Chapter 45: Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS).

Both HIV-1 and HIV-2 cause AIDS, but HIV-1 is found worldwide, whereas HIV-2 is found primarily in West Africa. This chapter refers to HIV-1 unless otherwise noted.

HIV is one of the two important human T-cell lymphotropic retroviruses (human T-cell leukemia virus is the other). HIV preferentially infects and kills helper (CD4) T lymphocytes, resulting in the loss of cell-mediated immunity and a high probability that the host will develop opportunistic infections. Other cells (e.g., macrophages and monocytes) that have CD4 proteins on their surfaces can be infected also.

HIV belongs to the lentivirus subgroup of retroviruses, which cause “slow” infections with long incubation periods (see Chapter 44). HIV has a cylinder-shaped (type D) core surrounded by an envelope containing virus-specific glycoproteins (gp120 and gp41) (Figures 45–1 and 45–2). The genome of HIV consists of two identical molecules of single-stranded, positive-polarity RNA and is said to be diploid. (Note that this is not double-stranded RNA, which consists of one positive strand and one negative strand.)

The HIV genome is the most complex of the known retroviruses (Figure 45–3). In addition to the three typical retroviral genes gag, pol, and env, which encode the structural proteins, the genome RNA has six regulatory genes (Table 45–1). Two of these regulatory genes, tat and rev, are required for replication, and the other four, nef, vif, vpr, and vpu, are not required for replication and are termed “accessory” genes.

The gag gene encodes the internal “core” proteins, the most important of which is the p24 protein. It is important medically as it is the antigen in the initial serologic test that determines whether the patient has antibody to HIV (i.e., has been infected with HIV). (See “Laboratory Diagnosis” section in this chapter.)

The pol gene encodes several proteins, including the virion “reverse transcriptase,” which synthesizes DNA by using the genome RNA as a template, an integrase that integrates the viral DNA into the cellular DNA, and a protease that cleaves the various viral precursor proteins. The env gene encodes gp160, a precursor glycoprotein that is cleaved to form the two envelope (surface) glycoproteins, gp120 and gp41.

Differences in the base sequence of the gp120 gene are used to subdivide HIV into subtypes called clades. Different clades are found in different areas of the world. For example, the B clade is the most common subtype in North America. Subtype B preferentially infects mononuclear cells and appears to be passed readily during anal sex, whereas subtype E preferentially infects female genital tract cells and appears to be passed readily during vaginal sex. Note that these clades (e.g., B and E) are subtypes of group M (Major), by far the most common group of HIV-1 worldwide.

Three enzymes are located within the nucleocapsid of the virion: reverse transcriptase, integrase, and protease (see Figure 45–2).

Reverse transcriptase is the RNA-dependent DNA polymerase that is the source of the family name retroviruses. This enzyme transcribes the RNA genome into the proviral DNA. Reverse transcriptase is a bifunctional enzyme; it also has ribonuclease H activity. Ribonuclease H degrades RNA when it is in the form of an RNA–DNA hybrid molecule. The degradation of the viral RNA genome is an essential step in the synthesis of the double-stranded proviral DNA. Integrase, another important enzyme within the virion, mediates the integration of the proviral DNA into the host cell DNA. The viral protease cleaves the precursor polyproteins into functional viral polypeptides.

One essential regulatory gene is the tat (transactivation of transcription)¹ gene, which encodes a protein that enhances viral (and perhaps cellular) gene transcription.

The Tat protein and another HIV-encoded regulatory protein called Nef repress the synthesis of class I major histocompatibility complex (MHC) proteins, thereby reducing the ability of cytotoxic T cells to kill HIV-infected cells. The other essential regulatory gene, rev, controls the passage of late mRNA from the nucleus into the cytoplasm. The function of the four accessory genes is described in Table 45–1.

The accessory protein Vif (viral infectivity) enhances HIV infectivity by inhibiting the action of APOBEC3G, an enzyme that causes hypermutation in retroviral DNA. APOBEC3G is “apolipoprotein B RNA-editing enzyme” that deaminates cytosines in both mRNA and retroviral DNA, thereby inactivating these molecules and reducing infectivity. APOBEC3G is considered to be an important member of the innate host defenses against retroviral infection. HIV defends itself against this innate host defense by producing Vif, which counteracts APOBEC3G, thereby preventing hypermutation from occurring.

