Mechanisms of CSF/plasma HIV discordance remain poorly defined. One hypothesis suggests that discordance can be seen in individuals who fail to show durable viral suppression on ART. In such individuals, drug-resistant plasma HIV secondarily infects the CNS and subsequent replication of CNS HIV leads to discordance. Another hypothesis is that more advanced immune suppression (as estimated by a low nadir CD4+ T-cell count) eases HIV entry into the CNS. In the CNS, HIV productively replicates within perivascular macrophages and microglia (M tropic HIV). The administration of ART drugs that reach higher concentrations in the CNS better suppress viral replication in these cells, although integrated provirus persists. Suboptimal adherence to ART or switch to drugs with lower distribution into the CNS allows the neurologic reservoir of HIV to replicate at low levels. Suboptimal CNS penetration of ART and multidrug-resistant CNS HIV leads to compartmentalized infection, which manifests in its severest form as HIV encephalopathy.[30,31] However, in our study, we did not find an association between nadir CD4 count and neurosymptomatic CSF/plasma HIV-1 discordance (P = .47).
Use of PI-based ART was associated with increased prevalence of neurosymptomatic CSF/Plasma HIV-1 discordance. In the present study, except for 1 case, all individuals with CSF/plasma HIV-1 discordance were on PI-containing ART. Out of 360 individuals who were on PI-based ART in our cohort, 19 (5.27%) developed neurosymptomatic CSF/Plasma HIV-1 discordance. Out of 43 patients who developed incident neurologic symptoms on PI-based ART, 19 (44.2%) had CSF/Plasma HIV-1 discordance (Table 1). As per the ART guidelines of WHO and Indian National AIDS Control Organization (NACO), PI-containing regimens (2 NRTI and 1 boosted PI or 1 boosted PI with 1 integrase inhibitor) are recommended as second-line treatment of HIV infected adults when NNRTI regimens (2NRTIs and 1 NNRTI) fail to suppress plasma VL. ATV/r is the preferred PI used in India, while boosted darunavir is preferred in resource-rich settings. ATV/r has subtherapeutic concentrations in CSF in a substantial proportion of adults and, accordingly, a low CPE value. The combination of CNS-compartmentalized HIV that may contain drug-resistant HIV archived during failed first-line therapy and subtherapeutic concentrations of ATV/r or another PI during second-line therapy could lead to functional dual or monotherapy. Among 9 patients undergoing CSF genotypic resistance testing in our cohort, 5 samples had triple-class resistance effectively leading to no active drug for viral suppression in the CNS compartment. In remaining 4 samples, NRTI and NNRTI resistance led to functional PI monotherapy in CNS compartment. Studies have shown a higher CSF HIV replication in patients taking double-boosted PI regimens, supporting possible functional monotherapy in the CNS. As PIs are substrates for drug efflux transporters that are expressed on brain microvascular endothelial cells and ependymal cells of choroid plexus, their concentrations in CNS can be subtherapeutic. These results supports the inference that shifting to a PI such as darunavir that has better CNS penetration than atazanavir and superior efficacy against triple-class resistant virus than lopinavir may reduce the risk of CSF/plasma HIV-1 RNA discordance.
The CPE method attempts to estimate the efficacy of ART drugs in the CNS. In cohort studies, higher CPE values, indicating better estimated efficacy of an ART regimen in the CNS, correlate with lower CSF HIV RNA. Evidence linking use of neuroactive ART regimens (regimens with higher CPE score) with improvement in cognitive performance,[43–45] lower incidence of CSF/Plasma HIV-1 discordance,[14,15] and prevention of multidrug-resistant CNS HIV[46,47] has been mixed. However, our results show that using ART regimens with better CPE values (≥6) were beneficial, being associated with a lower prevalence of neurosymptomatic CSF/plasma HIV-1 discordance. As per the Mind Exchange Consensus Report, patients presenting with worsening cognitive impairment and detectable CSF HIV should consider modifying their ART regimen as per the CPE method provided other risk factors (e.g., poor adherence to medication, virologic drug resistance, and comorbidities) have been addressed. An “adjusted” CPE score has been proposed as a more relevant score in CSF/plasma HIV-1 discordance, as it takes into account resistance profiles for the calculation of CNS ART effectiveness. All 9 cases with genotyping from CSF isolates had mutations that would result in resistance to at least 1 prescribed ART drug, resulting in a lower “adjusted” CPE score.
Our study has several limitations. First, as for all retrospective studies, some episodes of incident neurologic disease may be unreported leading to measurement bias and underestimation of prevalence of CSF discordance. Second, milder neurologic symptoms such as headache may not have triggered LP and measurement of CSF HIV-1 RNA, leading to unaccounted cases of mildly symptomatic CSF discordance. Third, neuropsychological testing for cognitive impairment was not performed at baseline or follow-up in our cohort and hence milder forms of HIV-associated neurocognitive disease could not be identified and CSF discordance in these patients could not be studied. Screening for functional impairment and mood disorders was not performed as well. Fourth, patients were classified into LLV and complete viral suppression on the basis of latest plasma VL record. Longitudinal analysis of VLs to identify patients with intermittent LLV, persistent LLV, and durable suppression was not done. Some patients with intermittent LLV could have been classified as complete viral suppression as a result. Fifth, genotypic HIV-1 resistance testing of CNS virus was not performed for all patients with CSF/plasma HIV-1 discordance. In spite of these limitations, our cases of neurosymptomatic CSF/plasma HIV-1 RNA discordance clearly demonstrate that HIV persistence in the brain remains a concern among patients on virologically suppressive ART in India.
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