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Reducing Viral load to Very Low and Keeping CD4s High Despite Viral Load Failure
Reported by Jules Levin
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In today's morning session there were several presentations of interest. I will highlight in this report two which I think are of particular clinical significance or interest. It's important to bear in mind that the Resistance Workshop is a gathering of the leading clinical and resistance researchers. At this meeting highly technical studies are presented and the findings are discussed among all the researchers. Oftentimes the study findings are not well understood in the context of how to use them in treating patients. For example, in the study discussed below from Diane Havlir she reports finding that if patients have <50 copies but above 2.5 copies you can reduce viral load further by adding abacavir to the regimen. Is this a clinically significant finding that is relevant to current practice in treating HIV -infected patients? It's not because we have no evidence that reducing viral load further is of real help in staying undetectable for longer or in other ways. At this meeting leading resistance researchers struggle with trying to understand the results of these studies and also struggle with trying to understand resistance to HIV drugs. In my opinion, HIV drug resistance has many aspects that are not understood. It is like looking into a deep black hole where you can only see several feet in front of you.
One of the subjects that came up today is the usefulness of resistance testing. Understanding resistance and the results from resistance testing is very complex. Many treating physicians do not understand resistance testing, how to interpret the results, and therefore how to use the results. One of the aspects of resistance testing discussed today is that testing results from commercially available tests do not detect resistance mutations that are present at low levels. Without realizing this wrong treatment decisions can be made. Using a patient's treatment history may be more helpful than resistance testing for certain doctors. However, to a leading resistance expert drug treatment history and genotypic and phenotypic resistance testing may all contribute to making a better treatment decision.
Still, perhaps it is time to consider using resistance testing for treatment-naive patients and in phase 2 and phase 3 clinical studies for treatment-naive patients. Since the incidence is increasing of patients being infected with drug resistant virus, resistance testing may help in choosing a patient's initial regimen and in understanding the results from clinical drug studies in treatment-naive patients.
Transmission of Drug Resistant HIV Exhibiting Lower Replication capacity is Associated with Higher CD4 Cell Counts (Robert Grant, UCSF)
As background Grant referred to a Steve Deeks study showing CD4 counts are partially preserved when virus is detectable and drug resistance is detectable. This is the experience of a number of doctors, that CD4 counts may remain elevated even if viral load becomes detectable for chronically infected patients.
Grant reported on a study of 130 patients diagnosed with recent HIV-infection between 1996 and 2001. They were treatment-naive. The aim of this study was to determine if drug resistant HIV in drug naive patients is also associated with higher CD4 counts, reduced replication capacity and lower viral load. In other words, Grant is trying to understand why patients who fail HAART still maintain increased CD4 counts above the level before therapy was started.
He referred to a cohort of 225 patients from SF diagnosed with recent HIV infection between 1996-2001 of whom 16% had NRTI resistance, 8% had NNRTI resistance, and 5.8% had PI resistance. This data is to underscore that increasingly newly infected patients are getting infected with HIV drug resistance. After viral load rebound patients have been found to still maintain on average an increase of 100 CD4s above their baseline CD4 count for a period of time.
Grant reported that patients had significantly higher CD4 counts if they had genotypic evidence of drug resistance or decreased replication capacity. Replication capacity, the ability of the virus to reproduce itself well and quickly, was significantly lower in patients with genotypic protease inhibitor resistance compared to patients with no resistance, and trended lower in patients with NRTI and NNRTI resistance. Grant reported finding 3TC resistance significantly reduced replication capacity. Overall, replication capacity varied greatly between patients, from 1% to 113%. Patients who had lower replication capacity tended to be more sensitive to protease inhibitors (defined as IC50 fold change <0.4 for any PI). Grant concluded that CD4 counts were higher in drug-naive patients recently infected with drug resistant HIV exhibiting reduced replication capacity, especially if PI resistance was present. In other words, recently infected patients who had HIV drug resistance can have higher CD4 counts and this may be due to decreased replication capacity which may be due to protease inhibitor resistance. To restate, PI resistance (or perhaps resistance to NRTIs or NNRTIs) may cause reduced replication capacity which may in turn lead to higher CD4 counts.
