The Buzz: The Disconnect Syndrome—A Controversial Dilemma

by Daniel S. Berger, MD

It is not uncommon for patients to have increasing viral loads while on treatment. However, patients can have a “disconnect”: they may have detectable viral load and yet still be deriving benefit from their “failing” regimen. Their CD4 T-cell counts are not plummeting and are often still increasing. Overall, their general health remains well. These individuals continue with their daily life and routine, without any clinical consequences. The discordance between T-cells and viral load is often referred to as the Disconnect Syndrome. It is not a new disease, just an observation of the difference between viral and immunologic lab measures (viral load test vs. T-cell count).

Usually, patients on antiretroviral treatment demonstrate a drop in viral load (often to undetectable levels) while improving their immune system with an accompanying T-cell rise. The disconnect syndrome of rising viral load along with stable or improving immune markers such as T-cells is more common among patients who have a longer history of being on several antiviral regimens. Viral drug resistance, which is associated with decreased efficacy of treatment, is not uncommon for these patients. They have fewer options than patients on their very first antiviral regimen.

Usually, patients with an overtly failing regimen need to undergo changes in their antiviral treatment. This is a basic tenet of care for the chronically HIV-infected individual. This is done to halt progression of HIV disease, to preserve immune system function and to avoid further resistance development.

The Dilemma

However, in the unique situation of the disconnect syndrome, a question may be posed: Does every discordant patient merit a change in antiretroviral therapy? Sometimes a clinician may consider the fact that the viral load (HIV RNA) has not reached levels high enough to merit exposing their patient to further antiretroviral drugs. Many patients in this disconnect situation have already been exposed to multiple antiviral agents. Since undetectability does not mean one is cured, one must weigh the risks and benefits of modifying the regimen in order to lower the viral load.

The discordance between T-cells and viral load is often referred to as the Disconnect Syndrome.

There exists a dilemma when considering altering a regimen in this unique situation. New antivirals to reduce viral load may forestall the emergence of more resistance mutations. On the other hand, one must consider that changing to yet another new regimen will reduce options for the future. This is critical in situations where new options for specific and heavily treated patients are not plentiful. Realistically, formulating a regimen for a heavily treated patient is often challenging because of the presence of multiple resistance mutations. Therefore the likelihood or durability of fully suppressing viral load with a new regimen is in question.

Thus management of patients who are highly treatment experienced and who have a discordant response is a real quandary. It is believed that continuing the failing regimen further selects for resistance mutations, therefore further limiting future therapeutic options. But when there is stability in the elevated viral load together with increasing CD4 counts going yet higher, patients are obviously still deriving clinical benefit. No large prospective clinical trial has been performed to help provide insight for this situation.

The Infamous 184V Mutation

Patients who manifest a disconnect do not have undetectable viral loads, so by definition they generally have mutations or resistance. These mutations occur in the virus itself, usually in response to drugs used against it. The mutations in turn allow HIV to develop drug resistance. This means what it says: HIV can resist the drug or drugs, therefore making the medications less effective in fighting the virus.

Individuals with a discordant response usually exhibit high numbers of mutations against the nucleoside drug class, which often includes the M184V mutation. This specific mutation of M184V (refers to a change in the amino acid switch in HIV’s viral gene strand) is most known for being the tell-tale sign of 3TC (Epivir) resistance. But having the 184V resistance mutation has also been associated with sustained responses to antivirals, confirmed in several studies. Generally, cross-resistance would be a concern. Mutations that resist one drug may also resist another, especially one in the same drug class. This may lower the efficacy of new drugs which a patient has never taken before. However, if one has the 184V, without other nucleoside mutations, it does not confer resistance to other nucleosides such as ddI, d4T, ddC or abacavir (Videx, Zerit, Hivid or Ziagen). Also, the M184V seems to result in re-sensitization of the virus to AZT (Retrovir) in patients who previously developed resistance to AZT. Finally, the presence of 184V in highly experienced patients is associated with a better antiviral response to the newest HIV agent, tenofovir (Viread).

Mechanisms & Theories

A complex interaction of viral and other factors are at play in discordant responses to HAART (highly active antiretroviral therapy). These include drug resistance mutations, replicative capacity and immunologic aspects.

The initial status of the patient, including CD4 T-cell count and presence of the 184V mutation before antiviral treatment, is predictive of responses to HAART and development of discordance. A lower CD4 count is more predictive of discordance. The more damaged one’s immune system has become prior to treatment, the more difficult it may be for the immune system to assist in suppressing viral load later.

Often, T-cells remain stable or rise despite not obtaining optimally suppressed viral loads because HIV (though resistant) becomes weakened by antiviral drugs, impairing its ability to replicate. Thus the immune system is able to continue its restoration process. In other words, the antiviral treatments cause a decreased replicative capacity of the virus. In fact, there is a firm relationship between the high numbers of mutations and decreased replicative capacity of virus from people with discordance.

The disconnect syndrome can be explained in an alternative way. The M184V and other mutations may result in the virus becoming less fit than wild type. (Wild type is virus that has not mutated, seen usually in non-treated individuals.) The less fit the virus, the less able it is to overcome the effects of other antivirals. Additionally, the reverse transcriptase enzyme, which HIV uses to reproduce itself, is also crippled despite the presence of resistance, and thus becomes less able to help make copies of the virus. HIV can not process its DNA strand (viral gene), and is therefore unable to replicate.

Finally, development of increased mutations does not interfere with immune recovery during HAART. Measured by immune cell proliferation and response to interleukin 15 (a specific cytokine, protein produced by immune cells used for research purposes to measure immune response), researchers found that discordant patients had responses similar to fully respondant patients (Stephano Vella and colleagues, 9th Retroviruses Conference, Seattle, February 2002).

Conclusion

Without attempting to advise whether patients in a disconnect situation should change or continue their treatment, the questions invoked here are placed on the table. The presence of primary resistance mutations can oddly enough be associated with the provision of some beneficial effects. However, developing resistance or discordance is not the preferred outcome. When a patient is facing this discordant predicament, the next path may not be always clear. Phenomena are occurring in the disconnect syndrome that are below the surface. A patient’s decisions are often complicated by various confounding issues.

This is compounded by the fact that data regarding the long-term outlook of patients continuing in this disconnect pattern is sorely lacking. Some researchers have demonstrated higher progression rates while others concluded that the immunologic deterioration is delayed by an average of three years (Stephen Deeks and colleagues, University of California at San Francisco). However large trials of “disconnected” patients who continue to maintain good clinical immunologic response to HAART for a specified duration would provide greater insight into the risks. It seems that patients manifesting a disconnect who continue their treatment are stable clinically and not developing opportunistic infections. However, with the ongoing epidemic of resistance, it would be helpful to understand what it all means to a patient’s health and longevity.

Daniel S. Berger, MD is Medical Director for NorthStar Healthcare; Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDS Infosource (www.aidsinfosource.com). He also serves as medical consultant and columnist for Positively Aware. Inquiries are welcomed by Dr Berger; he can be reached at DSBergerMD@aol.com or 773.296.2400.

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