There are several important antigens of HIV:

1. gp120 and gp41 are the type-specific envelope glycoproteins. gp120 protrudes from the surface and interacts with the CD4 receptor (and a second protein, a chemokine receptor) on the cell surface. gp41 is embedded in the envelope and mediates the fusion of the viral envelope with the cell membrane at the time of infection. The gene that encodes gp120 mutates rapidly, resulting in many antigenic variants. The most immunogenic region of gp120 is called the V3 loop; it is one of the sites that varies antigenically to a significant degree. Antibody against gp120 neutralizes the infectivity of HIV, but the rapid appearance of gp120 variants has made production of an effective vaccine difficult. The high mutation rate may be due to lack of an editing function in the reverse transcriptase.

2. The group-specific antigen, p24, is located in the nucleocapsid core and is not known to vary. Antibodies against p24 do not neutralize HIV infectivity but serve as important serologic markers of infection.

The natural host range of HIV is limited to humans, although certain primates can be infected in the laboratory. HIV is not an endogenous virus of humans (i.e., no HIV sequences are found in normal human cell DNA). The origin of HIV and how it entered the human population remains uncertain. There is evidence that chimpanzees living in West Africa were the source of HIV-1. If chimpanzees are the source of HIV in humans, it would be a good example of a virus “jumping the species barrier.”

In addition to HIV-1, two other similar retroviruses are worthy of comment:

1. Human immunodeficiency virus type 2 (HIV-2) was isolated from AIDS patients in West Africa in 1986. The proteins of HIV-2 are only about 40% identical to those of the original HIV isolates. HIV-2 remains localized primarily to West Africa and is much less transmissible than HIV-1. HIV-2 is closely related to a simian immunodeficiency virus (SIV) from a species of monkey called sooty mangabey. Accidental infection of a person with SIVsmm is thought to be the origin of HIV-2.

2. SIVs have been isolated from various nonhuman primates such as monkeys and chimpanzees (SIVcpz). SIVs cause persistent infection in these species and are thought to be the source of HIV in humans via accidental inoculation with blood of the nonprimate. For example, the genome RNA of HIV-1 is closely related to that SIVcpz. Unlike HIV in humans, SIV infection in nonhuman primates is often asymptomatic. However, an AIDS-like illness caused by SIVcpz does occur in some chimpanzees.

In general, the replication of HIV follows the typical retroviral cycle (Figure 45–4). The initial step in the entry of HIV into the cell is the binding of the virion gp120 envelope protein to the CD4 protein on the cell surface. The virion gp120 protein then interacts with a second protein on the cell surface, one of the chemokine receptors. Next, the virion gp41 protein mediates fusion of the viral envelope with the cell membrane, and the virion core containing the nucleocapsid, RNA genome, and reverse transcriptase enters the cytoplasm.

Chemokine receptors, such as CXCR4 and CCR5 proteins, are required for the entry of HIV into CD4-positive cells. The T cell-tropic strains of HIV bind to CXCR4, whereas the macrophage-tropic strains bind to CCR5. Mutations in the gene encoding CCR5 endow the individual with protection from infection with HIV. People who are homozygotes are completely resistant to infection, and heterozygotes progress to disease more slowly. Approximately 1% of people of Western European ancestry have homozygous mutations in this gene, and about 10% to 15% are heterozygotes. One of the best-characterized mutations is the delta-32 mutation, in which 32 base pairs are deleted from the CCR5 gene.

In the cytoplasm, reverse transcriptase transcribes the genome RNA into double-stranded DNA, which migrates to the nucleus, where it integrates into the host cell DNA. The viral DNA can integrate at different sites in the host cell DNA, and multiple copies of viral DNA can integrate. Integration is mediated by a virus-encoded endonuclease (integrase). Viral mRNA is transcribed from the integrated (proviral) DNA by host cell RNA polymerase (augmented by virus-encoded Tat protein) and translated into several large polyproteins. The Gag and Pol polyproteins are cleaved by the viral protease, whereas the Env polyprotein is cleaved by a cellular protease.

The Gag polyprotein is cleaved to form the main core protein (p24), the matrix protein (p17), and several smaller proteins. The Pol polyprotein is cleaved to form the reverse transcriptase, integrase, and protease. The immature virion containing the precursor polyproteins forms in the cytoplasm, and cleavage by the viral protease occurs as the immature virion buds from the cell membrane. It is this cleavage process that results in the mature, infectious virion.

Note that HIV replication is dependent on cell proteins as well as viral proteins. First, there are the cell proteins required during the early events, namely, CD4, and the chemokine receptors, CCR5 and CXCR4. Cell proteins, such as actin and tubulin, are involved with the movement of viral DNA into the nucleus. The cell protein cyclin T1 and the viral protein Tat are part of the complex that transcribes viral mRNA. Cell proteins are also involved in the budding process by which the virus exits the cell.

