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Infections in HIV-Infected Patients

  • Onyema Ogbuagu
  • R. Douglas Bruce
Chapter

Abstract

People living with human immunodeficiency virus (HIV) are at risk for serious and life-threatening infectious complications. Indeed, infections constitute the chief cause of mortality in untreated patients. While the majority of the infections occur in individuals with acquired immunodeficiency syndrome (AIDS), the vulnerability to certain infections remains high even in patients with higher CD4 counts as immune defects occur very early in infection and persist even in patients who have experienced immune reconstitution following the use of combination antiretroviral therapy (cART). The association between CD4 counts and vulnerability to certain infections allows the clinician to quite accurately predict which infections are likely or unlikely to occur in an individual based on the CD4 count. In addition, HIV interacts with other pathogens that impact the natural history of both infections and may result in accelerated sequelae of infection. This chapter will highlight the epidemiology, pathogenesis, clinical presentation, management, prognosis, and prevention of common infections that occur in HIV-infected patients.

Keywords

Human immunodeficiency virus (HIV) Acquired immunodeficiency syndrome (AIDS) Immune reconstitution inflammatory syndrome (IRIS) Human herpes virus (HHV) Antiretroviral therapy Mycobacterium tuberculosis Progressive multifocal leukoencephalopathy (PML) Toxoplasmosis Histoplasmosis 

Introduction

The acquired immunodeficiency syndrome (AIDS) was first recognized three and a half decades ago with the harbinger being the discovery of opportunistic infections initially in a cluster of young homosexual males in the United States who were, at the time, not known to have any known immune-compromising condition [1]. Subsequently, other risk groups for the syndrome were identified, other than homosexual or bisexual men, including hemophiliacs, heroin users, and Haitian immigrants [2]. The identification of AIDS among female partners of homosexual men drew attention to sexual transmission of the disease [3]. It took 2 years after the report on the first cluster of cases in 1981, primarily occurring in San Francisco and New York City [4], that the definitive link between the clinical syndrome and the etiologic virus, lymphadenopathy-associated virus (LAV) or human T-lymphotropic virus III (HTLV III), later termed the human immunodeficiency virus (HIV), was definitively isolated and described by French scientists, Francoise Barre-Sinoussi and Luc Montagnier, both of whom were eventually awarded Nobel prizes for their work 25 years later [5, 6, 7].

In the ensuing decades, there were reports from across the globe of confirmed cases of HIV/AIDS impacting millions of people [8]. As of 2014, 36.9 million people are living with HIV/AIDS (PLWHA) with approximately two million new infections occurring annually [9]. It is estimated that since 2000, 25 million died because of AIDS-related illnesses with 1.2 million in 2014 alone [9, 10]. A majority of PLWHA are in middle- and low-income countries with 66% of new adult and greater than 90% of pediatric cases occurring in sub-Saharan Africa – one of the hardest hit regions in the world [10].

The drivers of the epidemic remain sexual transmission primarily among men who have sex with men (MSM) and heterosexual sex, infected sexual partners who are either not aware of their infection or not receiving antiretroviral drug treatment, and sharing of unsterile syringes or paraphernalia among people who inject drugs [11]. Vertical transmission from infected mothers to their babies continues to occur primarily in low-resource settings where interventions to prevent mother-to-child transmission are lacking or insufficient [12, 13]. The risk of HIV transmission through blood transfusion or organ transplantation is very low due to improved screening of donors.

Since 1981, significant advances have occurred in the knowledge and understanding of HIV viral structure and pathogenesis, natural history, disease manifestation, treatment, and prevention. Highly effective, tolerable, and simplified treatment regimens have led to improved life expectancy among PLWHA though access and affordability remain barriers to optimal coverage globally [14]. In spite of these improvements, high rates of morbidity and mortality continue, especially among individuals in low-resource settings or globally among vulnerable populations including ethnic minorities, MSM and transgendered individuals, women, people with substance use disorders, sex workers, prisoners, the poor, children, and adolescents [15, 16].

The morbidity and mortality from HIV are a direct result of opportunistic infections, which take advantage of a weakened immune system and/or may occur as a consequence of off-target end-organ injury from an activated immune system’s efforts to control the virus. These include a wide array of clinical conditions including infections caused by a broad range of pathogens – bacterial, fungal, viral, and parasitic – which occur at a higher frequency than in immune-competent individuals, occur in unusual sites or may be disseminated, and/or are associated with neurologic disorders or cancers. Furthermore, with the aging of the HIV population, it is now appreciated that other conditions including renal disease, neurocognitive disorders, cancers, and cardiovascular and cerebrovascular disease may occur as long-term complications and are also contributing to morbidity and mortality [17, 18].

This chapter will focus specifically on infections that occur in HIV-infected individuals with an emphasis on the spectrum, epidemiology, pathogenesis, clinical presentation, management, and prevention of the infections.

Immune Defects in HIV-Infected Individuals

While CD4 T-cell depletion is the hallmark and a reliable measure of the degree of immune dysfunction in HIV-infected individuals, HIV broadly impacts multiple components of the immune system [19]. This was recognized early in the AIDS epidemic where studies showed that there were diminished CD4 and CD8 T-cell proliferation following exposure to antigens and anti-CD3 monoclonal antibody as well as decreased CD4 T helper cell activity in individuals with AIDS compared to those without HIV [20, 21]. Diminished immunoglobulin production by B-cells was observed in vitro following mitogen stimulation, in spite of the observed hyperproduction of immunoglobulins (specifically IgG) in vivo that occurs in specimens from patients with AIDS [20]. Similarly, decreased functioning of antigen-presenting cells (monocytes and dendritic cells) and natural killer cells has also been described [22, 23]. Some of these effects may occur prior to significant CD4 T-cell depletion but may become more prominent in individuals with long-term infection and/or who have developed AIDS [20, 24].

These studies have demonstrated the negative or altering impact of HIV infection on both innate and adaptive arms of the immune system. Together, the maladaptive responses underscore the increased risks for opportunistic infections that are not entirely reflected by and may occur independent of the decreased CD4 T-cell counts.

Natural History of HIV Infection and AIDS

Clinically, HIV infection progresses through three stages. First, a local is established at the site of inoculation, with subsequent regional spread and systemic dissemination, all of which occur during the acute phase of infection. Some individuals will develop signs and symptoms of an acute illness at the time of systemic viral dissemination (median time following infection 3–4 weeks) which auto-resolves even without any specific therapy. Subsequently, there is a variable period of clinical latency during which many individuals remain asymptomatic, followed by progression to AIDS.

The early events in HIV infection have been well elucidated. Following inoculation of the virus at vulnerable sites where infection may be promoted by certain host and local factors such as mucosal ulceration in the setting of a sexually transmitted disease (STD) [25], there is local replication of the virus and then regional spread to adjacent tissue and draining lymph nodes, after which there is widespread dissemination of the virus when it enters the blood stream. This phase of infection typically occurs within 2 weeks of infection at which time the virus can be detected in plasma by commercially available viral load assays. Coincident with this rise in viral load is a massive depletion of organ-specific (primarily in the gut) and peripheral blood lymphocytes, and this may be measured as a depletion of CD4 T-cells in the peripheral blood. During this period of disseminated infection, there is a concurrent establishment of organ-specific reservoirs in sites such as the central nervous system (CNS) and genitourinary system.

Following this acute rise in viremia, immune-mediated control of the virus occurs, which is driven principally by CD8 T-cell-mediated cytotoxicity and cytolysis directed against infected CD4-expressing cells. This may result in suppression of viral replication and establishment of a viral “set point” that is tightly regulated until late stages of the infection coincident with the development of AIDS. This viral set point determines the rate of CD4 decline over time.

Certain individuals do not experience a CD4 decline in spite of long-term infection with HIV. These are individuals typically with robust CD8 T-cell immune responses to viral infection or express certain immune phenotypes that confer an increased ability to suppress viral replication. These comprise elite controllers and long-term nonprogressors (viremic controllers) who suppress HIV viral loads to levels that are either undetectable by commercial viral load assays or to low levels, typically <10,000 copies, respectively. An understanding of how these individuals exert immune control of the virus has not been fully elucidated but remains a subject of keen interest as it might inform current and future strategies to cure, control, and/or prevent HIV.

