HTB

Resistance mutations continue to accumulate with low-level viral increases

By Brian Boyle MD, for hivandhepatitis.com

Highly active antiretroviral therapy (HAART) is generally effective at suppressing HIV replication, which allows for significant immune recovery and decreased morbidity and mortality among HIV-infected patients.

Drug resistance is a major cause of HAART failure and several studies have documented that resistant HIV can quickly emerge when viral suppression is incomplete, whether due to prior resistance, poor adherence, poor drug pharmacokinetics or other regimen problems.

Therefore, unless the patient has no other treatment options, it is generally considered ill-advised to continue patients with low-grade viremia on the same HAART regimen, since studies indicate that this treatment approach may lead to the development of further resistance mutations and a lower likelihood of treatment success with subsequent HAART regimens. In a study published in AIDS, investigators evaluated, in a ‘real-life’ setting, the appearance of drug resistance mutations when a patient is continued on a failing HAART regimen.

Fourteen patients were retrospectively evaluated, all of whom had a least one undetectable viral load followed by persistent low-grade viremia (< 1,000 copies/ml) or a slow increase in viral load to less than 4,000 copies/mL after at least one year of treatment. Five of the patients were on their first HAART regimen with two nucleoside reverse transcriptase inhibitors (NRTI) plus one protease inhibitor (PI), whereas seven patients were on their second and two on their third line of antiretroviral therapy.

Overall, new primary NRTI or PI mutations appeared in 93% of the patients during the low-grade viremia. In four patients, a drug to which the virus showed genotypic resistance was included in the new therapy and the mean time for viral rebound in these patients was shorter than in the remaining drug-experienced patients or in the naive patients (6.5 versus 10.4 versus 10.2 months, respectively).

Further, there was a trend for resistance mutations to be detected at a lower viral load in NRTI-experienced than NRTI-naive patients. Despite the accumulation of additional mutations, however, sustained increased CD4+ T cell counts could be seen in many of the patients, perhaps due to the decreased viral fitness resulting from the resistance mutations.

The authors conclude: “We have shown here that primary mutations associated with resistance to NRTI, NNRTI or PI can emerge in connection with very low viraemia in patients failing their first or second/third-line therapy. Serial accumulation of further mutations was seen without any significant viral rebound and sustained increased CD4 T cell counts for a long time.

“A low but detectable level of viraemia can thus be sufficient to generate viruses with several resistance mutations, with a possible risk of the exhaustion of future drug options.”

This study seems to reinforce the oft-stated guideline that patients failing antiretroviral therapy – even with relatively low levels of viral rebound – should, if possible, be changed to another regimen prior to further development of resistance mutations that may affect chances for therapeutic success.

Comment

Biological plausibility would suggest that if virus is detectable on current therapy it is likely to have advantage relative to other viruses and will be built on the back of a previously selected archived virus which had some, but not as great, an advantage.

It should also be remembered that despite the description ‘low level’ viraemia still represents a great deal of viral turnover in an individual.

Reference:

Aleman S, Soderbarg K, Visco-Comandini U et al. Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy. AIDS 2002 May 3;16(7):1039-44
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11953470&dopt=Abstract

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