INTRODUCTION — Since the original description in 1981 of an unusual cluster of cases of Pneumocystis carinii (now called Pneumocystis jirovecii) pneumonia and Kaposi sarcoma in previously healthy men who have sex with men, substantial advances in our understanding of the acquired immunodeficiency syndrome (AIDS) have been achieved. Evidence that a retrovirus was associated with AIDS in 1984 and the development of a diagnostic serologic test for human immunodeficiency virus (HIV) in 1985 have served as the basis for developing improvements in diagnosis.
In addition, therapy was dramatically altered with the introduction of antiretroviral drugs in 1987 and revolutionized by combination antiretroviral therapy (ART) in 1996. Despite the absence of a cure, the natural history of the disease was radically changed, and now, persons with HIV infection without other substantial comorbidities who are treated before significant immunosuppression can expect a life expectancy approaching that of the general population .
This topic reviews the case definition, stages, and natural history of HIV infection without ART, immunologic recovery and life expectancy with ART, and experimental efforts to interrupt the natural history of HIV to achieve sustained remission off ART. More detailed discussions of when to initiate ART, regimen selection, and prevention of opportunistic infections are presented elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Overview of prevention of opportunistic infections in patients with HIV".)
OVERVIEW OF STAGES OF HIV INFECTION — HIV infection can be divided into the following stages:
●Viral transmission (see 'Viral transmission' below)
●Acute HIV infection (also called primary HIV infection or acute seroconversion syndrome, among other terms) (see 'Acute and early HIV infection' below)
●Chronic HIV infection, which can be further subdivided into the following stages:
•Chronic infection, without AIDS (see 'Chronic HIV infection without AIDS' below)
Some experts use the term "advanced HIV infection" to describe those with a CD4 cell count <50 cells/microL (see 'AIDS and advanced HIV infection' below)
Case definitions to standardize the description of HIV infection based upon the CD4 count and clinical stage of disease have been established by the World Health Organization (table 2 and table 3)  and the United States Centers for Disease Control and Prevention (CDC) (table 1 and table 4 and table 5) . CDC guidelines characterize the status of HIV disease at a particular time. These case definitions were developed as surveillance case definitions and are not intended to serve as the bases for clinical decisions in individual patients.
VIRAL TRANSMISSION — HIV infection is usually acquired through sexual intercourse, exposure to infected blood, or perinatal transmission. Risk factors for HIV transmission include high viral load, certain sexual behaviors, presence of ulcerative sexually transmitted infections, lack of circumcision, as well as certain other host and genetic factors [4-6]. Detailed discussions of the modes of and risk factors for HIV transmissions are presented in separate topic reviews. (See "Global epidemiology of HIV infection", section on 'Modes of transmission driving the pandemic' and "HIV infection: Risk factors and prevention strategies", section on 'Risk factors for infection'.)
ACUTE AND EARLY HIV INFECTION — Different terms, including acute, recent, primary, and early HIV infection, have been used to refer to variable intervals following initial infection with the virus. In this topic, we use the term "acute HIV infection" to refer to the symptoms and signs that frequently occur just after HIV is transmitted. We use the term "early HIV infection" to refer to the approximate six-month period following HIV acquisition.
The following sections briefly discuss the stages and impact of acute and early infection on the natural history of HIV infection. The epidemiology, clinical manifestations, diagnosis, and management of acute and early HIV infection are discussed in detail elsewhere. (See "Acute and early HIV infection: Pathogenesis and epidemiology" and "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Acute and early HIV infection: Treatment".)
Stages of early infection — The viral and immunologic dynamics following HIV transmission can be characterized using the Fiebig classification, which consists of six stages (table 6) . Fiebig staging is typically used for research purposes. Detection of early HIV infection is facilitated by HIV tests that detect HIV p24 antigen prior to seroconversion (ie, prior to Fiebig stage 3) [8,9]. In addition, confirmatory tests that use a second immunoassay instead of Western blot also improve the likelihood of diagnosing HIV in the early stages. (See "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)
One advantage of recognizing early and acute HIV infection is that it allows early antiretroviral therapy (ART) initiation, which has several known and potential benefits, including reduction of transmission risk to others. (See "Acute and early HIV infection: Treatment", section on 'Rationale for initiation of ART in early infection'.)
Clinical presentation — Symptomatic acute HIV infection is characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, diarrhea, and headache (often described as a mononucleosis-like illness). However, up to 60 percent of individuals with primary HIV infection will be asymptomatic. In acute HIV infection, which is a period of rapid viral replication and infection of CD4 cells, the plasma viral RNA level is typically very high; HIV RNA levels greater than 1 million copies/mL are common. The CD4 cell count can drop transiently. The clinical features of acute and early HIV infection are discussed in detail elsewhere. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Clinical features'.)
The presence of a prolonged symptomatic illness (>14 days) during acute infection appears to correlate with more rapid progression to AIDS [10,11]. In one study, for example, the risk of progression to an AIDS-defining diagnosis within three years following seroconversion was substantially higher in those with acute symptoms lasting more than 14 days than in those who were asymptomatic or had only mild symptoms (78 versus 10 percent) . (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Signs and symptoms'.)