It was established early on in the HIV epidemic that certain opportunistic infections (OIs) tend to occur below specific CD4 thresholds such that the susceptibility to and occurrence of certain OIs can be reliably predicted based on measured CD4 T-cell counts in people with HIV, assuming no other coexistent immune compromising conditions [26]. In the absence of effective combination antiretroviral therapy (cART ), individuals with CD4 count <200 cells/mm3 and/or CD4% <14 will develop an opportunistic infection at a median duration of 12–18 months from the time of dropping below that threshold. Based on epidemiologic observations, these laboratory criteria comprise the surveillance definition of AIDS. Furthermore, individuals with advanced HIV infection, i.e., CD4 count <50cells/mm3, are susceptible to a broad range of opportunistic pathogens, which confer a poor prognosis. For these individuals, the median survival in the absence of cART is 12–18 months. Even when treated, these individuals experience higher rates of immunologic failure than those initiating therapy at higher CD4 counts (>50 cells/mm3), lending credence to the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) guidelines that support initiation of cART as soon as possible from the time of diagnosis for all individuals with HIV.

Viral Infections in HIV Infection

Human Herpesviruses

Introduction

Herpesviruses (HHVs) are a family of double-stranded DNA viruses, which, like HIV, have the unique ability to persist for the life of the human host. They do so by evading human immune responses and establishing latency in either neural tissue or tissues of the monocyte-macrophage system [27]. Human herpesvirus (HHVs 1–3), also referred to as alphaherpesviruses, establish latency in neural tissue, while HHVs 4–8 are lymphotropic, establishing latency in cells of the monocyte-macrophage system. The seroprevalence of HHVs among patients with HIV infection far exceeds seroprevalence rates among individuals without HIV. One study demonstrated that Epstein-Barr virus (EBV), HHV-8, cytomegalovirus (CMV), and herpes simplex virus-1 (HSV-1) were detected by polymerase chain reaction (PCR) in the saliva of people with HIV at a higher frequency (90%, 57%, 31%, and 16%, respectively) than controls without HIV (48%, 24%, 2%, and 2%, respectively) [28].

Herpesviruses carry epidemiologic and clinical significance in patients with HIV infection. Certain herpesviruses such as HSV-1 and HSV-2 can cause ulcerations or “cold sores” thereby disrupting mucosal integrity at vulnerable site such as male and female genitalia and, therefore, increase risk of HIV transmission during sexual intercourse [29]. Also, the presence of herpesvirus infections such as HSV-2, EBV, and cytomegalovirus (CMV) has been associated with increased HIV plasma viremia and is recognized as risk factors for faster HIV disease progression with morbidity and mortality implications [29, 30, 31]. Furthermore, the presence of CMV and EBV viremia has been associated with slower decay of HIV viral loads on ART [30]. Some positive interactions, however, have been reported such as the observation that HHV-6 and HHV-7 may decrease replication of HIV virus that exclusively utilize the chemokine co-receptor, CCR5, for entry into target cells and downregulate CD4 receptors on T-cells thereby slowing disease progression [32].

HIV, by virtue of its negative effect on the immune system, interacts synergistically with HHVs resulting in increased risk of viral reactivation and development of end-organ or disseminated disease and malignancies associated with the HHVs [27, 33]. While HHV infections in the healthy host may be benign or result in mild self-limited illnesses, the same infections may carry serious consequences in immune-compromised hosts (see Table 13.1). The epidemiology, clinical presentation, diagnosis, and management of these consequential HHV infections in HIV-infected individuals will be discussed below.
Table 13.1

Clinical syndromes associated with herpesviruses in HIV patients

Herpesvirus

Nomenclature

Associated clinical syndromes

HHV-1

HSV-1

Orolabial and genital ulcers, aseptic meningitis, cranial nerve (CN) VII paralysis, transverse myelitis, disseminated cutaneous disease, keratitis, retinitis, esophagitis, bronchitis, pneumonitis, hepatitis, proctitis, herpetic whitlow

HHV-2

HSV-2

Genital and orolabial ulcers, meningoencephalitis, transverse myelitis, disseminated cutaneous disease, proctitis

HHV-3

VZV

Meningoencephalitis, CN VII paralysis, transverse myelitis, disseminated cutaneous disease, keratitis, retinitis, pneumonitis, hepatitis

HHV-4

EBV

Burkitt Lymphoma, primary CNS lymphoma (PCNSL), hepatitis, oral hairy leukoplakia

HHV-5

CMV

Meningoencephalitis, polyradiculopathy, transverse myelitis, retinitis, pneumonitis, esophagitis, colitis, hepatitis, cholangiopathy

HHV-6

HHV-6

Meningitis, encephalitis

HHV-7

HHV-7

Hepatitis, myeloradiculoneuropathy

HHV-8

HHV-8/KSHV

Multicentric Castleman disease (MCD), Kaposi sarcoma (KS), primary effusion lymphoma

Herpes Simplex Virus (HSV )

The two types of viruses that make up this group are HSV-1, which predominantly causes orolabial ulcers and typically acquired early in life, and HSV-2, which primarily causes anogenital disease and is typically acquired following onset of sexual activity [34]. However, either virus can cause similar disease syndromes at either location, may involve visceral organs, or cause disseminated disease. Both viruses are similar with 70% of their genome being identical [35].

Epidemiology

The prevalence of seropositivity to HSV-2 among individuals with HIV disease ranges from 30% to 90% depending on the type of population studied [36, 37]. An incidence rate of 4.4/10 person-years (pys) was reported among participants of a US military HIV natural history study (NHS) and was higher among African Americans (6.45/100pys) compared to Caucasians (3.46/100pys) [36]. HSV-2 seroprevalence increases with age and occurs at relatively higher frequencies among MSM and female sex workers, as well as ethnic minorities in the United States (African American and Latino) [37]. Individuals of lower socioeconomic status and those with more sexual partners and pregnancies also have higher infection rates [38, 39]. Some studies have found higher HSV-2 prevalence among women with HIV compared to men [40]. HSV-1 infection is generally more prevalent than HSV-2, with rates ranging from 30% to 78% [37, 40]. HSV-1 seropositivity may protect against HSV-2 acquisition and vice versa, but this has not been uniformly shown across studies [40, 41].

The epidemiologic links between HIV and HSV are significant. HSV-2 infection is associated with a two to four times increased risk of HIV disease acquisition likely through the breakdown of a natural skin barrier [36, 42, 43, 44]. Similarly, as HSV-2 seropositivity is associated with increased plasma HIV viral loads, it may potentially increase disease transmission risk [45]. However, a study showed no effect of HSV-2 seropositivity or viral shedding on HIV viremia in seminal and cervico-vaginal secretions, thereby challenging the contribution of HSV-2 to HIV disease transmission [46]. Incident HSV-2 infections also serve as a marker of sexual risk behaviors that place an individual at increased risk of HIV acquisition. Herpes simplex virus is transmitted through direct contact with oral and genital secretions including from individuals with active lesions or who shed the virus during asymptomatic periods. The incubation period is approximately 2–13 days (average 3–6 days).

Pathogenesis

Following inoculation of the virus into epithelial surfaces (skin or mucous membranes), the virus is able to evade immune responses, accesses axon terminals, and establishes latency in sensory ganglia – trigeminal or sacral ganglia for oral or genital HSV infections, respectively. Viral replication is typically limited to the epidermis or epithelial surface of mucous membranes [47]. Initial human innate (toll-like receptors [TLRs] and cytokine products) and later adaptive immune responses (CD8 T-cells, antibodies directed against viral proteins) aim to control viral replication and subsequent reactivation [47]. Subclinical reactivation and shedding of viruses may occur with varying frequencies depending on multiple factors including host immune status and environmental factors including stress and concurrent illnesses, malnutrition, and pregnancy [47].

