AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Background

Human immunodeficiency virus (HIV) disease was first described in 1981 among 2 groups—one in San Francisco and the other in New York City. Numerous young homosexual men presented with opportunistic infections that, at the time, were typically associated with severe immune deficiency due to Pneumocystis pneumonia (PCP) or aggressive Kaposi sarcoma.¹ The HIV virus itself was not identified for another 2 years²; during that time, various other causes were considered, including lifestyle factors, chronic drug abuse, and other infectious agents.³

The HIV epidemic spread rapidly and silently in the absence of testing. However, clear clinical implications arose before society became aware of the disease; for example, prior to the recognition of HIV, only one case of Pneumocystis pneumonia not clearly associated with immune suppression was diagnosed in the Unites States between January 1976 and June 1980. In 1981 alone, 42 similar diagnoses were made, and, by December 1994, 127,626 cases of Pneumocystis pneumonia with HIV infection as the only identified cause of immune suppression had been reported to the Centers for Disease Control and Prevention (CDC). Also, Kaposi sarcoma is up to 30,000 times more likely to develop in persons with HIV infection than in immunocompetent persons.

HIV is a blood-borne, sexually transmissible virus. The virus is typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding. The most common route of infection varies from country to country and even among cities, reflecting the population in whom HIV was introduced initially and local practices. Co-infection with other viruses that share similar routes of transmission, such as hepatitis B, hepatitis C, and human herpes virus 8 (HHV8; also known as Kaposi sarcoma herpes virus [KSHV]), is common.

Two distinct species of HIV (HIV-1 and HIV-2) have been identified, and each is composed of multiple subtypes, or clades. All clades of HIV-1 tend to cause similar disease, but the global distribution of the clades differs. This may have implications on any future vaccine, as the B clade, which is predominant in the developed world (where the large pharmaceutical companies are located), is rarely found in the developing countries that are more severely affected by the disease.

HIV-1 probably originated from one or more cross-species transfers from chimpanzees in central Africa.⁴ HIV-2 is closely related to viruses that infect sooty mangabeys in western Africa.⁵ Genetically, HIV-1 and HIV-2 are superficially similar, but each contains unique genes and its own distinct replication process.

HIV-2 carries a slightly lower risk of transmission, and HIV-2 infection tends to progress more slowly to acquired immune deficiency syndrome (AIDS). This may be due to a less-aggressive infection rather than a specific property of the virus itself. Persons infected with HIV-2 tend to have a lower viral load than people with HIV-1^{6, 7}, and a greater viral load is associated with more rapid progression to AIDS in HIV-1 infections.^{8, 9} Because HIV-2 is rare in the developed world, most of the research and vaccine and drug development has been (perhaps unfairly) focused on HIV-1.

Electron microscopy of HIV-1 virions, courtesy of CDC/Dr. Edwin P. Ewing, Jr.

A considerable amount of stigma has been attached to HIV infection, mostly because of the virus's association with sexual acquisition and the inference of sexual promiscuity. Consequences of this stigma have included discrimination and reluctance to be tested for HIV infection. However, such attitudes are inappropriate because HIV is poorly transmissible without sexual contact or blood contact and because the expected survival is long in patients with HIV infection who are receiving treatment. HIV is not transmitted during casual contact and is readily inactivated by simple detergents. Much of the concern regarding HIV infection is due to the incurability of the infection and the relentless immune decline and eventual premature death in the vast majority of infected people.

The spread of HIV was retrospectively shown to follow the trucking routes across Africa from logging camps, and the bush-meat trade combined with aggressive logging and improved transportation in the mid-20th century may have allowed what was likely occasional cross-species transmission events to propagate across the country and, eventually, the globe.¹⁰

Since the discovery of HIV and its link to acquired immune deficiency syndrome (AIDS), great strides have been made in understanding its biology and in developing effective treatments. The difficulty in dealing with HIV on a global scale is largely due to the fact that HIV infection is far more common in resource-poor countries. In the developed world, antiretroviral therapy has greatly improved prognosis and increased survival rates. Public education programs have raised awareness such that testing and prevention of infection are more common. Both of these approaches are difficult in countries with undereducated or underfunded populations.

Political denial and inaction have also likely caused considerable damage. Several governments in countries with high HIV infection rates were slow to admit that they had an HIV epidemic, and at least one (South Africa) initially rejected that AIDS was even a problem, then that the disease was caused by HIV infection, and, most recently, that antiretroviral therapy was effective in treating HIV infection and preventing MTCT. Changes have now occurred but have been slow and have had an unknown cost.