Seroconversion — Seroconversion refers to the development of detectable antibodies against HIV antigens. The timing of seroconversion following infection with HIV depends upon the sensitivity of the serologic test (table 7). As serologic tests have become more sensitive, most persons with HIV have documented seroconversion during early infection (ie, within the first several weeks after infection). (See "Screening and diagnostic testing for HIV infection" and "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
Viral set point establishment — By approximately six months of infection, plasma viremia has reached a steady-state level (referred to as the viral set point); cytotoxic CD8 cells play a critical role in achieving that equilibrium and preventing further decline in the CD4 cell compartment [12,13]. In a prospective study of 33 individuals with early HIV-1 infection, those with higher frequencies of HIV envelope-specific memory CD8 cells had lower median plasma HIV RNA levels and a lower likelihood of progression to CD4 cell count <300 cells/microL at 18 months (20 versus 56 percent in patients with lower frequency CD8 cell responses) .
The viral set point level is closely associated with the rate of disease progression in the absence of ART; this level is highly variable [14-16]. As an example, in a prospective study of 218 female sex workers in Kenya, higher set point levels, in addition to lower early CD4 cell counts and symptomatic acute HIV infection, predicted faster progression to death after a median follow-up period of over four years .
A small proportion of people who acquire HIV demonstrate transient virologic control early in infection without ART. In an analysis of 2176 patients with documented acquisition of HIV infection, 145 patients (7 percent) spontaneously controlled viremia . Participants who identified as women, and those without symptoms at seroconversion, were more likely to achieve undetectable plasma HIV RNA. Most of these individuals do not durably sustain HIV control, and become viremic, eventually experiencing disease progression. (See 'HIV controllers' below.)
CHRONIC HIV INFECTION WITHOUT AIDS — Following primary infection, seroconversion, and establishment of the viral set point, there is a period of chronic HIV infection that is characterized by relative stability of the viral level and a progressive decline in the CD4 cell count. In the absence of antiretroviral therapy (ART), the average time from HIV acquisition to a CD4 cell count <200 cells/microL is approximately 8 to 10 years.
This section will review the natural history of chronic HIV infection in those who do not receive ART. The impact of treatment on HIV infection is discussed below. (See 'Impact of treatment' below.)
Clinical manifestations — Most persons with HIV have few to no symptoms prior to developing severe immunosuppression (when the CD4 count declines to <200 cells/microL). However, some patients experience generalized/nonspecific symptoms and signs such as fatigue, sweats, or weight loss. In addition, persons with HIV at this stage of disease can have generalized lymphadenopathy on physical exam. This is referred to as "persistent generalized lymphadenopathy" when the enlarged lymph nodes involve at least two noncontiguous sites other than inguinal nodes for more than three to six months without an alternative explanation . The lymph nodes in such patients are generally symmetrical, modestly enlarged, mobile, painless, rubbery, and located in the cervical, submandibular, occipital, and axillary chains . In patients with known HIV infection, further evaluation for the etiology of symmetrical lymphadenopathy is generally not warranted in those without severe immunosuppression or other clinical symptoms.
Certain clinical syndromes are also seen with greater frequency and severity in patients with HIV during this stage of infection, particularly as the CD4 count decreases (table 8). Although these complications worsen with severe immunosuppression, they can occur at CD4 cell counts >200 cells/microL.
●Many of these signs and symptoms involve the skin or mucous membranes. As examples:
•Patients can develop recurrent or persistent oropharyngeal or vulvovaginal candidiasis (picture 1) and oral hairy leukoplakia (picture 2). In addition, seborrheic dermatitis (picture 3) is a common early finding of chronic HIV infection.
•Bacterial folliculitis, particularly due to Staphylococcus aureus, is also common. The emergence of community-acquired, methicillin-resistant S. aureus (MRSA) has disproportionately affected individuals with HIV, who appear to have a higher burden of colonization with MRSA compared with persons without HIV [20,21].
•The manifestations of herpes simplex virus, varicella-zoster virus, human papillomavirus virus, and molluscum contagiosum infections are often more severe (eg, with recurrences or more rapid progression) in the setting of HIV infection.
In a study of over 7500 individuals with HIV from various urban sites in the United States done prior to the routine use of combination ART, among those with a CD4 cell count 200 to 499 cells/microL, thrush was reported in 21.3 percent, oral hairy leukoplakia in 9.2 percent, herpes zoster in 6.7 percent, peripheral neuropathy in 3.7 percent, and idiopathic thrombocytopenia purpura in 2.6 percent . Even among those with a CD4 count >500 cells/microL, thrush was reported in 11 percent. Recurrent or persistent candidal vulvovaginitis and cervical dysplasia were reported at similar frequencies among women who had CD4 counts <200 cells/microL or between 200 and 499 cells/microL. The presence of some of these infections (eg, thrush) classifies an individual as having AIDS (table 1 and table 3). (See 'AIDS and advanced HIV infection' below.)
●Other types of infections also occur with greater frequency in the setting of HIV infection, even in the absence of advanced immunosuppression, including Streptococcus pneumoniae infection. Sexually transmitted or sexually associated infections, such as syphilis, hepatitis B and C virus, and mpox infections, are also common because of shared routes of transmission, and they may have more severe outcomes in individuals with HIV who are not receiving ART. (See "Syphilis in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)".)
AIDS-defining illnesses (table 1 and table 3) may occasionally occur at CD4 counts >200 cells/microL. Their presence would, by definition, classify an individual as having AIDS. (See 'AIDS and advanced HIV infection' below.)
