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1 June 1996 | Volume 124 Issue 11 | Pages 984-994
The ability to quantitate human immunodeficiency virus (HIV) in blood and tissues from patients at all stages of disease has provided new insights into the pathogenesis of HIV disease. There is a dynamic equilibrium between HIV production and clearance even during the period of clinical latency, which may permit resistant virus to emerge with the imposition of drug pressure. Disruption of the equilibrium with effective drugs reduces circulating levels of HIV within 1 week, thus allowing the rapid assessment of new candidate drugs. To maximize the magnitude and durability of HIV RNA suppression, therapeutic strategies must be implemented that are effective against high levels of rapidly replicating virus that consist of many genetic variants.
As a result of these limitations, generalizations about the role of antiretroviral therapy in HIV disease evolved and paradigms for the evaluation of new drugs were established that are inconsistent with the current knowledge. The development of assays that detect and quantitate HIV in clinical specimens has permitted insights into viral burden, replication dynamics, and antiviral drug resistance in infected patients. These insights will expedite the development of new drugs and the design of therapeutic strategies and will support the implementation of earlier and more aggressive antiviral therapy for HIV infection.
Recognition of the great magnitude and turnover of HIV replication during this period of clinical latency resulted from two approaches for detecting HIV nucleotide sequences in clinical specimens: in situ hybridization and quantitative assays for HIV RNA. Although electron µgraphic and immunohistochemical demonstrations of ongoing HIV replication in the lymph nodes and central nervous system had been published during the preceding decade [14-22], in situ hybridization in lymphoid tissue graphically showed extremely high viral burdens at all stages of HIV disease, even in the absence of clinical signs and symptoms [23, 24]. If viral latency (defined as infection with nondefective viral DNA without productive virus replication) occurs in a subset of cells in the host, it is overwhelmed by persistent rounds of new infections of cells with high levels of replication even in the early stages of asymptomatic disease.
During the asymptomatic stage, HIV RNA can be detected at high levels throughout the lymphoid system, especially in the perifollicular regions of the germinal centers [14, 17-2123, 24]. Lymph node hyperplasia develops, and immunohistochemical studies suggest that HIV-1, perhaps complexed by antibody, is trapped in lymphatic tissue by the processes of follicular dendritic cells [14, 19-2123, 24]. As many as one third of CD4 lymphocytes in lymphoid tissue and peripheral blood have detectable HIV DNA [24-26], much of which may represent defective genomes. A significant proportion of these CD4 lymphocytes, 0.1% to 1%, expresses HIV RNA at any given time, indicating active replication [24, 25]. Because such cells may have short lives, they represent a relatively small population but one with high turnover. In patients with higher CD4 cell counts, the proportion of infected lymphocytes in the lymphatic tissue is at least as great as and may be 5 to 10 times greater than that in peripheral blood mononuclear cells. This high proportion suggests that viral load replicates and increases predominately in the lymphatic tissue early during clinical latency [23, 24, 27]. Although synthesis of HIV RNA can be detected in no more than 1% of infected cells, the large reservoir of newly generated uninfected susceptible cells is sufficient to sustain the generation of substantial numbers of new cycles of replication and viral progeny.
Several commercial assays are now available that quantitate HIV RNA in the blood using either genome amplification or signal amplification by branched-chain techniques [28-31]. These assays have different methods and sensitivity but produce similar results when applied to identical clinical specimens. The precision, reproducibility, and sensitivity of these assays have led to their use in place of or in addition to assays of viral infectivity in plasma and peripheral blood mononuclear cells for evaluating new antiretroviral treatments. Quantitative assays of viral infectivity are more costly, slower, less sensitive, and less precise than quantitation of HIV RNA; however, they generate observations concordant with HIV RNA assays and quantitate infectious virus, not just viral genomic material [32]. In HIV-infected cell culture supernatants and plasma, there are as many as 10 000 virions, each containing two copies of HIV RNA for every infectious particle [33, 34]. The quantitative RNA assay is thus more sensitive and has a greater dynamic range than assays of infectivity.
With the use of assays that are based on genome amplification, such as polymerase chain reaction (PCR), almost every untreated patient infected with HIV has measurable plasma levels of HIV RNA throughout the course of disease Figure 1 [35]. Approximately 105 to 107 HIV RNA copies/mL are present in the initial burst of viral replication that is associated with primary infection [33]. After 8 to 12 weeks, these levels are reduced approximately 100-fold with the development of the cytotoxic T-cell response [10, 33]. Published data are insufficient to correlate peak levels of plasma HIV RNA during primary HIV infection with subsequent clinical course, although symptoms during primary infection are associated with more rapid disease progression [36]. UPDATE
Viral Dynamics of HIV: Implications for Drug Development and Therapeutic Strategies
The recent advances in our understanding of human immunodeficiency virus (HIV) burden, dynamics, and resistance provide an opportunity to reassess the theoretical and practical approaches to the development of HIV therapies. In the last decade, the design, conduct, and analysis of clinical trials of antiretroviral agents was hindered by an inability to directly measure HIV during therapeutic interventions. Changes in circulating HIV p24 antigen, detectable in only a few patients, were used to guide the development of new drugs. Mortality and the development of opportunistic infections were used to evaluate antiviral efficacy in larger phase III trials. The conclusions from these clinical studies were heavily influenced by an over-representation of patients at the highest risk for progression to these end points.
Viral Burden and Dynamics: Current Concepts
Quantitation of viral infectivity in both plasma and peripheral blood mononuclear cells has confirmed that HIV infection is a remarkably dynamic process [1-8]. One week after the onset of clinical symptoms associated with primary infection, 100 to 10 000 infectious units of HIV can be detected per milliliter of plasma and per million peripheral blood mononuclear cells. Viral titers approach or exceed those seen in patients with advanced acquired immunodeficiency syndrome (AIDS). Within 1 to 2 months, the number of infectious HIV particles rapidly diminishes, often to levels below the limits of culture detection. This decline occurs in the absence of therapy, indicating either exhaustion of permissive host cells [9] or that the host immune response (probably cytotoxic T lymphocytes [10]) successfully suppresses much viral replication, at least temporarily. The rapid viral clearance and the resolution of the acute, clinical syndrome of primary HIV infection has supported the concept of a variable period of clinical latency after primary infection. This stage of infection is characterized by an absence of clinical symptoms, high levels of circulating HIV antibodies, and low or undetectable levels of plasma viremia and p24 antigenemia. Persistent replication of virus during this period can still be documented, however, through the isolation of virus from the peripheral blood mononuclear cells and cerebrospinal fluid of most patients at all stages of disease [11-13].
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Within 6 to 12 months after seroconversion, patients establish a steady-state level of plasma HIV RNA that varies from 102 to 106. These levels are highly predictive of subsequent disease course. Levels of HIV RNA tend to be higher in patients with more rapidly declining CD4 cell counts and symptomatic disease [33, 34, 37-39] (Figure 2). The viral burden in the few patients who escape CD4 cell decline and clinical progression for years (long-term nonprogressors) usually maintain fewer than 103 HIV RNA copies/mL [34, 40, 41]. Between these extremes are most patients, who maintain a range of 103 to 105 HIV RNA copies/mL and progress to AIDS in 8 to 10 years. Variability and exceptions exist, however, indicating that numerous factors (virus syncytium-inducing phenotype, other virus phenotypes, immune response, or immunogenetics) may contribute to varying natural histories.
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Plasma HIV RNA levels represent the steady state of a dynamic equilibrium between production and clearance of HIV RNA. Repeated measures over weeks or months show relatively constant plasma RNA levels in individual patients [33, 35]. The production of new virus is equal to the clearance of circulating virus. Immune stimulation through the administration of vaccine or new infections (such as influenza, reactivation of herpes simplex virus, or tuberculosis) produces transient increases in plasma viremia and HIV RNA levels [42-45]. The activation of CD4 lymphocytes by these processes probably generates additional permissive host cells for virus replication. Conversely, the administration of antiretroviral agents inhibits the production of new virus, thereby reducing the levels of HIV RNA. Reductions in viral burden in the lymph nodes may parallel reductions in plasma [46].
Shortly after the initiation of antiretroviral treatment, an exponential reduction of plasma HIV RNA permits the calculation of the viral clearance rates. In the studies of Ho and colleagues [47] and Wei and colleagues [48], plasma HIV RNA levels decreased exponentially during the first 1 or 2 weeks after initiation of therapy with several antiviral drugs [47, 48]. The estimated half-life of HIV in the plasma was 2 days. Thus, at least 30% of the plasma virus is replaced daily, implying that active de novo viral replication is primarily responsible for maintaining the level of plasma viremia. These rapid turnover rates are independent of the level of plasma viremia and CD4 cell count and are minimal estimates, because the calculations must assume complete inhibition of virus replication by the treatment intervention. The calculated clearance rates would be faster if the inhibition of virus production by the newly introduced antiviral drugs was less than complete. Moreover, the use of more frequent measures suggests that the half-life or turnover is actually less than 1 day rather than 2 days and perhaps as short as 6 hours [49, 50]. The plasma HIV RNA level only begins to decrease after about 36 hours of treatment, because cells that are already infected and producing virus must die for RNA levels to decrease [50]. Calculations starting after 36 hours, when new rounds of infection have been inhibited by drugs, show these faster clearance rates. An estimated 109, perhaps 1010, virions are generated in each infected patient daily [47, 48, 50]. The initial exponential decrease in HIV RNA seen after drug initiation is similar for nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. The nadir in HIV RNA occurs after 2 weeks with the nucleoside analogues and non-nucleoside reverse transcriptase inhibitors. Levels then gradually return to a steady state below baseline [51]. With protease inhibitor therapy, however, after the initial exponential decrease, HIV RNA levels continue to decline for months, albeit at a slower rate [52, 53]. This more gradual reduction may reflect drug activity on a population of cells with a slower turnover.
The circulating CD4 cells, which represent approximately 2% of the total population, are also in a dynamic equilibrium. It has been estimated that at least 106 CD4 cells in the circulation and 109 CD4 cells in the body are destroyed and replaced daily [47, 48]. These rates of production and destruction in patients infected with HIV may be 10 to 100 times the normal rates. These observations suggest that CD4 cell destruction is a direct consequence of persistently high levels of viral replication. The mechanism of CD4 cell destruction (HIV antigen-specific cytotoxic T lymphocytes or HIV-mediated apoptosis, for example) and the production of the new CD4 cells require elucidation. Initiation of effective antiretroviral therapy disrupts this equilibrium, and elevation in CD4 cell counts mirrors the reduction in plasma HIV RNA levels with a slight phase lag reflecting slower CD4 cell production. Peak increases in CD4 cell counts occur 8 to 12 weeks after the start of nucleoside and non-nucleoside reverse transcriptase inhibitor therapy, and continued increases are seen several months after the initiation of protease inhibitor therapy. The magnitude of restoration of numbers of CD4 cells may be limited, and the restoration of immunocompetent cells may be more important than the absolute number of CD4 cells.
Resistance and Evolutionary Fitness
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With the production of perhaps 108 to 1010 virions daily and a mutation rate of 3 x 10–5, it is likely that any given mutation, perhaps many combinations of mutations, exist when a selective pressure like drug treatment is introduced. Drug-resistance mutations to nucleosides, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors have been identified in previously untreated patients [49, 58-62]. For drugs such as lamivudine, nevirapine, and other non-nucleoside reverse transcriptase inhibitors, a single nucleotide change can confer 100-to 1000-fold reductions in drug susceptibility [63-67]. In clinical trials, most antiviral activity that results from treatment with these agents alone is largely reversed within 4 weeks after the initiation of therapy. This reversal is associated with the emergence of drug-resistant mutants [68-72]. These observations provide compelling evidence for the relation between the loss of antiviral drug activity and the emergence of drug resistance, and they are consistent with the existence of drug-resistant subpopulations in patients before treatment.
High levels of resistance to other drugs, such as zidovudine and protease inhibitors, require the cumulative acquisition of as many as five or more mutations. The selection of variants with such mutations requires ongoing high levels of replication in the face of drug pressure for 6 months to several years [73-75]. Either additional mutations are acquired in the presence of preexisting singly or doubly mutant virus, or genetic recombination occurs [76].
Mutations are rarely without cost. Compromises of replicative capacity may occur with almost all mutations [77]. Even small compromises in replicative capacity can render a mutant subpopulation unsuccessful if several rounds of replication occur [77]. Virus with a compromising mutation survives under the pressure of selection of protease inhibitors, for example, by a second compensatory mutation that restores original levels of viral replication [78]. Some mutations appear to diminish replicative capacity or attenuate the amount of virus little, if at all. For example, the mutation at amino acid residue 181 of the reverse transcriptase that confers resistance to nevirapine results in a virus population that generates the same steady-state levels of plasma HIV RNA and the same clinical disease progression as 181 wild-type virus [70, 72]. Moreover, this mutation persists for more than a year, even after withdrawal of nevirapine treatment [71].
The swarm of genetic variants in any patient is a mixture of viruses with varying selective advantages under the changing conditions (host cell type, immune response, or drug treatment) and with varying replicative capacities. The fitness of the predominant population (master sequence) changes in response to changing selective pressures [54]. Therapeutic strategies can address these dynamics only by suppressing replication and the emergence of variants or by forcing the emergence of genetic variants resulting in attenuated replication or decreased virulence. In this regard, measurements of HIV RNA levels may be limited in predicting clinical outcome because they do not distinguish among different levels of virulence.
Implications for Drug Development
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Numerous advantages are gained by using the plasma assay for HIV RNA to evaluate candidate antiviral compounds. First and foremost, assays of HIV RNA provide a precise and direct measure of the agent of HIV disease. Second, HIV RNA can be detected in patients regardless of CD4 cell count. This immediately provides the opportunity to assess the antiviral activity of new agents, even in populations with high CD4 cell counts that have previously been excluded from clinical trials [81].
A third advantage to using HIV RNA assays is rapid assessment of in vivo antiviral activity. With the rapid turnover of HIV that maintains the steady-state level, compounds that block new infection begin to reduce plasma HIV RNA levels as early as 36 hours after administration (Figure 3). Frequent sampling of HIV RNA in small numbers of patients during the first 2 weeks of administration of a new drug can thus provide both a qualitative and quantitative assessment of antiviral activity [31, 47, 48, 51]. In conjunction with pharmacokinetics data and safety profiles, this information about antiviral activity permits the identification of candidate drugs and drug doses that are sufficiently active to justify further development. This approach substantially reduces the time and resources needed to assess and develop drugs. For example, a promising protease inhibitor that attained high plasma levels but was shown to bind avidly to 
1 acid glycoprotein in plasma was discarded as ineffective after an efficient 2-week study [82].
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Serial measurements of HIV RNA levels can also be used to compare the antiviral activity of drugs and drug combinations in larger long-term clinical trials. Before these assays were available, phase III clinical trials were designed and statistically powered to detect differences in HIV disease progression (clinical and immunologic), development of opportunistic infections, and mortality. Improved treatment and care have decreased the rate of these outcomes, especially in asymptomatic patients; thus, clinical studies of thousands of patients for several years are now needed to detect differences between therapies. In the AIDS Clinical Trials Group protocol 175 [83, 84], 2467 patients with 200 to 500 CD4 cells/mm3 were randomly assigned to one of four nucleoside regimens. Differences in clinical end points and survival were detected among the treatment arms. In general, changes in plasma HIV RNA in a subset of patients paralleled the differences in clinical end points. However, it is important to note that in this trial and others, differences in clinical outcome are not entirely explained by HIV RNA changes. As more effective treatment regimens become the standard for comparison, clinical end point trials must be even larger and longer. As the available combination regimens of protease inhibitors and nucleosides proliferate, results from smaller trials that compare differences in the magnitude and duration of viral suppression are likely to directly influence management decisions before the results of phase III clinical end point trials are available.
Our current understanding of pathogenesis and natural history and the data generated from clinical trials all argue that higher levels of HIV RNA are associated with the progression of clinical disease and that sustained therapeutic reductions of viral burden are likely to confer clinical benefits on the recipient. In AIDS Clinical Trials Group protocol 116B/117 [85], patients pretreated with zidovudine were randomly assigned to continue zidovudine treatment or to switch to didanosine treatment. The pretreatment HIV RNA levels were independent predictors of disease progression [37]; disease progression rates were 23% higher for every twofold increase from baseline plasma HIV RNA level. A 27% decrease in risk for disease progression was noted for every 50% reduction from baseline HIV-1 RNA level at 4 weeks. Patients who switched to didanosine treatment developed fewer opportunistic infections and sustained higher CD4 cell counts [85]. Paralleling these results, HIV RNA levels had substantially decreased (50% from baseline) at 1 month in patients who switched to didanosine treatment and continued to increase in the patients receiving zidovudine. Similarly, the Veterans Administration trial 298 [86], which compared immediate and deferred zidovudine monotherapy in asymptomatic patients with 200 to 500 CD4 cells/mm3, showed that both lower baseline HIV RNA levels and greater therapeutic reductions of HIV RNA levels independently predicted slower disease progression. It is important to note that HIV RNA is not the sole predictor of disease progression. Other factors, such as CD4 cell count, syncytium-inducing pheno-type, and zidovudine resistance, are also important predictors [87, 88].
Therapeutic Strategies
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Unfortunately, the therapeutic goal of suppressing viral replication for years, if not decades, was not possible with the first available drugs. Despite the empiric observation that drugs fail and HIV RNA levels increase, the reasons for failure appear complex and are probably multifactorial. The most apparent explanation for HIV disease progression despite treatment with antiretroviral drugs is the limited potency of these compounds. Nucleoside monotherapy in previously untreated patients reduces plasma HIV RNA levels by 0.5 to 0.7 log10 copies/mL of plasma (three- to fivefold) [91] (Figure 4). This results in increases of 20 to 40 CD4 cells/mm3. These effects slowly dissipate over months even in the absence of drug resistance, thereby permitting progressive immunologic decline.
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Drugs may also fail because of pharmacologic factors. Nucleoside analogues are differentially phosphorylated in different cell types, suggesting that their activity, which is mediated by the triphosphorylated metabolite, may be restricted in different cells or cell types [92]. It is also conceivable that chronic nucleoside therapy could modulate enzyme levels to reduce the steady-state levels of the intracellular triphosphate. The induction of hepatic p450 enzymes both by non-nucleoside reverse transcriptase and by protease inhibitors may result in decreased plasma concentrations after prolonged treatment.
Resistance, as discussed above, also plays an important role in the loss of antiviral activity. The ability of HIV to survive and replicate, even in the face of compounds specifically designed to interfere with essential steps in viral replication, may depend primarily on the acquisition of mutations and facile selection of virus that is resistant to antiviral agents.
What therapeutic strategies can be implemented to achieve prolonged viral suppression and combat drug failure? The combination of two antiviral nucleosides with relatively modest activities is beneficial in terms of improving the magnitude and durability of viral suppression [91, 93-96] (Figure 5). Several nucleoside combinations have resulted in reductions of 1 to 1.5 log10/mL in plasma HIV RNA levels; these reductions have also been sustained more than is usually seen with nucleoside monotherapy [91, 94, 96]. Even more beneficial are the protease inhibitors (ritonavir, indinavir, and nelfinavir) that have produced reductions of HIV RNA levels in the plasma of some patients by as much as 3 log10/mL, with corresponding increases of 300 to 500 CD4 cells/mm3 [47, 48, 52, 97]. The addition of nucleosides adds to this activity of protease inhibitors. For example, Gulick and colleagues [53] found that indinavir in combination with zidovudine and lamivudine reduced HIV RNA levels to less than 500 copies/mL of serum at 6 months in 90% of clinical study patients, all of whom had been treated previously with zidovudine for at least 6 months. Although these data are encouraging and show that currently available drugs can reduce viral replication to plasma levels below the limits of detection of the current assays, ongoing HIV replication provides escaped mutants with the opportunity to emerge. Whether combinations of these potent protease inhibitors will provide further increments in viral suppression and delay in resistance is under investigation.
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Optimal antiviral therapy should provide suppression of HIV replication that is both sufficient and durable. Switching reverse transcriptase inhibitors increases the durability of viral suppression, but this effect is of limited duration [85, 98]. Combination therapy may temporarily delay resistance, but drug-resistant virus will probably be selected by any effective regimen that does not completely suppress virus replication. Therefore, therapeutic strategies that are active against resistant viral populations must be developed.
There are at least three theoretical mechanisms by which antiretroviral drugs can sustain activity in the face of drug-resistant virus. First, drugs can continue to exert antiretroviral activity if plasma concentrations of the drugs can be maintained that exceed the susceptibility of drug-resistant virus (assuming that the mutability of the target protein is constrained). This approach appears to apply to some patients in whom high levels of the non-nucleoside reverse transcriptase inhibitor, nevirapine, can be achieved [72]. Second, drug-resistant mutations that confer a clear selective advantage in the face of drug pressure can still impair the replicative capacity of the virus compared with that of the wild-type virus in the absence of treatment. Such attenuated virus can contribute to the activity of lamivudine and perhaps some protease mutants [68, 78]. Third, when two drugs are targeted to the same viral protein (convergent therapy), mutations induced by one drug may sensitize the virus to the second drug or may prevent the emergence of viable mutants to the second drug [99]. The mutation from methionine to valine at residue 184 of reverse transcriptase, which emerges with lamivudine treatment, suppresses the critical mutation at residue 215 that confers resistance to zidovudine [64]. Combinations of protease inhibitors may also exploit this strategy. It seems logical that a potent protease inhibitor could be designed that binds to the active site of viruses highly resistant to another potent protease inhibitor [100]. This combination may give the virus no options for escape.
Early Intervention and Perinatal Transmission
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The interruption of perinatal transmission may be the most important therapeutic intervention applied in the coming years to persons infected with HIV. In some countries of the developing world, as many as one third of pregnant women are infected with HIV. The risk for transmission of HIV from mother to infant ranges from 13% to 40% [104]. Viral load has been reported as an important risk factor associated with maternal-fetal transmission, but conflicting data exists in this area [51, 105-108]. Levels of HIV RNA are higher in the mothers of infants infected through perinatal transmission, but considerable overlap exists between the levels of mothers who do transmit HIV disease to their infants and the levels of mothers who do not. Clinical investigations are currently attempting to identify other determinants in the mother or infant that influence perinatal transmission.
Data from several studies suggest that at least 50% of cases of maternal-fetal transmission occur late in pregnancy and during delivery [109]. Thus, therapeutic strategies that aim to reduce viral burden in the mother at delivery or to treat the neonate after exposure may be effective in reducing HIV disease in infants born to infected mothers. In AIDS Clinical Trials Group protocol 076 [110], perinatal transmission was reduced by two thirds in the treatment arm, in which pregnant women and their infants received zidovudine instead of placebo. Much of the benefit of the regimen may have been due to postexposure prophylaxis in the newborn. Durability of viral suppression and selection of resistant virus are not likely to be important to the administration of nucleosides for the brief perinatal period. It is worth noting, however, that zidovudine-resistant virus has been transmitted through perinatal infection and that this must be addressed in the design of new therapies [111, 112].
Clinical Use of Plasma HIV RNA Assay
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The use of HIV RNA assays to manage individual patients is appealing and has been advocated by several clinicians and researchers. The most obvious application of these assays is to assist in two of the most difficult and controversial areas in the management of patients infected with HIV—when to start therapy and when to switch therapies. High levels of HIV RNA are predictive of disease progression; thus, current guidelines that suggest withholding antiretroviral therapy for all patients with CD4 cell counts greater than 500 cells/mm3 should be revised. A screening HIV RNA evaluation can identify patients with higher CD4 cell counts as candidates for antiretroviral therapy on the basis of their higher risk for disease progression. The optimal therapeutic approach in patients with CD4 cell counts greater than 500 cells/mm3 and lower HIV RNA levels is less certain. Some experts advocate withholding therapy in patients with fewer than 10 000 HIV RNA copies/mL of plasma. The data to justify this recommendation are not available, and this approach should be viewed with caution. There is considerable overlap in HIV RNA levels between long-term nonprogressors and others. Patients infected with HIV who have HIV RNA levels below this threshold can develop symptomatic disease. Delaying therapy for these patients could be detrimental. Moreover, even patients with low plasma levels of RNA have a dynamic turnover of the virus and might benefit from therapeutic interventions.
For patients receiving antiretroviral therapy, a decreasing CD4 cell count and clinical disease progression are indications that therapy should be switched. Changes in HIV RNA are measurable days after initiating, adding, or switching to therapy with an effective antiretroviral agent. Maximal decreases in HIV RNA are seen 2 weeks after nucleoside therapy is started and 2 to 4 months after protease inhibitor therapy is started. Existing data suggest that monitoring HIV RNA to guide therapeutic changes may improve patient outcomes. Clinicians and patients may wish to use this knowledge to guide patient management while ongoing clinical trials, done over many patient-years of observation, are carried out.
Conclusion
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Dr. Richman: Departments of Pathology and Medicine, 0679, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0679.
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References
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