Frequency and significance of viral load blips

Once it has been suppressed below 50 copies/ml, viral load may sometimes rise above 50 copies/ml without indicating that treatment is failing. An isolated result above 50 copies/ml is called a 'blip' and may be the result of variability in the testing process. Although most studies have shown that even when several such blips occur, people who experience them are not at increased risk of treatment failure compared to people who maintain viral load below 50 copies/ml, others have found that viral load blips can be a signal that virological failure may well occur soon.

Viral load blips are more likely to be identified with more frequent viral load testing, probably occur in the majority of people at some point and may often be the result of laboratory error rather than genuine viral load rebound.

One study, which looked at 241 individuals receiving AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and indinavir (Crixivan) for a median of 84 weeks found that 40% experienced one viral load blip above 50 copies/ml, and 32 of these patients experienced two consecutive increases in viral load above 50 copies/ml before viral load fell back below 50 copies/ml. Forty-seven of the 97 individuals who experienced a viral load blip eventually recorded a viral load above 200 copies/ml before it returned to a level below 50 copies/ml. A viral load blip was not associated with a greater risk of long-term viral rebound in this study, and blips continued to occur in patients who had been receiving the regimen for up to five years (Havlir 2001). The same group also found that subsequent re-suppression of viral load did not appear to be associated with HIV-specific immune responses, suggesting that blips do not prime the immune system to exert progressively greater control over HIV.

The Frankfurt and Swiss HIV Cohort studies found that 41% of patients with at least two consecutive viral load measurements below 50 copies/ml went on to experience blips during the following year. Patients were monitored every four weeks, which may explain why such a high frequency of blips was picked up. The level to which viral load rose during the blip was correlated with the subsequent likelihood of treatment failure, unsurprisingly. Persistent viraemia that lay between 50 and 500 copies/ml during the study period was associated with a much greater risk of treatment failure, as was the number of blips above 50 copies/ml (Greub 2001).

Analysis from the American HIV Outpatients Study (HOPS) indicated that 61% of 448 patients maintained viral suppression over three and a half years of follow-up. Twenty-seven percent experienced a viral blip during that time, of which 78% were low-level blips (between 50-400 copies/ml). More than one blip was detected in 7% of patients. A transient blip did not lead to virological failure in any cases and was not associated with virological failure in the longer term. Blips were associated with a higher average CD4 count (Sklar 2001).

Blips are significantly less frequent in people who begin treatment within six months of infection (during primary infection), according to a comparison of 76 acutely infected patients and 47 chronically infected patients. Patients who began treatment in chronic infection had approximately twice as many viral blips as people first treated during primary infection (Di Mascio 2004).

In people with extensive prior treatment experience, blips have the same prognostic significance as in people on first-line treatment.

Researchers had previously been concerned that a viral blip above 50 copies/ml or 200 copies/ml would be more likely to signal the emergence of drug-resistant virus in patients with extensive drug resistance, and the subsequent failure of the regimen. However, an analysis of three studies (ACTG 398 and 359, salvage studies of amprenavir (Agenerase), abacavir (Ziagen), adefovir (Preveon) and efavirenz (Sustiva) with or without a second protease inhibitor, and nelfinavir (Viracept) and saquinavir (Invirase / Fortovase) versus ritonavir (Norvir)-boosted saquinavir plus adefovir, delavirdine (Rescriptor) or both found no relationship between single blips above 50 copies/ml and subsequent treatment failure (defined as two consecutive measurements above 50 copies/ml). Even when the threshold was raised to 500 copies/ml, viral load blips still failed to predict rebound above 1000 copies/ml after 38 weeks of follow up.

The authors of the study pointed out that the findings have implications for definitions of success or failure in future clinical trials. In particular, defining virologic failure as the occurrence of one or more viral load measurements above 50 copies/ml, after initial suppression to below 50 copies/ml, is probably too stringent (Havlir 2002).

These findings have been confirmed in later studies, examining the effects of blips in patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors, showing no association between treatment failure and viral load blips. However, patients with blips have been shown to have evidence of low-level viral replication below the limits of detection of conventional tests, typically 50 copies/ml. This has been linked to lower CD4 cell counts during treatment in these patients (Martinez 2005)

The pattern of viral load blips has also been examined. An Italian group, which looked at 123 patients followed over approximately two and half years, found that the mean level of viral load reached during a blip above 50 copies/ml was 165 copies/ml, and half of patients experienced blips no higher than 110 copies/ml. The average interval of testing in this cohort was every 31 days, and 77% of the cohort was found to have at least one blip during the follow up period when tested at this high frequency. On average, one in ten viral load measurements found a blip, but a relatively small number of patients within the group accounted for the majority of the blips detected.

However, the research group which conducted this study argued that the peak of viral load during a blip may be much higher, and that it is characterised by a rapid early increase to a level between 500 and 1000 copies/ml, followed by a slow second phase of decline below the limit of detection.

Blips did not become more frequent as the length of time on treatment increased, and the researchers suggested that the random pattern of viral load blips is more likely to reflect occasional changes in drug concentration driven by other factors such as dietary changes or concomitant medications, or intercurrent infections, rather than declining adherence or efficacy of treatment (Di Mascio 2002).

