Cerebrospinal fluid response to structured treatment interruption after virological failure (PDF attached)
The authors of this study raise concerns after finding that HIV in CSF increases after an STI. To this observer this raises concerns about what happens to other compartments/reservoirs after an STI. We don't know that much about this. Although none of their patients in this study appeared to develop any changes in neurologic status, they discuss concerns: this study included only a small number of patients who were not severely immunosuppressed and who were, with one exception, neurologically normal, and the period of STI and subsequent follow-up may have been too short to witness development of more serious sequelae. Hence, the potential neurological implications of resurgence of virus and associated inflammation in the CSF, or in parallel within the brain, remain uncertain, and it is possible that neurological impairment would be more likely in individuals with active ADC or who harbour different, more neuropathicâl viral strains.
Richard W. Pricea; Ellen E.
Paxinosd; Robert M. Grantb,c; Birgit Drewc;
Annelie Nilssona; Rebecca Hohb; Nicholas S Hellmannd;
Christos J. Petropoulosd; Steven G. Deeksb
From the Departments of aNeurology and bMedicine, University of California San Francisco and San Francisco General Hospital, the cGladstone Institute of Virology and Immunology, San Francisco and dViroLogic, Inc., South San Francisco, California, USA.
Objective: Structured antiretroviral treatment interruption (STI) has been advocated as a therapeutic strategy for HIV-1 infection. We report initial observations of cerebrospinal fluid (CSF) HIV-1 infection in five patients undergoing serial lumbar punctures (LPs) during STI undertaken following virological failure.
Design and methods: In this prospective observational study we quantified HIV-1 RNA concentrations and assessed both phenotypic drug susceptibility profiles and genotypic antiviral drug resistance mutations in CSF and plasma during the period of treatment interruption. CSF white blood cells were also counted, and patients neurological status monitored.
Results: In four of the patients, CSF HIV-1 concentration increased more rapidly than that of the plasma, with consequent reduction in the ratio between plasma and CSF viral loads (pVL : cVL). Three individuals developed robust, though asymptomatic CSF lymphocytic pleocytosis. In all patients the predominant HIV-1 quasispecies shifted simultaneously in CSF and plasma from a drug-resistant to a more drug-susceptible phenotype with identical and simultaneous changes in genotypes associated with drug resistance.
Conclusions: STI may be accompanied by previously unrecognized changes in tissue viral exposures and lymphocyte traffic. Hence, despite˜virological failure as evidenced by persistent plasma viremia, ongoing antiretroviral treatment prior to its interruption appeared to suppress CSF HIV-1 infection (indeed more effectively than that of plasma) and restrain lymphocyte traffic into the CSF. Simultaneous change of resistance mutations in CSF and plasma was likely due to re-emergence and overgrowth of pre-existing strains with ready exchange of virus between these two compartments, either facilitated by or provoking a local CSF lymphocytosis.
Excerpts from article:
The increase in HIV-1 RNA in both compartments following treatment interruption suggests that despite "virological failure" as judged by blood analysis, the prior treatment was indeed having a salutary effect. Plasma viral load was partially suppressed, and there was an even greater suppressive effect on infection in the CSF.
A striking lymphocytic pleocytosis, with peak WBC counts between 31 and 46 ? 106 cells/l, accompanied the increases in CSF HIV-1 RNA in three patients. This provides further evidence of a biological effect of partially suppressive treatment in the face of drug resistance.
The current study provides a complementary observation cessation of HAART led to an increase in CSF cells and virus. The concomitant increases in CSF protein and CSF : serum albumin ratios also show that STI was accompanied by alteration of the blood brain or blood CSF barrier to protein.
Earlier in the epidemic, development of meningoencephalitis was reported in some patients upon stopping zidovudine monotherapy. It is possible that these early observations provide precedent for the findings in our patients, although in the most detailed report of this phenomenon, Helbert and colleagues described recrudescence or exacerbation of ADC without pleocytosis after patients stopped zidovudine monotherapy . None of the individuals in the current study developed symptoms or signs of meningitis, or indeed any other changes in neurological status as assessed by neurological history, physical examination and QNPZ-4 scores. This may imply that the perturbations in virus and lymphocyte exchange between blood and CSF in this particular setting are without clinical consequences, and therefore clinically benign. However, this study included only a small number of patients who were not severely immunosuppressed and who were, with one exception, neurologically normal, and the period of STI and subsequent follow-up may have been too short to witness development of more serious sequelae. Hence, the potential neurological implications of resurgence of virus and associated inflammation in the CSF, or in parallel within the brain, remain uncertain, and it is possible that neurological impairment would be more likely in individuals with active ADC or who harbour different, more "neuropathicâl" viral strains.