Clinical Presentation

The clinical spectrum of HSV disease ranges from asymptomatic to severe and prolonged illness predominantly occurring in individuals who are immunocompromised and are experiencing a first episode of HSV illness. Genital lesions in particular, beyond discomfort, can be stigmatizing for individuals who experience outbreaks. Oropharyngeal lesions may cause severe oral pain and interfere with swallowing and feeding. Visceral HSV disease is uncommon and occurs predominantly in individuals who are older, receiving steroids or other immunocompromising medications including those undergoing cancer chemotherapy or transplant recipients, and other immunocompromised patients such as individuals with HIV disease. HSV hepatitis and meningitis, which can be recurrent however, can occur in immunocompetent hosts. Mollaret’s meningitis, which is recurrent aseptic meningitis, most commonly results from recurrent HSV-2.

A typical HSV lesion is localized and progresses through multiple stages – a prodrome of burning or tingling, followed by development of papular lesions that progress to vesicles, which subsequently ulcerate. Regional lymph nodes may be enlarged. In immunocompromised patients, lesions may coalesce forming large superficial ulcers, which can persist for prolonged periods and may be mistaken for other lesions, such as decubitus ulcers in the perianal region. Lesions may become superinfected, but otherwise are not pustular. Resolution of the lesions is heralded by crusting and typically leaves no scarring.

HSV esophagitis typically presents as odynophagia, which can be frequently disabling and interfere with eating. HSV hepatitis may present with “anicteric hepatitis” syndrome, characterized by rapid rise in liver transaminases initially without hyperbilirubinemia or clinical jaundice, and may result in serious consequences including fulminant hepatic failure if unrecognized and untreated early. Ocular disease may present as keratitis with patients complaining of foreign body sensation, redness of eye, and pain. Acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) are feared complications of HSV ocular infection. Central nervous system disorders associated with HSV include Bell’s palsy, transverse myelitis, meningitis that could be recurrent (Mollaret’s meningitis), and a severe meningoencephalitis [35], the latter occurring in both adults and infants from vertical transmission. Rare clinical syndromes include pneumonitis and herpetic paronychia or “whitlow.”

Diagnosis

Genital herpes may be diagnosed clinically based on the characteristic appearance of the lesions. Unlike VZV, HSV lesions do not take on a dermatomal distribution but are more regional in distribution (e.g., orolabial or perianal). Other diseases may mimic HSV, and therefore definitive diagnosis requires laboratory testing. Swabs of active lesions (typically with a cotton tip or Dacron) can be sent for detection of HSV DNA by nucleic acid amplification/PCR, antigen detection, or culture [48]. Cytologic examination of smears of lesions or biopsy specimens with Tzanck or Papanicolaou stains, though inexpensive, has poor sensitivity and specificity. However, detection of antigens by immunofluorescence has improved detection rates with sensitivity ranging from 70% to 90% for smears of genital ulcers [48]. While viral culture remains the gold standard, HSV DNA detection by nucleic acid amplification testing (NAAT) or PCR remains the most sensitive and specific detection method (98% and up to 100%, respectively) and is the preferred method of testing [48]. As type-specific antibodies are usually absent in early HSV disease, antibody testing is best reserved to confirm prior exposure or past infections and has the advantage of distinguishing between HSV-1 and HSV-2.

Treatment/Management

Acyclovir, available in oral and intravenous formulations, is the first-line medication for treatment of HSV. Oral valacyclovir and famciclovir are alternatives with greater oral bioavailability and less frequent dosing than acyclovir. All require dosage adjustment for patients with renal insufficiency. IV acyclovir is used for more serious infections. Penciclovir has poor oral bioavailability; thus its use is limited to topical application to active lesions [49]. Prolonged duration of therapy may be required for immunocompromised patients with extensive mucocutaneous lesions to achieve a cure. Of the clinical syndromes caused by HSV, encephalitis is a medical emergency [35]. Intravenous acyclovir is the mainstay of therapy, and steroids may be used for individuals who develop severe brain edema. Mortality rates are high, and survivors have high frequencies of neurologic deficits.

Mutations in viral thymidine kinase may render HSV resistant to acyclovir and may be found in 5–25% of immunocompromised patients receiving acyclovir prophylaxis or treatment [50]. In these cases, foscarnet or cidofovir, the latter administered with probenecid to prevent nephrotoxicity, are alternative treatment options [50]. Medications in early phase clinical trials that have shown some promise include pritelivir and amenamevir, which belong to a new class of antivirals that are helicase-primase inhibitors [49].

Prevention

There are no available vaccines against HSV, but some candidates are in development [49]. Individuals at risk for recurrent disease reactivation can be maintained on antiviral prophylaxis, which may also serve to prevent disease transmission. Avoiding contact with active lesions and use of condoms during sexual intercourse are also effective ways of preventing disease transmission. HSV transmission, however, can result from asymptomatic viral shedding.

Varicella Zoster Virus

Introduction

Varicella zoster virus (VZV), a DNA virus, is distributed worldwide. While primary varicella zoster virus infection (chickenpox) can occur in any host (healthy or immune compromised), reactivation herpes zoster disease (shingles) typically occurs in the elderly and other immunocompromised hosts. In people with HIV, herpes zoster episodes are a harbinger of the development of AIDS. VZV can be potentially life-threatening in individuals with HIV, particularly individuals with low CD4 counts where it may present as prolonged or disseminated cutaneous or visceral disease typically associated with higher morbidity and mortality, especially when manifesting as a neurologic syndrome [51].

Epidemiology

Primary VZV infection typically occurs in childhood but can occasionally present in unvaccinated adolescents and adults [52]. In settings where varicella vaccines are not offered routinely, seroprevalence rates of 50% by age 3 and 94% by age 7 have been reported [53]. VZV is shed in oral secretions, but, unlike HSV, asymptomatic shedding is rare [54]. VZV is extremely contagious and may be transmitted by contact from individuals with active cutaneous lesions that have not undergone crusting. Respiratory droplets, however, are thought to be the primary mode of transmission [55]. Herpes zoster infection occurs more frequently among people with HIV than HIV-negative persons. A study of MSM showed that the incidence rate of herpes zoster was much higher among men with HIV (29.4 cases/100 person-years) versus 2.0 cases per 100 person-years among seronegative men [56]. While the risk of VZV reactivation in HIV-infected individuals in the cART era has decreased, there remains an increased risk of three times higher than that of the general population [57, 58]. Not unexpected is the observation in cohorts of people with HIV that low CD4 counts and not being on cART are identified risk factors for herpes zoster [59].

Pathogenesis

Following inhalational exposure to VZV, the virus invades the epithelial and immune cells of lymphoid tissue of the respiratory tract as well as the tonsils [47]. Thereafter, infected T-cells are thought to traffic the virus systemically and may initiate primary infection in the dermal tissue. Innate immune responses including toll-like receptor-mediated processes as well as humoral responses are then able to abort or control the primary infection; however the virus is able to evade complete eradication by, among other things, modulating interferon signaling [47]. The mechanism of VZV reactivation is poorly understood, but it is generally thought that cellular immunity plays a significant role in maintaining latency of VZV primarily in sensory neural tissue, and thus factors which impair those responses can lead to reactivation of infection.

Clinical Presentation

Primary varicella infection typically presents as a generalized rash that progresses from macular to papular and to vesicular lesions, which are occasionally intensely pruritic and spread in a centrifugal pattern. Lesions may appear over 4–5 days and therefore may be at different stages of evolution at the time of presentation [60]. Superinfection of the lesions may occur with scratching, with bacterial organisms like Staphylococcus aureus and beta-hemolytic streptococci predominating and, although uncommon, may lead to deeper soft tissue infections and septic shock [61]. Bullous or hemorrhagic lesions may occur in immunocompromised hosts [61].