Variability in the accuracy of viral load assays may also contribute to the appearance of viral blips. Samples from 249 patients at London's Chelsea and Westminster Hospital with first viral load blips after suppression below 50 copies/ml were retested. Fifty-nine per cent were found to give an undetectable reading (below 50 copies/ml) when retested. The remainder still had HIV RNA levels above 50 copies/ml, and a confirmed blip was predictive of subsequent viral rebound above 400 copies/ml (Mazen 2002). Another British team has reported that 35% of patients experience at least one viral blip each year, but this only signals treatment failure in 8% of cases (Moore 2002).

This view was strengthened recently by the publication of a study analysing the detection of viral load blips in ten patients, concluding that they are usually the result of statistical fluctuations in the testing procedure rather than treatment failure. The investigators measured viral loads in blood samples from these patients every three days for four months in two separate laboratories. Nine of the patients experienced at least one viral load blip, with the majority being brief (a median of 2.5 days) and low in magnitude (a median of 79 copies/ml). Importantly, however, only one of the 18 blips was detected by both laboratories at the same time, suggesting that laboratory error and not poor adherence or any other factor, was responsible for the aberrant viral load measurement (Nettles 2005).

These findings underline the importance of continuing to monitor viral load rather than switching immediately after it increases above 50 copies/ml. However, the drugs being taken at the time will also be a factor in this decision: research using an ultrasensitive resistance test found that mutations associated with resistance to 3TC could already be detected at a median viral load of 76 copies/ml in six individuals experiencing a viral load blip on their first regimen (Cohen-Stuart 2001). Secondary protease mutations were also detected in several of those who developed 3TC resistance.

CD4 cell counts and viral load blips

Despite the tendency for studies to show no association between viral load blips and virological failure, a number of studies have seen links between blips and alterations in CD4 cell count, although with divergent conclusions.

One study showed greater CD4 count rises over four years in those people with a low frequency of blips compared to those who maintained viral load below 50 copies/ml (Hunt 2003). In this study, 423 patients were observed for up to four years, and their data included only if their viral load remained below 1000 copies/ml. Those with a low frequency of viral load measurements between 50 and 1000 copies/ml (<20%) gained a mean of 134 cells/mm³ compared with those whose viral load remained consistently below 50 copies/ml. The authors speculate that higher CD4 rises drive, rather than depend upon, blips since there is a larger pool of CD4 cells for HIV to infect.

However, another study came to the opposite conclusion. Forty-three patients on NNRTI-containing HAART with undetectable viral load for at least 18 months were analysed. Those with viral load blips above 50 copies/ml during the 18-month follow-up period had significantly lower CD4 counts at 12 and 18 months after starting the regimen (Martinez 2005).

No link between adherence and blips

The majority of studies have failed to show any link between adherence and the occurrence of viral load blips. For example, investigators from Los Angeles assessed the relationship between adherence and transient blips in viral load in 128 HAART-treated patients. A total of 28 blips were observed in the study. Adherence in the month before the last undetectable viral load before the blip was 86%, 84% in the month of the blip, and 80% in the month after the blip when viral load returned to normal. Although such levels of adherence would be regarded as suboptimal, they were higher than the adherence seen in control patients who maintained an undetectable viral load for a three-month period. When adherence was compared on a weekly basis between blippers and control patients, it was found that, once again, individuals experiencing transient increases in viral load had higher adherence. The investigators concluded that there was no evidence that adherence lapses or variance in dose timing are associated with blips (Miller 2003).

This conclusion has been supported in later studies, which have shown that drug levels before, during and after viral load blips are often greater than the minimum drug concentrations recommended (Martinez 2005; Nettles 2005).

References

Cohen Stuart JWT et al. Transient relapses ("blips") of plasma HIV RNA levels during HAART are associated with drug resistance. J Acquir Immune Defic Syndr 28: 105-113, 2001.

DiMascio M et al. Viral blip dynamics during HAART. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 94, 2002.

Di Mascio M et al. Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early human immunodeficiency virus type 1 infection. J Virol 78): 10566-10573, 2004.

Greub G et al. Low level HIV viral rebound and blips in patients receiving potent antiretroviral therapy. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 522, 2001.

Havlir D et al. Prevalence and predictive value of intermittent viraemia with combination HIV therapy. JAMA 286: 171-179, 2001.

Hunt PW et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 17: 1907-1915, 2003

Havlir D et al. Are episodes of transient viraemia ("blips" in HIV RNA) predictive of virologic failure in heavily treatment-experienced patients? Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 93, 2002.

Martinez V et al. HIV-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS 19: 1065-1069, 2005.

Mazen Y et al. Evidence of low level viral replication (<50 copies/ml) predicts eventual virological failure. Eighth Annual Conference of the British HIV Association, York, abstract 011, 2002.

Miller LG et al. Episodes of transient HIV viraemia (blips) are not associated with drops in medication adherence. Antivir Ther 8: S396, 2003.

Moore AL et al. Raised viral load in patients with viral suppression on highly active antiretroviral therapy: transient increase or treatment failure? AIDS 16: 615-618, 2002.

Nettles RE et al. Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. JAMA 293: 817-829, 2005.

Ramratnam B et al. Antiretroviral intensification accelerates the decay of the latent reservoir of HIV-1 but does not eliminate ongoing virus replication. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 502, 2001.

Sklar P et al. Prevalence and clinical correlates of HIV viraemia ('blips') in patients with previous suppression below the limits of quantification. AIDS 16: 2035-2041, 2002.