For supplementary information, see the eMedicine articles Early Symptomatic HIV Infection and HIV Infection and AIDS.

Pathophysiology

Virology of HIV

HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA. There is no fixed site of integration, but the virus tends to integrate in areas of active transcription, probably because these areas have more open chromatin and more easily accessible DNA.^{11, 12} This greatly complicates eradication of the virus by the host, as latent proviral genomes can persist without being detected by the immune system and cannot be targeted by antivirals.

Genome layout of HIV-1 and HIV-2

HIV contains the 3 species-defining retroviral genes—gag (group-specific antigen; the inner structural proteins), pol (polymerase; also contains integrase and protease—the viral enzymes—and is produced as a C-terminal extension of the Gag protein), and env (envelope; the outer structural proteins responsible for cell-type specificity).

HIV-1 has 6 additional accessory genes—tat, rev, nef, vif, vpu, and vpr. HIV-2 does not have vpu but instead has the unique gene vpx. The only other virus known to contain the vpu gene is simian immunodeficiency virus in chimpanzees (SIV_cpz), which is the simian equivalent of HIV.⁴ Interestingly, chimpanzees with active HIV-1 infection are resistant to disease.¹³

The accessory proteins of HIV-1 and HIV-2 are involved in viral replication and may play a role in the disease process.^{14, 15} The outer part of the genome consists of long terminal repeats (LTRs) that contain sequences necessary for gene transcription and splicing, viral packaging of genomic RNA, and dimerization sequences to ensure that 2 RNA genomes are packaged. The dimerization, packaging, and gene-transcription processes are intimately linked; disruption in one process often subsequently affects another. The LTRs exist only in the proviral DNA genome; the viral RNA genome contains only part of each LTR, and the complete LTRs are re-created during the reverse-transcription process prior to integration into the host DNA.

The Biologic Basis for AIDS

The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS.^{16, 17, 18}

There is a specific decline in the CD4⁺ helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.^{19, 20} Immune responses to certain antigens begin to decline, and the host fails to adequately respond to opportunistic infections and normally harmless commensal organisms. Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral).

The pattern of opportunistic infections in a geographic region reflects the pathogens that are common in that area. For example, persons with AIDS in the United States tend to present with commensal organisms such as Pneumocystis and Candida species, homosexual men are more likely to develop Kaposi sarcoma because of co-infection with HHV8, and tuberculosis is common in developing countries.

Recent work has shown the importance of gut-associated lymphoid tissue (GALT) in HIV replication.²¹ Although the portal of entry for HIV infection is typically through direct blood inoculation or exposure of the virus to genital mucosal surfaces, the GI tract contains a large amount of lymphoid tissue, making this an ideal site for HIV replication.

GALT has been shown to be a site of early viral seeding and establishment of the proviral reservoir. This reservoir contributes to the difficulty of controlling the infection, and efforts to reduce the levels of HIV provirus through sustained antiretroviral therapy (alone or in combination with interleukin-2 activation of resting HIV-infected T cells) have consistently failed.²²

A feature of HIV replication in GALT is that it is compartmentalized, even among different areas of the gut.²³ Measurements of CD4⁺ T cells in GALT show relatively less reconstitution with antiretroviral therapy than that observed in peripheral blood.^{24, 25} At least one report has suggested that early treatment may result in better GALT CD4 T-cell recovery²⁵, but clinical data generally argue against early initiation of therapy, which has not been shown to improve long-term survival. In addition, HIV replication can be detected even in patients with supposedly suppressed replication, as judged by plasma viral load measurements. CD8⁺ killer T-cell responses to HIV occur in GALT and do not decline with antiviral therapy as much as peripheral measurements do.²⁶ These findings underscore the limitations of peripheral measurements in what is really a central viral replication.

One theory for the discrepancy between GALT and blood measurements is that ongoing viral replication in the lymphoid tissue, and the resulting immune activation, may actually hamper efficient CD4⁺ T-cell replenishment.²⁷

Studies of T-cell–replication kinetics have revealed that untreated HIV infection is characterized by rapid T-cell turnover but a defect in T-cell replication from the thymus.^{28, 29} These changes can be reversed with effective long-term antiviral therapy,^{30, 31} suggesting that they are due to a direct effect of the virus or are a feature of the immune response against HIV. It is known that normal cell cycling is necessary to produce a normal cytokine profile³² and that HIV causes cell-cycle arrest,³³ but whether this is the exact mechanism is unresolved.

