Editorial: Immune Reconstitution and HAART: An Update
Editorial: Immune Reconstitution and HAART: An Update
Through several editorials over the past 2 years, I've raised the issue of methods to assess recovery of the immune system following HAART and complete suppression of detectable viral load, as well as arguments concerning the incidence, clinical impact, and durability of such immune reconstitution. These discussions are themselves usually limited to the best scenarios: patients naive to antiretroviral therapy (ART), in virtually all of whom HAART should lead to suppression of viremia below the limits of detectability for at least 1 year.
The ability to sustain those initial responses, linked to patient adherence, viral resistance, and the substantial metabolic side effects of HAART, is another concern. Salvage therapies are available, but complete viral suppression is anticipated in fewer than a third of patients previously exposed to 2 or more classes of approved antiretrovirals. Several clinical researchers have suggested that protease inhibitor (PI)-sparing regimens be used as initial therapy, because, arguably, long-term adherence is more likely. In addition, nonnucleoside reverse transcriptase inhibitors (NNRTIs), which form the backbone of such therapies, have a much lower genetic barrier to resistance than do PIs. NNRTIs would be most efficacious, therefore, in totally suppressive regimens, a scenario most likely as initial therapy.
The ability to comply with NNRTI- versus PI-based regimens will not be the same for everyone, however. And newer combination medications, such as lopinavir-ritonavir, may have some pharmacokinetic advantages equal to those of potent NNRTIs, such as efavirenz.
We need new antiretrovirals, of course. Drs Montaner and Mellors recently noted that in salvage therapies, 3 promising strategies include the use of multidrug regimens of 6 or more approved antiretroviral drugs; use of low doses of the PI ritonavir to increase levels of other PIs via inhibition of the cytochrome P-450 3A4 pathway; and use of investigational drugs in new classes, such as the fusion inhibitor now in phase III clinical trials, T20.
Despite this need, in the year 2001, only 1 new antiretroviral, tenofovir disoproxil fumarate (PMPA, Viread), was approved by the FDA. Such staggered release of ARTs, through what Montaner and Mellors described as "uncoordinated programs of expanded access [and] lack of any requirements for studying new antiretroviral agents in patients with previous exposure to all 3 classes of drugs," makes it difficult to design appropriate multidrug salvage regimens.
Tenofovir's approval was quite welcome. It is the first nucleotide reverse transcriptase inhibitor (RTI) in clinical use, and it has activity against viral isolates resistant to standard nucleoside RTIs. In a double-blind, placebo-controlled study of ART-experienced patients conducted in London by Anton Pozniak, tenofovir (300 mg) was added to existing ART regimens in 368 patients, while 184 received placebo. The mean change in viral RNA levels was 20.61 log among treated patients. Twenty-two percent achieved viral RNA levels below 50 copies/mL, compared with only 1% in the placebo arm (P < .0001). In a parallel study by Cal Cohen, reverse transcriptase mutations occurred in only 3% of patients receiving tenofovir during 96 weeks of therapy.
Whatever initial or salvage HAART does for surrogate markers -- CD4 cell counts and plasma viral load -- and can't do for latent virus (because no current drugs affect this reservoir), the major issue is immune reconstitution tied to clinical outcome. I had been pessimistic about long-term outcomes in this regard, although recent clinical trials raise new hopes.
For example, Lederman's group at Cleveland investigated patients who had sustained viral suppression while receiving HAART for at least 12 months, classifying them as good responders if they also had a rise in CD4 cell count greater than 200/mL over baseline and poor responders if the CD4 cell count rose by less than 100/mL. Noncontrast chest CT scans were used to estimate changes in thymic volume. T-cell production rates were assessed by uptake of deuterium-labeled glucose and determination of labeled deoxyadenosine in CD4 T cells. The T-cell receptor excision circle (TREC) content of CD4 cells, measured by real-time polymerase chain reaction, was used to define naive cells (an early harbinger of a functional thymus) and immune reconstitution.
Overall, 10 (45%) of 22 were rated as good responders. As might be expected, 7 (39%) of the 18 patients tested for TREC classified as good responders by CD4 cell count had higher median TREC content than did the poor responders (27.5 3 10 cells/L vs 2.1 3 10 cells/L; P =.004). A significant correlation was also found between the thymic index and the absolute number of CD4 T cells, phenotypic naive T cells, and TREC-positive cells. Poor responders were generally older than good responders (46 vs 38 years).
Taken together, these data indicated that diminished thymic function most likely accounts for the failure of CD4 cell counts to rise by more than 100/mL, arguably the more important marker of eventual clinical outcome than viral load suppression. Similar data from a group at Rush-Presbyterian Hospital suggested that with maximal viral suppression and significant rises in T-cell count (greater than 100/mL, and usually much greater), TREC expression, and thus at least 1 major measure of thymic function, was equivalent between age-matched HIV-negative donors and treated HIV-positive patients.
In the future, one might anticipate segregating those patients with undetectable viral loads after 1 year of HAART into 2 groups based on number of CD4 TREC cells, thymic volume, and other similar measures of immunologic response. One might then take the 50% to 60% who are expected to have less than robust rises in functional T cells by these criteria and modify their therapies, using additional antiretrovirals and immune modulators such as granulocyte-macrophage colony-stimulating factor and interleukin-2.