Comorbid conditions due to immune activation — Some patients with chronic HIV infection develop evidence of comorbidities (eg, cardiovascular disease, osteoporosis, cognitive dysfunction, and certain malignancies) at younger ages as compared with individuals without HIV. This is thought to be related to chronic inflammation, immune activation, or immunosenescence [23,24]. Although ART attenuates this "premature aging," it does not completely eliminate it. More detailed discussions of comorbid conditions related to immune activation are discussed elsewhere. (See "HIV infection in older adults", section on 'Immune activation' and "Overview of kidney disease in patients with HIV" and "Cardiac and vascular disease in patients with HIV" and "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)
Viral dynamics and latency — Virologic studies in patients with asymptomatic HIV infection not taking antiretroviral treatment show high rates of HIV replication and destruction of an average of 109 CD4 cells daily [25,26]. However, cell death and replacement are in near balance during this phase of the infection; thus, the decline in CD4 cell count is typically slow and a relatively steady state of viral load is achieved despite remarkably high turnover rates of HIV and CD4 cells. As an example, the HIV RNA levels are usually stable over time, with only rare changes exceeding 1 log .
The half-life of HIV in serum is approximately 1.2 days, about 24 hours intracellularly, and about six hours as extracellular virus. About 30 percent of the total body viral burden is turned over daily. Furthermore, 6 to 7 percent of CD4 cells turn over each day, and the entire supply of CD4 cells turns over every 15 days. The implication of these observations is that "AIDS is primarily a consequence of continuous, high-level replication of HIV, leading to virus and immune-mediated killing of CD4 lymphocytes" .
The lymphoid tissue serves as the major reservoir for HIV. Studies of the lymph nodes at this stage reveal high concentrations of extracellular HIV on the follicular dendritic cell processes within germinal centers and intracellular HIV predominantly in its latent form . The viral burden in peripheral blood mononuclear cells is relatively low during this period. The lymph node architecture is disrupted and more HIV is released peripherally into the bloodstream as disease progresses.
Understanding of the viral latent reservoir has implications for HIV cure research and interventions, as discussed further below. (See 'Implications for cure research and interventions' below.)
CD4 cell count decline — In the absence of ART, most patients experience progressive decline in the CD4 T cell count, though there is considerable variation in the rate of decline. Generally, the rate of CD4 cell decline correlates with the viral load (HIV RNA level). (See 'Viral set point establishment' above.)
In one study, the CD4 cell count decreased on average 4 percent per year per log copies/mL of HIV RNA . Other factors, such as HIV subtype or host genetic background, are also associated with the pace of CD4 cell count decline [30,31].
Population-based studies of the natural history of HIV infection in men who have sex with men have suggested that the mean CD4 cell count is approximately 1000 cells/microL prior to seroconversion and decreases to 780 cells/microL at six months following seroconversion and to 670 cells/microL at one year . In a large, prospective study of patients with well-estimated dates of HIV infection (the Concerted Action on Seroconversion to AIDS and Death in Europe, or CASCADE cohort), the estimated median time from infection to CD4 cell count decline to <500 cells/microL was 1.19 years . Some patients have a substantially lower CD4 cell count at one year [34,35].
The rapid decline in peripheral CD4 cells in the early stages of HIV infection may reflect destruction of CD4 cells or a shift of CD4 cells from the peripheral blood to lymphatic tissue. After one year, the rate of CD4 cell decline slows, averaging about 50 cells/microL decrease per year, with a range of 30 to 90 cells/microL decrease per year [16,32,36-39]. Accordingly, there is a wide range of the time to progression to a CD4 cell count <200 cells/microL.
As with depletion of CD4 cells, humoral immunity wanes over time. B cells exhibit increased expression of markers of activation and proliferation . In addition, in advanced HIV infection, B cells undergo terminal differentiation, leading to increased immunoglobulin secretion , although many of these antibodies are nonspecific. This increased immunoglobulin level can be reflected on routine blood chemistries as an increased fraction of the total protein and can be a clue to undiagnosed HIV infection in a person not previously tested. The changes in humoral immunity contribute to increased susceptibility to certain infections, such as S. pneumoniae. In this regard, HIV causes immune dysregulation, not only immune deficiency.
AIDS AND ADVANCED HIV INFECTION
Definition — AIDS is the outcome of chronic HIV infection and consequent depletion of CD4 cells. It is defined as a CD4 cell count <200 cells/microL or the presence of any AIDS-defining condition (table 1) regardless of the CD4 cell count. (See 'Coinfections' below.)
The term advanced HIV infection is often used to refer to infection when the CD4 cell count is <50 cells/microL.
When patients achieve immune reconstitution (eg, increase in the CD4 cell count to >200 cells/microL) with antiretroviral therapy (ART) and have no AIDS-defining conditions, they are no longer considered to have AIDS.
AIDS-defining conditions — AIDS-defining conditions are opportunistic illnesses that occur more frequently or more severely because of immunosuppression. These include mainly opportunistic infections but also certain malignancies as well as conditions without clear alternative etiology thought to be related to uncontrolled HIV infection itself, such as wasting or encephalopathy. The AIDS-defining conditions listed by the United States Centers for Disease Control and Prevention (table 1) and the World Health Organization (table 3) criteria vary slightly.