Several of the HIV proteins directly affect T-cell function, either by disrupting cell cycling or down-regulating the CD4 molecule. The loss of T cells is clearly a primary issue, as the T-cell repertoire narrows in terms of which antigens the immune system will recognize and respond to. Antiviral therapy is able to reverse these changes,³⁴ but the degree of reversal is decreased if therapy is initiated very late in the infection and is further decreased when therapy is initiated when CD4 T-cell counts are 200/μL and below. Direct cytotoxic effects of viral replication are likely not the primary cause of CD4 T-cell loss; a significant bystander effect³⁵ is likely secondary to T-cell apoptosis as part of immune hyperactivation in response to the chronic infection. Infected cells may also be affected by the immune attack.

One interesting issue is that the co-receptor usage of the virus strains tends to change over time. The initial infection nearly always involves a strain that uses the chemokine receptor 5 (CCR5) co-receptor found on macrophages and dendritic cells. People who are homozygous for deletions in the CCR5 gene tend to be resistant to infection and may have some protection against progression.^{36, 37} Over time, the receptor usage shifts to chemokine-related receptor (CXCR4) and other related receptors found on CD4 T cells. These virus strains are more likely to cause cell fusion (syncytia formation). This trend is far from absolute but does correlate in many people with disease progression.³⁸

Regardless of the cause for the disruption, a loss of thymic replacements in the face of an induced state of immune activation and T-cell loss seems to be a key component of the mechanism by which HIV narrows the T-cell repertoire and progresses to AIDS.^{39, 40, 41}

Visible effects of HIV infection come in the form of disrupted lymph-node architecture. This disruption is temporal, and, at one point, lymph-node biopsy was considered as a form of staging the disease.^{42, 43} The disruption of the follicular dendritic network in the lymph nodes and subsequent failure of normal antigen presentation are likely contributors to the disease process. HIV replicates in activated T cells (its promotor is a nuclear factor kappa B [NF-kappa-B]–binding region, the same protein that promotes other proteins in activated T cells and macrophages), and activated T cells migrate to the lymph nodes. As such, much of the viral replication occurs outside of the peripheral blood, even though serum viral load is still a useful surrogate marker of viral replication.

For additional information, see Medscape's HIV Pathogenesis Resource Center.

Phases of HIV Infection

Clinical HIV infection undergoes 3 distinct phases—acute seroconversion, asymptomatic infection, and AIDS. Each is discussed below.

Acute seroconversion

During this phase, the infection is established, and a proviral reservoir is created.^{44, 45} This reservoir consists of persistently infected cells, typically macrophages, and appears to steadily release virus. Some of the viral release replenishes the reservoir, and some goes on to produce more active infection. The proviral reservoir, as measured by DNA polymerase chain reaction (PCR), seems to be incredibly stable. Although it does decline with aggressive antiviral therapy, the half-life is such that eradication is not a viable expectation.

The size of the proviral reservoir correlates to the steady-state viral load and is inversely correlated to the anti-HIV CD8 T-cell responses. Aggressive early treatment of acute infection may lower the proviral load, but, generally, treatment in newly infected (but postseroconversion) patients yields no long-term benefit.

At this point, the viral load is typically very high, and the CD4 T-cell count drops precipitously. With the appearance of anti-HIV antibodies and CD8 T-cell responses, the viral load drops to a steady state and the CD4 T-cell count returns to levels within the reference range, although slightly lower than before infection.

Seroconversion may take a few weeks, up to several months. Symptoms during this time may include fever, flulike illness, lymphadenopathy, and rash and develop in approximately half of all people infected with HIV.

Asymptomatic HIV infection

At this stage in the infection, persons infected with HIV exhibit few or no signs or symptoms for a few years to a decade or more. Viral replication is clearly ongoing during this time,⁴⁶ and the immune response against the virus is effective and vigorous. In some patients, persistent generalized lymphadenopathy is an outward sign of infection. During this time, the viral load, if intreated, tends to persist at a relatively steady state, but the CD4 T-cell count steadily declines. This rate of decline is related to, but not easily predicted by, the steady-state viral load.

No firm evidence has shown that the initiation of therapy early in the asymptomatic period is effective, although very late initiation is known to result in a less effective response to therapy and a lower level of immune reconstitution.

