HIV Therapeutics

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Douglas D. Richman

The author is at the San Diego Veterans Affairs Medical Center, and in the Departments of Pathology and Medicine, University of California, Clinical Sciences Building, Room 327, 9500 Gilman Drive, La Jolla, CA 92092-0679, USA.

After years of small but measurable advances that temporarily delayed disease progression, the chemotherapy of human immunodeficiency virus (HIV) infection now promises to suppress indefinitely the progression of disease, and conceivably to eradicate it altogether. Three factors have converged to provide important advances in antiretroviral chemotherapy: (i) improved understanding of the pathogenesis of HIV infection, (ii) the availability of standardized reliable quantitative assays of HIV RNA in the plasma (present as genomic RNA in virions), and (iii) more potent antiretroviral drugs. Each of these three factors has affected the others.

Surprisingly large amounts of virus are present in the extensive lymphoid tissues of HIV-infected individuals, even in asymptomatic patients early in the disease process (1, 2). The levels of virus in blood are less than in lymphoid tissues and almost certainly reflect the spillover from replication in that tissue. This large amount of virus turns over rapidly, as measured in blood, with a virion half-life of approximately 6 hours and an estimated 10 billion (10¹⁰) virus particles generated daily (3). Within a year after seroconversion, each infected individual establishes his or her own "set point" of quasi-steady-state levels of plasma HIV RNA (between 10² and 10⁶ copies per milliliter of plasma) that largely determines the rate at which CD4 T lymphocytes are lost. At sufficiently low levels of CD4 cells, patients are susceptible to opportunistic infections, malignancies, and death. Levels of HIV replication, measurable as plasma HIV RNA, thus drive the rate of immune destruction and in fact can be used to predict the natural history of the disease (4).

The measurement of plasma HIV RNA has been instrumental in elucidating this pathogenetic process, as well as in characterizing the magnitude and durability of antiviral activity of investigational drug regimens (5). Moreover, this reduction in measured viral "load" appears to account for most of the clinical benefit as measured by opportunistic events or death in study patients (6, 7). With the regimens of nucleoside analogs, even a reduction of plasma HIV RNA by severalfold corresponds to the reduced rates of disease progression observed with the natural history studies.

Several large trials with clinical endpoints in both adults and children have documented that a number of regimens containing combinations of nucleoside reverse transcriptase inhibitors are superior to zidovudine (3-azido-3-deoxythymidine, AZT) monotherapy (8, 9). The controversy raised by older studies about early versus delayed AZT monotherapy is moot. These newer nucleoside regimens reduce plasma HIV RNA levels to approximately one-tenth their initial value and on average maintain these levels below those present at the initiation of treatment for at least 2 years. This reduction is sufficient to delay the rate of disease progression, but not to prevent it.

In a field with such rapid accrual of new information and of drug approval (at least in the United States), clinical practice must proceed with new drug regimens even when long-term effects are still uncertain. Large phase III clinical endpoint trials (as yet unpublished) have been completed with only three nucleoside reverse transcriptase inhibitors [AZT, zalcitabine (dideoxycytosine, ddC), and didanosine (dideoxyinosine, ddI)] and one protease inhibitor (ritonavir), whereas five nucleosides and three protease inhibitors have received regulatory approval in the United States. An international panel recently generated consensus recommendations to provide guidance for practitioners while investigation proceeds (10).

Several inhibitors of a second viral enzyme, the aspartyl protease, have provided evidence of even more potent activity, with average reductions of plasma HIV RNA to between one-thirtieth and one-hundredth their initial value; in many patients even greater reductions have been seen. Suboptimal doses of these potent drugs result in loss of suppression after several months, which is associated with the cumulative acquisition of multiple mutations in the protease gene that confer high-level drug resistance (11). Patients with sustained suppression do not develop resistance, presumably because some level of replication must be maintained for generation of drug-resistant mutants that can emerge in the presence of the selective pressure of drug treatment (12).

