HIV AIDS natural history, complications, and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] ; Alejandro Lemor, M.D. [3]

Overview

There is currently no cure for HIV/AIDS. HIV infection leads to progressive decline in CD4+ T-lymphocyte count increasing the risk for opportunistic infections and malignancies. Despite having a variable rate of progression determined by specific host and viral factors, the median time from infection to the development of AIDS ranges from 8 to 10 years among untreated individuals. With the advent of highly active antiretroviral therapy (HAART), both morbidity and mortality have dramatically decreased. Survival and the rate of CD4-count recovery is influenced by age, baseline CD4 cell count, baseline viral load and initial and sustained viral suppression. In areas where HAART is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to near normal (assuming full compliance to HAART). HIV infection makes individuals highly susceptible to severe opportunistic infections and neoplastic disease. Major complications of HIV/AIDS include Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex infection, cryptococcal meningitis, cytomegalovirus retinitis, Kaposi sarcoma, and primary CNS lymphoma.

Natural History

In the early days of the HIV epidemic, knowledge about the natural history of HIV accrued rapidly. However, the widespread use of effective antiretroviral therapy (ART) brought a shift in focus of the research community away from studies of natural history to those of treated infection. HIV infection leads to progressive decline in CD4+ T-lymphocyte count increasing the risk for opportunistic infections and malignancies. Despite having a variable rate of progression determined by specific host and viral factors, the median time from infection to the development of AIDS ranges from 8 to 10 years among untreated individuals. With the advent of highly active antiretroviral therapy (HAART), both morbidity and mortality have dramatically decreased. Survival and the rate of CD4-count recovery is influenced by age, baseline CD4 cell count, baseline viral load and initial and sustained viral suppression.

Disease Progression

Natural history of untreated HIV - By Sigve - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=15383502

Acute HIV syndrome

Approximately half of patients that acquire HIV develop a mononucleosis-like syndrome within 3-6 weeks during which the viral titers are very elevated. Common symptoms include acute but brief and nonspecific influenza-like retroviral syndrome that can include fever, malaise, lymphadenopathy, pharyngitis, arthritis, or skin rash. This causes a rapid drop in CD4 T-Cell count as these cells are the primary host for viral replication. Within several weeks patients mount a strong immune response to the virus that causes a drop in the viral titers. However, this response is not adequate to completely suppress viral replication. Although viremia may become undetectable, replication persists in the lymphoid organs. Although a significant number of patients do not have an acute HIV syndrome, these processes do occur albeit without symptoms.

Clinical Latency

This period is sometimes called asymptomatic HIV infection or chronic HIV infection. After the initial phase, the majority of patients with HIV develop a clinical latency period that lasts several years. During this period, all patients have a progressive decline in immune status and gradual depletion of CD4 T-cells. This period does not represent a true microbiological or pathological latency, but rather defines a time period without clinically manifest disease. People who are on highly active antiretroviral therapy (HAART) may live with clinical latency for several decades.

Clinically Apparent Disease (AIDS)

The eventual outcome of most HIV infections is gradual immune system deterioration resulting in AIDS. Clinically apparent disease is classically diagnosed following an AIDS-defining illness i.e. an opportunistic infection or neoplasm that demonstrates a significant compromise of the immune system. Another diagnostic sign, although not strictly clinical, is the decline of CD4 T-cell count below 200 cells/mm³. Without treatment, individuals diagnosed with AIDS may survive approximately 1-3 years.

Distinct Patterns of Progression

The natural course of untreated HIV infection varies widely. The past decade has seen considerable interest in the identification of subgroups of HIV-positive persons who exhibit distinct patterns of disease progression:

• Long-term nonprogressors (LTNP) are individuals who remain asymptomatic for a prolonged period of time off ART with a high CD4 cell count. Although it is widely reported that 1–5% of the HIV-positive population are LTNP, these estimates are complicated by the fact that there is no standardized 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 cell counts) differ widely. LTNP status can be lost, and thus the reported prevalence of LTNP within a study will depend on the required period of follow-up. Predictors of loss of LTNP status are a high baseline HIV DNA level and a more rapid increase in HIV DNA over the first year of follow-up, suggesting the presence of ongoing (but low-grade) viral replication. Indeed, HIV RNA levels in plasma increased by 0.04 log10 copies/ml per year over the first 8 years after diagnosis. As such, it is likely that virtually all HIV-positive persons will eventually experience disease progression if left untreated.

• Elite controllers or viral controllers are individuals who are able to suppress HIV replication to such an extent that viral load levels remain undetectable in the absence of ART. As with LTNP, several studies have attempted to identify factors associated with elite controller status. Loss of naive CD4 T cells seems to be a universal feature of elite controllers, despite the ability of such individuals to maintain undetectable viral loads. However, CD4 naive lymphocytes from elite controllers tend to be less susceptible to HIV infection than such lymphocytes from progressors or uninfected individuals. This specific feature was linked with upregulation of a cellular kinase (p21). HIV-specific CD4 activation is a hallmark of viral control but, many other host factors have been linked with this phenotype, including cellular restriction factors such as APOBEC, tetherin, and SAMHD1. In addition, several viral factors may also play a role, including deletions or mutations with the viral genes that may have an impact on the ability of the virus to replicate.

Complications

HIV infection makes individuals highly susceptible to severe opportunistic infections and neoplastic disease. The following complications are classically observed among patients with significant immunocompromise and rarely manifest among patients with a CD4 count greater than 350 cells/mm³.

1. Infections

• Pneumocystis jirovecii pneumonia
• Tuberculosis
• Disseminated Mycobacterium avium complex
• Salmonellosis (Septicemia)
• Cytomegalovirus retinitis
• Candidiasis
• Cryptococcal meningitis
• Cerebral Toxoplasmosis
• Cryptococcal meningitis
• Disseminated Coccidiomycosis
• Disseminated Histoplasmosis
• Cryptosporidiosis
• Isosporiasis

2. Cancers

• Kaposi Sarcoma
• AIDS-related lymphomas

• Non-Hodgkin's Lymphoma
• Hodgkin's Lymphoma
• Primary CNS Lymphoma
• Burkitt's Lymphoma
• Large B-cell Lymphoma

• Invasive cervical cancer
• Invasive anal cancer

3. Other Complications

• HIV associated nephropathy
• HIV induced pericarditis
• HIV-associated wasting syndrome
• Aortitis
• AIDS dementia complex
• Lymphoid interstitial pneumonia

Prognosis

Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype, and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study. In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to near normal (assuming full compliance to HAART).