Prior to introduction and widespread use of combination ART, AIDS-associated illnesses were the principal cause of morbidity and mortality associated with HIV infection. In a study of individuals with HIV seen at selected sites in the United States, AIDS-defining opportunistic illnesses were diagnosed in 10,658 men and 2324 women between 1992 and 1997 . Pneumocystis jirovecii pneumonia was the most common initial opportunistic illness, occurring in 35.9 percent, followed by esophageal candidiasis, Kaposi sarcoma, wasting syndrome, and disseminated Mycobacterium avium complex (MAC) infection (12.4, 11.6, 7.8, and 6.4 percent, respectively).
These opportunistic illnesses typically occur when the CD4 cell count has decreased to <200 cells/microL, although they can occur at higher CD4 cell counts . In an analysis of data from a well-described cohort of HIV-infected men who have sex with men in the United States, the median CD4 count at the time of an AIDS-defining complication was 67 cells/microL, with approximately 10 percent of patients developing an AIDS-defining diagnosis with a CD4 count ≥200 cells/microL . Certain opportunistic infections, such as disseminated MAC infection, cytomegalovirus disease, and cryptococcal meningitis, occur predominantly with a CD4 cell count <50 cells/microL. In the absence of ART, the median time to an AIDS-defining condition once the CD4 cell count is below 200 cells/microL is estimated at 12 to 18 months .
See the dedicated topic reviews for more details on the clinical presentation, diagnosis, and management of these opportunistic conditions in individuals with HIV. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)
Additional findings — Beyond the classic opportunistic illnesses categorized as AIDS-defining conditions (table 1 and table 3), a myriad of other findings are common in the setting of severe immunosuppression from HIV infection.
●Some findings, such as mucocutaneous candidiasis, oral hairy leukoplakia, seborrheic dermatitis, and herpetic infections, can develop with higher CD4 counts but occur with greater frequency and severity when the CD4 count is <200 cells/microL. (See 'Clinical manifestations' above.)
●Additional common dermatologic findings in AIDS include eosinophilic folliculitis, xerosis, and prurigo nodularis. Molluscum contagiosum, bacillary angiomatosis, exacerbation of psoriasis, and scabies infections are also more frequent with advanced immunosuppression and can have severe, atypical presentations. These are discussed in detail elsewhere (see "HIV-associated eosinophilic folliculitis" and "Prurigo nodularis" and "Molluscum contagiosum" and "Bartonella infections in people with HIV"). These skin conditions also commonly occur or flare within the six months or so after initiating ART.
●Hematologic aberrations are also common in the setting of AIDS. Anemia, leukopenia, lymphopenia, and/or thrombocytopenia are found in over 40 percent of patients who present with CD4 count <200 cells/microL . (See "HIV-associated cytopenias".)
●Polyclonal hypergammaglobulinemia is often observed; many antibodies detected are nonspecific, which may partly explain the paradox between high circulating levels of immunoglobulins and an increased risk of bacterial infections (eg, recurrent pneumonia) that occurs in late-stage HIV infection. (See "Bacterial pulmonary infections in patients with HIV".)
Prognosis — While mortality from opportunistic illnesses has become much less common with the widespread use of effective ART, death from AIDS still occurs in individuals with late diagnosis and those who have difficulty engaging in care or adhering to ART. In the absence of effective ART, the median survival time for patients with advanced HIV infection (CD4 cell count <50 cells/microL) is 12 to 18 months [47-49]. Most patients who die of AIDS-related complications have CD4 cell counts in this range.
With ART, the prognosis for an individual with AIDS or advanced HIV improves dramatically. However, the predicted CD4 count recovery is less than that for an individual who started ART earlier in infection. In addition, for someone with a CD4 count below 200 cells/microL, and especially for a person with CD4 count below 50 cells/microL, the 6 to 12 months after initiating ART can be complicated by immune reconstitution inflammatory syndrome. A more detailed discussion of the impact of treatment is found below. (See 'Impact of treatment' below.)
FACTORS AFFECTING HIV DISEASE PROGRESSION — The rate of progression of HIV infection shows enormous individual patient variation in the absence of antiretroviral therapy (ART). Typically, individuals with HIV who do not take ART experience slow progressive loss of CD4 T cells and progress to AIDS over 5 to 10 years. However, some patients progress to AIDS relatively rapidly, even within one to two years of acquiring HIV, while other rare individuals maintain low viral loads and normal CD4 counts for >10 years without treatment (ie, "HIV controllers"). (See 'HIV controllers' below.)
In the San Francisco City Clinical Cohort of 341 men who acquired HIV from 1977 to 1980, 11-year follow-up revealed that 54 percent progressed to AIDS and 19 percent remained asymptomatic . The percentage who developed AIDS (according to the 1987 definition) following seroconversion was 0 at one year, 3 percent at three years, 12 percent at five years, 36 percent at eight years, 53 percent at 10 years, and 68 percent at 14 years . Analysis of this same cohort showed that the mean survival time following a CD4 count of 200 was 38 to 40 months . The most rapid progression from viral transmission to death from AIDS was 28 weeks .
This section will review factors that can influence the rate of HIV progression, such as baseline CD4 count, viral load, coinfections, host immune response and genetic factors, age, and possibly substance use.