Herpes zoster lesions, on the other hand, frequently involve multiple dermatomes in HIV-infected patients, coalesce to form large lesions, last for prolonged periods on the order of weeks, and take longer to heal with reepithelization. Disseminated herpes zoster infection may also occur in immunocompromised hosts and may be indistinguishable from varicella zoster or disseminated herpes simplex infection. A rare syndrome of herpes zoster reactivation manifesting as dermatomal or radicular pain without a rash referred to as zoster sine herpete has been described.

Pneumonitis is rare but presents as cough, dyspnea, and hemoptysis typically occurring after the rash has erupted [52]. Chest radiograph may reveal diffuse interstitial infiltrates, and mortality without treatment is approximately 30% [52]. Neurologic syndromes associated with VZV include encephalitis, cerebellar ataxia syndrome, aseptic meningitis, Bell’s palsy, Ramsay Hunt syndrome (Bell’s palsy plus herpes zoster oticus), transverse myelitis, and Guillain Barre syndrome. A post-infectious granulomatous angiitis may result in ischemic injury or hemorrhage. Ocular disease may involve multiple structures including necrotizing retinal syndromes – acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN). Headache, fever, and altered mentation are typical symptoms of VZV encephalitis, which is the most feared of the neurologic syndromes with up to 20% of survivors having residual neurologic sequelae [52]. Focal neurologic signs include cranial nerve palsies and seizures [62]. Other visceral diseases, such as hepatitis, are rare.

Diagnosis

It is possible to diagnose primary VZV infection on clinical grounds based on the characteristic appearance and spread of its rash, sometimes described as “dew drops on a rose petal” that reflects vesicular lesions on an erythematous base. Otherwise, lesions may be unroofed, and a VZV monoclonal antibody test or viral culture may identify and/or isolate the virus, respectively [60]. PCR is the most sensitive test and can be used on a wide range of biologic specimens including cerebrospinal fluid, blood, amniotic fluid, tissue, and bronchoalveolar lavage specimens [60]. For patients with VZV meningoencephalitis, cerebrospinal fluid analysis typically reveals a mononuclear pleocytosis, frequently with red blood cells, and an elevated protein [63]. Detection of VZV antibodies has limited diagnostic utility for active infection except when isolated in the CSF. IgM antibodies may not be detectable early in infection and have suboptimal sensitivity, and false-positive tests occur [60]. In general, testing for VZV-specific IgG should be limited to the identification of which susceptible individuals require active and/or passive immunization to prevent infection.

Treatment/Management

The nucleoside analogue acyclovir and prodrugs valacyclovir (acyclovir) and famciclovir (penciclovir) are treatment options for VZV [60]. The latter two drugs have better oral bioavailability, but all drugs may decrease the severity and duration and reduce the risk of complications associated with VZV infection. They may also be used for prophylaxis against herpes zoster in people with HIV [64]. Intravenous acyclovir is the formulation of choice for CNS disease. Acyclovir is generally well tolerated, but gastrointestinal, hepatic, and renal toxicities may occur. Similar to HSV, mutations in viral thymidine kinase may render VZV resistant to acyclovir, and in those instances, intravenous foscarnet may be used [60]. Antiviral resistance is rare and typically occurs in immunocompromised patients, such as those with AIDS, and prolonged antiviral agent exposure allowing for the selection of resistant viral mutants.

Prognosis/Prevention

Varicella infection may be prevented by receipt of two doses of a live attenuated vaccine (Varivax), which is universally recommended for all children beginning at age 12–15 months with a protective efficacy of about 90% [65]. Adolescents and adults may receive catch-up vaccinations at any time; however, being a live vaccine, it is contraindicated in immunocompromised individuals and pregnant women. For people with HIV, the vaccine may be safely administered at CD4 counts >200 cells/uL. On the other hand, vaccination against herpes zoster is recommended for individuals aged 50 years and older. Similar to the VZV vaccine, it may be administered cautiously in patients with CD4 count >200 cells/uL [66]. A herpes zoster vaccine, Zostavax, has been shown in the short term (<7 years post receipt), to decrease reactivation episodes by about 40–70% and the complication of postherpetic neuralgia by 60–83% [67]. A newer non-live adjuvanted subunit vaccine, Shingrix, was approved by the US FDA in October 2017 and has replaced Zostavax as the recommended vaccine to prevent herpes zoster (efficacy of >90%) and postherpetic neuralgia (efficacy of 91%) [68]. As with many vaccines, protective effectiveness may decline over time.

In the hospital, HIV-positive patients with VZV infection should be placed on both airborne and contact isolation until lesions have crusted [69].

Epstein-Barr Virus

Introduction

Human herpesvirus 4, Epstein-Barr virus (EBV), is one of the most common viral infections in the world. Among people with HIV, chronic EBV infection is associated with a wide spectrum of clinical disorders including benign conditions such as oral hairy leukoplakia and more serious life-threatening conditions including primary CNS lymphoma and Burkitt’s and other non-Hodgkin’s lymphomas (NHL). The epidemiology, pathogenesis, clinical presentation, and management of EBV infection are discussed below.

Epidemiology

EBV is very common worldwide with seroprevalence of >90% in adults. In a review of participants of the US NHANES, among children aged 6–19 years, non-Hispanic blacks had a higher prevalence than non-Hispanic whites, and risk factors include older age, low household income, and absence of health insurance coverage [70]. The primary route of transmission is saliva; therefore shared utensils or drinking cups and toothbrushes may be vectors. Other means of acquisition of the virus include sexual contact, organ transplant, and blood transfusion. Incubation is approximately 6 weeks [71].

Pathogenesis

Following introduction into the oral cavity, EBV infects epithelial cells wherein it replicates and then spreads to involve the lymphoid tissue of the Waldeyer’s ring from where it disseminates hematogenously. Primarily, CD8 T-cell lymphocytes exert immune control over EBV replication. Dendritic cells and other antigen-presenting cells promote T-cell activity [72].

Clinical Presentation

Primary EBV infection is usually asymptomatic. It can cause a mononucleosis syndrome with cardinal symptoms including fever, myalgias, pharyngitis, swollen lymph glands particularly of posterior cervical chain, rash, and hepatosplenomegaly. The splenomegaly may occasionally be massive and leaves the individual prone to life-threatening splenic rupture with abdominal trauma. Classically, use of ampicillin may provoke a rash. Symptoms typically last for about 2 weeks, but prolonged fatigue lasting months is common. Oral hairy leukoplakia typically manifests as white coloration on the lateral aspect of the tongue in patients with immunodeficiency and may be misdiagnosed as oral candidiasis.

EBV-associated malignancies commonly present with “B symptoms” of fevers, weight loss, night sweats, and lymphadenopathy; and in HIV-infected patients, the diagnosis may be delayed as providers may attribute the symptoms to and pursue an evaluation for a chronic infection. Primary CNS lymphoma typically manifests as a solitary space-occupying lesion on brain imaging, which may be accompanied by edema with neurologic symptoms reflecting the location of the tumor. Seizures may complicate the syndrome and may frequently be the presenting symptom.

Diagnosis

While atypical lymphocytes may be noted on a peripheral blood smear, it is not pathognomonic for EBV infection. The heterophile or monospot antibody test is useful to diagnose primary EBV infection but has suboptimal sensitivity but with greater specificity depending on the assay used ranging from 70% to 92% and 96–100%, respectively [73]. The monospot test is also prone to false negative very early in infection. Acute EBV infection may be diagnosed by detection of IgM or rise in IgG antibodies to EBV capsid antigen. While not used routinely for diagnostic purposes, an EBV viral load assay will be positive in patients with infectious mononucleosis but has the limitation of being unable to differentiate reactivation from primary infection. The role of viral load assays for the diagnosis of primary CNS lymphoma is limited but may be useful as the specificity of detection of the virus in CSF is upward of 79% [74]; the sensitivity of CSF cytology is very poor (15%), but flow cytometry for clonal B-cells may improve case detection [75]. The definitive diagnosis of primary CNS lymphoma may require biopsy where other modalities fail. Burkitt’s lymphoma and other NHL may be diagnosed by lymph node or bone marrow biopsies.

