Over the last three years, advances in many areas of clinical research have led to widespread use of potent combination antiretroviral therapies, which have substantially improved treatment outcomes in HIV disease. An improved understanding of the pathogenesis of HIV disease provided the underpinning of these treatments. Advances in basic science have helped draw a much clearer picture of the mechanisms of HIV infection, especially the dynamics and kinetics of in vivo viral replication. Molecular biology has also revealed much about the mechanisms of HIV virulence and the emergence of drug resistance. This article will briefly review these recent advances.
HIV Eradication Revisited
At the beginning of the epidemic, virologic data suggested that shortly after infection, HIV enters a long phase of clinical and virologic latency. Now, though, with the development of techniques for quantifying HIV levels in plasma and other compartments (e.g., lymphoid tissue), it has become clear that HIV actively replicates at all stages of infection. Although many aspects of HIV infection remain to be clarified — particularly the reasons for differences in progression among individuals and the precise role of the immune system (extensively reviewed in the January 1998 issue of ACC — we now have a model of HIV pathogenesis that better elucidates the natural history of HIV infection and disease progression.
We now know that following primary infection and the initial viremic burst, the HIV plasma level usually reaches a plateau that remains relatively constant over time. During this quasi-steady state, production almost equals clearance of the virus, at least for some number of years. The rate of this replication is accurately measured by the plasma HIV RNA level, which also correlates well with RNA levels in lymph nodes. The number of plasma HIV particles also correlates with the number of acutely infected cells, with the annual rate of CD4 cell loss, and, ultimately, with the rate of disease progression.
The discovery that HIV replication during the plateau phase is very rapid (daily production of up to 1010 particles) had a major influence on the development of new principles of antiretroviral therapy and provided the rationale for more aggressive and earlier treatment. Further studies of viral and cellular turnover led to the development of a mathematical model of HIV viral dynamics.The model was based on the following estimates:
- The average half-life of plasma viral particles is about 6 hours.
- Infected CD4 cells, with half-lives of 0.6 to 1.9 days, produce over 90% of plasma HIV virions.
- The half-life of cells in the compartments responsible for the remaining percentage of plasma virions (macrophages and other long-lived infected cells and, to a lesser degree, dendritic cells and latently infected cells) is estimated to be one to four weeks, based on the second phase of the observed HIV RNA decay curve following potent antiretroviral treatment. According to this two-phase decay model, some hypothesized that HIV could be cleared from all known cellular and tissue compartments after about three years of “completely” suppressive treatment.
However, the model was flawed both by unproven assumptions (e.g., that antivirals could completely suppress HIV replication) and by underestimation of important compartments (e.g., sanctuary sites where HIV may not be reached by drugs). More important, it did not take into account the prolonged lifespan of latently infected cells. Two research groups recently showed that infectious HIV could be obtained from peripheral lymphocytes of patients who had attained undetectable levels of plasma HIV RNA following antiretroviral therapy. Replication-competent HIV DNA was found in resting CD+ cells in almost all individuals examined, including those who had been on maximally suppressive therapy for up to 30 months. HIV can therefore remain potentially active even in the presence of long-term antiretroviral therapy.
Thus, the hope of being able to stop treatment after some years is now vanishing. Because of the long half-life of resting memory cells (the major reservoir for integrated HIV DNA), current antiretroviral therapy seems unlikely to be sufficient to eradicate HIV. Future research should now focus on shortening the half-life of latently infected cells and locating other possible cellular reservoirs.
Virologic Response to Antiretroviral Therapy
In natural history studies, the plasma HIV RNA level has been shown to be the strongest predictor of progression to AIDS, with a continuum of risk and no lower-limit threshold. Plasma HIV RNA levels indicate the magnitude of HIV replication, while CD4 cell counts indicate the extent of immune damage already suffered. Measurements of plasma HIV RNA level and CD4 cells should therefore guide the initiation of antiretroviral therapy (although the exact timing remains a debatable issue).
A number of clinical studies have now proved that therapy-induced inhibition of HIV replication predicts clinical benefit, with a linear relation between the degree of reduction in viral load and clinical benefits. Plasma HIV RNA levels should therefore be preferentially used to monitor antiretroviral treatment.
The durability of virologic success can be predicted by the extent of RNA suppression: the lower the nadir of the plasma HIV RNA level, the longer the duration of response. A plasma HIV RNA level below 400 to 500 copies/ml was until recently considered a reasonable therapeutic goal. However, a number of recent studies — although based only on virologic endpoints — have shown that levels below 50 copies/ml are necessary to significantly delay rebounds in viral load and development of resistance. So while regular assays, with a cutoff of about 500 copies/ml, may still be used to screen new patients, more sensitive assays may soon become the standard for monitoring therapy.
The time needed to achieve maximal virologic response (i.e., to reach undetectable plasma levels) under a given therapeutic regimen is related to baseline HIV RNA levels, the potency of the combination, and the sensitivity of the assay. Studies have shown that the nadir of plasma HIV RNA level is usually reached after 20 weeks of treatment, although sometimes not until 24 to 28 weeks, particularly if an ultrasensitive assay is used and/or the patient’s baseline level was high.
A confirmed return of viral load to detectable levels in a regimen-adherent patient should be regarded as evidence of loss of response, and treatment should be changed to prevent the evolution of drug-resistant mutants. Treatment change should be triggered by plasma HIV RNA levels of 500 to 1000 copies/ml. Although initial treatment should always aim to drive HIV RNA to below detection, the relative scarcity of therapeutic options when the initial regimen has failed suggests using this slightly more conservative determinant of the need for a new regimen.