CD4 count and viral load — The CD4 cell count and the viral load are independent predictors of HIV progression [54-56]. Discussions of how to measure and interpret CD4 count and viral load results are presented elsewhere. (See "Techniques and interpretation of measurement of the CD4 cell count in people with HIV" and "Techniques and interpretation of HIV-1 RNA quantitation".)
Natural history studies performed prior to the introduction of effective ART found that the average viral load is 30,000 to 50,000 copies/mL and the average rate of decline of CD4 cells ("CD4 slope") is about 50/microL per year [54-56]. In one study of 522 injection drug users, the five-year risk of progressing to AIDS ranged from 0 percent in those with a baseline viral load <500 copies/mL and a CD4 cell count ≥500/microL to 81 percent in those with a baseline viral load ≥10,000 copies/mL and a CD4 cell count <200/microL . In a report of 1604 men with HIV-1 infection from the Multicenter AIDS Cohort Study, 3.6 percent of patients with a baseline CD4 count >750/microL and a viral load <500 copies/mL developed an AIDS-defining condition by nine years, compared with 76 percent of patients who had a CD4 count between 350 and 750 cells/microL and a viral load between 10,000 and 30,000 copies/mL .
Early studies suggested that viral load was the main determinate of CD4 decline [54-56]. However, it is not the only factor. In a study of more than 2700 antiretroviral-naïve, chronically infected persons, presenting HIV RNA levels only minimally predicted the degree of CD4 count decline for the individual patient . Thus, there are other unmeasured factors that contribute to CD4 cell loss. One potential variable is immune activation due to persistent viremia and residual virus in blood and sanctuary sites. (See 'Comorbid conditions due to immune activation' above.)
Other viral factors — Characteristics of the virus itself may also influence the rate of HIV progression.
●HIV-1 versus HIV-2 – In general, HIV type 1 (HIV-1) leads to faster disease progression than HIV type 2 (HIV-2) . HIV-1 causes most HIV infections worldwide, although HIV-2 is an important cause of infection in certain regions of the world, such as West Africa or areas with historic ties to West Africa, such as Portugal, Spain, and Goa, India. The natural history of HIV-2 infection is similar to that of HIV-1 infection (ie, acute infection followed by prolonged, asymptomatic chronic infection and ultimate immunosuppression with greater risk for additional infection and other comorbidities) but is characterized by lower levels of viremia, slower declines in the CD4 cell count, and a longer asymptomatic period of chronic infection. A detailed discussion of the natural history and clinical features of HIV-2 infection is found elsewhere. (See "Epidemiology, transmission, natural history, and pathogenesis of HIV-2 infection" and "Clinical manifestations and diagnosis of HIV-2 infection".)
●HIV subtype – Various HIV-1 subtypes (clades A to J) within group M may vary in immunogenicity, replication kinetics, patterns of transmission, and pathogenesis, and subtype may also influence disease progression . For example, a small but growing body of evidence suggests that HIV-1 subtype D may be more virulent than other subtypes . (See "Global epidemiology of HIV infection", section on 'Molecular epidemiology of HIV'.)
●Coreceptor – While the majority of new HIV infections enter the CD4 T cells via the CCR5 coreceptor, those less common infections that use the CXCR4 coreceptor may be more virulent and lead to faster disease progression (some, but not all, studies examining this phenomenon have found faster CD4 decline and progression to advanced disease with X4 tropism at or near the time of HIV acquisition) [60,61]. (See "Acute and early HIV infection: Pathogenesis and epidemiology", section on 'Pathogenesis'.)
Immunologic and genetic factors — Certain immunologic and genetic factors can impact disease progression. These include :
●CD8 T cells – In the setting of acute HIV infection, plasma viremia levels fall precipitously when virus-specific CD8+ cytotoxic T lymphocytes emerge. Low absolute numbers of HIV specific CD8+ T cells correlate with poor survival outcomes. (See "Acute and early HIV infection: Pathogenesis and epidemiology", section on 'Cellular immune response'.)
●HLA-B57 allele – The presence of the HLA-B57 allele has been linked to a lower viral set point after acute HIV infection . It is also associated with long-term HIV control and hypersensitivity to abacavir. (See 'HIV controllers' below and "Abacavir hypersensitivity reaction".)
●CCR5-delta 32 mutation – Individuals who are CCR5-delta 32 homozygotes (people who inherited the allele from both parents) are highly resistant to HIV infection. Patients who are heterozygous for the 32-base pair deletion can acquire HIV infection but have a slower rate of progression. Alterations of the CCR5 coreceptor have been a focus of cure research. (See "Acute and early HIV infection: Pathogenesis and epidemiology", section on 'Genetic susceptibility' and 'Alterations in the CCR5 coreceptor' below.)
Variations in CYP enzyme isoforms do not impact disease progression but can affect drug clearance and may impact the response to treatment. (See "Overview of antiretroviral agents used to treat HIV", section on 'Efavirenz'.)
Coinfections — Coinfection with certain pathogens may accelerate the rate of HIV progression [64-67]. As examples:
●Coinfection with Mycobacterium tuberculosis accelerates HIV-associated immunodeficiency and increases levels of viremia.
●Infection with Treponema pallidum can impact HIV disease status. In a retrospective study of 52 men with HIV and primary or secondary syphilis, HIV RNA levels increased and CD4 counts declined with the acquisition of syphilis . These trends reversed with effective treponemal therapy. The effect of syphilis on viremia and immunologic status was most marked in those patients with HIV who were not taking ART.
