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Mixed Findings on Value of Brain-Penetrating Antiretroviral Scores
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from Jules: my feeling is that there are numerous factors involved in an individual patient develops cognitive impairment. HIV enters the CNS shortly after infection and generally never leaves so the duration a patient goes before starting therapy may dictate that a high CPE score HAART may improve the risk for developing cognitive impairment but mat not prevent it, perhaps such a regimen may delay it, perhaps if the first HAART regimen has a low CPE score but the most recent regimen has a high CPE score that most recent regimen may not be as effective. I am speculating with one example but there could be numerous ways in which a patient's cognitive impairment develops. What about a patient who was not adherent and has ongoing viral replication for years before finally achieving full suppression with a regimen with a high CPE score, is that patient more or less likely to benefit from HAART with a reasonably high CPE score or does that patient require HAART with a very high CPE score to benefit; what about a patient with discordance between CD4 and viral load in response to HAART and is unable to ever mount a very good CD4 response, how does this effect the capacity of a HAAART regimen with a reasonably good CPE score to provide benefit?
17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
Two studies at the Conference on Retroviruses reached seemingly divergent conclusions on whether picking antiretrovirals for their ability to penetrate the central nervous system (CNS) helps people clinically. But the studies had different designs and goals.
Tracking almost 20,000 adults taking antiretrovirals, UK CHIC cohort collaborators found that neither the first CNS penetration effectiveness (CPE) score measured in cohort members nor their latest CPE score predicted the risk of a CNS complication during follow-up [1]. Looking only at test-determined neuropsychological performance in a much smaller case-control study, Italian investigators found that regimens rated neuroactive did improve performance [2].
Two earlier studies yielded contrary results on whether antiretrovirals considered good brain penetrators do a better job in improving mental function. One study found that a better CPE score predicted better mental function in people taking antiretrovirals [3]. But a study by researchers who devised the CPE score did not find that good brain breachers improved mental function [4]. The study that found a positive correlation [3] was larger and used different methods to measure mental function.
To see whether CPE score affects mortality or development of CNS complications, the UK CHIC team focused on 19,828 people who started combination antiretroviral therapy, calculating the CPE score of all their regimens and recording how many people died or suffered a CNS complication, including HIV encephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy.
The study group had a median age of 36 years, 25% were women, 59.4% were white, and 25.7% were black Africans. Median pretreatment CD4 count stood at 190 (interquartile range [IQR] 91 to 290), and median viral load at 4.6 log copies/mL (about 40,000 copies, IQR 4.1 to 5.3). Of the first-line regimens these people took, 7.9% had a CPE score below 1, 42.6% had a score of 1 to 1.5, 47.3% had a score of 2 to 2.5, and 2.2% scored 3 or more.
Follow-up for this analysis stretched from 1996 through 2007, and median follow-up measured 4.5 years (IQR 1.9 to 8.2). Three factors predicted starting a regimen with a CPE score of 3 or more--higher pretreatment viral load (P = 0.005), starting treatment between 2000 and 2003 (P < 0.0001), and starting a nonnucleoside-containing regimen (P < 0.0001). Women infected during sex with men were less likely to begin a regimen that scored 3 or more than were other HIV transmission groups (P < 0.0001).
Only 224 of the 19,828 people studied (1%) had a new CNS diagnosis during follow-up to yield an incidence of 2.4 cases per 1000 person-years. CNS complications were more likely in people whose first regimen had a CPE score below 1 than in those whose regimen scored 3 or higher. But neither initial nor latest CPE score affected the risk of CNS complications in a multivariate analysis that considered age, gender, mode of HIV transmission, ethnicity, pretreatment and latest CD4 count and viral load, calendar year, and whether a person had taken one or two antiretrovirals before starting combination therapy.
During follow-up 1256 people (6.3%) died to yield a death rate of 13 per 1000 person-years. Multivariate analysis reckoned that CPE score did affect the risk of death. Compared with an initial-regimen score below 1, a score of 2 to 2.5 lowered the death risk 12% (RR 0.82, 95% CI 0.68 to 0.99, P = 0.04). The correlation was stronger for the CPE score of the latest regimen. Compared with a score below 1, a score of 1 to 1.5 decreased the death risk 42% (RR 0.58, 95% CI 0.51 to 0.67, P = 0.0001) and a score of 2 to 2.5 cut the risk 48% (RR 0.52, 95% CI 0.44 to 0.60, P = 0.0001). But a CPE score of 3 or higher was not protective in this analysis.
The UK CHIC team suggested that the CPE score associations with mortality probably reflect "the effect of clinical status upon prescribing practice."
The Italian study had a different design and different endpoints [2]. Researchers at Cotugno Hospital in Naples limited the study population to people with a stably undetectable viral load, an unchanged regimen for 6 months, age under 60, at least 8 years of education, no depressive symptoms, no major neurologic or psychiatric disorders, and no current illicit drug use.
The study population was 80% male, had a median age of 42 years, and had a median 11 years of education. Thirty people had a CPE score of 2 or higher and 15 controls had a lower score. Research psychologists blinded to antiretroviral regimens administered a battery of seven standard tests of neuropsychological performance. Cases performed significantly better than controls on three tests: verbal memory span, verbal fluency, and symbol digit modalities test.
The investigators believe their findings "suggest the need for routine neurocognitive screening to guide the optimal management of milder but potentially relevant neuropsychological deficits."
Scott Letendre (University of California, San Diego) presented an updated CPE ranking at conference [5]:
· 4 Best penetrators: zidovudine, nevirapine, indinavir/ritonavir
· 3 Moderately good penetrators: abacavir, emtricitabine, delavirdine, efavirenz, darunavir/ritonavir, fosamprenavir/ritonavir, unboosted indinavir, lopinavir/ritonavir, maraviroc, raltegravir
· 2 Moderately poor penetrators: didanosine, lamivudine, stavudine, etravirine, atazanavir/ritonavir, unboosted atazanavir, unboosted fosamprenavir
· 1 Poor penetrators: tenofovir, zalcitabine, nelfinavir, ritonavir, saquinavir/ritonavir, unboosted saquinavir, tipranavir/ritonavir, enfuvirtide
References
1. Garvey L, Winston A, Sabin C, and the UK CHIC Study Group. Does cART with greater CNS penetration prevent the development of CNS opportunistic diseases? 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 427.
2. Starace F, de Stefano M, D'Abrosca A, Gargiulo M, Chirianni A. Neuropsychological performance is better in HIV-infected subjects treated with neuroactive HAART. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 433.
3. Tozzi V, Balestra P, Salvatori MF, et al. Higher CPE score improved cognition, changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. JAIDS. 2009;52:56-63.
4. Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS. 2009;23:1359-1366.
5. Letendre S, FitzSimons C, Ellis R, et al, and the CHARTER Group Correlates of CSF viral loads in 1221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 172.
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