Why did HIV therapy have some benefits for a man with resistance to nearly every antiretroviral?

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A French gay men infected with a strain of HIV that was resistant to virtually every antiretroviral drug nevertheless derived immunological benefit from therapy, remained asymptomatic and experienced some reduction in viral suppression of HIV, according to a case report in the January 2nd edition of AIDS. The case has some similarities with a case in New York, which another gay man infected with extensively drug-resistant HIV.

French investigators have, however, adopted a much more measured approach to this case than that of public health officials in New York, who summoned the world’s media to a press conference and sparked panic about “untreatable HIV”. The French doctors also emphasise in their paper that this appears to be an isolated case, possibly of co-infection or superinfection at seroconversion with different strains of HIV.

The investigators suggest that one possible reason why HIV therapy was partially effective in the presence of such extensive resistance was the shift in the patient’s virus to CCR5-tropic.

Glossary

capacity

In discussions of consent for medical treatment, the ability of a person to make a decision for themselves and understand its implications. Young children, people who are unconscious and some people with mental health problems may lack capacity. In the context of health services, the staff and resources that are available for patient care.

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

genotypic resistance testing

In HIV, genotypic resistance tests are assays that identify mutations of the virus that can confer antiretroviral drug resistance. Resistance testing can be used to guide selection of an HIV regimen when initiating or changing antiretroviral therapy (ART). 

strain

A variant characterised by a specific genotype.

 

tropic

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

Doctors from the Aquitaine Cohort in south western France performed retrospective resistance tests on all patients who had seroconverted and entered the cohort between 1996 and 2005. The overall prevalence of transmitted drug-resistant HIV was 16%, a figure consistent with that observed in the UK and other industrialised countries where there is access to antiretroviral therapy.

Of the 229 patients identified with transmitted resistance, one was infected with HIV that resistant to drugs from all three of the main classes of antiretrovirals. The patient was a 27 year-old gay man, and the investigators estimate he seroconverted in April 2001.

A genotypic resistance test detected resistance to all the available antiretroviral drugs except 3TC (lamivudine, Epivir), FTC (emtricitabine, Emtriva) and T-20 (enfuvirtide, Fuzeon).

For the next 16 months, the patient was monitored but did not receive therapy with antiretrovirals. During this time his CD4 cell count fell rapidly from 419 cells/mm3 to 184 cells/mm3. A further genotypic resistance test was performed at this time and found that the patient remained resistant to most reverse transcriptase and protease inhibitors. In addition, a phenotypic resistance test indicated that the patient was infected with a dual/mixed tropism HIV strain that had a replication capacity similar to that of wild-type, or drug-sensitive HIV – this is surprising as resistant HIV is often less efficient at replicating.

Two years after seroconverting, the patient started anti-HIV therapy with 3TC, tenofovir (Viread) and Kaletra. This regimen was modified 13 months later when the Kaletra was replaced by atazanavir/ritonavir because of gastrointestinal side-effects. At this time the patient’s CD4 cell count was 304 cells/mm3 and his viral load was 1,210 copies/ml. A further genotypic resistance test showed little genetic evolution in the patient’s HIV other than the emergence of the M184V mutation that confers resistance to 3TC. A phenotypic resistance test was also performed at this time and indicated that there was resistance to all of the main anti-HIV drugs with the exception of tenofovir.

However, the investigators also noted that the replicative capacity of HIV had reduced by 36% and that the patient’s HIV had shifted to become CCR5-only tropic.

At month 57 after seroconversion, the patient remained asymptomatic with a CD4 cell count of over 300 cells/mm3 and a viral load of 10,000 copies/ml.

The investigators comment, “the relative benefit of this incomplete viral suppression could be caused by the decrease in viral replication capacity (probably driven by the additional selection of M184V), by residual drug activity, and by the shift to CCR5-only tropism.”

References

Masquelier B et al. Virological characterization of an infection with a dual-tropic, multidrug-resistant HIV-1 and further evolution on antiretroviral therapy. AIDS 21: 103 – 106, 2007.