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Even Small Viral Load Reduction Is Beneficial for People with Highly Resistant HIV

Antiretroviral therapy (ART) can help raise CD4 T-cell counts even if it does not produce undetectable HIV RNA due to extensive drug resistance, indicating that treatment likely has immunological benefits even for people with few therapeutic options, according to a report in the March 1, 2013 Journal of Infectious Diseases.

For most people with HIV, ART reduces viral load to a very low or undetectable level. Once viral replication is suppressed, CD4 cells are no longer under attack and can begin to recover. Some people, however, do not have good CD4 cell recovery despite viral suppression, while others are unable to achieve undetectable viral load due to prior treatment experience and development of resistance to multiple antiretroviral drug classes.

Investigators with the Pursuing Later Treatment Option II (PLATO II) Project Team of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) looked at factors affecting CD4 T-cell counts after triple-class treatment failure.

The analysis included 2424 HIV positive individuals from the COHERE database who started ART since 1998. Most (67%) were men, the median age was 40 years, and the median CD4 count was 270 cells/mm³.

Participants had been on ART for a median of 4 years and experienced virological failure using the 3 oldest classes of antiretroviral drugs  (nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor [NNRTIs], and protease inhibitors). Most were still taking drugs from these 3 classes; few were taking newer classes including fusion inhibitors (7%), integrase inhibitors (9%), or CCR5 antagonists (1%).

During follow-up participants collectively contributed 23,992 CD4 cell count measurements. The researchers constructed a mathematical model to predict changes in CD4 cell levels after emergence of triple-class treatment failure, from a baseline level of 300 cells/mm³.

Results 

• In an adjusted model excluding current viral load and year, CD4 counts were significantly higher for people taking regimens that included boosted protease inhibitors (average increase of 22 cells/mm³) compared with those taking NNRTIs.
• CD4 counts were also significantly higher for participants taking drugs from newer classes (average increase of 39 cells/mm³).
• These associations disappeared, however, when models were adjusted to take into account current viral load or calendar year.
• Higher viral load levels were consistently -- and nearly linearly -- associated with lower CD4 counts:

          ^o     300-3000 copies/mL (2.5-3.5 log): decrease of 51 cells/mm³ vs < 300 copies/mL;

          ^o     3000-31,500 copies/mL (3.5-4.5 log): decrease of 84 cells/mm³;

          ^o     31,500-316,000 copies/mL (4.5-5.5 log): decrease of 137 cells/mm³;

          ^o     > 316,000 copies/mL (> 5.5 log): decrease of 186 cells/mm³.

"The approximately linear inverse relationship between log₁₀ viral load and CD4+ T-cell count indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads," the study authors concluded. "This is important for patients with low CD4+ T-cell counts and few drug options."

"We have shown that current virus concentration in plasma is the single most important predictor of the current CD4 cell count," they elaborated in their discussion.

In the past, people with extensive drug resistance were often advised to wait to start a new drug until 2 or more active agents were available, in order to avoid using a new drug as monotherapy and encouraging resistance. But the authors advised that people with low T-cell counts may be better off taking the best drugs they currently have available, because even a small reduction in viral load leads to CD4 count increases.

"While in those with high CD4 count it may be possible to wait until new active drugs are available, for those with low CD4 count it is important to use the regimen most likely to achieve maximal viral suppression," they recommended. Improving adherence -- even by a modest amount -- would also likely provide a benefit in reducing the risk of disease progression due to immune suppression, they suggested.

2/15/13

Reference

A Audelin, A Castagna, D Costagliola,B Ledergerber, et al (Pursuing Later Treatment Option II (PLATO II) Project Team of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Predictors of CD4+ T-Cell Counts of HIV Type 1-Infected Persons After Virologic Failure of All 3 Original Antiretroviral Drug Classes. Journal of Infectious Diseases 207(5):759-767. March 1, 2013.