SUMMARY: People who become infected with HIV that already has at least 1 drug-resistance mutation are more likely to experience subsequent antiretroviral treatment failure, according to a presentation at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna. Virological failure was more common among people taking NNRTI-based regimens, suggesting that protease inhibitors may be advisable if pre-treatment genotypic resistance testing is not available.

By Liz Highleyman

Mutations that confer resistance to antiretroviral drugs typically evolve in an individual if viral replication is not fully suppressed, for example due to suboptimal therapy or poor adherence. In some cases, however, people can be initially infected with HIV that has already developed such mutations, known as primary resistance.

Investigators with the EuroCoord-CHAIN Joint Project Team studied the impact of transmitted drug resistance on treatment outcomes during the first year of combination antiretroviral therapy (ART).

The analysis included 10,458 participants from 25 cohorts making up 4 networks of the EuroCoord project -- CASCADE, COHERE, EuroSIDA, and PENTA-EPPICC. Patients were taking first-line ART regimens consisting of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor.

Using the World Health Organization (WHO) 2009 list of HIV drug-resistance mutations and the Stanford algorithm (v6.0.5), the researchers classified participants into 3 categories: no resistance mutations, 1 or more mutation but receiving a fully active regimen, and 1 or more mutation and demonstrating at least low-level resistance to at least 1 prescribed drug. They then assessed time to virological failure, or the first of 2 consecutive viral load measurements > 500 copies/mL after 6 months of therapy.

Results

	Most participants -- 9505, or 90.9% -- had no evidence of resistance mutations.
	476 patients (4.5%) had at least 1 resistance mutation but were nevertheless on a fully active ART regimen consisting of drugs not compromised by resistance.
	The remaining 477 patients (4.6%) had 1 or more viral mutations and were resistant to at least 1 drug in their regimen.
	Patients with resistance to at least 1 drug had a 2.6-fold higher risk of virological failure compared to patients without resistance mutations.
	There was no significant difference in the likelihood of treatment failure between patients without transmitted resistance mutations and those with transmitted resistance but receiving a fully active ART regimen (hazard ratio 1.2; P = 0.34).
	People with 1 or more resistance mutations who were taking a NNRTI plus 2 NRTIs and were predicted to be on a fully active regimen tended to have a higher risk of virological failure compared with patients on protease inhibitor-based regimens (P = 0.08, not reaching the statistical significance threshold of 0.05).
	Immunological responses, or CD4 cell increases, were consistent with virological responses.

These findings led the researchers to conclude that "Transmitted drug resistance caused a poor virological and immunological response when patients received combination ART containing > 1 drug classified with at least low-level resistance."

"A higher trend for virological failure was found in [the] presence of > 1 mutation in patients receiving 2 NRTIs + 1 NNRTI classified to be fully active," they continued. Thus, first-line combination ART regimens should be carefully selected using genotypic testing, and drugs classified as already compromised by low-level resistance should be avoided.

Current antiretroviral treatment guidelines recommend genotypic resistance testing -- or seeing if the viral gene sequence includes known resistance mutations -- before starting antiretroviral therapy in order to determine if specific drugs are unlikely to work.

Genotypic testing, however, may not detect resistant strains that make up only a small proportion of the total viral population. The greater likelihood of virological failure, though not significant, indicates that low-level resistant virus may be more likely in people taking NNRTI-based regimens. For this reason, the researchers suggested, protease inhibitor-based regimens may be preferable in areas where pre-treatment resistance testing is not widely available.

Investigator affiliations: INSERM U897, ISPED, Université Victor Segalen, Centre of Epidemiology and Biostatistics, Bordeaux, France.

8/20/10

References
L Wittkop, G Chêne, Hannah Castro. Impact of transmitted drug resistance (TDR) on virological and immunological response to initial combination antiretroviral therapy (cART) - EuroCoord-CHAIN joint project. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB108.

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