Transmission of HIV occurs primarily by sexual contact and by transfer of infected blood. Perinatal transmission from infected mother to neonate also occurs, either across the placenta, at birth, or via breast milk. It is estimated that more than 50% of neonatal infections occur at the time of delivery and that the remainder is split roughly equally between transplacental transmission and transmission via breast feeding. There is no evidence for airborne, waterborne, or insect transmission of HIV.

Infection occurs by the transfer of either HIV-infected cells or free HIV (i.e., HIV that is not cell-associated). Although small amounts of virus have been found in other fluids (e.g., saliva and tears), there is no evidence that they play a role in infection. In general, transmission of HIV follows the pattern of hepatitis B virus (HBV), except that HIV infection is much less efficiently transferred (i.e., the dose of HIV required to cause infection is much higher than that of HBV). People with sexually transmitted diseases, especially those with ulcerative lesions such as syphilis, chancroid, and herpes genitalis, have a significantly higher risk of acquiring HIV. Uncircumcised males have a higher risk of acquiring HIV than do circumcised males.

Transmission of HIV is significantly reduced by drug treatment because it lowers the amount of virus in the blood and other body fluids. When the viral load is undetectable, the likelihood of transmission is very low leading to the expression “undetectable equals untransmittable.”

Transmission of HIV via blood transfusion has been greatly reduced by screening donated blood for the presence of antibody to HIV. However, there is a “window” period early in infection when the blood of an infected person can contain HIV but antibodies are not detectable. Blood banks now test for the presence of p24 antigen in an effort to detect blood that contains HIV.

The Centers for Disease Control and Prevention (CDC) estimates that at the end of 2017, there were approximately 1.1 million people infected with HIV living in the United States. The transmission rate has declined markedly, primarily due to increased prevention efforts and improved treatments for HIV; the latter reduces the number of people with high titers of HIV. CDC estimates that approximately 38,500 new infections occur each year. CDC also estimates that 15% of those who are infected with HIV do not know it because they have not been tested.

As of 2017, it is estimated that approximately 37 million people worldwide are infected, two-thirds of whom live in sub-Saharan Africa. Three regions, Africa, Asia, and Latin America, have the highest rates of new infections. AIDS is the fourth leading cause of death worldwide. (Ischemic heart disease, cerebrovascular disease, and acute lower respiratory disease are ranked first, second, and third, respectively.)

As a result of public health measures such as condom use, plus the use of antiretroviral drugs that lower the viral load, the number of new HIV cases fell by 36% worldwide between 2000 and 2017. Similarly, the number of HIV-related deaths fell by 38% during the same period.

In the United States and Europe during the 1980s, HIV infection and AIDS occurred primarily in men who have sex with men (especially those with multiple partners), intravenous drug users, and hemophiliacs. Heterosexual transmission was rare in these regions in the 1980s but is now rising significantly. Heterosexual transmission is the predominant mode of infection in African countries.

Very few healthcare personnel have been infected despite continuing exposure and needle-stick injuries, supporting the view that the infectious dose of HIV is high. The risk of being infected after percutaneous exposure to HIV-infected blood is estimated to be about 0.3%. The transmission of HIV from healthcare personnel to patients is exceedingly rare.

HIV infects helper T cells (CD4-positive cells) and kills them, resulting in suppression of cell-mediated immunity. This predisposes the host to various opportunistic infections and certain cancers such as Kaposi’s sarcoma and lymphoma. HIV does not directly cause these tumors because HIV genes are not found in these cancer cells. The initial infection of the genital tract occurs in dendritic cells that line the mucosa (Langerhans’ cells), after which the local CD4-positive helper T cells become infected. HIV is first found in the blood 4 to 11 days after infection.

HIV infection also targets a subset of CD4-positive cells called Th17 cells. These cells are an important mediator of mucosal immunity, especially in the gastrointestinal tract. Many mucosal Th17 cells are killed early in HIV infection. Th17 cells produce interleukin-17 (IL-17), which attracts neutrophils to the site of bacterial infection. The loss of Th17 cells predisposes HIV-infected individuals to bloodstream infections by bacteria in the normal flora of the colon, such as Escherichia coli.

HIV also infects brain monocytes and macrophages, producing multinucleated giant cells and significant central nervous system symptoms. The fusion of HIV-infected cells in the brain and elsewhere mediated by gp41 is one of the main pathologic findings. The cells recruited into the syncytia ultimately die. The death of HIV-infected cells is also the result of immunologic attack by cytotoxic CD8 lymphocytes. Effectiveness of the cytotoxic T cells may be limited by the ability of the viral Tat and Nef proteins to reduce class I MHC protein synthesis (see later).

