HIV AIDS natural history, complications, and prognosis

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

Overview

Currently there is no cure for AIDS but taking treatment dramatically increased the amount of time people with HIV remain alive. Research continues in the areas of drug treatments and vaccine development. Unfortunately, HIV medications are not always available in the developing world, where the bulk of cases now occur. Opportunistic infections and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection.

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), survival increases and CD4 cell recovery occurs at varying rates. The rate of 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

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. 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

Cognitive Impairment in HIV

For AIDS dementia complex , click here

Anatomical Areas Involved

• HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the basal ganglia, deep white matter, and hippocampal regions.
• Neuroimaging studies of HIV patients indicate that significant volume reductions are apparent in the frontal white matter, whereas subcortically, hypertrophy is apparent in the basal ganglia, especially the putamen.
• Some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment. Cerebral brain volume is associated with factors related to duration of the disease and CD4 nadir; patients with a longer history of chronic HIV and higher CD4 nadir present with greater cerebral atrophy.
• CD4 lymphocyte counts have also been related to greater rates of brain tissue loss.
• Current factors, such as plasma HIV RNA, have been found to be associated with brain volumes as well, especially with regards to basal ganglia volume and total white matter.
• Changes in the brain may be ongoing but asymptomatic, that is with minimal interference in functioning, making it difficult to diagnose HIV-associated neurocognitive disorders in the early stages.

Behavioral Aspects of Neurocognitive Impairments

Cognitive Impairments

• Cognitive impairments associated with HIV occur in the domains of attention, memory, verbal fluency, and visuospatial construction. Specifically for memory, the lowered activity of the hippocampus changes the basis for memory encoding and affects mechanisms such as long-term potentiation.
• Severity of impairment in different domains varies depending on whether or not a patient is being treated with HAART or monotherapy.
• Studies have shown that patients exhibit cognitive deficits consistent with dysfunction of fronto-striatal circuits including associated parietal areas, the latter of which may account for observed deficits in visuospatial function.

Psychological Dysfunction

• In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of clinical depression and alexithymia, i.e., difficulty processing or recognizing one’s own emotions. Patients also have more difficulty recognizing facial emotions.
• Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV. HIV patients in early stages show mild difficulties in concentration and attention. In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed. Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.
• The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes. The severity of neurocognitive impairment is associated with nadir CD4, suggesting that earlier treatment to prevent immunosuppression due to HIV may help prevent HIV-associated neurocognitive disorders.

Benefits of Staging the System

• Easy to evaluate for new treatments
• Define prognosis and guide patient counselling
• Frame work for management and follow up
• Contribute to the quality of the care of individuals who are HIV infected.

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 about 20 years.

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