HIV disease progression

Phases of HIV disease

HIV disease is characterised by three phases: acute or primary infection (often referred to as seroconversion illness or primary HIV infection syndrome), asymptomatic chronic infection and symptomatic chronic infection. The rate of progression from one phase to another is highly variable.

Following transmission, HIV initially replicates in regional lymph nodes. This results in a rapid rise in plasma HIV RNA to levels in excess of one million copies/mL This phase is accompanied by dissemination of HIV to cells in other lymphoid tissues, ^[63] including those of the gut and genital tract. Following the peak in viraemia, plasma HIV viral load decreases co-incident with the development of host cellular immune responses.^[64] The peak in plasma HIV viral load and development of HIV-specific immune responses, including antibody responses, is associated with a primary HIV infection syndrome (seroconversion illness) in 60-90% of patients.^[65], ^[66] The following features of primary HIV infection are associated with a poorer prognosis: ^[67-69]

• Symptomatic primary HIV infection syndrome
• Longer duration of primary HIV infection syndrome
• Neurological symptoms
• Presence of oral candidiasis
• Greater number of signs and symptoms
• Greater severity of symptoms.

The following laboratory test markers during primary HIV infection have been associated with a poorer prognosis: ^{[70] [ 71]}

• Low CD4+ T cell count
• High cellular HIV DNA level
• Slow decay of plasma HIV viral load

While the peak HIV viral load during primary HIV infection is not predictive of HIV disease progression, it is associated with severity of symptoms, which has been linked to a poorer prognosis.^[72]  A primary HIV infection syndrome generally resolves spontaneously within 14 days.^[73]  On resolution of a primary HIV infection syndrome, the HIV-infected person enters a prolonged, clinically asymptomatic period. Nevertheless, virological and immunological progression occurs during this period, driven by immune activation and dysfunction.

Progressive, HIV-induced immunopathology results in the development of symptomatic HIV disease, which is divided into two phases that are not necessarily contiguous: symptomatic HIV infection (non-AIDS) and acquired immune deficiency syndrome (AIDS). Patients may present with an AIDS-defining illness without preceding HIV-related symptoms.

Rates of HIV disease progression

The rate of HIV disease progression is highly variable among individuals, ranging from 6 months to more than 20 years. In the absence of ART, the median time to develop AIDS is 10-11 years.^[74]  The median survival following AIDS in the absence of ART is dependent on the CD4+ T cell count at AIDS diagnosis: 3.7 years if the CD4+ T cell count is < 200/μL and 1.3 years if the CD4+ T cell count is < 70/μL.^[75] However, rates of disease progression to AIDS vary from rapid progression within 6 months of seroconversion,^[76] to no significant progression.

Individuals with no disease progression were previously referred to as long-term non-progressors (LTNP). By definition, these people had CD4+ T cell counts > 500/μL and were asymptomatic despite more than 10 years of infection without ART. Between 1-5% of people with HIV infection fall into this category.^{[77] [78]} These estimates are complicated by the fact that there is no standardised definition of a LTNP, and thus definitions used (and the way in which they are applied, particularly in the presence of varying follow-up and irregularly measured CD4+ T cell counts) are not consistent. However, with longer follow-up and the use of improved prognostic models, these people do eventually experience HIV disease progression suggesting that rather than representing a distinct group of HIV-infected individuals, LTNP are more likely to represent individuals at one end of a normal distribution curve. ^[78]

The term HIV controller refers to people with HIV-1 infection who maintain undetectable HIV viral loads in the absence of ART. Approximately 0.6% of people with HIV infection are considered elite controllers (HIV RNA < 50 copies/mL)^[79], while people who naturally control HIV infection with plasma HIV RNA levels between 50 and 2000 copies/mL have been referred to viraemic controllers^{. [78]}. Elite controllers exhibit-stronger HIV specific immune responses compared with people who do not control viral replication and are also more likely to possess alleles of human leucocyte antigen (HLA)-B genes that are associated with slow progression of HIV disease, such as HLA-B*5701; however these factors do not explain the elite controller phenotype in the majority of people.^[80] Notably, in one study, 10% of such people had CD4+ T cell counts < 350/mL and 3% had AIDS, which were associated with greater immune activation, when compared with HIV-negative controls, and appeared to be related to increased plasma levels of lipopolysaccharide.^[81] Therefore, CD4+ T cell depletion may occur despite optimal control of HIV replication. Although there is clearly an overlap between the LTNP and elite controller groups, not all LTNP have a low HIV viral load, and not all elite controllers have high CD4+ T cell counts.

