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Transmitted NNRTI Drug Resistance Results in Higher Viral Loads
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"Transmitted NNRTI Drug Resistance is Associated with Higher Steady state Viral Load Measures in Untreated Subjects with Primary HIV Infection"
Reported by Jules Levin
SUMMARY: Little found that baseline viral loads were significantly lower among patients with high-level genotypic resistance to one or more NRTIs (n=35) (-0.7 log, p<0.001) or protease inhibitors (PIs=24) (-0.5 log, p<0.05) (alone or in combination), BUT was significantly higher in those patients with resistance to NNRTIs (n=53) (+0.6 log), p<0.001) compared to subjects without transmitted drug resistance. Elevated viral loadsassociated with transmitted NNRTIresistance (genotypic and phenotypic) persisted after the acute stage of infection, but it was not associated with higher replication capacity, lower cd4 counts or higher decline rates in cd4 counts, although followup times were short (median 55 days). Higher viral loads associated with NNRTI resistance may contribute to the high frequency of transmitted NNRTI resistance. Baseline viral load predicts setpoint viral load. Although I don't recall Little mentioning this point, perhaps higher viral loads associated with NNRTI resistance may increase risk for HIV transmission during both the potentially more infectious acute stage of HIV infection & during chronic stage.
Susan Little (University of California, SD) presented results from this study in an oral talk at the XIII International HIV Drug Resistance Workshop (June 8-12, 2004, Tenerife, Canary Islands, Spain). Little provided this background information. Many drug resistance mutations impair protease and reverse transcriptase function and reduce replication capacity in vitro compared to wild-type virus in the absence of drug. The effect of transmitted drug resistance on the natural history of HIV infection is unknown. It is hypothesized that resistant virus would have impaired viral fitness and thus be associated with a lower steadt state viral load. Viral loads at presentation are comparable between recently infected subjects with drug resistant and sensitive virus.
The objective of this study is to compare the baseline & steady state viral loads among untreated patients with primary HIV infection with transmitted drug resistant or drug sensitive virus.
Baseline drug resistance was assessed for 340 treatment-naïve patients with primary HIV infection. ABI or TruGene sequence analysis of pol (RT & PR) was used to identify drug resistance mutations. Drug susceptibility and replication capacity (RC) were measured in vitro using patient-derived RT & PR sequence dor a subset of patients (n=53). Mathematical models were used to estimate setpoint: models allowed inclusionof individuals who chose to initiate therapy prior to reaching steady state viremia.
Little used a random effects model to obtain individual level estimates of viral "setpoint" that pools statistical power across patients. Rather than estimate time since infection, they control for time of follow-up. Nonlinear dynamics over time are modeled using slines that allow a flexible fit to the data. They control for total duration of follow-up and short-term fluctuations in viral loads using a first order continuous autoregressive structure.
At presentation the patients (n=340) had median age of 38; 94% men; 68% white non-hispanic; 4.8 log HIV RNA. The number of patients with high level resistance: NRTI 35; NNRTI 53; PI 24; multi-drug resistance (2-class) 21; MDR (3-class) 7.
RESULTS
Baseline viral load was the same in drug resistant to 1 or more classes (4.85 log) and patients with drug sensitivity (4.68 log), p=0.187.
However, baseline viral load was higher for patients (n=53) with genotypic resistance to one class of drugs being NNRTIs (+0.6 log) compared to wild-type virus (5.0 log), p<0.001. Patients with genotypic resistance to the one class of drugs being protease inhibitors (n=24) had lower viral load (-0.5 log) compared to wild-type virus (5.0 log), p<0.05. Patients with genotypic resistance to one class being NRTIs (n=35) had lower viral load (-0.7 log) compared to wild-type virus, p<0.001. Patients with genotypic resistance to NRTI+PI had lower baseline viral load than wild type by about 0.7 log compared to wild-type; patients with genotypic resistance to NRTI+NNRTI had lower baseline viral load than wild-type by about 0.4 log; patients with NNRTI+PI genotypic resistance had lower viral load by about 0.6 log compared to wild-type virus; and patients with multi-drug resistance (MDR) had higher viral load by about 0.3 log compared to wild-type.
SETPOINT VIRAL LOAD RELATIVE TO BASELINE RESISTANCE (by class)
With a follow-up of up to 200 days, setpoint viral load was 0.5 log higher for patients with NNRTI resistance compared to patients (n=129) with wild-type virus.
But, for patients with NRTI and/or PI resistance setpoint viral load was 0.8 log lower than for patients with wild-type virus (n=129). Follow-up is at least 200 days.
There was no association between replication capacity and viral setpoint, higher viral load setpoint did not result in higher replication capacity. For patients with EFV fold change IC50 <5 there was no effect on viral setpoint, but having EFV FC IC50 >10 resulted in higher viral setpoint.
Little summarized that VL at presentation is correlated with setpoint VL. The lower plasma VL setpoints associated with resistance to NRTI and PI are correlated with fitness cost of resistance mutations to these drugs.
The mechanism by which NNRTI-resistant virus results in higher VLs is unknown, but is not associated with higher pol RC: transmitted NNRTI-R variants demonstrate pol RC values comparable to WT virus. The plasma VL may appear comparable between recently infected subjects with drug resistant and drug sensitive virus because the positive VL effect of NNRTI resistance offsets the negative VL effect of NRTI and PI resistance.
Little reported in the abstract book that elevated viral loads associated with transmitted NNRTI resistance (genotypic and phenotypic) persisted after the acute phase of infection, but were not associated with a higher replication capacity, lower CD4 count, or higher rates of CD4 decline, although followup times were short (median followup 55 days). She added lower viral loads associated with resistance to NRTIs and PIs are consistent with a fitness cost of resistance mutations to these drugs. The mechanism by which NNRTIs result in higher viral loads is unknown, but is not associated with a higher replicative capacity. Higher viral loads associated with NNRTI resistance may contribute to the high frequency of transmitted NNRTI resistance.
Little went on to say that source subjects with higher viral loads and more fit virus who receive ARV therapy are more likely to select for drug resistance and more likely to transmit. Envelope may play the dominant role in selecting for the most "fit" transmissible variants. Envelope fitness is better demonstrated by whole genome fitness assays. This hypothesis suggests that NNRTI resistance in chronically infected subjects should be associated with higher steady state viral load levels.
Little suggested these clinical implications. These data do not address the use of ARV among subjects with transmitted drug resistance. Higher steady state VL levels warrant monitoring to determine:
--the natural history of NNRTI-resistant virus in untreated subjects;
--the consequences of acquired NNRTI-resistance in resource-limited settings where NNRTI-based therapies from the mainstay MTCT prevention & adult ARV treatment regimens;
--whether the higher VLs associated with NNRTI resistance may contribute to the high frequency of transmitted NNRTI resistance.
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