●Fungal infection (eg, oropharyngeal candidiasis, cryptococcosis, histoplasmosis) was found to be a risk factor for HIV disease progression in the EuroSIDA cohort in the era of combination ART .
●Helminthic infections may also affect disease progression. Three randomized controlled trials in Africa have demonstrated that deworming therapy for patients with HIV and helminthic infections is associated with declines in HIV viremia and improvements in CD4 cell counts [68-71].
There are conflicting results as to whether cytomegalovirus (CMV) infection is associated with HIV disease progression [72-75]. One study of patients taking ART found that CMV viremia was associated with disease progression after controlling for CD4 count and viral load . It is unclear, however, whether CMV viremia is acting as a cofactor promoting progression or is simply a marker of worse immune status. There are also conflicting data as to whether hepatitis C virus coinfection may influence the rate of HIV progression.
Unlike other infections, coinfection with either human T-lymphotropic virus type-I (HTLV-I) or human T-lymphotropic virus type-II (HTLV-II) may raise the absolute CD4 count [77,78]. In one study that followed 533 persons who inject drugs (96 with HIV/HTLV-II coinfection and 437 with HIV monoinfection) for an average of 13 years, HIV/HTLV coinfection was associated with older age and higher CD4 and CD8 cell counts compared with patients with HIV alone; however, no difference was seen in HIV viral RNA levels .
Demographics — Rates of progression appear similar by sex, race, and HIV risk category, if adjusted for the quality of care [36,80-87]. However, multiple studies have demonstrated that increasing age at the time of HIV infection is associated with more rapid progression to AIDS in the absence of ART [80-82]. (See "HIV infection in older adults".)
Substance use — There are theoretic concerns that injection drug use could affect HIV disease progression. Drugs, such as opioids, may increase HIV replication in vitro [88,89]. Furthermore, drug use may adversely affect medication adherence and access to care , although clinical trial data are conflicting [91-93].
Alcohol use has been demonstrated to depress levels of CD4 counts [94,95]. One prospective study evaluated the effect of alcohol use on CD4 T cell counts in 595 patients with HIV . In patients not on ART, heavy alcohol consumption was associated with a lower CD4 cell count compared with patients who had a history of abstinence.
IMPACT OF TREATMENT — All individuals should be offered antiretroviral therapy (ART), regardless of the CD4 count or viral load. (See "When to initiate antiretroviral therapy in persons with HIV".)
Treatment results in sustained suppression of HIV RNA, improved cellular immunity (ie, CD4 count), reduced HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T cell activation), and decreased HIV transmission to others. However, access to care and treatment outcomes can differ depending upon demographic and psychosocial factors .
Immunologic recovery — With ART and effective viral suppression, the expected CD4 cell response is an increase of approximately 50 to 150 cells/microL at one year, followed by slower incremental increases of 50 to 100 cells/microL per year until a steady state level is reached [96-98]. In one study, approximately a quarter of individuals experienced a plateau in CD4 count rise after year 4 . Factors that correlate with reduced CD4 recovery include older age, male sex, and the presence of certain coinfections (eg, hepatitis C virus) [100,101].
Several studies have demonstrated that the baseline CD4 cell count affects the extent of immune recovery, suggesting that patients with advanced immune compromise may have limited immunologic reserve [99,102-106]. As an example, a study of 5550 eligible individuals found that 15 percent did not reach a CD4 count >200 cells/microL after three years of viral suppression on ART, and factors associated with poor CD4 count recovery included: increasing age, lower pre-ART CD4 cell count, longer time from initiation of ART to viral suppression, and others . Importantly, those individuals who still had a CD4 count below 200 cells/microL after three years of viral suppression had increased mortality as compared with those who achieved a CD4 count above 200 cells/microL.
In another analysis in which investigators assessed CD4 count changes for 366 individuals with HIV who maintained viral suppression (<1000 copies/mL in this study) for at least four years, nearly all (95 percent) who started ART with a CD4 count of at least 300 cells/microL attained a CD4 count of 500 cells/microL on therapy, whereas 44 percent who started ART with a CD4 count below 100 cells/mL and 25 percent who started with a CD4 count of 100 to 200 cells/microL never reached that threshold.
When interleukin-2 was administered to patients with HIV in conjunction with ART, there was an absolute increase in CD4 cell counts compared with ART alone, but no discernible clinical benefit .
Risk of IRIS — Some patients who initiate ART can develop an immune reconstitution inflammatory syndrome (IRIS). This is manifested as worsening of a known opportunistic infection that had been improving with treatment (paradoxical IRIS) or new signs or symptoms and diagnosis of a previously occult opportunistic infection (unmasking IRIS). This occurs due to the inflammatory response created by a reconstituting immune system. IRIS typically occurs in the first six months following initiation of ART. Beyond this period, with progressive increase in the CD4 count, the risk of IRIS diminishes. A more detailed discussion of IRIS is presented elsewhere. (See "Immune reconstitution inflammatory syndrome".)
Life expectancy and comorbid conditions — ART dramatically changes the course of HIV, leading to a near-normal lifespan, particularly when treatment is initiated early in the course of infection and at high baseline CD4 count [108-113]. A meta-analysis of studies of life expectancy for persons with HIV found that life expectancy has improved over time since the introduction of ART and, in high-income countries, life expectancy for a person with HIV is approximately 43.3 years at age 20 and 32.2 years at age 35, though these estimates are lower for individuals with HIV in low-/middle-income countries . Similarly, significant disparities in mortality and life expectancy exist based on sex/gender, race/ethnicity, transmission category, and other demographic variables .
