Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

Two Four-Drug Therapy Studies at IAS: are 4 drugs better than 3?
     written for NATAP by Michael Norton, PA

Abstract #221 - Combivir, Abacavir, Efavirenz

Entry Criteria
-- ARV Naïve
-- CD4+ T-cells = no restrictions
-- VL originally > 50,000 but amended to 1,000 copies/ml due to low accrual

Baseline Characteristics
-- N = 38
-- Men = 33, Women = 5
-- Median VL = 5.10 log10 copies/ml
-- # of participants with VL > 100,000 copies/ml = 26
-- Median CD4+ T-cell = 285 cells/mm3

Design
-- 48-week, prospective, multi-center, open-label, non-comparative study.
-- Primary Objective: Potency and safety/tolerability of COM/ABC and Trizivir plus EFV.
-- Secondary Objectives:
    1 - Changes in immunologic response,
    2 - Development of phenotypic and/or genotypic resistance,
    3 - Adherence to these regimens.
-- One arm: For the first 24 weeks, participants took Combivir 1 tab bid, Abacavir 300mg bid, and Efavirenz 600 qd,
                 the second 24 weeks consist of Trizivir 1 tab bid and Efavirenz 600 qd.

Results 24 week interim data

Viral Load at 24 weeks:

-- ITT (M=F) < 400 copies/ml - 76.0%
-- AT (31 patients) < 400 copies/ml = 85.0% however poster gave two separate values 94% and 85%.
-- ITT (M=F) < 50 copies/ml = 68.0%
-- AT (31 patients) < 50 copies/ml = 84.0%
-- < 3 copies/ml = 59% or 16 of the 27 participants who were < 50 copies/ml at 24 weeks.

CD4+ T-cell changes:

-- Median increase CD4+ T-cells (35/38) = 101cells/mm3

AE's:

-- # of pts who d/c'ed at least one drug due to drug related AE = 5 (13.2%)
-- # pts. with possible ABC hypersensitivity = 3 (7.89%)

Adherence:

-- 84% of all subjects, at the week 24 visit, reported taking all of their prescribed doses during the previous 7 days.

Commentary:
For clinicians and patients who are uncomfortable with the potency of AZT, 3TC, and ABC, especially in high viral loads, this regimen may offer an acceptable alternative. The weakness of this data is that it is small numbers and most importantly, non-comparative. Still, we can learn some encouraging insights here. By week 8 all patients who were to reach < 50 copies/ml had done so. Missing from this analysis, but probably forthcoming at another meeting will be the lipid profiles. Questions arising from these type of 4 drug regimens are: whether the 4 drugs offered any clinical benefit over 3 drugs? whether 4 drugs are required for the duration of therapy and if not when it would be safe to drop the 4th drug? which drug should be dropped?

Abstract #61 - 4 drug regimen vs. 3 drug regimen: Immune Activation Markers

Entry Criteria
-- Participants had to present with symptomatic Primary HIV Infection and be confirmed by <4 Western Blot bands
-- ARV Naïve
-- CD4+ T-cells = no restrictions
-- VL = no restrictions

Baseline Characteristics
-- N = 35 (17 in the 3 drug arm, 18 in the 4 drug arm)
-- Median VL 4 drug arm = 6.1 log10 copies/ml
-- Median VL 3 drug arm = 6.3 log10 copies/mlDesign
-- 48-week, multi-center, open-label, comparative study.

Objectives:
To determine whether more intensive antiretroviral therapy affects the rate of viral decay and immunological recovery in patients treated prior to HIV seroconversion. Plasma VL and T-lymphocyte markers: including: CD4+, CD8+, CD38+, HLA-DR, CD28, and RO were accessed monthly and compared to baseline.

-- Two arms:
   •  ZDV 300mg bid+ 3TC 150mg bid + IDV 800 tid or NFV 1250 bid
   •  ZDV 300mg bid + 3TC 150mg bid + ABC 300mg bid + AMP 1250 bid

Results 48 week data

Viral Load:

-- 1st and 2nd stage decay rates no difference
-- Median decrease in VL from baseline approximately 4.5 log10 copies/ml

CD4+ T-cells:

-- Total number of Cd4+'s = no difference between arms
-- Activation marker CD38+HLA-DR+ on CD4+'s = no difference between
arms.

CD8+ T-cells:

-- Total number of CD8+'s - Those on 4 drug regimen had less than those on 3-drug regimen
- -Independently markers CD38+, CD38+HLA-DR+, CD28-, CD45RO+ were all
significantly higher in the 3 drug arms versus the 4 drug arm.
-- Most marked difference where 3 drug arm had significantly more then 4-drug arm = CD8+CD38+ subset

Adherence:

-- "Analysis was only done on patients who stayed on therapy through 48 weeks"

AE's:

-- Not discussed.

Discussion
During the Q & A Franco Lori stated that CD38+ is a very early marker of viral replication. He noted that it has been observed that folks who blip from undetectable have increased # of CD38+ CD8+'s when compared to those who remain fully suppressed. Someone else stood up to confirm that this has been noted in the pediatric literature and cited an article in the Journal Virology on the subject.

Commentary:
Once again yet another report at this conference substantiating that our 3-drug HAART regimens are not maximally potent. What remains to be answered is whether there are long term clinical benefits associated with increasing the potency offered by taking more drugs. Adding more drugs may increase challenges that already exist with adherence and/or toxicities. A question I had after reading this abstract and attending the oral presentation was that I couldn't figure out how many patients were included in the final analysis. It was my impression that this study was not prospective but rather a retrospective of a PHI cohort who stayed on therapy for 48 weeks. That would give you 35 in the final analysis, 17 in the 3-drug regimens and 18 who took the 4 drugs. Even if this is incorrect, it is important to know how many participants did not stay on therapy for 48 weeks,
especially among that 4 drug arm which contained 20 tabs/caps total per day.

No one has yet shown that more then 3 drugs are needed to keep someone HIV-infected from progressing to AIDS. This is yet another piece of information showing us more potent HAART regimens are possible. It is not unrealistic to imagine that future studies may provide insights into clinical benefits (perhaps durability of regimen) associated with this increased potency.