Grant concluded from this study that lower replication capacity is associated with higher CD4 counts in both drug naive and experienced patients, when drug resistance is present and when virus is wild-type; although when drug resistance is present reduced replication capacity appears to increase CD4 count more. Thes findings were independent of the duration of infection, no matter how long a patient was infected with HIV.
In other words, Grant is saying that if a person has a viral rebound from undetectable but CD4s stay elevated this may be due to reduced replication capacity and HIV drug resistance, particularly PI resistance. I think Grant also said that a patient may also have a lower viral load along with the reduced replication capacity.
Productive Infection Maintains A Dynamic Steady State of Residual Viremia in Patients Treated with Suppressive Antiretroviral Therapy for 5 Years ((Diane Havlir, UCSD)
In this study Havlir found that if a patient had less than 50 copies (between 2.5 & 30 copies) for 5 years adding abacavir to regimen reduced viral load 4-fold. She concluded that this means that the HIV present in blood even if patient is <50 copies is not from the latently infected memory cells but from ongoing or active reproducing cells. The implication is that perhaps by reducing viral load to as low as possible the risk of eventual viral load rebound is reduced. This is speculative as there is no evidence to date that having less then 2 copies is less likely to lead to viral rebound than having 30-50 copies. And the adding of an additional drug to regimen has baggage, more potential side effects, greater adherence demands.
We know that even when patients have <50 copies of viral load there is ongoing virus present. But we are uncertain where this virus is coming from. Is it coming from ongoing viral replication or is it leaking ongoingly and slowly from latently infected cells. This study was conducted to try to understand where the ongoing viremia is coming from and what may occur if viral load is reduced further in patients with <50 copies/ml.
14 intensely monitored patients treated with indinavir plus efavirenz only and who had <50 copies/ml for >5 years were studied. But viral load was detectable using a sensitive assay with a level of detection of <2.5 copies/ml. There were no known treatment interruptions, during which HIV viral load can rebound and drug resistance could develop. HIV DNA was measured using the HIV DNA Roche assay. Average Cd4 count was 260. Average viral load was close to 100,000 copies/ml (4.9 log). On average patients had 10 months of prior NRTI experience.
Here's a tidbit of data you not find of interest. If its not meaningful to you, just skip over it. During phase 1 of viral load decline after starting therapy, HIV half-life was 1.2 days (+/- .8), and duration was 2.5 days (2.1-4.9). During phase 2 of viral load decline viral load declined more slowly, as expected: half-life 24 (+/- 16) days. Duration of this phase was 68 days (33-260).
Havlir found that patients reached a steady state of viral load after 6-9 months, most by 6 months. And it stayed at that level for 5 years. Patients reduced their viral load to from 2.5 copies/ml to 30 copies/ml, and it varied between patients. And it stayed at the same level for 5 years. Havlir found that the patient's baseline HIV DNA level predicted the level of HIV viral load a patient leveled off at, but this was not predictable by HIV RNA, baseline CD4, or time it took to reach <50 copies/ml.
During the second part of this study Havlir offered patients to intensify their regimen with abacavir (Ziagen). When adding abacavir CD4 count was 600 compared to 756 in patients declining adding abacavir. In the 9 patients who intensified (1 added abacavir, 1 added ritonavir) HIV RNA levels declined rapidly. The estimated half-life of an infected cell was 3.5 days. Consistent with a decrease in viral replication there was a decrease in activated memory cells, and a reduction in gamma interferon production to HIV gag and p24 antigen. There were no virological or immunologic changes observed in the patients that did not ad abacavir.
6 of 6 patients with detecable viral load (>2.5 copies/ml) at week 0 experienced at least a two-fold decrease in viral load (average decrease 4-fold or .6 log). Only I of 9 patients has a decrease in HIV DNA.
So, what does this mean? Havlir concluded that even after years of highly suppressive therapy adding abacavir (or RTV) lead to rapid decline in viral load, and she feels this suggests that productive ongoing viral replication contributes to residual viremia. She also found addition of abacavir & lower viral load resulted in immune activation.
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