Durable HIV treatment benefit despite low-level viraemia: reassessing definitions of success or failure
Steven G. Deeks, MD for JAMA
Left untreated, human immunodeficiency virus (HIV) replicates at a rapid rate, with the eventual production of billions of new virus particles per day.
Given the propensity of HIV to mutate, the possibility exists that each newly produced virus contains at least 1 new mutation. Thus, from a darwinian perspective, ongoing viral replication in the presence of therapy should result in the rapid selection of drug resistance mutations and subsequent virologic rebound.
These basic principles have provided the theoretical context for the “hit hard” therapeutic approach to HIV disease. According to current treatment guidelines,1-3 complete viral suppression should be the goal of therapy. Once therapy is initiated, plasma viraemia, as measured by the concentration of viral RNA in plasma, should decrease to below the level of detection using the most sensitive assay available. [2, 3] Persistent viraemia suggests ongoing viral replication and treatment failure. The findings from 2 articles in this issue of JAMA raise questions about this conceptual framework, and based on data from the 2 studies, it may be argued that “complete” viral suppression may not be a prerequisite for durable treatment benefit.
Hermankova and colleagues  present studies involving patients who had achieved and maintained an undetectable plasma HIV RNA level (<50 copies/mL). Using sensitive techniques to amplify plasma viral RNA, virus was identified in plasma in 10 of 20 patients. Genotypic analysis of the isolated viral RNA revealed no evidence of new drug-associated mutations clearly related to the current regimen. The findings indicate that viral replication (defined by the release of virus into plasma) can be identified in patients apparently responding to combination therapy, but that this level of replication appears to be insufficient to select for drug resistance.
Havlir and colleagues  addressed a similar question in a completely different manner. Patients enrolled in a long-term treatment study were identified retrospectively and stratified into 2 groups: those whose plasma HIV RNA levels remained consistently below the level of detection (<50 copies/mL) and those whose plasma HIV RNA levels were transiently detectable (>50 copies/mL of RNA with a subsequent measured level of <50 copies/mL) and who were categorized as having intermittent viraemia.
Despite evidence of higher levels of viral replication in the latter group (although not uniformly statistically significant), both groups had similar rates of virologic failure. The occurrence of 2 consecutive HIV RNA levels greater than 200 copies/mL was considered virologic failure.
Before discussing the implications of these data, it is critical to assess whether the presence of HIV RNA in plasma signifies ongoing viral replication. Hermankova and colleagues4 suggest low-level viraemia may simply reflect the release of archived virus from long-lived cellular reservoirs into plasma and not necessarily continuous rounds of productive infection. The hypothesis that viral replication is ongoing in patients with low-level viraemia is supported by several independent lines of evidence. First, genetic evolution within viral envelope sequences has been observed in a small number of treated patients with transient viremia. [6, 7] Second, unintegrated viral DNA and unspliced viral messenger RNA, both markers of recent cellular infection, are commonly detected in patients even after several years of effective therapy. [7-10] Third, drug-specific mutations may emerge in cellular reservoirs of patients with undetectable or low-level plasma viremia.  Fourth, patients with low-level viraemia often have increasing amounts of replication-competent virus in cellular reservoirs.  Thus, when viewed as a whole, it appears that viral replication persists in patients with low-level viraemia, and that complete viral suppression is rarely achieved with current therapies.
If antiretroviral therapy is only partially effective at suppressing viral replication, why were drug resistance mutations and virologic failure observed to be uncommon in patients with low-level plasma viremia? [4, 5] One reason may relate to the complex interaction between drug resistance and viral replicative capacity (ie, viral “fitness”). As shown in vitro, [13, 14] the initial mutations associated with protease inhibitor resistance result in a virus that is unable to replicate efficiently, perhaps as a consequence of impaired protease function. Only with the accumulation of compensatory mutations does a replication-competent, drug-resistant virus emerge. The level of viral replication in patients with low-level plasma viraemia may be insufficient to select for these compensatory mutations.
Another plausible mechanism for the lack of virologic failure in patients with low-level viraemia relates to HIV-specific immunity. Progressive HIV disease is associated with the loss of HIV-specific T-cell immunity, perhaps as a result of the cytopathic effect of HIV on CD4 T cells.  Complete viral suppression with combination therapy leads to recovery of T-cell function but lack of sufficient antigenic exposure precludes the generation of effective anti-HIV immunity. Theoretically, partial suppression of viral replication to a low but nonzero level results in a level of viraemia sufficient to generate effective anti-HIV immunity but insufficient to deplete HIV-specific CD4 T cells. 
