Increased Rate of HIV-1 Elimination with a Four-Drug
Antiretroviral Regimen in Treatment-Naive Patients
Authors suggests-
Generally, greater rapidity of viral load decay is possible than we normally see for 3 drug regimens. Although you can see below the time it took to reach <500 copies/ml varied from 3 days to 56 days and the time to reach <50 copies/ml varied from 19 to 252 days
This suggests to the author there is incomplete inhibition of HIV replication by 1 and 3 drug regimens
In order to shut down replication more effectively, more viral load suppression is required in the initial treatment period to prevent the emergence of resistant isolates
M Polis and others from the NIH conducted this cutting edge research. A research group from Amsterdam is conducting similar work. The Amsterdam group's initial data was reported at the Retrovirus meeting in Feb '98. A report appeared in our May '98 newsletter, NATAP Reports (you can read that article by clicking here). In a retrospective analysis, the Amsterdam group compared the initial decay rate of virus for 3, 4 and 5 drug regimens. They found that the there was no difference between the decay rates in the first 8 weeks between the 3 and 4 drug regimens, but that the 5 drug regimen had a greater slope of virus decay. The lack of a difference of decay rate between 3 and 4 drugs and the difference with 5 drugs may have been a function of the drugs used in the regimens.
The Amsterdam group compared--AZT/3TC+ritonavir vs AZT/3TC+nelfinavir+saquinavir vs AZT/3TC+abacavir+indinavir+nevirapine. All participants were treatment-naive. The 5-drug regimen was obviously a potent regimen. However, individuals taking the 5-drug regimen experienced more side effects than those on the triple regimen. The Amsterdam group suggested that a more rapid decline in virus load should result in reducing viral load to <50 copies/ml sooner and therefore increase durability. They said at the Retrovirus meeting that they will continue following the participants.
In Geneva, a European research group reported data from an induction/maintenance study. The viral load of most of the participants rebounded after switching from the more potent induction phase regimen to the less potent maintenance phase regimen. Except for the individuals who had a more rapid virus decay rate. These individuals remained undetectable after switching to the less potent maintenance regimen (you can read more details of that study in our Geneva highlights report. Click here to link to it).
Back to this study. Polis said previous studies that have explored the decay rate of plasma HIV in response to therapy have ranged from 0.49 to 0.61 day-1 with mono- and PI triple therapy. He also said that modeling of the virus decay kinetics under potent antiretroviral therapy has been limited by infrequent plasma sampling.
The purpose of this study was to explore and model the kinetics of viral decay in antiretroviral naive patients during the period immediately following the initiation of potent therapy; and, to determine if the rate of viral decay could be higher in response to a 4-drug combination using drugs from each of the 3 available classes of drugs compared with 1 or 3 drug combinations.
Participants were stratified by CD4 count >300 cells or <300 cells. Individuals >300 CD4s had no prior use of any antiretroviral therapy. Those with <300 CD4s had no prior use of protease inhibitors, or nevirapine. They performed regular sampling of plasma, PBMCs (peripheral blood mononuclear cells), lymph nodes, bone marrow and CSF. But, today's report will primarily discuss results from plasma sampling. The regimen initially used in this study was AZT+3TC+indinavir+nevirapine.
Plasma sampling was performed every 6 hours for the first two days following the start of therapy (for the first 9 patients), daily for the next 4 days, then twice weekly for the next 3 weeks. Samples were assayed for HIV-RNA by both the bDNA (Chiron) and RT-PCR (Roche) methodologies.
Polis described the initial results for the first 17 patients who had been treated for a median of 10 months (range 1-18 months). Baseline viral load ranged from about 5,000 to greater than 1 million/ copies/ml with a median of about 54,000 copies/ml.
Using the bDNA 2nd generation assay, the time to decrease of viral load to (n=16)--
Viral Load <500 copies/ml |
Viral Load <50 copies/ml | |
median |
14 days |
126 days |
mean |
14 days |
129 days |
range |
3 to 56 days |
19 to 252 days |
Polis did not differentiate between the two stratification groups of <300 CD4> and treatment naive or experienced. He showed a graph of the curves of the viral load decays for 16 patients for the first 23 days. He pointed out that although there was a big difference between the individuals in baseline viral loads, the slopes of the rates of drop in plasma virus decay were similar for most of the 16 patients. He showed a graph with two curves comparing the average slopes of decline for the 16 people using either the bDNA or RT-PCR assays. Although, the viral load was about 3-fold higher using the RT-PCR, the rates of decline were about the same for the two methodologies used.
He displayed a graph of curves and lines showing the decay slopes or kinetics for the average of the 16 patients from day 0. He said it was important to point out that most studies in the past have looked at viral decay (kinetics) from day two, because of some pharmacologic delay (delay in virus decay after starting therapy), to day 14 (slope 2).
This does not accurately represent the decay curve that you see when you take plasma samples on a daily basis. He compared the two curves and when you take samples on a daily basis (slope 1) you can see a more gradual slope of decline in the curve. By looking at both slope 4 and slope 1 you can see the real decay curve for day 1 through day 10. By looking at the slope 2 decay curve of day 2 to 14 you can see it underestimates the rapdity of decay that you can see when you take daily samples and plot the changes for the first 6 days. To a greater extent it underestimates the even greater rapidity of decay you see in days 1 through 3 (slope 4). So, during days 1-3 you see the greatest rate of decay. During days 3-6 (slope 1) you see the next greatest rate of decay. After that the rate of decay slows.
Slope 1 is the decay rate curve when sampling is taken on a daily basis. As you can see, the curve is more gradual for slope 1, when sampling is not taken on a daily basis. Daily sampling more accurately depicts the slope of decline. Slope 4 is the decay rate over the first 3 days and is the steepest. Slope 3 depicts the decay from day 0 to day 10. Decay from day 3 to day 6 is the next steepest. and, You can see that the slope of day slows after that. Following are the actual decay rates.
Average Rates of Decline (Rate Constants -K) for 16 Subjects
K1-3
K1-6
K3-6
K2-14
So, Polis said that when looking at initial viral decay rates you must look to see if the decay rates are based on daily sampling and which days the rates apply to.
Polis concluded by saying that the rate constant of HIV decline in plasma over the first 3 days after starting therapy is much faster than has previously been reported. This rate constant is significantly greater than the rate constant from days 3-6. These rates of decline cannot be approximated with a rate over more than a few days. The rate constants for this 4-drug regimen are larger than reported rate constants over comparable periods for 1 and 3 drug regimens. This suggests that there is incomplete inhibition of HIV replication by 1 and 3 drug regimens. More than 3 of the available drugs are required to shut down HIV replication in the initial treatment period and prevent the emergence of resistant isolates. Since previous estimates of time to eradication of HIV infection were based on the assumption of complete inhibition of HIV replication, the time required for potential eradication of HIV infection is expected to be longer than previously calculated.