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CROI 2012: How Detrimental Is Low but Detectable HIV Viral Load?

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Having low but detectable viral load is associated with problems including cardiovascular disease and cancer in people with HIV, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last month in Seattle.

Effective combination antiretroviral therapy (ART) reduces HIV RNA levels and dramatically lowers the risk of AIDS-related opportunistic infections. But HIV positive people on ART still have higher rates of a variety of non-AIDS conditions. The consequences of low-level residual virus among people on ART are not yet fully understood.

Very Low Viral Load

Giuliana Cologni and colleagues from Ospedali Riuniti in Bergamo, Italy (abstract 348)conducted a study to assess whether low-level viral load in patients on stable ART could predict the risk of virological failure.

This prospective cohort study included 1214 participants who had been on stable ART for an average of about 8 years. About three-quarters were men and the average age was 46 years. At study entry all participants had confirmed viral load < 50 copies/mL and the mean baseline CD4 T-cell count was high, at 611 cells/mm3.

Participants underwent viral load monitoring every 4 months for 1 year using a highly sensitive PCR test with a lower limit of detection of 3 copies/mL.

Results

  • At baseline 71.5% of participants had viral load < 3 copies/mL (that is, undetectable even with the sensitive test), while the rest had levels between 3 and 50 copies/mL.
  • Over the 12-month observation period, there were 43 cases (3.6%) of virological failure -- defined as confirmed viral load > 50 copies/mL -- and 31 cases (2.6%) of viral rebound > 200 copies/mL.
  • 3.2% of people experienced ART failure within 4 months of having a measurable low-level viral load, compared with 0.4% of patients with consistently < 3 copies/mL, a significant difference (P < 0.0001).
  • A similar pattern was seen when using the 200 copies/mL cut-off for virological failure (2.0% vs 0.4%, respectively).
  • The risk of viral rebound was 1.2% among patients with consistently undetectable viral load, 1.9% among people with variable viral load (sometimes detectable, sometimes not), and 34.2% among patients with HIV RNA levels consistently between 3 and 50 copies/mL.
  • Genotypic testing revealed that 13 patients (30.2% of cases) had drug-resistance mutations that could compromise the efficacy of their current ART regimen.
  • Patients treated with a NNRTI-based regimen were more likely to maintain viral load <3 copies/mL throughout the study than those using either boosted or non-boosted protease inhibitors (45.2%, 33.1%, and 29.8%, respectively; P < 0.0001).

"According to current treatment guidelines, an HIV RNA level < 50 copies/mL is the goal of [ART]. Our data suggest that this goal may need to be revised to a lower cut-off value," the researchers suggested.

"A [low-level viral load] >3 copies/mL is linked to a significant increment of risk of virological failure and predisposes to genotypic resistance," they continued. "Clinical management of patients with measurable [low-level viral load] should be tailored to better evaluate, over time, the risk of failure and to limit its consequences."

Viral Load 20-50 Copies/mL

Charlotte Charpentier from Bichat-Claude Bernard Hospital in Paris and colleagues (abstract 349) conducted a similar analysis, but looked at somewhat higher viral loads, between 20 and 50 copies/mL.

The researchers previously determined that 5.8% of their patients on stable ART had persistent low-level viral load. This study compared outcomes among 413 people with consistent HIV RNA < 20 copies/mL and 25 people with 20-50 copies/mL who had at least 3 HIV RNA measurements during 1 year of follow-up.

Results

  • Over 1 year of follow-up, 65% of the undetectable group had all viral load tests < 20 copies/mL, compared to 44% of those with prior low-level viral load, a difference with borderline significance (P= 0.05).
  • 2% of undetectable participants had 2 HIV RNA measurements > 50 copies/mL during follow-up, compared with 16% in the low-level viral load group, which was a significant difference (P= 0.002).
  • However, 4% of undetectable participants experienced virological failure during follow-up -- defined as 2 successivemeasurements > 50 copies/mL -- compared with 8% of those with low-level viral load, which did not reach significance (P= 0.32).
  • Median HIV RNA levels at the time of virological failure were 250 and 88 copies/mL, respectively.
  • 29% of people in the undetectable group and 32% of patients in the low-level viral load group had a single isolated viral load blip > 50 copies, again not significant.
  • There was also no difference in "blip ratio," or number of viral loads > 50 copies/mL divided by number of measurements.

