Ask the Experts - Do Data Support Treating Early HIV Infection?
Ask the Experts - Do Data Support Treating Early HIV Infection?
The most recent HAART guidelines, although somewhat more conservative in terms of when to start therapy, still say it should be offered for patients known to have seroconverted within the past 6 months. How compelling are the data that support this? I'm thinking specifically of patients with excellent CD4+ cell counts (greater than 500 cells/mm), measurable viral loads, and without symptoms (ie, not acutely seroconverting).
Matthew Lim, MD
The recent change in the Department of Health and Human Services (DHHS) HIV treatment guidelines reflect a growing uncertainty as to the correct time to start antiretroviral therapy. There is ample evidence that untreated HIV infection progresses fairly relentlessly in most infected individuals and that this progression can be predicted by the rate of decline in CD4+ cell count and by the plasma HIV-1 RNA level. There is equally compelling evidence that treating HIV infection stops this progression, preventing loss of immunity, AIDS, and death. Thus, it makes perfect sense to argue that therapy should be given early in infection. However, delaying therapy until later in the disease process -- but still before the onset of clinically apparent immunodeficiency -- seems to be effective as well; the majority of treated patients recover lost immune function, and this delay defers side effects and potentially serious toxicities from drugs. Thus, there is sufficient uncertainty about the true risk:benefit equation for the DHHS panel to decide not to make a firm recommendation for patients with CD4+ cell counts greater than 350 cells/mm and relatively low plasma HIV-1 RNA levels. Instead, the guidelines now say that experts differ: some would and some would not start therapy.
It is important to note that these recommendations do not state that starting treatment at higher CD4+ cell counts is wrong or unethical. Indeed, there may be situations in which treating at higher levels is appropriate -- for example, symptomatic patients or those with rapidly falling CD4+ cell counts, very high viral loads, or both. Acute HIV infection is another setting in which therapy should be seriously considered, irrespective of the CD4+ cell count. Studies of antiretroviral therapy initiated shortly after acute HIV infection (usually within 3-6 months) suggest that complete suppression of plasma viremia is associated with preservation of specific anti-HIV immune responses, especially both CD4+ and CD8+ T-lymphocyte responses. This finding has, in turn, led to the hypothesis that a course of antiretroviral therapy during acute HIV infection might result in better immune control of HIV replication and a lower viral set-point if therapy is discontinued, with better long-term outcome. Indeed, results from a small number of patients who received early treatment after acute seroconversion and then participated in studies of structured treatment interruption (STI) indicate that, in some patients, it may be possible to maintain suppression of viral replication after antiretroviral therapy is withdrawn.
It is important to view these experiments in context. Relatively small numbers of patients have been studied, and to date, all studies of aggressive therapy during primary infection have been uncontrolled. In the absence of therapy, most patients with early HIV infection will have relatively low viral loads and a relatively slow progression to immunodeficiency. Thus, without a randomized controlled trial, it is impossible to say that aggressive early therapy is beneficial in terms of long-term management of HIV. Although the results of the STI studies in early infection are encouraging, at present it is probably the case that most patients who start treatment will need to continue it for life.
This sobering thought should trigger consideration of the other major question: Is the patient ready for and committed to therapy? Most patients in the United States who have acute HIV infection are young, and are increasingly from minority populations. Acute infection is a time of high psychological stress, and adding complex, potentially toxic treatment to that situation may compound the situation. Moreover, given the critical importance of adherence to success of therapy, starting aggressive therapy in a patient who is not yet ready and who may not have yet come to terms with his or her HIV status is more likely to be unsuccessful. Nonadherence may lead to resistance, making subsequent therapy -- when it is indeed indicated and when the patient is indeed ready -- more difficult. The fact that the patient may not need such therapy until 8-10 years in the future should also make the treater pause. Finally, this analysis does not include any consideration about the long-term toxicity of treatment and the prospect that future treatments may be simpler and less toxic.
In summary, there should be no absolute rules for treatment. Guidelines are just that -- a road map from which one may veer often for special circumstances. The decision to treat should be made on an individual basis, after careful discussion between patient and physician, and should include consideration of stage of illness, pace of progression, symptoms, and patient desires.