AIDS

When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. For surveillance purposes in the United States, a CD4 T-cell count less than 200/μL is also used as a measure to diagnose AIDS, although some opportunistic infections develop when CD4 T-cell counts are higher than 200/μL, and some people with CD4 counts under 200/μL may remain relatively healthy.

Many opportunistic infections and conditions are used to mark when HIV infection has progressed to AIDS. The general frequency of these infections and conditions vary from rare to common but are uncommon or mild in immunocompetent persons. When one of these is unusually severe or frequent in a person infected with HIV and no other causes for immune suppression can be found, AIDS can be diagnosed.⁴⁷

The following are such opportunistic infections and conditions:

• Candidiasis of bronchi, trachea, or lungs
• Candidiasis, esophageal
• Cervical cancer, invasive*
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal (duration >1 mo)
• Cytomegalovirus disease (other than liver, spleen, or nodes)
• Cytomegalovirus retinitis (with vision loss)
• Encephalopathy, HIV-related
• Herpes simplex - Chronic ulcer or ulcers (duration >1 mo) or bronchitis, pneumonitis, or esophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal (duration >1 mo)
• Kaposi sarcoma
• Lymphoma, Burkitt (or equivalent term)
• Lymphoma, immunoblastic (or equivalent term)
• Lymphoma, primary, of the brain
• Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary
• Mycobacterium tuberculosis infection, any site (pulmonary* or extrapulmonary)
• Mycobacterium infection with other species or unidentified species, disseminated or extrapulmonary
• Pneumocystis pneumonia
• Pneumonia, recurrent*
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia, recurrent
• Toxoplasmosis of the brain
• Wasting syndrome due to HIV infection

*Added in the 1993 AIDS surveillance case definition

Timeline of CD4 T-cell and viral load changes over time in untreated HIV infection, from Wikipedia, based on an original from Pantaleo et al (1993).

Frequency

United States

The most recent frequency data concerning HIV infection in the United States are from 2006. According to data from states that have confidential name-based reporting, the national-average incidence of HIV infection is 18.5 per 100,000 population. The incidence rate of late HIV disease (AIDS) is 12.3 per 100,000 population. With improved estimation methods, the number of new HIV infections in 2006 has been estimated at 56,300. Approximately 1 million persons have been diagnosed with AIDS since 1981, and more than 500,000 people have died with AIDS (although reporting limitations mean that not every "death with AIDS" is directly attributable to AIDS itself). Approximately 1.1 million people currently have HIV infection in the United States.

US rates vary by state. See the latest Centers for Disease Control (CDC) surveillance report for full details (maps 1 and 2).

The overall figures may give a false impression that the HIV epidemic is relatively homogenous. In fact, the HIV epidemic is best viewed as numerous separate epidemics among distinct risk groups, although the various epidemics clearly have some level of overlap. In any given area, the infection may be most prevalent among users of intravenous drugs who share needles. In another, the main risk group may be men who have sex with other men. And in yet another, the main risk group may be female sex workers.

These sub-epidemics each follow their own pattern, although there is some degree of interdependence. Nearly all early cases of HIV infection detected in the Western Hemisphere were in homosexual men, but female partners of bisexual men with HIV infection gave rise to an increased spread among heterosexual persons. Contributing to the increased cross-prevalence were persons with hemophilia who had been infected with HIV from contaminated factor VIII and persons who used intravenous drugs, an activity that transcends all sexual preferences. Currently, less than half of new HIV infections are reported in homosexual men, and infected heterosexual women outnumber infected heterosexual men nearly two to one.⁴⁸

Incidence of HIV infection by risk group. From the CDC Web site (copyright-free) derived from the revised 2006 estimated figures.

International

Worldwide, approximately 39.5 million people (1% of the global adult population aged 15-49 y) are infected with HIV. UNAIDS estimates that 4.3 million people were newly infected with HIV and that 2.9 million people died from AIDS in 2006. The vast majority of infections remain in sub-Saharan Africa, where nearly 6% of the population is thought to be infected.

Between 2004 and 2006, the prevalence of HIV infection in central and eastern Asia and Eastern Europe increased by 21%. During this period, the number of new HIV infections in persons aged 15 to 64 years rose by 70% in Eastern Europe and central Asia.

The infection rates in many developed countries remain stable, and some developing countries have achieved significant gains in controlling and even reversing the effects of the HIV epidemic. However, this is partially due to deaths in HIV-infected people, together with simultaneous prevention of new infections. These figures together show that global HIV infection is in a state of flux.