Treatment/Management

The antiviral acyclovir has activity against EBV; however treatment of the primary infection is limited to symptomatic therapy including antipyretics and anti-inflammatory agents as the antiviral drug has been shown to have no effect on the disease course. Oral hairy leukoplakia typically resolves with immune reconstitution in patients with HIV, but treatment with acyclovir and topical podophyllin or retinoic acid will lead to faster resolution but with high rates of recurrence.

The mainstay of treatment for primary CNS lymphoma is brain irradiation and chemotherapy [76]. For other HIV-associated lymphomas, outcomes improve with both targeted chemotherapy for the malignancy and immune reconstitution with antiretroviral therapy [77]. Therapy of lymphomas depends on the histologic type with varying chemotherapeutic regimens used such as R-EPOCH (rituximab, etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) used for the treatment of diffuse large B-cell lymphoma and Burkitt’s lymphoma. High-dose chemotherapy with hematopoietic stem cell transplant is an attractive option that carries a high risk of complications but with high cure rates [77].

Prognosis/Prevention

The prognosis of EBV-associated infectious mononucleosis is excellent. Very rarely, individuals with primary infection develop an encephalitis which may be fatal. Splenomegaly associated with EBV may last for a month after the infection, so during that time individuals may wish to avoid contact sports or other conditions that may predispose to abdominal trauma. Among individuals with HIV, the prognosis of EBV-associated lymphomas is historically poor, but outcomes have improved with cART -mediated immune reconstitution and chemotherapy with 2-year survival rates for diffuse large cell B lymphomas and Burkitt’s lymphoma at 67% and 75%, respectively. There is no preventative vaccine for EBV infection.

Cytomegalovirus (CMV)

Introduction

Cytomegalovirus, a lymphotropic beta-herpesvirus, is the largest of the human herpes viruses. It is also referred to as human herpes virus 5. At the time that the AIDS syndrome was first recognized, CMV disease was identified as a frequent opportunistic infection that contributed significantly to morbidity among patients with the syndrome, typically manifesting as a sight-threatening retinitis. With the availability of cART , however, the contribution of CMV to morbidity among people with HIV has decreased significantly.

Epidemiology

CMV is a common infection worldwide, in part owing to its transmissibility in a wide range of bodily fluids, including saliva, breast milk, urine, and seminal and cervicovaginal secretions. CMV can be transmitted transplacentally from mother to child, by blood transfusion and transplanted organs. In the United States, the CDC estimates that 50–80% of adults are infected with the virus by the age of 40. Risk factors for CMV infection include infection with other herpes viruses, poor nutritional status, and living in crowded dwellings [78]. Individuals caring for young children and babies are at particularly high risk. Among cohorts of people with HIV, MSM have higher seropositivity rates compared to other risk groups. Seroprevalence rates are also higher in developing compared to developed countries [78].

Pathogenesis

CMV, like other herpes viruses, establishes latency in the human host. Patients with advanced HIV infection (AIDS) are at risk for CMV reactivation and organ disease. Studies suggest that both humoral- and cellular-mediated immune responses are involved with the control of CMV replication. The virus is able to avoid full eradication by evasive mechanisms including elaboration of proteins, which protect infected cells against lysis by natural killer cells [79].

There have been various reported interactions between HIV and CMV, which impact the pathogenesis of HIV disease. CMV infection may increase infection of CD4 T-cells by HIV, promote T-cell depletion by apoptotic mechanisms, and may promote reactivation of latent virus and HIV viral replication [78].

Clinical Presentation

The majority of individuals with primary CMV infection are asymptomatic. Similarly, an overwhelming majority of individuals with reactivation viremia show no signs or symptoms of end-organ involvement. Symptomatic individuals are likely to be those with compromised immune systems such as people with HIV, transplant recipients, and individuals undergoing intensive chemotherapy. Symptomatic primary CMV infection is rarely life-threatening and typically manifests, after an incubation period of 28–60 days, as a mild “flu-like” illness with symptoms and signs such as fever, fatigue, lymphadenopathy, sore throat, and splenomegaly. An erythematous rash and hepatomegaly may also be noted on physical examination. The clinical syndrome is frequently accompanied by hallmark laboratory abnormalities including leukopenia, lymphopenia, or lymphocytosis with atypical cells, thrombocytopenia, and elevated serum transaminases (aspartate > alanine aminotransferase).

Women who acquire CMV during pregnancy, especially during the first half, are at risk of fetal infection complicated by adverse events including severe neurologic disease and disability. The majority (80%) of infants with vertical CMV infection, however, never develop symptoms. Congenital CMV disease may manifest as microcephaly, sensorineural hearing loss, mental retardation, neuromuscular disorders, and ocular disease including optic atrophy and chorioretinitis [80].

Individuals with high levels of CMV reactivation viremia are more likely to have end-organ disease. CMV can infect almost every organ and may manifest as meningitis, encephalitis, myelitis, polyradiculopathy, retinitis, pneumonitis, esophagitis, hepatitis, cholangiopathy, and colitis. In patients with advanced HIV infection, CMV retinitis is a common manifestation, and regular symptom screening for ocular symptoms and ophthalmologic exams should be performed in patients with AIDS and CD4 count <50/ul.

Diagnosis

CMV viremia may be detected using nucleic acid assays in plasma specimens. The diagnosis of end-organ disease requires a compatible clinical syndrome and confirmation of the presence of the virus either by its detection in tissue (e.g., ulcerative lesions or tissue biopsy specimens) by antigen or nucleic acid testing or evidence of its characteristic cytopathic effect on tissue specimens on microcopy. CMV retinitis is diagnosed through funduscopic visualization of pathognomonic retinal changes including white exudates with or without hemorrhage and/or areas of retinal necrosis in a susceptible symptomatic host. A definitive diagnosis of encephalitis or radiculopathy may be made if CMV is detected in cerebrospinal fluid in patients with neurologic symptoms matching the syndrome and with brain imaging showing periventricular or meningeal enhancement and spine imaging with thickened nerve roots, respectively [81].

Treatment/Management

Antivirals with activity against CMV include ganciclovir, valganciclovir, foscarnet, and cidofovir. Ganciclovir and its prodrug valganciclovir are typically first-line drugs used for treatment of CMV disease. Mutation in CMV’s phosphotransferase -gene (UL97) confers resistance to ganciclovir, while mutations in the polymerase gene (UL54) make virus resistant to foscarnet, cidofovir, and ganciclovir [82]. In such cases, maribavir and brincidofovir are other antiviral agents that have activity against CMV [83]. A pyrimidine synthesis inhibitor, leflunomide, has also been used successfully to treat multidrug-resistant CMV infection [84].

Prognosis/Prevention

Studies have shown that CMV reactivation is a predictor of both end-organ disease and mortality in patients with AIDS [85, 86]. While CMV infection causes severe morbidity, it is likely that the increased mortality observed is a reflection of vulnerable hosts succumbing to other life-threatening infections associated with severe immune deficiency. Certainly, central nervous system end-organ diseases carry a worse prognosis than others. There is mixed data on the efficacy of preemptive anti-CMV treatment for patients with AIDS to mitigate this mortality risk [85, 86]. Furthermore, anti-CMV treatment is frequently associating with severe toxicities.

Individuals at risk for CMV infection include those who work with young children and babies. Pregnant women are advised to wash hands with soap and water after contact with bodily fluids including urine and saliva to prevent primary infection. Healthcare workers who adhere to standard infection control precautions do not appear to have higher rates of primary CMV infection compared to that of the general population.

There is no effective vaccine for the prevention of CMV infection or reactivation.

Human Herpesviruses 6 and 7 (HHV-6 and HHV-7)

Introduction

The relevance of human herpes virus 6 (HHV-6) infection in patients with HIV infection is unclear. The viral infection has been associated with a lymphadenopathy syndrome in patients, but its role in the development of lymphoproliferative disorders is still speculative at best as the detection of HHV-6 in tumor cells does not prove a causal role [87]. Observations suggest that HHV-6 coinfection in HIV individuals may lead to higher viral replication and thereby promote progression to AIDS [87]. HHV-7 is not thought to cause any significant clinical syndrome in people with HIV, so this section will include information on HHV-6 alone.