Resistance to Antiretroviral Drugs
Drug resistance remains a major obstacle to the ability of antiretroviral drugs to delay disease progression. A Darwinian model can be applied to the emergence of resistance: HIV variability drives the continuous production of variants that emerge over the wild strain under the selective pressure of antiretroviral therapies. According to this model, resistance cannot develop if viral replication is completely suppressed.
This is confirmed by many controlled studies demonstrating that combination antiretroviral therapy suppressing HIV replication to undetectable levels can delay or prevent the emergence of drug-resistant virus. However, a viral load below the limits of detection by very sensitive assays does not always mean that viral replication has been completely suppressed. Moreover, the difficulty of adhering to the complex medication regimens of aggressive antiretroviral therapy favors the emergence of resistance.
Resistance can be measured by genotypic or phenotypic assays. Genotypic assays, which identify, in a defined gene sequence, the presence of a specific mutation, are relatively rapid but give only an indirect measure of resistance. They cannot detect minor species (i.e., those comprising less than 20% of viral load) and do not always correlate with phenotype.
Research is needed into a number of questions about these assays: Does such an assay accurately reflect the past history of drug exposure and the likelihood of future responsiveness? What specific mutation(s) merit changes in therapy? Is the mutation profile sufficiently defined for combination regimens, which may lead to different mutations, compared with single-drug regimens? Does the absence of detection rule out the presence of significant reservoirs of resistant virus?
Phenotypic assays, which measure the in vitro growth capabilities of an isolate in the presence of a drug, are a more direct measure of resistance but are slower to perform, may give results differing from true in vivo phenotypic resistance, and, like genotypic assays, are insensitive to minor species.
The clinical utility of either type of resistance assay remains to be established. At present, baseline genotypic or phenotypic resistance testing in all patients (with the possible exception of pregnant HIV-infected women) prior to initiation of antiretroviral therapy is not recommended. The assays also presently have only limited application to the design of salvage regimens. The results of resistance testing should be considered to reflect only the selective pressure of the current regimen, since viral subpopulations may not be detected and evolving minor quasispecies may be missed. Decisions about drug regimens should be based on the patient’s actual therapeutic history.
Clinical Implications and Future Therapeutic Strategies
The optimum time to initiate antiretroviral therapy remains an issue of extensive debate. Immune damage is seen in nearly all HIV-infected persons, and long-term survival free of clinically significant immune dysfunction is exceptional. This suggests that all HIV-infected persons with detectable HIV RNA levels should be treated. However, recent data on the difficulty of HIV eradication indicate that antiretroviral therapy, once initiated, may become a lifelong commitment. Because of the limitations of current antiretroviral agents, many suggest deferring initiation of therapy in patients with stable early disease, high CD4 cell counts, and very low or undetectable plasma HIV RNA levels.
Virologic studies strongly indicate that once the decision to start has been made, therapy should be maximally suppressive, because this is the only way to limit the potential for selection of resistant variants. Two nucleoside reverse transcriptase inhibitors (NRTIs) and a protease inhibitor (PI) or two NRTIs plus a nonnucleoside reverse transcriptase inhibitor (NNRTI) are currently recommended for initial therapy, but a number of other potent options are being tested or are already available, such as two PIs and one NRTI or NNRTI; one PI, one NNRTI, and one NRTI; or three NRTIs. Some patients may need more potent regimens to achieve a complete virologic response.
In designing therapeutic regimens, one should remember that pathogenic principles are not routinely applicable to all HIV-infected people, because of both the difficulty of identifying early HIV infection and the practical implications of long-term aggressive therapy. For the latter problem, lack of adherence is a major factor determining virologic failure. Patients in clinical trials generally have much more success with the complex regimens of combination therapy than the average patient.
A change to a salvage regimen should be strongly considered if virus levels rise to values approaching 500 copies/ml. This decision should be carefully considered because the number of effective regimens is still limited and any change in antiretroviral therapy increases future therapeutic constraints (many advanced-stage patients may have already received all the available treatments). Although some of the drugs in development may have a partially different resistance pattern with respect to existing drugs, some level of cross resistance is likely to exist between all members of the same class of presently available antiretrovirals.
New strategies for long-term control of viral replication are being tested now. Controlled trials are investigating whether aggressive therapy may be followed by a better-tolerated “maintenance” (or de-intensifying) regimen. Unfortunately, the recent results of ACTG 343, showing significantly fewer virologic failures with prolonged standard triple therapy as compared with cutting back on maintenance therapy, clearly show that the road to less complex regimens may be long and difficult. Other strategies, such as intensification (adding agents if initial response is good but not optimal) and consolidation (adding an agent to an already successful regimen to promote durability) are now under investigation.
Despite some limitations, potent antiretroviral combinations have clearly produced a significant reduction of disease progression, morbidity, and mortality in HIV-infected individuals. New classes of antiretrovirals and less burdensome regimens may eventually expand treatment options and increase the long-term efficacy of treatments through better tolerability and adherence profiles.
— Stefano Vella, MD
Dr. Vella is an Associate Editor of ACC and Chair of the Italian HIV Clinical Research Program.
Published in AIDS Clinical Care March 1, 1998
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