The mortality rate in some countries has greatly increased. In South Africa (a country that, despite having a relatively late-onset HIV epidemic, has developed one of the highest prevalence rates), the all-cause HIV-associated mortality rate increased by 79% between 1997 and 2004. In women aged 25-34 years, mortality rates increased by 500% during this period.

Swaziland has the highest overall prevalence of HIV infection (>33.4% of all adults).

The Ministry of Health in Zambia predicts that, without therapy and assuming current levels of prevalence, young adults have a 50% lifetime risk of dying from AIDS.

In developing nations, co-infection with HIV and tuberculosis is very common. The immunosuppressed state induced by HIV infection contributes not only to a higher rate of tuberculosis reactivation but also to an increased disease severity, as with many other opportunistic infections.

Further details of the global epidemic can be found in the Joint United Nations Programme on HIV/AIDS 2006 Epidemic Update.

Mortality/Morbidity

Untreated HIV infection carries an overall mortality rate of more than 90%. The CD4 T-cell counts remain stable in a small percentage of people with HIV infection. This is usually associated with strong anti-HIV CD8 T-cell responses, a low viral load, and low proviral reservoir. The average interval between initial HIV infection and progression to AIDS is 8-10 years.

Once infection has progressed to AIDS, the survival period is usually less than 2 years in untreated patients. Persons in whom the infection does not progress long-term may not develop AIDS for 15 years or longer, although many still exhibit laboratory evidence of CD4 T-cell decline or dysfunction.^{50, 51, 52, 53}

The appropriate use of combination antiretroviral therapies and prophylaxis for opportunistic infections dramatically improves survival and greatly decreases the risk of secondary opportunistic infections.^{54, 55, 49} The risk of AIDS-associated lymphoma is not altered by antiviral therapy and, as such, has grown in prevalence among overall AIDS-defining conditions. Sackoff et al found that, since 1999, the HIV-related mortality rate in New York City has decreased by approximately 50 deaths per 10,000 people with AIDS per year. The rate of non–HIV-related deaths has also seen a more modest but consistent decline, with about 7.5 fewer deaths per 10,000 people with AIDS per year.⁵⁵ Importantly, many researchers have consistently shown that the primary risk factor for infection affects mortality. For example, the mortality rate among intravenous drug users tends to be higher, whether related to HIV disease or non-HIV disease.

Overall, with the increasing use of antiretroviral therapy and the introduction of better antiviral regimens, survival with HIV infection has increased over time, although it is not yet equivalent to that in uninfected individuals.

Changes in survival of people infected with HIV. As therapies have become more aggressive they have been more effective, although survival does not quite reach that of uninfected people. Modified from an original published by Lohse et al 2007, "Survival of persons with and without HIV infection in Denmark, 1995-2005."

Race

In the United States, the prevalence of HIV infection is highest in blacks (71.3 cases per 100,000 population). The prevalence is also high among Hispanic persons (27.8 per 100,000 population). These increased rates are due to socioeconomic factors rather than genetic predisposition.

Sex

In the developed world, HIV infection is much more common in males. Among heterosexuals, females are more likely to acquire HIV infection from an infected male than a male is from an infected female, but a large proportion of infections in males are due to homosexual contact, with or without injection drug use. Males are also more likely to acquire HIV infection from injection drug use alone.

Males were also more likely to acquire HIV infection through contaminated blood products during treatment of hemophilia before universal testing of the blood supply was instituted. (The procedures used in purifying factor VIII and producing cryoprecipitate are effective in preserving biologic activity of HIV. To negate this, heat treatment was added to the purification of factor VIII to inactivate HIV and other viruses). This is a small contribution to the predominance of HIV infection in males.

In the developing world, HIV infection is equally common in males and females. The primary route of HIV transmission in the developing world is heterosexual contact.

Age

Young adults tend to be at higher risk of acquiring HIV, typically through high-risk activities such as unprotected sexual intercourse or intravenous drug use.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

History

The history should be carefully taken to elicit possible exposures to human immunodeficiency virus (HIV). Risk factors include the following:

• Unprotected sexual intercourse, especially receptive anal intercourse (8-fold higher risk of transmission)
• A large number of sexual partners
• Prior or current STDs: Gonorrhea and chlamydia infections increase the HIV transmission risk 3-fold, syphilis raises the transmission risk 7-fold, and herpes genitalis raises the transmission risk up to 25-fold during an outbreak.
• Sharing of intravenous drug paraphernalia
• Receipt of blood products (before 1985 in the United States)
• Mucosal contact with infected blood or needle-stick injuries
• Maternal HIV infection (for newborns, infants, and children): Steps taken to reduce the risk of transmission at birth include cesarean delivery and prenatal antiretroviral therapy in the mother and antiretroviral therapy in the newborn immediately after birth.