Epidemiology

HHV-6 infection is more common in people with HIV compared to those without [88]. PCR tests performed on gastric and colon biopsy specimens to detect HHV-6 DNA showed that 50% and 70% of HIV-infected individuals harbored the virus at these sites, respectively [88]. Seropositivity as high as 100% has also been reported [89]. Infection in immunocompromised patients may be caused by either variant A or B HHV-6. the former causing disease more frequently in immunocompromised individuals . HHV-6 is thought to be transmitted primarily by oral secretions.

Pathogenesis

HHV-6 has a trophism for certain host cells including monocytes, macrophages, T- and B-cells, NK cells, glial cells, and megakaryocytes. It establishes latency in peripheral blood mononuclear cells (PBMCs) and other sites including the oropharynx, salivary glands, female genital tract, and brain tissue [90]. Clinical disease in HIV-infected persons typically results from reactivation of latent infection. Some studies have demonstrated excess seropositivity of HHV-6 and detected HHV-6 sequences in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma [90].

Clinical Presentation

HHV-6 infection can cause hepatitis or a mononucleosis syndrome indistinguishable from primary infection associated with other herpes viruses or HIV infection [90]. Fever and maculopapular rash that occur few days after fever are most common with primary infection. Gastrointestinal, respiratory, and central nervous symptoms may also occur. On exam, there may be hepatosplenomegaly. Hepatitis and encephalitis are clinical syndromes suggesting end-organ involvement. A prolonged benign lymphadenopathy syndrome may also occur subsequently in people with HIV.

Diagnosis

The diagnosis of HHV-6 infection is made by positive serologic tests (antibodies) or by detection of HHV-6 DNA by PCR testing or culture on body fluid specimens (blood, saliva, stool, or urine) or tissue specimens. The virus can also be detected by immunohistochemical staining of tissue or culture of body fluids and tissue. As “benign” reactivation of HHV-6 can occur without causing any end-organ disease, positive tests have to be interpreted in light of the patient’s presenting syndrome to support a causal relationship.

Treatment/Management

There is no specific treatment for HHV-6 infection other than supportive measure, although the antivirals, ganciclovir and foscarnet, have been used in some cases.

Prognosis/Prevention

HHV-6 infections typically have an excellent prognosis in immunocompetent individuals; however, in people with AIDS, disseminated infection can result in death.

Human Herpesvirus 8 (HHV-8)

Introduction

Human herpes virus 8 (HHV-8) is responsible for three distinct clinical syndromes in people with HIV: Kaposi sarcoma, primary effusion lymphoma (also known as body cavity lymphoma), and multicentric Castleman disease (angiofollicular lymph node hyperplasia), all of which are neoplastic disorders. Kaposi sarcoma is the most common of the three and can occur in people with HIV regardless of CD4 count. A newer clinical syndrome yet to fully elucidated is an inflammatory cytokine condition with high mortality which lacks abnormal pathologic findings on lymph node histology [91]. A brief overview of the epidemiology, clinical presentation, and management of the syndromes is discussed below.

Epidemiology

Multicentric Castleman disease (MCD), a more aggressive form of angiofollicular lymph node hyperplasia, tends to occur predominantly in men and presents in the fifth to sixth decade of life [92]. The disease frequently coexists with Kaposi sarcoma (KS). AIDS-related KS (the epidemic form) differs from endemic KS in that it affects a younger population and has a more aggressive clinical course [93]. Primary effusion lymphoma (PEL), like MCD, frequently coexists with KS, and patients with the disease share the same clinico-demographic profiles.

Pathogenesis

Human herpesvirus 8 (HHV-8) infects a variety of host cells including monocytes and endothelial and B-cells in which it is able to establish latency by evading host immune processes and can induce proliferation and prevent apoptosis. Multiple viral proteins encoded by HHV-8 have been implicated in angiogenesis and oncogenesis [94]. Also encoded is a viral interleukin 6, and together with dysregulated human interleukin 6, they play a role in the pathogenesis of the HHV-8-associated clinical syndromes. Infection of activated lymphocytes by HHV-8 has been implicated in MCD.

Clinical Presentation

KS commonly presents as nodules or macules on skin or mucous membranes, which are often violaceous and with a range of colors including purple, red, or brown [93]. Lesions may be painful and can ulcerate and bleed. Lymphadenopathy is a common feature and may represent reactive or involved lymph nodes or may represent a separate opportunistic infection or neoplasm. Lesions in the bowel and lungs are only visible with invasive procedures with risk of bleeding with biopsy attempts. Other viscera that may rarely be affected include the liver, spleen, and bones.

Patients with MCD typically present with fever, lymphadenopathy, hepatosplenomegaly, and, less commonly, pulmonary symptoms, edema and ascites [92]. Patient with PEL may have lymphocytic effusions in the pleura, peritoneum, or pericardium. Extracavitary disease is rare.

Diagnosis

KS lesions show characteristic spindle-shaped cells in which HHV-8 can be detected by immunostaining. MCD is diagnosed by biopsy of affected lymph nodes for histology. For MCD, the plasma cell variant tends to predominate over the hyaline vascular variant (80–90% of cases), or there may be cases with mixed histology [92]. For PEL, the virus may be detected in malignant B-cells (which may be coinfected with EBV).

Treatment/Management

Mucocutaneous KS may respond to initiation of ART with immune recovery alone. The addition of chemotherapy to its management may lead to faster resolution of lesions but does not impact overall survival [95]. However, for visceral disease and extensive or complicated mucocutaneous disease, chemotherapy should be included in management of those forms of KS.

ART with immune reconstitution is insufficient to control MCD. Rituximab alone, CHOP, and a combination of the two are the most popular chemotherapeutic regimens. Due to the few cases of the disorder, trials to compare regimens are lacking, and there is no data on the comparative effectiveness of these regimens. Patients with copresenting KS and MCD may have a flare of KS with the use of rituximab alone; therefore concurrent treatment with liposomal doxorubicin or other chemotherapeutic agent with activity against KS is advocated [94]. Steroid use has also been associated with a flare in KS lesions [93]. Stem cell transplantation may be attempted in relapsed MCD after second remission with chemotherapy [92].

PEL is treated with R-EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) or CHOP (cyclophosphamide , doxorubicin, vincristine, and prednisone). Other agents under investigation include pomalidomide or lenalidomide [94].

Prognosis/Prevention

The mortality rate of MCD in HIV-infected patients appears to be better than that of noninfected patients (44% vs 65%) [92]. Patients with PEL have a 2-year survival of 30–40% even following chemotherapy. Mortality from all three disease syndromes appears to have improved in the cART era supporting a beneficial role of cART. No preventive vaccines exist for HHV-8 to prevent HHV-8-associated diseases.

Polyoma Viruses (JC Virus )

Introduction

The polyoma viruses, JC and BK viruses, were first recognized in 1965 and 1971, respectively. Both viruses were named after the individuals from whom the viruses were first identified, John Cunningham virus (JCV) and BK virus (BKV). Both viruses cause unique clinical syndromes in immunocompromised patients. JCV is associated primarily with a severe demyelinating neurologic syndrome called progressive multifocal leukoencephalopathy (PML). BKV is associated with hemorrhagic cystitis and allograft loss in patients who have renal transplants. While BK viremia and viruria may be identified in people with HIV, it is not clear that there are clinical consequences of the infection.

Epidemiology

While infections with JCV occur rarely in people with AIDS (mean CD4 at diagnosis 84–104 cells/mm3) [96], clinical disease from BKV in HIV-positive patients occurs in the context of other conditions and/or treatments, e.g., renal transplantation and hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based surveys of HIV patients reveal that 8–33% have been exposed to BK virus [97, 98] and 16–50% have evidence of JCV [99, 100, 101]. Prior to the availability of cART , 5–10% of AIDS patient developed PML. The mode of transmission is unclear, but the tonsils, GI tract, and kidneys may be reservoirs of the virus [101].

