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RE-EXAMINING WHEN TO BEGIN HIV THERAPY & D4T USE & LIPOATROPHY
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Reported by Jules Levin
Gary Blick raised these questions in a poster he and colleagues reported at the VX Intl AIDS Conference in Bangkok, Thailand, July 2004. Blick concluded these points from his study, details of which are reported below:
"The 2003 US DHHS and British HIV Association (BHIVA) Guidelines, fashioned to delay and/or reduce "drug related adverse events" by delaying HAART until CD4 >200 and <350 cells/mm3, may be placing patients at significantly increased risk of developing lipoatrophy, peripheral neuropathy, and possibly, lactic acidosis. Strong consideration should be given to revising Treatment Guidelines to recommend treating patients earlier in disease (nadir CD4% >=18, nadir CD4 count >=350) to reduce the potential toxicities being attributed to HAART".
"D4T can be used safely as a first-line thymidine analogue (nuke) in patients with higher nadir CD4% and cell counts. D4T can be safely used as a second-line thymidine analogue in patients with higher nadir CD4% and cell counts. HIV co-infection with HCV may be a risk factor for development of lipoatrophy when d4T is used 2nd line".
SUMMARY OF RESULTS BY BLICK
The actual data results from Blick are reported below this section. Some of the analyses are based on a small number of patients and statistical analyses don't appear to have been performed, but the results are at times provocative and of interest.
In the cohort who took HAART containing d4T as a first-line thymidine analog, d4T had a favorable safety and toxicity profile:
--baseline at start of d4T: CD4% 20, CD4# 426, log 5.01
--time on d4T/time on HAART: 44m/63m
--nadir CD4% and cell count: 19,% 368
--9% developed lipoatrophy (13% developed lipodystrophy)
--7% developed peripheral neuropathy
--0% developed lactic acidosis
In the cohort who took HAART containing d4T as a second-line thymidine analogue following HAART containing AZT as a first-line thymidine analogue, d4T had a less favorable safety and toxicity profile:
--baseline at start of AZT: CD4% 15, CD4# 242, log 5.08
--baseline at start of d4T: CD4% 22, CD4# 314, log 4.32
--Time on AZT/time on d4T/time on HAART: 42m, 43m, 127m
--40% developed lipoatrophy (51% developed lipodystrophy)
--33% developed peripheral neuropathy
--7% developed lactic acidosis
Regardless of whether d4T was used as a 1st or 2nd line agent, nadir CD4% and cell count was significantly lower in those who developed lipoatrophy when compared to those who did not:
--d4T 1st line: 13% & 211 cells vs 20% & 387
--d4T 2nd line: 8% & 104 vs 20% & 315
Regardless of whether d4T was used as a 1st or 2nd line agent, nadir CD4% % cell count was significantly lower in those who developed peripheral neuropathy when compared to those who did not:
--d4T 1st line: 13% & 165 cells vs 19% & 379
--d4T 2nd line: 10% & 136 vs 16% & 336
Regardless of whether d4T was used as a 1st or 2nd line agent, lipoatrophy occurred more frequently when nadir CD4% was below18% or CD4 count was <350:
--d4T 1st line- CD4% <18 vs >18: 17% vs 4%; CD4# <350 vs >350: 13% vs 5%
--d4T 2nd line: CD4% <18 vs >18: 71% vs8%; CD4# <350 vs >350: 59% vs 0
Regardless of whether d4T was used as a 1st or 2nd line agent, peripheral neuropathy occurred morefrequently when nadir CD4% was below18% or CD4 count was <350:
--d4T 1st line: CD4% <18 vs >18: 17% vs 0%; CD4# <350 vs >350: 44% vs 0%
67% of those co-infected with HCV developed lipoatrophy when d4T was used 2nd line vs 0% when used 1st line; when d4T was used 2nd line, lipoatrophy occurred more frequently in HCV coinfected individuals than in those without HCV (67% vs 32%).
