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  7th International Congress on Drug Therapy in HIV Infection
November, 14-18, 2004
Glasgow, UK
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Report From Final Oral Late Breaker Session at Glasgow: Reasons For Stopping HAART in EuroSIDA Cohort
 
 
  Reported by Jules Levin
 
--GI problems, rash/hypersensitivity, abnormal fat redistribution, CNS side effects were leading reasons for stopping therapy; HCV+ & individuals with lower weight may be more likely to stop therapy due to toxicities; compared to taking a single PI, persons taking dual PIs may be more likely to stop therapy; treatment-experienced patients were more likely to discontinue therapy than treatment-naïve patients to stop therapy due to toxicities; patients with higher CD4 counts (50% higher) were more to stop therapy due to toxicities--
 
Another gloomy weather day in Glasgow, appears to be the norm; rainy, windy, overcast. But I like Glasgow. The conference ended this morning at about 12 noon after several interesting oral presentations including RESIST-2 (tipranavir), 96-weeks BMS 045 Study comparing Kaletra to Reyataz/r, a study from the EuroSIDA database reporting reasons why patients discontinued HAART, 24-weeks results from Study 934 comparing tenofovir/FTC+ efavirenz to Combivir (AZT/3TC)+efavirenz, and a report from Spain on couples with one who is HIV+ getting pregnant by sexual relations. As well, Rob Murphy provided a nice review of new drugs in development. I head back to the other side of the pond, the USA, tomorrow with a need to get back onto the running track to work off the fatty diet here.
 
"Amanda Mocroft (Royal Free & University College Medical School, London, UK) reported "Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen". Mocroft provided this background. HAART regimens are complex and often associated with toxicities. This results in discontinuations of specific antiretroirals, sub-optimal therapy, and treatment failure. HAART can also lead to hepatoxticity, particularly in patients with concomitant HIV infection. Frequency of toxicities are often described in clinical trials, but not so thoroughly in clinic populations where data on HCV status is often missing. This was I think the first analysis of this study and a further analysis is expected.
 
The objectives of this study are to determine factors related to stopping antiretrovirals in first HAART regimen due to treatment failure (TF) or toxicities and patient/physician choice (TOX). And to describe the role of coinfection with HCV in incidence of stopping antiretrovirals due to TOX in first HAARt regimen.
 
There are 11,161 patients in EuroSIDA where they collect demography data, CD4 & viral loads, other markers, AIDS defining illnesses/deaths, disease specific prophylaxis, HCV/HBV status, antiretrovirals start & stop dates, and from 1/1/99 reasons for stopping each ARV drug started for treatment failure, toxicity, patient/physician choice, other & unknown. The first EuroSida cohort started in May 1994 with 3100 patients, Cohort 2 1300 in '96, Cohort 3 with 2600 in '97, cohort 4 with 1200 in '99, cohort 5 with 1250 in '01, and cohort 6 with 1350 in '03.
 
This study of 1198 patients started HAARt for the first time after 1/1/99. CD4/VL was measured in 6 months prior to starting HAART. 49% were taking an NNRTI regimen, 16% boosted PI, 7% nucs, I think 26% single PI regimen, 2% other.
 
PATIENT CHARACTERISTICS
72% male
38% homosexual; 32% heterosexual; 22% IDU
18% prior AIDS
66% ARV naïve
61%/4%/35% HBV --ve/+ve/unknown
49%/21%/30% HCV --ve/+ve/unknown
 
AT BASELINE, median
CD4 249
VL 4.66 log
Age 37.4 yrs
Baseline 8/00
 
CHANGES TO A FIRST HAART REGIMEN
 
After 4 years (n=286), about 25% of patients remained on their original HAART regimen with no changes & no interruptions from their regimen. About 65% made any change to their regimen but remained on treatment, which includes intensification or switch from their original drugs. Around 10% have stopped all treatment after 4 years.
 
Kaplan-Meier Curve time to first discontinuation of any antiretroviral drug in first HAART regimen: after 12 months (n=729) 30% discontinued at least one drug in their original regimen. The incidence of stopping any antiretroviral from 1999 to 2002 was 35 per 100 person years of followup and in 2001 it was about 25 per 100 person years of followup.
 
The proportion of patients discontinuing for treatment failure has declined from 1999 through 2002 from 20% in 1999 to about 8% in 2002, suggesting that we are getting better at adherence perhaps due to better education, better selection of regimens, and easier to tolerate & simplified regimens.
 
Patients with a higher VL had a higher rate of stopping any drug in initial HAART regimen due to treatment failure.
 
Compared to using a single PI-HAART regimen, patients taking a dual PI or NNRTI regimen had a lower rate of discontinuing any drug in initial HAART regimen due to treatment failure. Patients who were treatment-naïve had lower rates of stopping a drug due to treatment failure. Patients with prior AIDS had a higher rate of stopping a drug due to failure. (model adjusted for region of Europe).
 
There were 190 patients who stopped due to toxicities: rash or hypersensitivity in 17% of patients, GI toxicities 28%, abnormal fat distribution 16%, CNS-associated toxicities in 14%, renal toxicities 6%, hematologic toxicities 4%, other 15%.
 
INCIDENCE RATE RATIOS FOR stopping any drug in an initial regimen due to toxicities or patient/physician choice (TOX): (model adjusted for viral load, region of Europe, & year of starting HAART)
 
Patients with HCV had a 46% higher rate of stopping compared to patients without HCV (1.46 IRR). Compared to taking a single PI (1.00 IRR) patients taking dual PI (1.61 IRR) had a higher rate of stopping due to TOX; NNRTI (0.77 IRR, p=0.035). Females had a higher incidence of stopping due to TOX (1.31 IRR). Patients with a higher CD4 (50% higher) had a higher incidence of stopping due to TOX (1.11 IRR). Patients on HAART for at least 6 months (0.57 IRR) & ARV naïve patients (0.63 IRR) had lower incidence of stopping due to TOX.
 
SUMMARY BY AUTHOR
 
When considering first treatment failure, treatment experienced patients and those with higher viral loads are more likely to discontinue HAARt due to treatment failure. Both of these reasons have been previously reported to be observed in clinical trials and observational studies. (treatment failure was defined as immunologic, clinical or viral).
 
Of patients with known HCV status in EuroSIDA about 30% have HCV. These patients had a higher incidence of stopping treatment due to TOX. The presenter said that although coinfection increases risk for hepatotoxicity the number of patients stopping specifically due to liver toxicity was small & they were uncertain of the reasons for stopping. It was suggested that perhaps HCV+ patients experienced more toxicities due to higher drug blood levels. The study was unable to identify regimens associated with HCV-related toxicities. Patients with higher CD4 counts had higher incidence of stopping due to TOX. The presenter said perhaps these patients felt that since their CD4 counts were high there was less need to continue therapy and withstand toxicities compared to patients with lower CD4s where the immediate risk for clinical progression would be higher. The author suggested that the higher incidence of stopping due to TOX could be due to lower body weights & higher drug concentrations, because when adjusting for body weight among patients for whom they had weights there was no longer a higher incidence of stopping among females.
 
Managing adverse events remains a key intervention in keeping patients on therapy. There is a need for more powerful studies to understand the role of HCV coinfection in discontinuation of HAART.