Laboratory test markers of HIV disease progression

Laboratory test findings, such as rising plasma HIV viral load, falling CD4+ T cell counts and increasing CD38 expression on CD8+ T cells, are non-clinical markers of disease progression. These markers of disease progression correspond to fundamental aspects of HIV disease pathogenesis, namely viral replication, immunodeficiency and increased immune activation, respectively.

CD4+ T cell count

The CD4+ T cell count was the earliest laboratory test marker used in HIV management. ^[82] [83] Absolute CD4+ T cell count, CD4+ T cell percentage and CD4+ T cell rate of decline have all been demonstrated to predict progression to AIDS.^[84] [85]  Furthermore, the risk of development of certain opportunistic infections can be stratified according to CD4+ T cell count. For instance, the relative risk of developing Pneumocystis jiroveci pneumonia in patients with CD4+ T cell counts of < 200/μL or CD4+ T cell proportions < 14% is 4.9.^[86]

The CD4+ T cell count declines during HIV disease progression with the rate of decline accelerating over time, averaging 80-110 cells/μL per year.^[87] Interestingly, host immune function, including thymic function, prior to HIV infection predicts subsequent CD4+ T cell decline.^[88] The CD4+ T cell count is predictive of progression to AIDS across all HIV viral load strata, although its predictive value increases with duration of HIV infection.^[75] [89]  The CD4+ T cell count in blood, however, does not reflect total body numbers of CD4+ T cells, which predominantly reside in lymphoid tissue. The gut-associated lymphoid tissue is affected early in HIV infection, which leads to a dramatic loss of the total body CD4+ T cell pool, and remains depleted throughout the natural history of untreated HIV infection.^[90]

Plasma HIV viral load

Plasma HIV viral load is predictive of disease progression at all stages of HIV infection and across all CD4+ T cell strata. Early studies suggested that, following an initial peak during acute  HIV infection, plasma HIV viral load declined to a setpoint and remained stable during the asymptomatic phases of HIV infection, and then increased again a few years before the  development of AIDS.^[91] [92]

Transmission studies assessing the factors associated with HIV viral load setpoint have observed that the HIV viral load of the donor was closely associated with the HIV viral load at presentation in the seroconverting partner.^[93] Overall, the HIV viral load setpoint was a function of the source partner HIV viral load, the sex of the seroconverter, the HLA class I alleles of the seroconverter, and the sharing of HLA-class I alleles between partners in a transmission pair.^[94]  HIV viraemia dynamics and the evaluation of a setpoint therefore require consideration of host and viral genetics. Despite its use in research studies, there is still no standard method for determining HIV-1 viral load setpoint, with multiple methods and definitions having been used. Determination of HIV viral load set point therefore has little value in clinical practice. Proviral DNA levels in peripheral blood mononuclear cells also predict progression to AIDS independently of both plasma HIV RNA level and CD4+ T cell count.^[95]

There has been interest in determining whether HIV isolates have become more virulent in recent years. However, large cohort analyses have provided inconclusive evidence based on analyses of the rate of CD4+ T cell decline from HIV viral setpoint.^[96]

CD38 expression on CD8+ T cells

CD38 is a cell-surface glycoprotein that is detected on lymphocytes, including CD8+ T cells. Its expression is increased on activated lymphocytes. Upregulation of CD38 expression on CD8+ T cells during primary HIV infection ^[97] and other stages of HIV disease ^[98] is predictive of a subsequent decline in CD4+ T cell count. Furthermore, elevated expression of CD38 by CD8+ T cells late in HIV disease is a strong predictor of disease progression.^[99] These observations underscore the importance of immune activation in the pathogenesis of HIV disease.