Transmission of drug resistant virus does not revert to wild-type and does not appear ‘less fit’

Several studies looked at the natural history of transmitted drug resistance, finding results that are opposite to general assumptions.

The development and detection of drug resistance in patients infected with wild-type virus that develops when using antiretroviral treatment is well described. Reversion to majority wild-type population generally occurs shortly after discontinuation of the drug associated with that resistance, and the resistant strain remains archived in proviral DNA or existing as minority populations.

This does not appear to be the case for patients whose baseline infection is due to drug resistant virus.

Little and colleagues described the resistance profile over time (median 177 days, range 82-1,019) of 10 patients diagnosed with drug resistance during primary HIV infection (median 65 days from infection) who chose to defer treatment. Seven out of 10 had evidence of resistance to NNRTIs, 1/10 to PI and RTI, 1/10 to NNRTI and PI and 1/10 with resistance to all three classes.

Median baseline was 5.5 log (range 2.5-7.4) and replicative capacity (RC) was 87% that of wild-type (WT). Reversion of 103N to mixed N/K populations was a median 196 days (95% CI 153-238 days). No reversion of PI mutations was detected out to 64, 191 and 342 days in those three patients. Only one patient reverted to wild-type at 1,019 days. Reversion of resistance when it was detected was gradual and usually incomplete. Replicative capacity remained high in all patients indicating an additional concern in the management of future treatments for these patients.

Delaugerre and colleagues presented two cases of sexual transmission of multidrug resistant virus that persisted at two years without selective pressure of treatment and all mutations were found archived in cellular reservoirs. Viral load and CD4 counts for both these patients remained unchanged during the period of follow-up.

Coral and colleagues also reported little difference between viral load and CD4 responses in 46 seroconverters, 20% of whom were infected with drug resistance virus. Over median follow-up period of 3.5 years patients in each group lost an average of 46 cells/mm3 a year.

While this may provide some reassurance in the short-term, response and choice of available treatment when it is required, is likely to be significantly different.

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These data suggest that in individuals newly infected with drug resistance virus, this resistant virus becomes that individual’s “wild type”. The only way they can lose these mutations is by the process of back mutation and this can take time, thus explaining the timeframe in these abstracts. This can give rise to “reversion mutants” such as the 215 D/S/N/C that can provide a clue to the transmission of drug resistant HIV - a so-called “fossil record” of resistance. People infected with resistant virus can subsequently go on to infect others with the same resistant virus. [4]

References:

1. Little SJ et al - Persistence of transmitted drug-resistant virus among subjects with primary HIV infection deferring antiretroviral therapy. Abstract 115.

2. Delaugerre C et al - Persistence of multidrug-resistant HIV-1 without any antiretroviral treatment two years after sexual transmission. Abstract 80.

3. Corral A et al - Impact of transmission of drug-resistant HIV viruses on viral load, CD4 counts and CD4 decline in recent seroconverters. Abstract 81.

4. Taylor S, Cane P, Hue S et al. Identification of a Transmission Chain of HIV Type 1 Containing Drug Resistance-Associated Mutations. AIDS Res Hum Retroviruses 2003; 19:353-61.

	HIV Treatment Bulletin Vol 4 No7 August / September 2003