Regardless of whether d4T was used as a 1st or 2nd line agent, the following variables appeared to influence the development of lipoatrophy:
--duration of HIV+: 92 mo vs 73 mo (1st line), 137 mo vs 115 mo (2nd line)
--history of AIDS: 20% vs 3% (1st line), 71% vs 15% (2nd line)
Regardless of whether d4T was used as a 1st or 2nd line agent, the following variables did not appear to unfluence the development of lipoatrophy:
Age
Gender
Race
Risk factor
Highest PCR recorded
Time on d4T
Time on AZT
Time on HAART
Degree of change in CD4% or cell count from baseline
Duration of time since AIDS diagonis
BACKGROUND FROM BLICK
D4T has recently fallen into disfavor dueto reports associating it with higher incidences of: lipoatrophy, peripheral neuropathy, lactic academia/acidosis, hypercholesterolemia, hypertrygliceridemia. The 2003 British HIV Association Guidelines say " Combinations including d4T are not recommended for initial therapy dueto possible risks of more rapid development of lipoatrophy. A value of 200 CD4 cells represents the minimum level at which treatment should be advise. Treatment should be offered, although controversial (when CD4s >200 but <350). The DHHS rationale for delaying HAART until CD4 >200 but <350 is:
ADATPTED FROM THE JULY 14, 2003 DHHS GUIDELINES:
Table 4. Potential Risks and Benefits of Early Versus Delayed Therapy Initiation For the Asymptomatic HIV-Infected Patient
Potential Benefits & Risks of Delayed Therapy
potential benefits of delayed therapy
--avoid negative effects on quality of life
--avoid drug-related adverse events
--delay in development of drug resistance
--preserve future treatment options
potential risks of delayed therapy
--possible risk of irreversible immune system compromise
--possible greater difficulty in viral suppression
--possible risk of HIV transmission
Potential Benefits & Risks of Early Therapy
potential benefits of early therapy
--earlier suppression of viral replication
--preseveration of immune function
--prolongation of disease-free survival
--lower risk of resistance with complete viral suppression
--possible decreased risk of HIV transmission
potential risks of early therapy
--drug-related adverse effects on quality of life
--drug-related serious toxicities
--earlier development of drug resistance due to sub-optimal viral suppression
--risk of transmission of virus resistant to antiretroviral drugs (if suboptimal suppression)
--limitation of future treatment options
--unknown durability of current available therapy
HIV OUPATIENT STUDY (HOPS): Lichtenstein et al JAIDS 2003;32(1):48-56 says
"Analysis that controlled for the severity of HIV illness demonstrated no significant association with use or time on any antiretroviral agent or class of agents and the development of lipoatrophy. The most significant predictor for the development of lipoatrophy was the nadir CD4 count. Blick then quotes the DHHS Guidelines: "The face and extremeties are most commonly affected by fat atrophy, and variability exists in severity. Prevalence of this toxicity has been reported to increase with long-term exposure...(references)...Although d4T has been frequently reported in cases of lipoatrophy, this might be amarker of long term treatment exposure...(references)..."
BLICK'S STUDY
Objectives:
--to evaluate the safety of d4T when used in HAART as a first-line thymidine analogue and as a second-line thymidine analogue fellowing AZT
--to evaluate the incidence of lipoatrophy, peripheral neuropathy, and lactic acidosis in HIV/AIDS patients who took d4T as a first-line thymidine analogue and as a second-line thymidine analogue following AZT
--to evaluate factors associated with the development of lipoatrophy, peripheral neuropathy, and lactic acidosis in HIV/AIDS patients who took d4T as a first-line thymidine analogue and as a second-line thymidine analogue following AZT
