised to note that 19% of patients acquired NNRTI mutations (with or without 184V) plus either the K70E or K65R mutations. 16% of the patients had pan-nucleoside resistance which corresponded to K65R or K70E and additional multi-nucleoside resistance mutations, most commonly the 151 complex and/or rarely 69 insertions. All in all resistance to 3TC was present in 81%, to first generation NNRTIs in 93%, and pan-nucleoside resistance in 17%. According these data, between 22-50% of patients had no fully active drugs in the recommended second line backbone, highlighting the need to re-evaluate the definition of clinical or immunological criteria to change therapy in low resources settings. For slides and figures, click here


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Combined darunavir (DRV) and etravirine (TMC125; ETR) resistance analysis of the pooled DUET trials: When can we spare the other new classes?

TUPE0048

Haubrich R, Schapiro J, Vingerhoets J, et al.


For the first time in DUET, researchers performed a retrospective analysis of 406 DUET enrollees not using enfuvirtide in their darunavir/etravirine salvage regimen. The researchers also excluded anyone who quit the study before week 24 for reasons other than virologic failure. All study participants took darunavir/ritonavir (600/100 mg BID) plus etravirine (200 mg QD) and background NRTI which was selected by the investigators for each patient based on resistance testing. The study also evaluated two mutational scoring systems for etravirine, the original with 13 etravirine mutations and a revised with 17 etravirine mutations. The investigators classified -<50-copy response rates according to whether patients had (1) 0, 1, 2, 3, or > 3 darunavir-associated mutations before salvage and 0, 1, 2, 3, or > 3 etravirine-associated mutations before salvage, or (2) < 10-fold, 10- to 40-fold, or > 40-fold decrease in susceptibility to darunavir before salvage, and < 3-fold, 3- to 13-fold, or > 13-fold decrease in susceptibility to etravirine before salvage. These analyses, which used an etravirine scoring system of 13 mutations, showed that at least 67% of people with no darunavir mutations and up to 3 etravirine mutations had a viral load < 50 copies at week 24, and at least 73% with no etravirine mutations and up to 3 darunavir mutations had a <50 response at 24 weeks. Thirteen of 14 people (93%) with 2 etravirine mutations and 1 darunavir mutation had a 24-week viral load under 50 copies. Among those with less than a 3-fold change in susceptibility to etravirine and a 10- to 40-fold decrease in susceptibility to darunavir (intermediate resistance), 65% had an undetectable load at week 24. No one with more than 3 etravirine mutations plus more than 3 darunavir mutations or 40-fold resistance to darunavir plus more than 3-fold resistant to etravirine responded by week 24 in this 406-person analysis. The authors noted that the 65% response cutoff suggests that assessing response to a salvage regimen may be improved by algorithms that can account for two of the agents in the regimen.


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Additional Reading: