Report of the NIH Panel To Define Principles of Therapy of HIV Infection

The Magnitude of HIV Replication in Infected Persons Determines Their Rate of Disease Progression

Plasma HIV RNA can be detected in virtually all HIV-infected persons although its concentration can vary widely depending on the stage of the infection (Figure 1) and on incompletely understood aspects of the host-virus interactions. During primary infection in adults when there are numerous target cells susceptible to HIV infection without a countervailing host immune response, concentrations of plasma HIV RNA can exceed 10⁷ copies/mL.⁽⁸³⁾ HIV disseminates widely throughout the body during this period, and many newly infected persons display symptoms of an acute viral illness, including fever, fatigue, pharyngitis, rash, myalgias, and headache.^(84-86) Coincident with the emergence of antiviral immune responses, concentrations of plasma HIV RNA decline precipitously (by 2 to 3 log₁₀ copies or more). After a period of fluctuation, often lasting 6 months or more, plasma HIV RNA levels usually stabilize around a so-called set-point.^{(5,6,10,27,31,86)} The determinants of this set-point are incompletely understood but probably include the number of susceptible CD4+ T cells and macrophages available for infection, the degree of immune activation, and the tropism and replicative vigor (fitness) of the prevailing HIV strain at various times following the initial infection, as well as the effectiveness of the host anti-HIV immune response. In contrast to adults, HIV-infected infants often have very high levels of plasma HIV RNA that decline slowly with time and do not reach set-point levels until more than a year after infection.^(14-18)

Different infected persons display different steady-state levels of HIV replication. When populations of HIV-infected adults are studied in a cross-sectional manner, an inverse correlation between plasma HIV RNA levels and CD4+ T cell counts is seen.^(87,88) However, at any given CD4+ T cell count, plasma HIV RNA concentrations show wide interindividual variation.^(87,88) In established HIV infection, persistent concentrations of plasma HIV RNA range from <200 copies/mL in extraordinary persons who have apparently nonprogressive HIV infection to >10⁶ copies/mL in persons who are in the advanced stages of immunodeficiency or are at risk for very rapid disease progression. In most HIV-infected and untreated adults, set-point plasma HIV RNA levels range between 10³ and 10⁵ copies/mL. Persons who have higher steady-state set-point levels of plasma HIV RNA generally lose CD4+ T cells more quickly, progress to AIDS more rapidly, and die sooner than those with lower HIV RNA set-point levels^(5-7,10,27) (Figures 2-4). Once established, set-point HIV RNA levels can remain fairly constant for months to years. However, studies of populations of HIV-infected persons suggest a gradual trend toward increasing HIV RNA concentrations with time after infection.⁽¹⁰⁾ Within individual HIV-infected persons, rates of increase of plasma HIV RNA levels can change gradually, abruptly, or hardly at all.⁽¹⁰⁾ Progressively increasing plasma HIV RNA concentrations can signal the development of advancing immunodeficiency, regardless of the initial set-point value.^(10,75)

Plasma HIV RNA levels provide more powerful predictors of risk of progression to AIDS and death than do CD4+ T cell levels; however, the combined measurement of the two values provides an even more accurate method to assess the prognosis of HIV-infected persons.⁽²⁷⁾ The relationship between baseline HIV RNA levels measured in a large cohort of HIV-infected adults and their subsequent rate of CD4+ T cell decline is shown (Figure 3).⁽²⁷⁾ Progressive loss of CD4+ T cells is observed in all strata of baseline plasma HIV RNA concentrations, but substantially more rapid rates of decline are seen in persons who have higher baseline levels of plasma HIV RNA (Figure 3).⁽²⁷⁾ Likewise, a clear gradient in risk for disease progression and death is seen with increasing baseline plasma HIV RNA levels^(5,6,10,27) (Figures 2 and 4).