At the Resistance Workshop in the Summer of 2000, Diane Havlir from UCSD reported data on the likelihood of viral load "blips" leading to viral failure. In her study, treatment-naïve patients received indinavir/3TC/AZT and had well suppressed viral load (<50 copies/ml). The patients were only followed for 84 weeks. Viral load blips were defined as >50 copies/ml and failure was defined as 2 tests >200 copies/ml. In essence, she found that having a couple of viral load tests of 75 copies/ml did not lead to viral load failure. It may be relevant to bear in mind that the PI used in this study was indinavir, which has a relatively higher barrier for failure. In other words, you need a number of mutations to fail indinavir. There were 241 patients in this study. Havlir concluded that in this study population, where they saw 343 intermittent blips, the blips did not lead to viral rebound within the time frame they looked at (84 weeks): 9/96 (9.3%) of patients with intermittent viremia had viral rebound; 20/145 (13.8%) with viral suppression (without blips) had viral rebound.

At the recent Retrovirus Conference, Greub and colleagues reported on a large group of patients with "low-level" viral load of up to 500 copies/ml, which is higher than the "blips" in the Havlir study. In this study, patients had <50 copies/ml. In essence, Greub found that 2 or more consecutive blips of viral load of 100-500 could lead to viral load rebound over 500 copies/ml. Importantly, Greub found that patients who changed therapy after the third viral load blip were more likely (2.65 times) to stay <50 copies/ml than people who did not change therapy. Greub also found that people who had ART experience prior to their current HAART regimen were more likely to experience viral load rebound following 3 consecutive blips (100-500), but this was not statistically significant.

Greub found that the more viral load blips a patient experienced to 101-500 copies/ml, the more likely they were to experience viral load failure to >500 copies/ml: patients with 2 viral load values 51-500 increased likelihood of viral failure. When 2 consecutive tests were 51-500, only 40%-70% went back down to <50 copies/ml. The higher the viral load went to the more likely viral failure was to occur. For example, if viral load values were 51-100 (n=118), 70% went back down to <50 copies, and about 20% experienced viral load failure to >500 copies/ml. Among patients with viral load blips to 101-300 (n=118), about 45% went back down to <50 copies/ml, and about 45% experienced viral load failure to >500 copies/ml. For patients whose viral load blipped to 301-500 (n=17) about 53% went back down to <50 copies/ml, and about 30% experienced viral load failure.

The likelihood of going back down to <50 copies/ml was less in the group experiencing 3 low-level rebounds than in individuals with 2 consecutive values 51-500. When values were 301-500, 55% experienced viral load failure to >500 copies/ml. When viral load values were 101-300 40% experienced viral load failure. And, 5% to 20% of these patients had their viral load remain between 51-500, they did not go back down to <50 copies/ml. If the third value was 301-500, patients had an 80% less chance of getting back to <50 copies/ml (p=0.004), compared to if the third value was 51-100. If the third value was 101-300, patients had a 60% (p=0.04) reduced chance of going back down to <50 copies/ml. In patients who had a viral load of 51-500 but then went back down to <50 they were about 2 times more likely to experience failure (>500) compared to patients with consistent viral loads <50. But, patients who had sustained viral loads 51-500 who were not able to get back down to <50 copies were 5 times more likely to experience viral load failure.

Greub concluded the majority of low level viral rebound resolve spontaneously. But, spontaneous resolution is associated with a modest increase in risk for subsequent failure. The risk of viral failure increases with repeated observations of values 51-500, and with the level of the most recent viral load within this range. Grueb did not reveal what the various regimens were that patients were taking, as opposed to the Havlir study in which everyone was receiving an indinavir regimen.

Intensification & Potent HAART May Prevent Viral Rebound
In abstract 404, B. Ramratnam reports findings suggesting that increasing the potency of HAART with intensification decreases the frequency of intermittent viremia. This suggests that using a more potent HAART regimen may decrease the risk of viral failure over time. In this study, the investigators intensified HAART with abacavir (n=4) or abacavir+efavirenz (n=1), and found this reduced the incidence of intermittent viremia compared to a group of 5 control patients. This also suggests that using a more potent regimen from the initiation of therapy may prevent viral failure over the course of time on therapy. If a patient is experiencing viral load "blips" or low level rebound, doctor & patient should discuss the best approach to addressing concerns in preventing viral load failure. Potential solutions could be intensification or changing regimen. In addition, adherence problems could be the cause of the blips or low level rebound. In which case, this should be discussed as a separate issue.

Laboratory testing errors or inapprorpriate handling of samples can cause a random error in reporting of viral load test results. Testing should be repeated if viral load is detectable after being undetectable. Patients in this study were initially receiving AZT/3TC plus nelfinavir or ritonavir+saquinavir. Both the control group & the patients intensifying had comparable baseline characteristics. Intensification was added after a mean of 34 months and the mean duration of intensification was 14 months.

Prior to intensification there was no statistically significant difference in the median frequency of intermittent viremia (viral load blips or low level rebound) between the control & intensification groups (3.3 per year vs 2.8 per year). When compared to the control group, the intensification patients had a more accelerated decay rate of virus in the latent reservoir (31 months vs 10 months) after intensification. The frequency of intermittent viremia per year decreased in 4/5 patients following intensification (2.4 per year vs 0.8 per year).

The authors concluded that ongoing virus replication during HAART is due in part to inadequate potency of HAART. And, although intensification improves potency & decreases intermittent viremia, HIV replication is still not completely suppressed