ART has also resulted in both a decreased incidence of HIV-related comorbid conditions and an improvement in outcomes among those who develop a comorbid disease. Suppression in HIV RNA leads to a reduction in HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T cell activation), which can otherwise lead to end-organ damage (eg, coronary artery disease, liver and kidney disease, neurologic disease, malignancy), as discussed above. (See 'Immunologic recovery' above.)
More detailed discussions of the benefits of ART are presented in separate topic reviews. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "When to initiate antiretroviral therapy in persons with HIV".)
HIV CONTROLLERS — A small percentage of persons with HIV infection maintain very low or undetectable levels of HIV RNA in the absence of antiretroviral therapy (ART), even when highly sensitive assays are used. Such individuals may also maintain high CD4 cell counts for prolonged periods. These individuals are often referred to as "HIV controllers," and those without detectable virus by standard assays are referred to as "non-viremic" or "elite" controllers.
Non-viremic controllers represent a small minority of individuals with HIV (approximately 1 in 300 patients), and the mechanisms that lead to spontaneous virologic control without treatment have been the subject of extensive investigation. In such patients, viral load suppression has been observed to be comparable to that seen in patients who are taking ART [114,115]. The median viral load in two cohorts of non-viremic controllers was 2 copies/mL, although there were fluctuations over time [114,116-118].
Disease progression with CD4 cell count decline is unusual in elite controllers. In a cohort of 63 non-viremic controllers followed at the United States National Institutes of Health for a median of 19 years, disease progression has not been documented . However, modest rates of disease progression have been reported in other cohorts [119,120].
Several factors may be responsible for spontaneous virologic control among individual non-viremic controllers, including infection with a defective HIV variant or host genetic polymorphisms. The human leukocyte antigen class I allele most consistently associated with elite control of HIV is B57 . One study evaluated cellular and humoral immune responses and host genetics in 64 non-viremic controllers, 50 persons with low levels of detectable viremia (<2000 copies/mL, "viremic controllers"), and additional patients with progressive infection . This study showed that HIV gag protein was preferentially targeted by CD8 cell responses in non-viremic and viremic controllers compared with patients with progressive infection. The non-viremic controller group also had a higher frequency of HIV-specific CD4 and CD8 T cells producing interferon gamma and interleukin-2 and a paucity of broadly cross-reactive neutralizing antibodies compared with the other two groups.
Whether non-viremic or elite controllers should be offered ART has been a source of controversy and is discussed elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'HIV controllers'.)
Additional studies, including viral and host genetic analyses, are underway. Information on studies of HIV controllers is available through the National Institutes of Health in the United States.
IMPLICATIONS FOR CURE RESEARCH AND INTERVENTIONS — Interruption of HIV transmission and the HIV natural life cycle is the focus of experimental cure interventions.
Eradication of the latent reservoir — The lymphoid tissue serves as the major reservoir for HIV. (See 'Viral dynamics and latency' above.)
Eradication of the latent reservoir of HIV has been a focus of novel interventions aimed at curing the infection. However, diagnostic techniques are not yet sensitive enough to accurately confirm elimination of the viral reservoir. This was illustrated in a highly publicized study of two patients with HIV who were on antiretroviral therapy (ART) and underwent stem cell transplants for hematologic malignancies . Following the transplants, while the patients continued ART, they had undetectable plasma viral levels, and quantitative polymerase chain reaction (PCR) and co-culture assays did not detect viral RNA or proviral DNA in peripheral blood mononuclear cells or gut-associated lymphoid tissue from rectal samples. However, when ART was discontinued, both patients experienced symptomatic rebound viremia several months later. Phylogenetic analysis of the viral sequences in each patient suggested only a few latently infected cells contributed to the viral rebound.
Alterations in the CCR5 coreceptor — At least two individuals with HIV have achieved long-term, sustained remission with stem cell transplants that altered the CCR5 coreceptor, which is generally required for HIV entry into CD4 T cells. (See "Acute and early HIV infection: Pathogenesis and epidemiology", section on 'Pathogenesis'.)
●In one case, a man with suppressed HIV on ART and acute myeloid leukemia received two stem cell transplants from a human leukocyte antigen (HLA)-matched donor who was homozygous for the CCR5-delta 32 mutation (a 32-base pair deletion that renders T cells resistant to HIV entry) [124,125]. The second procedure led to complete remission of the patient's acute leukemia. He discontinued ART following transplantation, and over 45 months later, he was considered effectively cured of HIV with no active replicating HIV detected in the peripheral blood, bone marrow, or rectal mucosa as assessed by RNA and proviral DNA assays.
●Another man with HIV and Hodgkin lymphoma received an HLA-matched stem cell transplant from a CCR5-delta 32 mutation homozygous donor, and HIV RNA remained undetectable for over 18 months off ART . In contrast to the first case, this person did not require total body irradiation, received a somewhat less aggressive conditioning chemotherapy regimen, and achieved sustained remission with only one stem cell transplant.