Another mechanism hypothesized to explain the death of helper T cells is that HIV acts as a “superantigen,” which indiscriminately activates many helper T cells and leads to their demise. The finding that one member of the retrovirus family, mouse mammary tumor virus, can act as a superantigen lends support to this theory. Superantigens are described in Chapter 58.

Persistent noncytopathic infection of T lymphocytes also occurs. Persistently infected cells continue to produce HIV, which may help sustain the infection in vivo. Lymphoid tissue (e.g., lymph nodes) is the main site of ongoing HIV infection.

In addition, a true latent infection can occur in which no HIV is produced. This occurs in resting CD4-positive memory T cells within which an integrated HIV genome is found. The latent period can last for months to years, but if the resting cell is activated, HIV can be produced. HIV replication depends on host cell transcription factors made in activated, but not resting, CD4-positive cells.

A person infected with HIV is considered to be infected for life. This seems likely to be the result of integration of viral DNA into the DNA of infected cells. Although the use of powerful antiviral drugs (see “Treatment” section later) can significantly reduce the amount of HIV being produced, the silent, latent infection in CD4-positive memory T cells can be activated and serve as a continuing source of virus.

Elite controllers are a rare group of HIV-infected people (less than 1% of those infected) who have no detectable HIV in their blood. Their CD4 counts are normal without using antiretroviral drugs. The ability to be an elite controller does not depend on gender, race, or mode of acquisition of the virus. Although the mechanism is unclear, there is evidence that certain HLA alleles are protective and that an inhibitor of the cyclin-dependent kinase known as p21 plays an important role.

In addition, there is a group of HIV-infected individuals who have lived for many years without opportunistic infections and without a reduction in the number of their helper T (CD4) cells. The strain of HIV isolated from these individuals has mutations in the nef gene, indicating the importance of this gene in pathogenesis. The Nef protein decreases class I MHC protein synthesis, and the inability of the mutant virus to produce functional Nef protein allows the cytotoxic T cells to retain their activity.

Another explanation why some HIV-infected individuals are long-term “nonprogressors” may lie in their ability to produce large amounts of α-defensins. α-Defensins are a family of positively charged peptides with antibacterial activity that also have antiviral activity. They interfere with HIV binding to the CXCR4 receptor and block entry of the virus into the cell.

In addition to the detrimental effects on T cells, abnormalities of B cells occur. Polyclonal activation of B cells is seen, with resultant high immunoglobulin levels. Autoimmune diseases, such as thrombocytopenia, occur.

The main immune response to HIV infection consists of cytotoxic CD8-positive lymphocytes. These cells respond to the initial infection and control it for many years. Mutants of HIV, especially in the env gene encoding gp120, arise, but new clones of cytotoxic T cells proliferate and control the mutant strain. It is the ultimate failure of these cytotoxic T cells that results in the clinical picture of AIDS. Cytotoxic T cells lose their effectiveness because so many CD4 helper T cells have died; thus, the supply of lymphokines, such as interleukin-2 (IL-2), required to activate the cytotoxic T cells is no longer sufficient.

There is evidence that “escape” mutants of HIV are able to proliferate unchecked because the patient has no clone of cytotoxic T cells capable of responding to the mutant strain. Furthermore, mutations in any of the genes encoding class I MHC proteins result in a more rapid progression to clinical AIDS. The mutant class I MHC proteins cannot present HIV epitopes, which results in cytotoxic T cells being incapable of recognizing and destroying HIV-infected cells.

Antibodies against various HIV proteins, such as p24, gp120, and gp41, are produced, but they neutralize the virus poorly in vivo and appear to have little effect on the course of the disease.

HIV has three main mechanisms by which it evades the immune system: (1) integration of viral DNA into host cell DNA, resulting in a persistent infection; (2) a high rate of mutation of the env gene; and (3) the production of the Tat and Nef proteins that downregulate class I MHC proteins required for cytotoxic T cells to recognize and kill HIV-infected cells. The ability of HIV to infect and kill CD4-positive helper T cells further enhances its capacity to avoid destruction by the immune system.

The clinical picture of HIV infection can be divided into three stages: an early, acute stage; a middle, latent stage; and a late, immunodeficiency stage (Figure 45–5). In the acute stage, which usually begins 2 to 4 weeks after infection, a mononucleosis-like picture of fever, lethargy, sore throat, and generalized lymphadenopathy occurs. A maculopapular rash on the trunk, arms, and legs (but sparing the palms and soles) is also seen. Leukopenia occurs, but the number of CD4 cells is usually normal. A high-level viremia typically occurs, and the infection is readily transmissible during this acute stage. This acute stage typically resolves spontaneously in about 2 weeks. Resolution of the acute stage is usually accompanied by a lower level of viremia and a rise in the number of CD8-positive (cytotoxic) T cells directed against HIV.