The patient may present with signs and symptoms of any of the stages of HIV infection. Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash.

The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom.

AIDS manifests as recurrent, severe, and occasionally life-threatening infections and/or opportunistic malignancies. The signs and symptoms are those of the presenting illness, meaning that HIV infection should be suspected as an underlying illness when unusual infections present in apparently healthy individuals.

HIV infection itself does cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause).

Physical

No physical findings are specific to HIV infection. The physical findings are those of the presenting infection or illness.

• Generalized lymphadenopathy is common.
• Weight loss may be apparent.
• Evidence for risk factors or minor concurrent opportunistic infections (eg, herpetic lesions on the groin, widespread oral candidiasis) may be clues to HIV infection.
• Many patients with AIDS develop cytomegalovirus retinitis with severe vision loss.

Causes

HIV disease is caused by infection with HIV-1 or HIV-2, both of which cause very similar conditions. They differ in transmission and progression risks.

There is less evidence that treatment of HIV-2 infection slows progression, and certain antiretroviral medications are not effective against HIV-2. The HIV-1 viral-load assays are much less reliable, if they work at all. HIV-2 viral load assays have been developed, but none has been approved by the FDA except as blood donor–screening tools.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Other Problems to be Considered

Any of the opportunistic infections or acquired immune deficiency syndrome (AIDS)–associated cancers can occur in the absence of human immunodeficiency virus (HIV) infection, although they usually develop in the setting of some other form of immune suppression or defect. The possibility of HIV infection must be considered on a case-by-case basis. For example, a young adult with leukemia undergoing chemotherapy is at high risk for many different opportunistic infections.

Other causes of immune suppression (eg, chemotherapy, immune disorders, severe combined immune deficiency [SCID], severe malnutrition) should be considered.

For a list of AIDS-defining opportunistic infections and conditions, see Pathophysiology.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Lab Studies

Serologic tests are the most important studies in the evaluation for HIV disease. Recent guidelines in the United States encourage routine HIV screening in all adults in acute health care settings such as emergency departments and as part of routine physical examinations.

• An enzyme-linked immunoabsorbent assay (ELISA; high sensitivity) should be used for screening. Most ELISAs can be used to detect human immunodeficiency virus (HIV)–1 types M, N, and O and HIV-2.
• A positive ELISA result should be followed with confirmatory testing in the form of one or more Western blot assays or similar specific assay. Specific diagnostic criteria vary by test. Results are typically reported as positive, negative, or indeterminate.

Staging of HIV disease is based partially on clinical presentation, but other laboratory tests can help in deciding whether to initiate or modify treatment.

• The CD4 T-cell count is a reliable indicator of the current risk of acquiring opportunistic infections. CD4 counts vary, and serial counts are generally a better measure of any significant changes. The reference range for CD4 counts is 500-2000 cells/μL. After seroconversion, CD4 counts tend to decrease (around 700/μL on average) and continue to decline over time. For surveillance purposes, a CD4 count under 200/μL is considered AIDS-defining in the United States owing to the increased risk of opportunistic infections at this level.
• Viral load in peripheral blood is used as a surrogate marker of viral replication rate. This is a surrogate because most of the viral replication occurs in the lymph nodes rather than in the peripheral blood. The test is a quantitative amplification of the viral RNA using nucleic acid sequence-based amplification (NASBA), reverse-transcription PCR (RT-PCR), or similar technologies. Quantitative viral-load assays should not be used as a diagnostic tool because several false-positive misdiagnoses have been reported in the literature. The rate of progression to AIDS and death is related to the viral load, although, on an individual level, it is poorly predictive of the absolute rate of CD4 T-cell loss. Patients with viral loads greater than 30,000/μL are 18.5 times more likely to die of AIDS than those with undetectable viral loads.

With therapy, viral loads can often be suppressed to an undetectable level. At the same time, the CD4 count rises and the risk of opportunistic infections and death is reduced. Complete inhibition of viral replication appears impossible and may be unnecessary.