Through several editorials over the past 2 years, I've raised the issue of methods to assess recovery of the immune system following HAART and complete suppression of detectable viral load, as well as arguments concerning the incidence, clinical impact, and durability of such immune reconstitution. These discussions are themselves usually limited to the best scenarios: patients naive to antiretroviral therapy (ART), in virtually all of whom HAART should lead to suppression of viremia below the limits of detectability for at least 1 year.
The ability to sustain those initial responses, linked to patient adherence, viral resistance, and the substantial metabolic side effects of HAART, is another concern. Salvage therapies are available, but complete viral suppression is anticipated in fewer than a third of patients previously exposed to 2 or more classes of approved antiretrovirals. Several clinical researchers have suggested that protease inhibitor (PI)-sparing regimens be used as initial therapy, because, arguably, long-term adherence is more likely. In addition, nonnucleoside reverse transcriptase inhibitors (NNRTIs), which form the backbone of such therapies, have a much lower genetic barrier to resistance than do PIs. NNRTIs would be most efficacious, therefore, in totally suppressive regimens, a scenario most likely as initial therapy.
The ability to comply with NNRTI- versus PI-based regimens will not be the same for everyone, however. And newer combination medications, such as lopinavir-ritonavir, may have some pharmacokinetic advantages equal to those of potent NNRTIs, such as efavirenz.
We need new antiretrovirals, of course. Drs Montaner and Mellors recently noted that in salvage therapies, 3 promising strategies include the use of multidrug regimens of 6 or more approved antiretroviral drugs; use of low doses of the PI ritonavir to increase levels of other PIs via inhibition of the cytochrome P-450 3A4 pathway; and use of investigational drugs in new classes, such as the fusion inhibitor now in phase III clinical trials, T20.
Despite this need, in the year 2001, only 1 new antiretroviral, tenofovir disoproxil fumarate (PMPA, Viread), was approved by the FDA. Such staggered release of ARTs, through what Montaner and Mellors described as "uncoordinated programs of expanded access [and] lack of any requirements for studying new antiretroviral agents in patients with previous exposure to all 3 classes of drugs," makes it difficult to design appropriate multidrug salvage regimens.
Tenofovir's approval was quite welcome. It is the first nucleotide reverse transcriptase inhibitor (RTI) in clinical use, and it has activity against viral isolates resistant to standard nucleoside RTIs. In a double-blind, placebo-controlled study of ART-experienced patients conducted in London by Anton Pozniak, tenofovir (300 mg) was added to existing ART regimens in 368 patients, while 184 received placebo. The mean change in viral RNA levels was 20.61 log among treated patients. Twenty-two percent achieved viral RNA levels below 50 copies/mL, compared with only 1% in the placebo arm (P < .0001). In a parallel study by Cal Cohen, reverse transcriptase mutations occurred in only 3% of patients receiving tenofovir during 96 weeks of therapy.
Whatever initial or salvage HAART does for surrogate markers -- CD4 cell counts and plasma viral load -- and can't do for latent virus (because no current drugs affect this reservoir), the major issue is immune reconstitution tied to clinical outcome. I had been pessimistic about long-term outcomes in this regard, although recent clinical trials raise new hopes.
For example, Lederman's group at Cleveland investigated patients who had sustained viral suppression while receiving HAART for at least 12 months, classifying them as good responders if they also had a rise in CD4 cell count greater than 200/mL over baseline and poor responders if the CD4 cell count rose by less than 100/mL. Noncontrast chest CT scans were used to estimate changes in thymic volume. T-cell production rates were assessed by uptake of deuterium-labeled glucose and determination of labeled deoxyadenosine in CD4 T cells. The T-cell receptor excision circle (TREC) content of CD4 cells, measured by real-time polymerase chain reaction, was used to define naive cells (an early harbinger of a functional thymus) and immune reconstitution.
Overall, 10 (45%) of 22 were rated as good responders. As might be expected, 7 (39%) of the 18 patients tested for TREC classified as good responders by CD4 cell count had higher median TREC content than did the poor responders (27.5 3 10 cells/L vs 2.1 3 10 cells/L; P =.004). A significant correlation was also found between the thymic index and the absolute number of CD4 T cells, phenotypic naive T cells, and TREC-positive cells. Poor responders were generally older than good responders (46 vs 38 years).
Taken together, these data indicated that diminished thymic function most likely accounts for the failure of CD4 cell counts to rise by more than 100/mL, arguably the more important marker of eventual clinical outcome than viral load suppression. Similar data from a group at Rush-Presbyterian Hospital suggested that with maximal viral suppression and significant rises in T-cell count (greater than 100/mL, and usually much greater), TREC expression, and thus at least 1 major measure of thymic function, was equivalent between age-matched HIV-negative donors and treated HIV-positive patients.
In the future, one might anticipate segregating those patients with undetectable viral loads after 1 year of HAART into 2 groups based on number of CD4 TREC cells, thymic volume, and other similar measures of immunologic response. One might then take the 50% to 60% who are expected to have less than robust rises in functional T cells by these criteria and modify their therapies, using additional antiretrovirals and immune modulators such as granulocyte-macrophage colony-stimulating factor and interleukin-2.
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