HIV, and most single-stranded RNA viruses, undergo approximately 3 × 10⁵ mutations per nucleotide per replication cycle (13). What drives the appearance of genetic variation of HIV within patients is the persistent, high levels of virus replication (14). With the production of perhaps 10 billion virions daily and a genome size of 10⁴ nucleotides, virtually all possible mutations, and perhaps many combinations of mutations, are generated in each patient daily. Moreover, recombination that rapidly selects for combinations of resistance mutations can occur rapidly with the diploid genome of HIV (15). Although most mutations compromise virus replication to confer a selective disadvantage, the range of possible genetic variants confers adaptive advantages in the face of varying host cells, immune responses, and drug treatments. The outgrowth of resistant variants can be prevented only with potent chemotherapeutic regimens effective against a broad range of potential mutations.

The combination of two nucleoside analogs, AZT and lamivudine (3TC), and a potent protease inhibitor (indinavir) has reduced virus levels in blood from between 20,000 and 1,000,000 RNA copies per milliliter of plasma to below the levels of detection as measured by polymerase chain reaction (PCR) and by culture. This reduction has lasted for periods up to 1 year in at least 90% of treated patients (16). (HIV can be cultured and plasma HIV RNA can be detected in the blood from all but a few percent of untreated, infected patients. The threshold of detection of plasma HIV RNA with current assays is 200 to 400 copies per milliliter.) Encouraging results have been seen with a number of combination regimens containing various nucleoside and protease inhibitors. The levels of virus in the blood, as measured by virus culture and PCR for HIV RNA, are below those seen in the individuals (termed long-term nonprogressors) who have remained clinically stable without treatment for over a decade after being infected with HIV (17, 18).

The clearance of any evidence of virus replication raises a number of questions that previously could not be considered or at least experimentally addressed: (i) Does the magnitude of reduction in the circulation reflect that in the lymphoid tissue? (ii) Given the greater concentrations of HIV in lymphoid tissue, if no detectable virus is in the circulation and virus replication in these two compartments is cleared in parallel, then how much additional reduction will be necessary to suppress all replication in the lymphoid tissue? (iii) If replication can be completely suppressed, will infection be eradicated? There are several corollaries to this last question: (i) Is there a pharmacologic sanctuary that requires special consideration, such as the central nervous system? (ii) Is there a long-lived, latently infected cell population (quiescent lymphocytes and stem cells) that may reactivate infection upon withdrawal of suppressive chemotherapy?

If eradication is possible, then aggressive early treatment becomes a relatively easy decision. This prospect raises the issue of the susceptibility of such cured patients to reinfection, with great implications for vaccine development. If eradication cannot be achieved, the proper implementation of chronic suppression must consider several competing factors. The current practice of adding one additional drug to the treatment regimen of individuals as they progressively deteriorate is ideally suited to select for resistant virus and preclude the benefits of potent combination therapy. The premature use of such potent regimens involves a financial commitment, risk of toxicity, and patient inconvenience. Treatment can be considered premature only if the pathologic process is sufficiently reversible to justify delay. Arguments for earlier use of potent regimens are that chemotherapeutic success with many diseases occurs in a greater proportion of patients and can often be less aggressive when the disease is less extensive. Moreover, the immunopathology of HIV infection is progressive and not completely reversible. The progressive deletion of the immunologic repertoire, at least in adults (who normally have reduced thymic function), is a concern that has not been sufficiently characterized. The progressive fibrosis and loss of normal nodal histology has been well characterized (2). The convenience of chronic suppression will be enhanced if a simple maintenance regimen to sustain chronic suppression can be identified.

In less than a year, the prospects for treatment of HIV-infected patients, at least those socioeconomically privileged, have improved dramatically. Important new questions about HIV pathogenesis can now be asked and investigated. Nevertheless, the prospects of drug resistance, the toxicities of current drugs, and the need for even greater antiretroviral activity will require the discovery and development of still more and better drugs.

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Volume 272, Number 5270, Issue of 28 June 1996, pp. 1886-1888
©1996 by The American Association for the Advancement of Science.