These considerations raise the question of a viral threshold. [4, 5] Is there a level of viral replication below which the degree of viral turnover is insufficient to allow for the emergence and establishment of a drug-resistant and replication-competent variant? Or is there a level of viral replication below which HIV-specific CD4 T cells are generated but not depleted? It is interesting in this regard that 1 patient (A57) in the report by Hermankova et al had a high level of viraemia (400-1000 copies/mL) and was the only patient whose virus evolved over time in ways clearly related to the current regimen.  Thus, it is possible that resistance and treatment failure may emerge only when the degree of viral replication is sufficiently high.
This concept of a viral threshold is more than an academic question, because if such a threshold exists, then the immediate goal of therapy should be to suppress the virus to below this level. Partially suppressive regimens that achieve this goal, are well tolerated, and preserve future options may be preferred to more potent regimens that are not as well tolerated and do not preserve future options. [1, 3] Thus, it is possible that using the most potent regimen possible to completely prevent all viral replication may cause more harm than benefit.
How then should patients with low-level plasma viraemia be managed? Is it necessary to revisit the basic principles upon which current therapeutic strategies are based and allow incomplete viral suppression? While it is reasonable to assume that no virus is preferred to a small amount of virus, it needs to be emphasized that the current approach to antiretroviral therapy (complete viral suppression whenever possible) is based largely on theory and current understanding of disease pathogenesis. [1-3] New insights into pathogenesis can and should have an immediate impact on how antiretroviral therapy is administered.
Before consideration is given to modifying therapy in patients with low-level viraemia, the patient’s commitment to therapy and level of adherence should be assessed. Intermittent viraemia may simply reflect intermittent nonadherence. Assuming that adherence is not the primary concern, clinicians have 1 of 4 therapeutic options: continue the current regimen with close observation; label the current regimen a failure and switch to a new regimen (“salvage therapy”); add a drug to the current regimen (“intensification”); or stop therapy altogether and reassess the need for therapy at a future date. The optimal approach will likely depend on each patient’s unique situation. The data from Hermankova et al and Havlir et al suggest that careful observation without treatment modification is certainly reasonable. The larger issue still to be addressed concerns circumstances in which careful observation is not a reasonable option for patients continuing therapy despite detectable viraemia.
Despite these intriguing findings, it is worthwhile to consider the limitations of the data from these 2 studies. First, the apparent lack of virologic failure and drug resistance in patients with low-level viraemia should be considered a preliminary observation. The median follow-up after the first episode of detectable viraemia in AIDS Clinical Trials Group (ACTG) 343 was only 46 weeks.  A relationship between low-level viraemia and subsequent virologic failure may become apparent with long-term observation. Similarly, much of the data regarding the lack of resistance in patients with low-level viraemia are cross-sectional.  Without prospective long-term observation, it is not possible to definitively conclude that a virus population, such as that involved in this study, is static.
Second, the current literature largely applies only to patients receiving long-term protease inhibitor therapy. Protease inhibitor-sparing regimens are now popular, particularly for treatment-naive patients. [2, 3] Because mutations associated with protease inhibitor resistance may have greater fitness costs than mutations associated with other therapeutic drug classes, it is possible that low-level viraemia with regimens that do not contain a protease inhibitor may be associated with rapid rates of virologic failure.
These limitations notwithstanding, the data from Hermankova et al and Havlir et al deserve careful consideration by clinicians and by those drafting treatment guidelines. It must now be accepted that current therapeutic regimens may not be able to completely suppress viral replication, even when used under optimal conditions. Fortunately, complete viral suppression does not appear to be a prerequisite for durable virologic and presumably, clinical benefit. Thus, categorizing the response to therapy as a dichotomy (undetectable or detectable, completely suppressed or incompletely suppressed, success or failure) may be misleading. Combination therapy is often only partially effective. The question now is how much viral suppression is required to achieve durable virologic, immunologic, and clinical benefit.
Source: Journal of the American Medical Association. Vol. 286 No. 2, July 11, 2001.
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