PROCAARE: CLINICAL SCIENCE--ANTIVIRALS

["Gerard J. Nau (Jerry)" <gnau@usa.healthnet.org>]

KEYWORDS:  MONOTHERAPY/ COMBINATION THERAPY/ REVERSE TRANSCRIPTASE INHIBITORS
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References:

Hammer, S.M., et al. for the AIDS Clincal Trials Group Study 175.  (1996) 
A trial comparing nucleoside monotherapy with combination therapy in 
HIV-infected adults with CD4 Cell counts from 200 to 500 per cubic 
millimeter.  New Eng J Med  335:1081-1090.

Saravolatz, L. D., et al. for the Terry Beirn Community Programs for 
Clinical Research on AIDS.  (1996)  Zidovudine alone or in combination 
with didanosine or zalcitabine in HIV-ionfected patients with the 
acquired immunodeficiency syndrome or fewer than 100 CD4 cells per cubic 
millimeter.  New Engl J Med 335:1099-1106.

These two studies addressed the issue of monotherapy versus combination 
therapy with reverse transcriptase (RT) inhibitors.  The first, ACTG175, 
showed a significant advantage to using zidovudine (ZDV) in combination 
with another agent: didanosine (ddI) or zalcitabine (ddC), or using ddI 
monotherapy.  In a group of almost 2500 patient with CD4 counts 200-500, 
with or without prior therapy with ZDV there was a reduction of 
progression to endpoints of AIDS-defining event or death - hazard ratios 
compared to ZDV alone: 0.64 (ZDV+ddI), 0.77 (ZDV+ddC), and 0.69 (ddI alone).

The second study evaluated over 1100 patient who already had the 
diagnosis of AIDS (CD4 count less than 200, other AIDS-defining 
illness).  Patients received either ZDV, ZDV+ddI, or ZDV+ddC.  The 
results showed no significant difference between the various treatment 
arms in either survival or disease progression (although ZDV+ddI showed 
some reduction in relative risk of aquiring Pneumocystis carinii 
infection and systemic MAI).

The findings of ACTG175 are consistent with those of the European Delta 
trial where there was a benefit to combination therapy in patients with 
CD4 counts 50-350 and who had not previously been treated with an RT 
inhibitor.  While the results from Saravolatz et al. appear to be 
contradictory, this study had very different patient population;  
patients were further along in their course, and one might expect a more 
limited response to therapy.  

These studies may help in the management of HIV infection in areas that 
have limited resources.  Combination RT inhibitor therapy would appear to 
be most helpful to patients earlier in the course of their disease rather 
than later, and available medications could be directed to that patient 
group.  However, it is unclear whether regimens with a combination of RT 
inhibitors are comparable to regimens containing a protease inhibitor.   
Alternatively, the group with advanced disease may benefit from 
combination therapy with an RT inhibitor and a protease inhibitor rather 
than ZDV monotherapy.