Antibodies to HIV typically appear 10 to 14 days after infection, and most patients will have seroconverted by 3 to 4 weeks after infection. Note that the inability to detect antibodies prior to that time can result in “false-negative” serologic tests (i.e., the person is infected, but antibodies are not detectable at the time of the test). This has important implications because HIV can be transmitted to others during this period. If the antibody test is negative but HIV infection is still suspected, then a polymerase chain reaction (PCR)-based assay for viral RNA in the plasma should be done.

Of those who become seropositive during the acute infection, approximately 87% are symptomatic (i.e., about 13% experience an asymptomatic initial infection).

After the initial viremia, a viral set point occurs, which can differ from one person to another. The set point represents the amount of virus produced (i.e., the viral load) and tends to remain “set,” or constant, for years. The higher the set point at the end of the initial infection, the more likely the individual is to progress to symptomatic AIDS. It is estimated that an infected person can produce up to 10 billion new virions each day. This viral load can be estimated by using an assay for viral RNA in the patient’s plasma. (The assay detects the RNA in free virions in the plasma, not cell-associated virions.)

The amount of viral RNA serves to guide treatment decisions and the prognosis. For example, if a drug regimen fails to reduce the viral load, the drugs should be changed. As far as the prognosis is concerned, a patient with more than 10,000 copies of viral RNA/mL of plasma is significantly more likely to progress to AIDS than a patient with fewer than 10,000 copies.

The number of CD4-positive T cells is another important measure that guides the management of infected patients. It is used to determine whether a patient needs chemoprophylaxis against opportunistic organisms, to determine whether a patient needs anti-HIV therapy, and to determine the response to this therapy. The lower limit of CD4 count considered as normal is 500 cells/μL. People with this level or higher are usually asymptomatic. The frequency and severity of opportunistic infections significantly increase when the CD4 counts fall below 200/μL. A CD4 count of 200/μL or below is an AIDS-defining condition.

In the middle stage of HIV infection, a long latent period, measured in years, usually ensues. In untreated patients, the latent period typically lasts for 7 to 11 years. The patient is asymptomatic during this period. Although the patient is asymptomatic and viremia is low or absent, a large amount of HIV is being produced by lymph node cells but remains sequestered within the lymph nodes. This indicates that during this period of clinical latency, the virus itself does not enter a latent state.

A syndrome called AIDS-related complex (ARC) can occur during the latent period. The most frequent manifestations are persistent fevers, fatigue, weight loss, and lymphadenopathy. ARC often progresses to AIDS.

The late stage of HIV infection is AIDS, manifested by a decline in the number of CD4 cells to below 200/μL and an increase in the frequency and severity of opportunistic infections. Table 45–2 describes some of the common opportunistic infections and their causative organisms seen in HIV-infected patients during the late, immunocompromised stage of the infection.

The two most characteristic manifestations of AIDS are Pneumocystis pneumonia and Kaposi’s sarcoma. However, many other opportunistic infections occur with some frequency. These include viral infections such as disseminated herpes simplex, herpes zoster, and cytomegalovirus infections and progressive multifocal leukoencephalopathy; fungal infections such as thrush (caused by Candida albicans), cryptococcal meningitis, and disseminated histoplasmosis; protozoal infections such as toxoplasmosis and cryptosporidiosis; and disseminated bacterial infections such as those caused by Mycobacterium avium-intracellulare and Mycobacterium tuberculosis. Many AIDS patients have severe neurologic problems (e.g., dementia and neuropathy), which can be caused by either HIV infection of the brain or by many of these opportunistic organisms.

Two cancers are very common in AIDS patients, namely non-Hodgkin’s B-cell lymphoma caused by Epstein-Barr virus and Kaposi’s sarcoma caused by human herpesvirus-8 (Kaposi’s sarcoma-associated herpesvirus). Cancers caused by human papilloma virus, namely anal, cervical, oral, pharyngeal, penile, and vulvar also occur commonly in AIDS patients.

The diagnosis of early HIV-1 and HIV-2 infection is made by using immunoassays that detect antibody to HIV-1 and HIV-2, and p24 antigen in serum. This combination (“Combo”) test is useful for the diagnosis of early infections because p24 antigen is typically detectable earlier in infection than antibody (Figure 45–6). Specimens positive in the Combo test proceed to an antibody test to distinguish HIV-1 from HIV-2 and to a PCR-based test (nucleic acid amplification test, NAT) to detect viral RNA.

