Intensifying effective HIV therapy with the addition of an extra drug that crosses the blood-brain barrier does not reduce residual levels of viral replication in cerebrospinal fluids or the blood, an international team of investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.
The researcher also found that patients continued to have evidence of immune activation and inflammation in the brain.
“Treatment intensification with a potent CNS [central nervous system]-penetrating antiretroviral drug does not reduce residual CSF [cerebrospinal fluid] HIV RNA levels or intrathecal immune activation”, write the investigators.
Effective combination antiretroviral therapy has dramatically reduced rates of illness and death in patients with HIV. Recent advancements in antiretroviral treatment mean that an undetectable viral load is a realistic goal for the vast majority of patients.
When combination treatment first became available in 1996 there were initially hopes that long-term suppression of HIV in the blood would eventually lead to eradication of the virus. However, it soon became apparent that HIV levels in blood were being repopulated from latent CD4 cells that were infected with the virus.
Moreover, ultrasensitive viral load tests have shown that the majority of patients taking treatment continue to have very low levels of HIV in their blood.
Residual viral load (2 to 20 copies/ml) has also been observed in the cerebrospinal fluid of individuals with undetectable blood viral loads. In addition, many patients taking HIV therapy, even if taking drugs capable of crossing the blood-brain barrier have evidence of intrathecal immune activation and inflammation.
Because of these findings, investigators wished to see if adding an extra antiretroviral drug to regimens that were already suppressing viral load would reduce residual HIV levels in the cerebrospinal fluid and immune activation and inflammation in the brain.
Their study involved ten patients. These individuals had had an undetectable blood viral load (below 50 copies/ml) for a median of 6.5 years. Their median CD4 cell count was 465 cells/mm3, eight were men and their average age was 52.
The study lasted eight weeks. Lumbar punctures were performed on entry to the study, at baseline, after four weeks of treatment, and again at the end. Viral load was measured in cerebrospinal fluid and markers of intrathecal immune activation and inflammation were also monitored.
Treatment was intensified by the addition of either maraviroc (Celsentri) or lopinavir/ritonavir (Kaletra), both of which have good penetration into the central nervous system, or with T-20 (enfuvirtide, Fuzeon), which does not.
During the first four weeks of the study, the patients received a brain-penetrating drug, after which they switched to T-20.
At baseline, median blood viral load was 5 copies/ml, and median viral load in cerebrospinal fluids was 2 copies/ml. Immune activation or inflammation in the brain was evident in the majority of patients.
Intensification of therapy did not further reduce residual viral load levels in cerebrospinal fluids which remained unchanged through the eight weeks of the study. Seven patients had detectable viral load in this compartment at least once. Viral load in blood was also unaffected, as were markers of intrathecal inflammation and immune activation.
Concentrations of maraviroc and Kaletra were well within their therapeutic ranges, and maraviroc was detectable in the cerebrospinal fluids of seven patients.
“We show that treatment intensification has no effect on either residual CSF HIV RNA levels or intrathecal immune activation over the course of 4 weeks with an antiretroviral drug that penetrates in the CNS”, comment the authors. “We could not detect any significant changes in the level of residual plasma viremia during the total treatment intensification period of 8 weeks.”
The investigators do not believe that their findings have any immediate implications for HIV care. Rather, they are of interest regarding “HIV persistence and reservoirs…these findings argue against the hypothesis that ongoing cycles of viral replication are the main source of residual CSF viremia and intrathecal immune [activation].”
Yilmaz AY et al. Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr, online edition, 2010 (link to abstract and paid for full text).