METHODS
Retrospective chart review of 100 patients in 2 different clinics:
--Mt Vernon Hospital HIV/AIDS Clinic: inner city clinic
--CIRCLE Medical LLC: ptivate practice setting
Patients were stratified into 2 groups:
--group A: patients who took HAART containing d4T as first-line thymidine analogue, n=45
--group B: patients who took HAART containing d4T as second-line thymidine analogue following use of HAART containing AZT as a first-line thymidine analogue, n=55
RESULTS
DEMOGRAPHICS
Table 1. Age, Gender, Time HIV+, %AIDS, %Co-infected
| Group A | Group B | | n=45 | n=55 | | Mean age(yrs) | 46 | 45 | | Gender: | | | | -female | 33% | 31% | | -male | 67% | 69% | | Race: | | | | -Caucasian | 33% | 60% | | -African-American | 62% | 25% | | -Hispanic | 5% | 15% | | Risk: | | | | -MSM | 22% | 51% | | -IVDU | 38% | 33% | | -heterosexual | 40% | 16% | | Time HIV+ - mean(yrs) | | | | AIDS | 33% | 51% | | HIV/HCV+ | 33% | 33% |
DEMOGRAPHICS
Table 2. Nadir CD4% & CD4 Cell Count, Highest PCR Recorded
| Group A | Group B | | Nadir CD4% | 19% | 13% | | Nadir CD4 Count | 368 | 203 | | Highest PCR | log 5.30 | log 5.29 | | --copies/ml | 200,000 | 194,000 |
HAART HISTORY
Table 3. HAART History
| Group A | Group B | | -Time to d4T from HIV diagnosis | 17 mo | 54 mo | | -Time to AZT from HIV diagnosis | na | 17 mo | | -Time on d4T | 44 mo | 43 mo | | -Time on AZT before d4T | na | 42 mo | | -Baseline CD4,% | 20,%426, | 22,%314, | | CD4#, PCR at d4T initiation | 101,000 c/ml | 20,000 c/ml | | - Baseline CD4,% | na | 15,%242, | | CD4#, PCR at AZT initiation | | 120,000 c/ml | | -Time on HAART | 5yr3mo | 10y7mo |
CLINICAL EVENTS
Table 4. Incidence of Lipoatrophy/Lipodystrophy, Factors Influencing Development of Lipoatrophy: Nadir CD4,% Nadir CD4#, Duration of HIV
| Group A | Group B | | Overall incidences: | | | | -%lipodystrophy (LD): | 13%(n=6) | 51%(n=28) | | -%lipoatrophy (LA): | 9%(n=4) | 40%(n=22) | | -%lipohypertrophy (LH): | 2%(n=1) | 7%(n=4) | | -%mixed (LA/LH): | 2%(n=1) | 4%(n=2) |
| Nadir CD4,% CD4#: | | | | -lipoatrophy (+): | 13,% 211 | 8,% 104 | | -no lipoatrophy (-): | 20,% 387 | 20,% 315 | | Mean Duration HIV+, months: | | | | -lipoatrophy(+): | 92 mo | 137 mo | | -no lipoatrophy(-): | 73 mo | 115 mo |
Table 5. Factors Influencing Development of Lipoatrophy: stratified nadir CD4 percent and nadir CD4 cell count, history of AIDS, presence of HCV co-infection
| Group A | Group B | | Nadir CD4%: | | | | -CD4% >=18 | 4%(1/27) | 8%(2/24) | | -CD4%<18 | 17%(3/18) | 71%(22/31) | | Nadir CD4 count: | | | | -CD4 >350 | 5%(1/21) | 0%(0/14) | | -CD4 <350 | 13%(3/24) | 59%(24/41) | | History of AIDS: | | | | -AIDS(+)/lipoatrophy(+) | 20%(3/15) | 71%(2/28) | | -AIDS(-)/lipoatrophy(+) | 3%(1/30) | 15%(4/27) |
| HIV/HCV Coinfection: | | | | -HCV+/lipoatrophy | 0%(0/15) | 67%(12/18) | | HCV(-)/lipoatrophy | 13%(4/30) | 32%(12/37) |
The following variables did not appear to unfluence the presence of LA:
--highest PCR recorded
--degree of change in CD4 count or % from baseline
--time on d4T, AZT, or HAART
--duration time since AIDS diagnosis
--demographics: age, gender, race, risk factors
Table 6. Incidence of Peripheral Neuropathy, Lactic Acidosis
| Group A | Group B | | % peripheral neuro | 7%(n=3) | 33%(n=18) | | Nadir CD4,% CD4# | | | | --peripheral neur(+) | 13,%165 | 10,%136 | | --peripheral neur(-) | 19,%379 | 16,%336 | | Nadir CD4% | | | | --CD4#>18 | 0(0/27) | 8%(2/24) | | --CD4%<18 | 17%(3/18) | 52%(16/31) | | Nadir CD4 count | | | | --CD4>350 | 0(0/21) | 0(0/14) | | --CD4<350 | 14%(3/21) | 44%(18/41) | | Lactic acidosis | 0 | 7%(n=4) |
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