OraQuick is a rapid, screening immunoassay for HIV antibody that uses an oral swab sample in an enzyme-linked immunosorbent assay (ELISA)-type test that can be done at home. Because there are some false-positive tests with oral specimens and dried blood spots, a Western blot (immunoblot) test is performed on positive specimens. Figure 64–9 depicts a Western blot (immunoblot) test used to diagnose HIV infection.

After HIV infection has been established, the amount of viral RNA in the plasma (i.e., the viral load) can also be determined using PCR-based assays. The amount of viral RNA is used to guide treatment decisions and to predict the risk of progression to AIDS.

Other laboratory tests that are important in the management of an HIV-infected person include CD4 cell counts and tests for drug resistance of the strain of HIV infecting the patient. Drug resistance tests are described at the end of the “Treatment” section in this chapter. HIV can be grown in culture from clinical specimens, but this procedure is available only at a few medical centers.

The treatment of HIV infection has resulted in a remarkable reduction in mortality and improvement in the quality of life of infected individuals. The two specific goals of treatment are (1) to restore immunologic function by increasing the CD4 count, which reduces opportunistic infections and certain malignancies and (2) to reduce viral load, which reduces the chance of transmission to others. There is evidence that starting drug therapy as soon as possible after making the diagnosis of HIV infection is the best way to achieve these goals.

Unfortunately, no drug regimen results in a “cure” (i.e., eradicates the virus from the body), but long-term suppression can be achieved. However, if drugs are stopped, the virus resumes active replication, and large amounts of infectious virus reappear.

Transmission of HIV is significantly reduced by drug treatment because it lowers the amount of virus in the blood and other body fluids. Although drugs do not cure the infection, they can lower the amount of virus so that the frequency of transmission is very low. Adherence to drug treatment regimens is important both for the health of the infected patient as well as to protect uninfected individuals. When the viral load is undetectable, the likelihood of transmissions is very low leading to the expression “undetectable equals untransmittable.”

Treatment of HIV infection typically involves multiple antiretroviral drugs. The use of a single drug (monotherapy) for treatment is not done because of the high rate of mutation to drug resistance.

The choice of drugs is complex and depends on several factors (e.g., whether it is an initial infection or an established infection, the number of CD4 cells, the viral load, the resistance pattern of the virus, and whether the patient is pregnant or is coinfected with HBV or hepatitis C virus [HCV]). Table 45–3 describes the mechanism of action of the drugs and their main adverse effects. The number of drugs and the various determining factors mentioned previously make describing all the treatments beyond the scope of this book. The reader is advised to consult the Department of Health and Human Services Antiretroviral Therapy Guidelines or other reliable sources, such as the Medical Letter.

The seven drug combinations recommended in 2019 for the treatment of newly infected adults are listed in Table 45–4. In brief, most of them consist of an integrase inhibitor plus two nucleoside reverse transcriptase inhibitors. Four of the five contain tenofovir alafenamide and emtricitabine. One regimen contains only two drugs, dolutegravir (integrase inhibitor) and lamivudine (nucleoside reverse transcriptase inhibitor). Another regimen containing only two drugs is dolutegravir (integrase inhibitor) and rilpivirine (non-nucleoside reverse transcriptase inhibitor).

In January 2021, the FDA approved an injectable treatment consisting of a combination of cabotegravir and rilpivirine (Cabenuva). Two monthly doses are given, each drug is injected separately. The treatment suppressed HIV to undetectable levels for two years.

These combinations are known as highly active antiretroviral therapy (HAART). HAART is very effective in prolonging life, improving quality of life, and reducing viral load but does not cure the chronic HIV infection (i.e., replication of HIV within CD4-positive cells continues indefinitely). Discontinuation of HAART almost always results in viremia (a return of the viral load to its pretreatment set point) and a fall in the CD4 count.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Table 45–3 describes six nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine) and a single nucleotide reverse transcriptase inhibitor (tenofovir). These drugs are characterized by not having a 3′ hydroxyl group on the ribose ring and therefore are chain-terminating drugs. They inhibit HIV replication by interfering with proviral DNA synthesis by reverse transcriptase. They cannot cure an infected cell of an already integrated copy of proviral DNA. Additional information on these “nucleoside analogue” drugs and the other antiretroviral drugs can be found in Chapter 35. Note that zalcitabine (Hivid), an NRTI analogue of cytosine, is no longer available.

