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4 Drug HAART Regimen vs 3 Drug Regimen: Combivir vs Trizivir plus SQV/r (1000/100 mg bid)
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Reported by Jules Levin 9th EACS Conference October 26-29, 2003 Warsaw, Poland
The idea of using 4 HAART drugs for HIV treatment rather 3 has been the subject of several recent studies. Controversy persists on whether 4 drugs is more potent and ultimately more effective than 3. This therapeutic approach is of particular interest for patients who present initially with advanced HIV—high viral load and low CD4 count—a potent 4 drug regimen may be more effective in achieving <50 copies/ml viral load, sustaining this, and in maximally increasing CD4 count. Of course, quick reduction of viral load to <50 copies is a key to sustaining this and to preventing drug resistance. The tolerability and potential for added side effects and toxicities are a concern as well as the convenience factor.
At EACS, a direct comparison of Combivir plus saquinavir/r vs Trizivir plus saquinavir/r in patients with high viral load and low CD4 was reported.
Schlomo Staszewski and colleagues reported on a small study in 59 patients called the Quad Study. He said the QUAD Study was designed as a pilot study to create the first data comparing 3 vs 4 drugs in advanced-stage, treatment-naïve patients. This is a randomized, open-label, single center study of patients who are ART-naïve, CD4 <100, HIV RNA >50,000 copies/ml. All patients received saquinavir/r (1000/100 mg bid); and then received either quadruple bid regimen with Combivir (fixed dose, AZT+3TC) in addition to the saquinavir/r or triple bid regimen with Trizivir in addition to the saquinavir/r. Each regimen consists of 7 pills per dose (bid). In summary, the authors reported both the TZV and CBV regimens deomstrated high potency and there was no difference detected between the two regimens with regard to viral load reduction, CD4 increase, disease progression, or safety/tolerability.
Switch was defined as patients who, after starting their designated treatment, switched one or more drugs but continued to take a regimen containing 2-3 NRTIs plus 1boosted PI. Discontinuation was defined as patients who, after starting their designated regimen, stopped therapy, changed classes, intensified >3 nukes or >1 PI/r, or simplified <2 nukes or <1 PI/r.
BASELINE CHARACTERISTICS
All patients have highly advanced HIV disease. Average HIV RNA was 300,000 copies/ml in each group. Average CD4 count was 22-31 cells. 12 patients in CBV+SQV/r arm and 13 patients in TZV+SQV/r arm had had Stage C3 disease. The median time between C-diagnosis and start of therapy was 3-4 weeks. 5 patients, divided between the 2 study groups, were diagnosed with cryptococcis, CMV colitis, PCP, and TB.
PATIENT DISPOSITION (n=59)
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CBV+SQV/r |
TZV+SQV/r |
| Randomized |
30 |
29 |
| On stable treatment for 48 wks |
18 |
17 |
| switched |
4 |
5 |
| discontinued |
6 |
4 |
| switched+disct |
1 |
3 |
| never dosed |
1 |
- |
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SWITCH
7 patients switched in CBV regimen vs 9 in TZV regimen. 5 patients switched from TZV to CBV. There were no switches from CBV to TZV. 5 patients in CBV arm and 2 patients in TZV arm switched from AZT to d4T. 2 patients in each group switched from SQV/rto LPV/r (Kaletra).
DISCONTINUATION
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CBV |
TZV |
| Discontinuation (total) |
7 |
6 |
| Disease progression |
1 |
0 |
| Lost to f/up |
6 |
1 |
| Toxicity |
0 |
4 |
| Drug interaction |
0 |
2 |
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ADVERSE EVENTS
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CBV |
TZV |
| GI disturbances |
21 |
23 |
| CNS |
5 |
5 |
| Skin |
6 |
6 |
| Depression |
2 |
1 |
| Anemia |
4 |
3 |
| Fatigue |
11 |
9 |
| Others |
4 |
2 |
| HSR suspected |
- |
4 |
| HSR confirmed |
- |
1 |
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VIRAL RESPONSES
There was a median 4 log reduction in HIV RNA after 48 weeks on therapy. Based on graph it appears that by week 20 the median HIV RNA was <50 copies/ml. About 60% of patients in both groups had <400 c/ml after 48 weeks. About 55% in the TZV and 51% in the CBV arms were <50 c/ml after 48 weeks. So the ITT (I think, disct+switch=failure) viral responses were very similar. By observing the graphs presented, for patients remaining on therapy for 48 weeks (observed treatment analysis), 90% or more were <400 c/ml on SQV/r+CBV or TZV+SQV/r and 90% were <50 c/ml on TZV+SQV/r. For patients taking CBV+SQV/r it appears about 82% had <50 copies. I don’t know if these differences are significant.
Median CD4 counts increased about 170 for each group after 48 weeks.
The reasons for finding no difference is unknown. These findings based on a small pilot study might suggest there is not a difference between these regimens. Although discontinuation rates were similar between the 2 arms, 6 in the CBV arm were lost to follow-up and 4 in the TZV arm discontinued due to toxicity (4 patients had suspected HSR), 1 case was confirmed). A larger better designed study could perhaps find differences between the regimens used in this study or different drug regimens.
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