Secondary testing that may be performed to assist with diagnosis or staging include the following:

• Viral culture: This is expensive and time-consuming and is less sensitive in patients with low viral loads. Viral culture may be performed as part of phenotypic drug-resistance testing.
• Lymph node biopsy: Lymph node architecture is disrupted during HIV infection. HIV DNA, RNA, and proteins may be detected with molecular techniques, and electron microscopy may reveal virions.
• Proviral DNA PCR: This test is usually performed only in newborns because conventional serologic testing is useless in these patients (maternal antibodies may persist for ≥9 mo). Two or more negative results separated by at least one month is considered a negative result.
• Genotyping of viral DNA/RNA: Because patterns of mutations that lead to resistance to specific drugs or drug classes are now well-recognized, sequencing of the viral genome allows for the selection of specific antivirals that are more likely to elicit a response.
• Several PCR-based tests are approved for screening of blood products but are not diagnostic.

Imaging Studies

Chest radiography is useful in evaluating for tuberculosis infection and should be performed in people with a positive purified protein derivative (PPD) test result upon first presentation.

Other Tests

Baseline laboratory studies for other infections are important in the initial workup of a patient with newly diagnosed HIV infection.

• Placement of a PPD skin test to evaluate for tuberculosis infection
• Serology for cytomegalovirus infection
• Syphilis testing: Rapid plasma reagent [RPR] testing can be used initially, but more specific testing should be used for follow-up, as RPR can yield false-positive results. Lumbar puncture is used to evaluate neurologic symptoms.
• Rapid amplification testing: This is used to evaluate for gonococcal infection and chlamydia in cases of sexual HIV transmission. Pelvic examination is performed in females (with met mount for trichomoniasis).
• Hepatitis A, B, and C serology: This is used to determine the need for vaccination or treatment and to evaluate for chronic infection. Patients infected with hepatitis C may be candidates for treatment. Genotyping and baseline liver function tests are crucial.
• Anti-Toxoplasma antibody: Prior Toxoplasma infection requires prophylaxis if CD4⁺ T-cell counts drop below 100/µL.

Histologic Findings

Certain histologic findings are characteristic of various features of HIV infection and AIDS.

The lymph node architecture is progressively disrupted; this can be reversed with effective antiviral therapy. Findings include hyperplasia, multinucleated syncytia of T cells, and loss of the normal follicular dendritic network. Nucleic acid or immunohistochemical stains for viral antigens shows virus localizing to macrophages, T cells, and dendritic cells. Electron microscopy may reveal virions or intracellular virus within phagosomes in macrophages.

Multinucleated giant cells are a characteristic finding in patients with HIV encephalopathy. Myelin pallor and microgliosis may also be observed.

Staging

The CDC classifies HIV infection according to CD4⁺ T-cell count and the presence of certain infections or diseases.⁵⁶ These conditions may be exacerbated by the HIV infection or represent true opportunistic infections.

Category A is asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions.

Category B is HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection. These include, but are not limited to, the following:

• Bacillary angiomatosis
• Oropharyngeal candidiasis (thrush)
• Vulvovaginal candidiasis, persistent or resistant
• Pelvic inflammatory disease (PID)
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Oral hairy leukoplakia
• Idiopathic thrombocytopenic purpura
• Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting more than 1 month
• Peripheral neuropathy
• Herpes zoster (shingles), involving 2 or more episodes or 1 or more dermatomes

Category C is HIV infection with AIDS-defining opportunistic infections, as outlined in Pathophysiology.

These 3 categories are further subdivided based on the CD4⁺ T-cell count. Categories A1, B1, and C1 are characterized by CD4⁺ T-cell counts greater than 500/µL. Categories A2, B2, and C2 are characterized by CD4⁺ T-cell counts between 200/µL and 400/µL. HIV infections with CD4⁺ T-cell counts under 200/µL are designated as A3, B3, or C3.

Importantly, once an HIV infection has been staged into a higher clinical category, it permanently remains in that category. In addition, the infection is classified based on the lowest CD4⁺ T-cell count in that patient. For example, although a given HIV-positive patient may recover from a bout of Pneumocystis pneumonia (PCP) and the CD4⁺ T-cell count improves from 50/µL to 250/µL, that patient’s HIV infection remains classified as C3. Persons with A3, B3, and C1-3 HIV infection are considered to have AIDS. This is important to recognize, as this designation is not based solely on the previous occurrence of opportunistic infections but rather on the current risk of infection based on a reduced CD4⁺ T-cell count.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Medical Care

The treatment of human immunodeficiency virus (HIV) disease depends on the stage of the disease and any concomitant opportunistic infections.⁵⁷

In general, the goal of treatment is to prevent the immune system from deteriorating to the point that opportunistic infections become more likely. Immune reconstitution is less likely in patients whose immune systems are weakened to this point. However, early treatment of asymptomatic infection has not been shown to improve survival. Current guidelines suggest initiating antiretroviral therapy before the CD4 count drops to less than 200/μL but recommend against initiating therapy in patients with CD4 counts above 500/μL who do not have clinical evidence of immune deficiency.

Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) dramatically decreases the risk of Pneumocystis pneumonia (PCP) and should be initiated when the CD4⁺ T-cell count drops to below 200/µL. When TMP-SMX cannot be used, alternatives include dapsone (after screening for glucose-6-phosphatase dehydrogenase [G-6-PD] deficiency) and atovaquone. TMP-SMX also prevents toxoplasmosis and should be administered when the CD4⁺ T-cell count drops to below 100/µL. CD4⁺ counts below 50/µL place the patient at risk for Mycobacterium avium complex infection, and weekly azithromycin or clarithromycin is recommended as prophylaxis.

Prophylaxis for fungal or viral infections is not routinely necessary, but some have recommended fluconazole in patients with CD4⁺ T-cell counts under 50/µL to prevent candidal or cryptococcal infections and to protect against endemic fungal infections in geographic locales of hyperendemicity for histoplasmosis or coccidioidomycosis. However, the emergence of resistant Candida strains is a realistic concern. Oral ganciclovir is indicated for prophylaxis of cytomegalovirus infection in patients with advanced AIDS and is about 50% effective in reducing invasive disease.⁵⁸ As with fluconazole, there are concerns about resistance, and prophylaxis should be reserved for those with CD4⁺ T-cell counts under 50/µL and evidence of previous cytomegalovirus infection.

Treatment of opportunistic infections is paramount. Although the prevention of HIV replication reduces the risk of acquiring an opportunistic infection and reverses the effects of many opportunistic infections (eg, Kaposi sarcoma, cytomegalovirus retinitis), aggressive treatment of life-threatening or otherwise serious infections may necessitate a temporary stay of antiretroviral therapy to avoid drug interactions or cumulative toxicity.

Consultations

Consultation with an infectious disease or HIV specialist should be strongly considered for all new cases of HIV infection. Studies have clearly shown that the successful management of patients with HIV is related to the expertise and HIV caseload of the treating physician. In particular, pediatric cases of HIV infection are handled differently; age-based cutoffs for CD4 counts at which prophylaxis would be recommended and antiviral drug availability (on- or off-study for experimental drugs or regimens) differ.

Input from an infectious disease consultant may be helpful in the management of other unrelated illnesses in patients infected with HIV.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Effective antiretroviral therapy is the most important intervention in terms of improving longevity and preventing opportunistic infections. Therapy should involve combinations of drugs—two nucleoside-analogue reverse-transcriptase inhibitors combined with either a protease inhibitor or a non-nucleoside–analogue reverse-transcriptase inhibitor.^{57, 59} Antiretroviral drug classes and agents within each class are listed in Table 1 (see individual medication tables for more detail). As of January 2008, a total of 25 antiretroviral drugs have been approved for use in HIV-infected adults and adolescents; 14 of these have an approved pediatric treatment indication and 13 are available as a pediatric formulation or capsule size. Of the 25 antiretroviral drugs that have been approved, 3 are no longer being manufactured either because of the development of improved formulations (ie, amprenavir replaced by fosamprenavir) or because of limited use (ie, delavirdine and zalcitabine [ddC]).

Table 1. Antiretroviral Drug Classes

*No longer available on market

Ritonavir, a protease inhibitor that may be used in its own right, was found to boost blood levels of other protease inhibitors. Because of this, the required dosage of the coadministered drug is reduced. Various products have been formulated to include PIs combined with ritonavir. Several medications may be found in multidrug combinations (including ritonavir-boosted protease inhibitors). Numerous combination products are available on the market to assist patients with compliance and decrease the daily number of tablets and capsules required (see Table 2).

Table 2. Antiretroviral Combination Products

Drug Category: Antiretroviral agent, protease inhibitor

These agents inhibit protein precursors necessary for human immunodeficiency virus (HIV) infection of uninfected cells.

Drug Category: Antiretroviral agent, nucleoside reverse-transcriptase inhibitor

These agents inhibit viral replication by inhibiting viral RNA–dependent DNA polymerase.