The most recent HAART guidelines, although somewhat more conservative in terms of when to start therapy, still say it should be offered for patients known to have seroconverted within the past 6 months. How compelling are the data that support this? I'm thinking specifically of patients with excellent CD4+ cell counts (greater than 500 cells/mm), measurable viral loads, and without symptoms (ie, not acutely seroconverting).
Matthew Lim, MD
The recent change in the Department of Health and Human Services (DHHS) HIV treatment guidelines reflect a growing uncertainty as to the correct time to start antiretroviral therapy. There is ample evidence that untreated HIV infection progresses fairly relentlessly in most infected individuals and that this progression can be predicted by the rate of decline in CD4+ cell count and by the plasma HIV-1 RNA level. There is equally compelling evidence that treating HIV infection stops this progression, preventing loss of immunity, AIDS, and death. Thus, it makes perfect sense to argue that therapy should be given early in infection. However, delaying therapy until later in the disease process -- but still before the onset of clinically apparent immunodeficiency -- seems to be effective as well; the majority of treated patients recover lost immune function, and this delay defers side effects and potentially serious toxicities from drugs. Thus, there is sufficient uncertainty about the true risk:benefit equation for the DHHS panel to decide not to make a firm recommendation for patients with CD4+ cell counts greater than 350 cells/mm and relatively low plasma HIV-1 RNA levels. Instead, the guidelines now say that experts differ: some would and some would not start therapy.
It is important to note that these recommendations do not state that starting treatment at higher CD4+ cell counts is wrong or unethical. Indeed, there may be situations in which treating at higher levels is appropriate -- for example, symptomatic patients or those with rapidly falling CD4+ cell counts, very high viral loads, or both. Acute HIV infection is another setting in which therapy should be seriously considered, irrespective of the CD4+ cell count. Studies of antiretroviral therapy initiated shortly after acute HIV infection (usually within 3-6 months) suggest that complete suppression of plasma viremia is associated with preservation of specific anti-HIV immune responses, especially both CD4+ and CD8+ T-lymphocyte responses. This finding has, in turn, led to the hypothesis that a course of antiretroviral therapy during acute HIV infection might result in better immune control of HIV replication and a lower viral set-point if therapy is discontinued, with better long-term outcome. Indeed, results from a small number of patients who received early treatment after acute seroconversion and then participated in studies of structured treatment interruption (STI) indicate that, in some patients, it may be possible to maintain suppression of viral replication after antiretroviral therapy is withdrawn.
It is important to view these experiments in context. Relatively small numbers of patients have been studied, and to date, all studies of aggressive therapy during primary infection have been uncontrolled. In the absence of therapy, most patients with early HIV infection will have relatively low viral loads and a relatively slow progression to immunodeficiency. Thus, without a randomized controlled trial, it is impossible to say that aggressive early therapy is beneficial in terms of long-term management of HIV. Although the results of the STI studies in early infection are encouraging, at present it is probably the case that most patients who start treatment will need to continue it for life.
This sobering thought should trigger consideration of the other major question: Is the patient ready for and committed to therapy? Most patients in the United States who have acute HIV infection are young, and are increasingly from minority populations. Acute infection is a time of high psychological stress, and adding complex, potentially toxic treatment to that situation may compound the situation. Moreover, given the critical importance of adherence to success of therapy, starting aggressive therapy in a patient who is not yet ready and who may not have yet come to terms with his or her HIV status is more likely to be unsuccessful. Nonadherence may lead to resistance, making subsequent therapy -- when it is indeed indicated and when the patient is indeed ready -- more difficult. The fact that the patient may not need such therapy until 8-10 years in the future should also make the treater pause. Finally, this analysis does not include any consideration about the long-term toxicity of treatment and the prospect that future treatments may be simpler and less toxic.
In summary, there should be no absolute rules for treatment. Guidelines are just that -- a road map from which one may veer often for special circumstances. The decision to treat should be made on an individual basis, after careful discussion between patient and physician, and should include consideration of stage of illness, pace of progression, symptoms, and patient desires.
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