Two main problems limit the use of NTRIs: the emergence of resistance and adverse effects. The main adverse effects are described in Table 45–3. For example, the long-term use of zidovudine (ZDV) is limited by suppression of the bone marrow leading to anemia and neutropenia. This hematotoxicity is due to the inhibition of the mitochondrial DNA polymerase. Nevertheless, ZDV is used in postexposure prophylaxis (PEP) and to prevent vertical transmission from mother to fetus. Lamivudine and its analogue emtricitabine have the same mechanism of action as ZDV but are better tolerated, and one or another is a common component of HAART. Abacavir is also commonly used. Patients who have an HLA-B1701 allele are more likely to have a severe hypersensitivity reaction to abacavir. Patients should be tested for this gene before being prescribed abacavir.

Nonnucleoside Reverse Transcriptase Inhibitors

Table 45–3 describes five nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine) that are effective against HIV. Unlike the NRTIs, these drugs are not base analogues. Efavirenz (Sustiva) and nevirapine (Viramune) are the most commonly used drugs in this class. Efavirenz is a common component of HAART regimens, especially a single pill containing efavirenz, tenofovir, and emtricitabine (Atripla). Nevirapine is often used to prevent vertical transmission of HIV from mother to fetus. Both nevirapine and efavirenz can cause skin rashes and Stevens-Johnson syndrome. Rilpivirine is available as Odefsey, a fixed drug combination containing emtricitabine and tenofovir.

Protease Inhibitors

Table 45–3 describes the currently available protease inhibitors (amprenavir atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and a combination of lopinavir and ritonavir). Protease inhibitors, when combined with nucleoside analogues, are very effective in inhibiting viral replication and increasing CD4 cell counts and are commonly used in HAART regimens. Lopinavir and ritonavir are given in combination because ritonavir inhibits the degradation of lopinavir by cytochrome P450 enzymes, thereby increasing the concentration of lopinavir. A briefer way of saying that is ritonavir “boosts” lopinavir.

Another drug that inhibits cytochrome P450 enzymes is cobicistat. It is particularly effective in enhancing the antiviral effect of elvitegravir, an integrase inhibitor. It is used in two four-drug, fixed-dose combinations marketed as Stribild and Genvoya. Both drugs contain elvitegravir, cobicistat, emtricitabine, and a tenofovir derivative. Cobicistat is also useful in enhancing the effect of protease inhibitors. The drug Prezcobix contains darunavir plus cobicistat and the drug Evotaz contains atazanavir and cobicistat.

Mutants of HIV resistant to protease inhibitors can be a significant clinical problem. Resistance to one protease inhibitor often conveys resistance to all; however, the combination of two protease inhibitors, namely, ritonavir and lopinavir (Kaletra), is effective against both mutant and nonmutant strains of HIV. Also, darunavir is effective against many strains of HIV that are resistant to other protease inhibitors. Mutants of HIV resistant to both protease inhibitors and reverse transcriptase inhibitors have been recovered from patients.

A major side effect of protease inhibitors is abnormal fat deposition in specific areas of the body, such as the back of the neck (Figure 45–7). The fat deposits in the back of the neck are said to give the person a “buffalo hump” appearance. These abnormal fat deposits are a type of lipodystrophy; the metabolic process by which this occurs is unknown. Saquinavir and indinavir are infrequently used because of toxicity and nelfinavir is no longer recommended.

Treatment for acute HIV infection with two reverse transcriptase inhibitors and a protease inhibitor is often used. With this regimen, the viral load drops below the level of detection, CD4 cell counts rise, and CD8 activity increases. The long-term effect of this approach on rate of progression to AIDS has yet to be determined.

Pregnant women infected with HIV should be treated with two nucleosides and a protease inhibitor. A typical regimen would include lamivudine, ZDV, and lopinavir/ritonavir. In addition, ZDV should be given to the neonate. These drugs appear not to damage the fetus, although rare instances of mitochondrial dysfunction and death attributed to ZDV have been reported. The reader is urged to consult the current information regarding the use of these drugs in pregnancy. A full discussion is beyond the scope of this book.

Entry Inhibitors

Table 45–3 describes three entry inhibitors, enfuvirtide, maraviroc, and ibalizumab. Enfuvirtide (Fuzeon) is the first of a new class of anti-HIV drugs known as fusion inhibitors (i.e., they prevent the fusion of the viral envelope with the cell membrane). Enfuvirtide is a synthetic peptide that binds to gp41 on the viral envelope, thereby blocking the entry of HIV into the cell. It must be administered by injection and is quite expensive.

Maraviroc (Selzentry) also prevents the entry of HIV into cells. It blocks the binding of the gp120 envelope protein of HIV to CCR-5, which is an important coreceptor on the cell surface. Before prescribing maraviroc, a laboratory test (Trofile assay) should be performed to ensure that the tropism of the patient’s strain of HIV is CCR5. Maraviroc should be used in combination with other antiretroviral drugs in patients infected with CCR5-tropic strains of HIV and in treatment-experienced adults infected with an HIV strain that is resistant to other antiretroviral drugs.