Pathogenesis

PML results from cytolysis and demyelination associated with JCV replication within astrocytes and oligodendrocytes. With declining T-cell immunity, loss of immune control allows for reactivation of latent virus from tissue reservoirs particularly the kidneys [101]. Interestingly, it has been demonstrated that for patients with BK virus coinfection, antibodies against BKV capsid protect against the development of PML [102].

Clinical Presentation

JCV results in four distinct clinical syndromes. It can cause PML, a fulminant variant of encephalopathy involving cortical pyramidal neurons [103], meningitis, and a granule cell neuronopathy which preferentially affects the cerebellum with clinical symptoms of ataxia, nystagmus, and tremor. Because PML can affect any area of the brain, typically with multisite involvement, symptoms differ widely between patients. In people with HIV, motor symptoms predominate over cognitive and language deficits [101]. Common symptoms include weakness, gait changes, sensory symptoms, cognitive impairment, visual symptoms, headache, behavioral abnormalities, and seizures. Fever is unusual and should prompt a search for a concurrent or an alternative diagnosis.

Diagnosis

Radiologically, PML presents as multifocal demyelination involving white matter of the brain with parieto-occipital and frontal lobes of the brain most commonly involved, and occasionally deep gray matter structures are involved [101]. Brain MRI is more sensitive than CT scans and the lesions, which are frequently coalescent and measure up to a few centimeters and are hypointense on T1 and hyperintense on T2 and flair sequences. Occasionally PML lesions show gadolinium enhancement. There is typically no edema associated with PML lesions. Detection of JCV DNA by PCR in the CSF is 92% sensitive [104]. The use of PCR may prevent the need for tissue biopsy to confirm or differentiate the diagnosis of PML from other diseases like multiple sclerosis. If a biopsy is performed, however, a classic triad of “bizarre astrocytes,” demyelination, and enlarged oligodendroglial nuclei is pathognomonic of PML [96].

Treatment/Management

PML and other clinical syndromes associated with JCV represent an antiretroviral treatment emergency as immune reconstitution is the only means of controlling disease progression. Following initiation of cART , immune reconstitution inflammatory syndrome (IRIS) may develop and can mimic disease progression. Treatments which have shown some promise for JCV virus-associated disease, but that have not been rigorously evaluated in clinical trials, include mirtazapine, cidofovir, mefloquine, and dimethyl fumarate [105].

Prognosis

Mortality in patients with PML ranges from 20% to 80%, and survivors typically suffer persistent neurologic deficits [106].

Chronic Hepatitis B and C

Introduction

Hepatitis B and C contribute disproportionately to morbidity and mortality among people with HIV. These infections are particularly prevalent among HIV cohorts as they share similar routes of transmissions – sexual and vertical transmission as well as by exposure to blood or infected bodily fluids. Complications caused by these infections, including liver fibrosis with progression to cirrhosis and the development of hepatocellular carcinoma, may be accelerated in people with HIV. Because of this, liver-related mortality has surpassed AIDS and its complications as the leading cause of death in people with HIV [107]. Chronic viral hepatitis, however, is both preventable and treatable (and curable for HCV).

Epidemiology

The prevalence of HCV infection among cohorts of people with HIV ranges from 2.4% to 82.4%, with most regions averaging around 30% coinfection rates [107, 108]. Hepatitis B virus infection is much less common with prevalence rates ranging from 6% to 20% with highest coinfection rates reported in Asia and Africa where vertical transmission is the most common mode of infection [109]. Risk factors for HBV infection include intravenous drug and cocaine use and low educational level. There are ten genotypes for hepatitis B and six main viral genotypes for hepatitis C that are distributed worldwide.

Pathogenesis

HIV-infected patients have lower rates of spontaneous clearance of HCV infection compared to uninfected counterparts, although increased clearance has been reported with initiation of ART [107, 110]. For those with chronic HCV and HBV infection, HIV infection accelerates progression to cirrhosis and hepatic decompensation presumably through multiple mechanisms including its effect on pro-fibrosis mediators, induction of hepatocyte apoptosis, and HIV-associated immune dysregulation [109]. Unlike patients with HCV, individuals with HBV may frequently develop hepatocellular carcinoma in the absence of liver cirrhosis [109].

Clinical Presentation

While symptoms with acute infection may occur in patients with HBV infection after an incubation period of 1–6 months, it is very rare in patients with HCV infection. In HBV, prodromal phases of symptoms including fever, anorexia, malaise, nausea, vomiting, abdominal pain, and jaundice are frequently reported symptoms. Jaundice, hepatomegaly, and splenomegaly may also be present. HBV flares may occur and resemble symptoms of acute infection. HBV has been linked to polyarteritis nodosa (PAN). People with HCV are mostly asymptomatic, but pruritus, fatigue, arthralgia, paresthesia, myalgias, and sicca syndrome are potential extrahepatic manifestations. HCV has been linked to porphyria cutanea tarda and mixed cryoglobulinemia. Epidemiologically, HCV is associated with type 2 diabetes. Fulminant acute hepatitis is rare for both HBV and HCV infections.

Diagnosis

A positive hepatitis B surface antigen (HBsAg) suggests the presence of replicating virus. Detection of IgM antibodies to hepatitis B core antigen suggests acute infection. Persistence of HBsAg for 6 months confirms the diagnosis of chronic infection. These tests examine the host response to HBV, while quantitation of serum HBV DNA is used to assess active viral infection. Hepatitis C infection is diagnosed based on the detection of antibodies to hepatitis C; however, the test does not discriminate between cleared, cured, and active infection. A reflex HCV RNA assay is recommended to determine the presence of the virus. Assessment of response to therapy for both chronic HBV and HCV infections is based on serial assessment of viral load detection.

Treatment/Management

The treatment of HCV has been revolutionized since the approval of the first ever direct-acting antiviral drugs (DAAs) in 2011. The DAAs provide shorter treatment durations, higher cure rates, and greater regimen tolerability than previous interferon- and ribavirin-based regimens. HCV-HIV coinfected patients should have priority for treatment given the synergy of both viral infections, which results in higher rates of liver-related morbidity. The currently approved treatment regimens for HCV disease in HIV-infected patients are listed below (see Table 13.2). Reports of HBV flares in untreated HBV patients undergoing HCV therapy have prompted recommendation that HBV screening be performed routinely in patients for whom HCV therapy is being considered [111].
Table 13.2

Recommended initial HCV treatment regimens for HIV-infected patients by genotype and significant antiretroviral (ARV) drug interactions (American Association for the Study of Liver Diseases [AASLD] and endorsed by the Infectious Diseases Society of America [IDSA], October 2016)

 

Recommended treatment regimens

Contraindicated ARVs

HCV genotypes 1a and 1b

Elbasvir/grazoprevir × 12 weeksa, b, c

Cobicistat, efavirenz, etravirine, nevirapine, any protease inhibitor

Ledipasvir/sofosbuvir × 12 weeksb, c

Tipranavir. Risk of increased tenofovir levels with boosted regimens (cobicistat or ritonavir)

Paritaprevir/ritonavir/ombitasvir/dasabuvir × 12 weeksc, f

Darunavir, efavirenz, ritonavir boosted lopinavir and tipranavir, etravirine, nevirapine, cobicistat or rilpivirine

Simeprevir/sofosbuvir × 12 weeks

Cobicistat, efavirenz, etravirine, nevirapine, any protease inhibitor, tipranavir

Sofosbuvir/velpatasvir × 12 weeksb, c

Efavirenz, etravirine, nevirapine or tipranavir

Sofosbuvir/daclatasvir × 12 weeks

Tipranavir

HCV genotype 2

Sofosbuvir/velpatasvir × 12 weeksd

As above

HCV genotype 3

Sofosbuvir/velpatasvir × 12 weeksd

As above

Sofosbuvir/daclatasvir × 12 weekse

As above

HCV genotype 4

Paritaprevir/ritonavir/ombitasvir + ribavirin × 12 weeksd, f

Darunavir, efavirenz, ritonavir boosted lopinavir and tipranavir, etravirine, nevirapine, cobicistat, rilpivirine, didanosine, stavudine, or zidovudine