"The 1-year follow up of patients with [low-level viral load] did not evidence a higher rate of virological failure than in patients with all HIV-1 RNA values < 20 copies/mL," the research team concluded. "[Low-level viral load] seems to be a transient and dynamic phenomenon with about 40% of patients shifting from [low-level viral load] status to complete viral load suppression."

Cardiovascular Risk and Lymphoma

The 2 studies of virological failure reached conflicting conclusions about the hazards of low-level HIV. But what about clinical outcomes?

Anders Boydand fellow investigators with the Collaboration in HIV, Inflammation and Cardiovascular Disease (abstract 803) looked at inflammation markers and carotid artery intima media thickness (IMT) in people on ART with low viral load. IMT is a measure of thickening of artery walls indicating atherosclerosis, which can lead to heart attacks and strokes.

This analysis included 47 HIV positive men, with an average age of about 42 years, who had never smoked. The average duration of HIV infection was about 12 years; all had been on ART for at least 4 years and had plasma viral load < 40 copies/mL. Using an ultra-sensitive test, they were classified as having HIV RNA of 1-40 copies/mL or < 1 copy/mL, both during a single visit and longitudinally based on stored samples collected a year before.

Nearly one-third of participants (30%) had low-level residual viral load, while 70% had undetectable viral load using even the sensitive test. Levels of pro-inflammatory biomarkers tended to be higher among patients with residual versus ultra-low viral load, but the difference only reached statistical significance for IL-18 (not for CRP, IL-6, or D-dimer). Patients with residual HIV also tended to have higher levels of anti-inflammatory markers, but only IL-10 was significant.

Common carotid artery IMT was significantly higher among people with low-level viral load than among those with complete viral suppression. But total carotid IMT (measured at 3 sites) was higher only based on longitudinal (not single-visit) viral loads.

Finally, Chad Achenbach from Northwestern University and colleagues (abstract 131) looked at incidence and predictors of non-Hodgkin lymphoma (NHL) among people who maintain virological suppression on ART.

This analysis included more than 10,000 HIV positive patients enrolled in the CFAR Network of Clinical Systems at 7 sites in U.S. Most (80%) were men and 53% were white. All had started combination ART and achieved HIV RNA suppression < 500 copies/mL within 1 year; 85% achieved viral loads < 50 copies/mL. While current CD4 counts were relatively good, many had previously experienced advanced immune impairment, with a nadir (lowest-ever) level of 180 cells/mm3.

A total of 76 patients developed NHL after virological suppression and 35 did so while suppressed, yielding incidence rates of 15 and 14 cases per 10,000 person-years, respectively. As seen in prior studies, NHL incidence was higher among people with lower nadir CD4 counts (19 and 12 cases during viral suppression per 10,000 person-years, respectively, among people with < 50 and > 50 cells/mm3).

After adjusting for age, race, transmission route, and nadir CD4 count, other factors independently associated with higher NHL incidence during viral suppression included current CD4 cell count and low HIV viral load between 50 and 500 copies/mL.

"[F]urther reduction of NHL incidence will depend on early detection of HIV infection, prompt initiation of ART at higher CD4 cell counts, and maximal sustained HIV suppression," the researchers concluded. 

4/3/2012

References

G Cologni, A Callegaro, C Bernardini, et al. Low-level Viremia during HAART. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 348.

C Charpentier, R Landman, C Laouenan, et al. Virological Outcome of Patients Displaying Persistent Low-level Viremia Comprised between 20 and 50 Copies/mL. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 349.

A Boyd, J-L Meynard, L Morand-Joubert, et al. Intima Media Thickness Is Associated with Residual Plasma Viremia in Treated Patients with Controlled HIV Infection. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 803.

C Achenbach, S Cole, J Kahn, et al. Incidence and Predictors of NHL among HIV+ Patients on Suppressive ART. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 131.