Ibalizumab (Trogarzo) is a monoclonal antibody against CD4 protein that blocks entry of HIV. It is a “post-attachment” inhibitor, which means it blocks HIV from binding to CCR-5 or CXCR4 coreceptors after HIV has bound to the CD4 protein. It is approved for patients infected with multidrug resistant HIV.

Integrase Inhibitors

Raltegravir (Isentress) is the first drug to inhibit the HIV-encoded integrase (see Table 45–3). It is recommended for use in patients who have been treated with other antiretroviral drugs but continue to produce significant levels of HIV. Three additional integrase inhibitors are available: dolutegravir (Tivicay), elvitegravir (available as either Stribild or Genvoya in fixed combination with other drugs), and bictegravir (available as Biktarvy in fixed combination with emtricitabine and tenofovir). Dolutgravir is available in fixed combination with lamivudine (Dovato) and with rilpivirine (Juluca). The collective abbreviation INSTI is often used for these drugs. INSTI stands for INtegrase Strand Transfer Inhibitor.

Cabotegravir is an injectable integrase inhibitor with a long-half life that is effective in preventing HIV infection for up to two months. The long-half-life is achieved by packaging the drug in nanoparticles. The structure of cabotegravir is similar to that of dolutegravir.

Resistance to Antiretroviral Drugs

Drug-resistant mutants of HIV have emerged that significantly affect the ability of both reverse transcriptase inhibitors and protease inhibitors to sustain their clinical efficacy. Approximately 10% of newly infected patients are infected with a strain of HIV resistant to at least one antiretroviral drug. Laboratory tests to detect mutant strains include both genotypic and phenotypic analysis. Genotyping reveals the presence of specific mutations in either the reverse transcriptase (RT) or protease (PR) genes. Phenotyping determines the ability of the virus to grow in cell culture in the presence of the drug. One method of phenotyping recovers the RT and PR genes from the patient’s virus and splices them into a test strain of HIV, which is then used to infect cells in culture. Another laboratory test can determine the tropism of the patient’s isolate (i.e., whether it uses CCR5 as its coreceptor). If so, then maraviroc can be used for treatment.

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) may occur in HIV-infected patients who are treated with a HAART regimen and who are coinfected with other microbes such as HBV, HCV, M. tuberculosis, M. avium complex, Cryptococcus neoformans, and Toxoplasma gondii. In this syndrome, an exacerbation of clinical symptoms occurs because the antiretroviral drugs enhance the ability to mount an inflammatory response. HIV-infected patients with a low CD4 count have a reduced capacity to produce inflammation, but HAART restores the inflammatory response, and as a result, symptoms become more pronounced. To avoid IRIS, the coinfection should be treated prior to instituting HAART whenever possible.

No vaccine is available. Multiple trials of a variety of experimental vaccines have failed to induce protective antibodies, protective cytotoxic T cells, or mucosal immunity. Prevention consists of taking measures to avoid exposure to the virus (e.g., using condoms, not sharing needles, and discarding donated blood that is contaminated with HIV).

Postexposure prophylaxis (PEP), such as that given after a needle-stick injury or a high-risk nonoccupational exposure, employs three drugs: the preferred regimen consists of the combination of tenofovir and emtricitabine (given as Truvada) plus raltegravir. Three alternative drug regimens are available. PEP should be given as soon as possible after exposure and continued for 28 days.

Preexposure prophylaxis (PrEP) using Truvada is indicated for individuals at high risk of infection, such as men who have sex with men. Trials using injectable cabotegravir prevented HIV infection for as long as two months. This promises to be a useful form of PrEP as it bypasses the need to take a daily Truvada pill.

Two steps can be taken to reduce the number of cases of HIV infection in children: antiretroviral therapy should be given to HIV-infected mothers and neonates, and HIV-infected mothers should not breast feed. The choice of antiretroviral drugs is dependent on several factors, so current guidelines should be consulted. In addition, the risk of neonatal HIV infection is lower if delivery is accomplished by cesarean section rather than by vaginal delivery. Circumcision reduces HIV infection.

Several drugs are commonly taken by patients in the advanced stages of AIDS to prevent certain opportunistic infections (Table 45–5). Some examples are trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia, fluconazole to prevent recurrences of cryptococcal meningitis, ganciclovir to prevent recurrences of retinitis caused by cytomegalovirus, and oral preparations of antifungal drugs, such as clotrimazole, to prevent thrush caused by C. albicans.