However, a third individual who received a stem cell transplant from a CCR5-delta 32 mutation homozygous donor experienced rebound of HIV RNA after stopping ART . The reason was determined to be a result of pre-transplant minority CXCR4 variants in the transplant recipient, emphasizing that to eliminate HIV infection, a person must have HIV virus that is 100 percent CCR5-tropic pre-transplant with no minority variants and must achieve complete CCR5-delta 32 chimerism (meaning complete elimination of the CCR5 coreceptor) post-transplant to achieve sustained remission off ART. In the case of this patient with minority X4 variants, viral tropism shifted from predominantly R5-tropic prior to transplant to predominantly X4-tropic post-transplant, demonstrating that viral escape through a shift of tropism can occur in this setting.
There has been increasing interest in the use of gene therapy in HIV cure research [128,129]. In one report, CRISPR-edited, CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) were transplanted into a patient with HIV-1 infection and acute lymphoblastic leukemia . Although long-term engraftment of the CRISPR-edited allogeneic HSPCs was achieved, the level of CCR5 disruption in peripheral CD4-positive cells was low, and HIV rebound rapidly occurred when ART was interrupted approximately 200 days after transplantation. Whether gene therapy can alter the natural history of HIV infection remains to be determined.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: HIV/AIDS (The Basics)" and "Patient education: Tests to monitor HIV (The Basics)")
●Stages of HIV infection – Human immunodeficiency virus (HIV) infection can be divided into acute HIV infection with seroconversion and chronic HIV infection with or without evidence of acquired immunodeficiency syndrome (AIDS). (See 'Overview of stages of HIV infection' above.)
●Acute HIV infection – Symptomatic acute HIV infection is characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache; however, many patients with primary HIV infection are asymptomatic. Early HIV infection is a period of rapid viral replication with typically very high viral RNA levels. By approximately six months of infection, plasma viremia reaches a steady-state level. (See 'Acute and early HIV infection' above and "Acute and early HIV infection: Clinical manifestations and diagnosis".)
●Chronic HIV infection without AIDS – The period of chronic HIV infection following seroconversion and early infection, but prior to the development of severe immunosuppression, is characterized by relative stability of viral levels and a progressive decline in CD4 cell count. The rate of CD4 cell decline correlates with the level of viremia. (See 'Chronic HIV infection without AIDS' above.)
•During this stage, many persons with HIV are asymptomatic, although some may have generalized lymphadenopathy or nonspecific symptoms. In addition, certain HIV-associated clinical findings, such as oral thrush, seborrheic dermatitis, and infections with herpesviruses, human papillomavirus, bacterial pneumonia, and tuberculosis, may occur despite a CD4 cell count >200 cells/microL. These conditions become more frequent and often more severe as the CD4 count approaches 200 cells/microL. (See 'Clinical manifestations' above.)
•Some patients may also develop comorbid conditions (eg, cardiovascular disease, renal disease, osteoporosis, cognitive dysfunction, and certain malignancies), which are seen at relatively younger ages compared with individuals without HIV. This may be related to chronic inflammation, immune activation, or immunosenescence. (See 'Comorbid conditions due to immune activation' above.)
●AIDS and advanced HIV infection – AIDS is defined by a CD4 cell count <200 cells/microL or the presence of any AIDS-defining condition (table 1), regardless of the CD4 cell count. AIDS-defining conditions are opportunistic illnesses or malignancies that occur more frequently or more severely in immunocompromised persons. These include mainly opportunistic infections, such as Pneumocystis jirovecii pneumonia, toxoplasmosis, and disseminated Mycobacterium avium complex infection. Certain malignancies (Kaposi sarcoma, lymphoma), as well as conditions without clear alternative etiology thought to be related to uncontrolled HIV infection itself, such as wasting or encephalopathy, are also AIDS-defining conditions. (See 'AIDS-defining conditions' above.)
●Factors affecting disease progression – Certain viral and host factors are associated with faster decline in CD4 count and progression to AIDS. Similarly, low pre-antiretroviral therapy (ART) CD4 counts are associated with poor immune recovery following ART initiation. This emphasizes the importance of early diagnosis and ART for all infected individuals. (See 'Factors affecting HIV disease progression' above.)
●Impact of ART – Effective ART results in sustained suppression of HIV RNA, improved cellular immunity (ie, CD4 count), and reduced HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T cell activation). The life expectancy for a person with HIV with virologic suppression on ART approaches that of the general population, though certain comorbidities remain more common, and disparities in life expectancy based on sex/gender, race/ethnicity, and other demographic variables persist. Individuals who start ART at low baseline CD4 counts have higher mortality than those who initiate ART earlier in HIV infection. (See 'Impact of treatment' above.)
●HIV controllers – A minority of individuals with HIV maintain low or nondetectable viremia in the absence of ART. They are called HIV controllers. Some of these patients are referred to as non-viremic or elite controllers because they have no detectable viremia, even on ultrasensitive diagnostic testing. (See 'HIV controllers' above.)
●Cure research – Interventions that interrupt the natural history of HIV infection have been the focus of experimental cure interventions. These include stem cell transplants from CCR5-delta 32 homozygous donors, which result in the inability of HIV to enter CD4 cells, and have led to rare cases of sustained HIV remission. Further efforts to modify the CCR5 receptor and achieve sustained remission of HIV in the absence of ART are ongoing. (See 'Implications for cure research and interventions' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John G Bartlett, MD, who contributed to an earlier version of this topic review.
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