Sofosbuvir/velpatasvir × 12 weeksd

As above

Elbasvir/grazoprevir × 12 weeksd

As above

Sofosbuvir/ ledipasvir × 12 weeksd

As above

HCV genotypes 5 and 6

Sofosbuvir/velpatasvir × 12 weeksd

As above

Sofosbuvir/ledipasvir × 12 weeksd

As above

aFor patients with no baseline resistance-associated variants (RAVs), 16 weeks of treatment is recommended when RAVs are present

bTreatment regimens may also be used for patients with genotype 1a with compensated liver cirrhosis

cTreatment regimens may also be used for patients with genotype 1b with compensated liver cirrhosis

dCan be used for patients with no liver cirrhosis and compensated liver cirrhosis

eShould be extended to 24 weeks for patients with compensated liver cirrhosis (with or without ribavirin)

fThis regimen containing ritonavir should only be used in patients on antiretroviral therapy

The mainstay of HBV treatment is nucleoside analogues: tenofovir, emtricitabine, lamivudine, and entecavir [112]. While lamivudine monotherapy has been used for HBV treatment, its low barrier to resistance limits the therapeutic length of this medication. Compared with other nucleoside analogues, tenofovir has the advantage of a high resistance barrier, retains activity against lamivudine resistant virus, and, like lamivudine and emtricitabine, has activity against HIV [113]. Oral adefovir and subcutaneously administered interferon monotherapy have largely been abandoned due to toxicity profiles and/or low resistance barrier. In general, patients with HIV and HBV coinfection should be treated for both concurrently given the availability of antiviral drugs with activity against both viruses. HBV viral load (DNA) measurements are useful for monitoring response to HBV treatment and also to assess for antiviral resistance for chronically treated patients. A viral load, however, is not predictive for a treatment endpoint and sustained response once medications are discontinued. For HBeAg-positive patients, treatment endpoints include loss and seroconversion of HBeAg, loss of HBsAg, and, the most elusive endpoint, development of hepatitis B surface antibody (HBsAb) [113]. The latter two treatment endpoints also apply to HBeAb-negative patients.

Prognosis/Prevention

The liver-related complications of HBV and HCV can be prevented with early diagnosis and treatment. Recent studies have shown, however, that patients with cirrhosis may experience regression of their fibrosis (up to 50% of individuals); however, in spite of successful treatment, a minority of patients may still develop hepatocellular cancer (HCC). Extrahepatic manifestations can occur with both viral infections and contribute significantly to morbidity and mortality including renal complications. Hepatitis B may be prevented by vaccination. Unvaccinated persons who are exposed to HBV may be administered with hepatitis B immune globulin (HBIG) to prevent infection. Antiviral agents and administration of HBIG post-delivery may be used to prevent vertical transmission of HBV infection. There is no vaccine against HCV.

Human Papilloma Virus (HPV)

Introduction

As in the general population, HPV seroprevalence is high among HIV-infected individuals. There is a recognized interaction between HPV and HIV, as development of HPV-associated cancers occurs at a much higher frequency in people with HIV, particularly anal cancer among MSM and cervical cancer in women, the second most common cancer worldwide for that demographic. Routine screening for these cancers allows for early detection and improved patient outcomes.

Epidemiology

HPV is transmitted between individuals through skin-to-skin contact and via bodily fluids and is implicated in the pathogenesis of cervical, anal, penile, and certain head and neck cancers [114]. High-risk genotypes that predispose to these cancers include 16, 18, 31, 33, 35, 95, 45, 51, 52, 56, 58, 59, 68, 73, and 82 [115]. The prevalence of these high-risk genotypes varies in population studies. In women with HIV, surveillance studies have shown that 33–64% harbor at least one high-risk genotype and up to 12% have more than one [116, 117, 118]. The prevalence may be higher in young women (<20 years), women with indicators of high-risk sexual behavior (history of STDs and number of sexual partners), and women with HIV infection who have low CD4 counts and use oral contraceptives [115, 116, 119]. While higher sexual activity indices are associated with higher prevalence of HPV infection in men, it is not clear that circumcision is protective [120]. Anal HPV infection is associated with receptive anal intercourse, and in MSM with HIV, prevalence rates may be up to 93%, with 73.5% having high-risk genotypes [121]. Unlike HIV, female-to-male transmission of HPV is thought to be higher than male-to-male transmission [122].

Pathogenesis

The HPV genome encodes 8 early and late genes which encode 6 early proteins and 2 late proteins. Much of their roles have been elucidated. For example, early proteins 6 and 7 (E6 and E7, respectively) are both involved in cell-cycle entry and cell proliferation, as well as degrading the tumor suppressors p53 and pRb, respectively [123]. When HPV infects epithelial cells, its genome is integrated into the host cell where expression of its oncoproteins results in cellular transformation [123, 124]. High-risk HPV genotypes are able to drive proliferation of the cells typically in the basal layer of the epithelium, while low-risk HPV genotypes do not appear to cause abnormal proliferation of the cells they infect [123].

Clinical Presentation

HPV disease is asymptomatic in most individuals. Certain HPV strains cause warts that may be present on the penis, scrotum, perineum, cervix, vagina, urethra, vulva, and anus. HPV lesions may appear as keratotic lesions (less common) or the typical cauliflower-like lesions which may be smooth, flat, or dome shaped [120]. Among people with HIV, particularly people with AIDS, these lesions may grow very large in size creating unsightly and disfiguring lesions with resultant complications (e.g., urethral HPV causing outflow obstruction). HPV-associated cancers are the most severe manifestation [120].

Diagnosis

HPV disease (warts) may be diagnosed clinically based on the appearance of its characteristic skin lesions. Biopsies may be performed if they appear atypical and/or there is concern for a malignancy. Abnormal cervical or anal bleeding should prompt evaluation for cancerous lesions.

Treatment/Management

Topical imiquimod is effective for the treatment of anogenital warts with clearance rates of up to 29% after 16 weeks of application [121, 122]. Podofilox, sinecatechins, bichloracetic acid, and trichloroacetic acid are topical alternatives. Cryotherapy is also used with varying degrees of success; surgical removal may be indicated for complicated warts such as those causing penile meatal obstruction or that are refractory to medical therapy [122]. The treatment arsenal for HPV-associated malignancies include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents, and treatment modalities are tailored to the type of cancer, stage, and patient characteristics [124].

Prognosis/Prevention

Regression of HPV disease does occur frequently after infection; one study found that 60% of women with HIV had regression of genital warts without treatment in the 1st year of their diagnosis and up to 82% when followed further out (13 years) [121]. Cervical cancer screening should begin at age 21, with cervical cytology performed every 3 years. Women older than 30 should have cervical cytology and HPV testing every 5 years or using the same strategy outlined for younger women up to age 65 [125]. Women with HIV should have three negative annual cervical cytology screens prior to initiating screenings every 3 years [125]. There is no data on the optimal screening strategy and frequency for anal cancers in men in spite of the recognition that HPV disease constitutes a significant disease burden to men with HIV. Most clinics caring for this patient population perform annual screening for MSM with referrals for high-resolution anoscopy with any abnormal cytology result.

Bivalent, quadrivalent, and nanovalent vaccines exist for the prevention of HPV disease and may be administered to children up to the age of 26. These vaccines all protect against the major genotypes that cause HPV-associated cancers (HPV 16 and 18) and decrease dysplasia [114, 121]. Importantly, condoms do not offer complete protection against HPV disease [120].

Bacterial Infections in HIV Infections

Clinical Bacterial Syndromes

It was recognized early in the HIV epidemic that people with HIV were particularly vulnerable not just to opportunistic pathogens but that they also experience recurrent bacterial infections such as pneumonia, sinusitis, meningitis, skin and soft tissue infections, and other pyogenic processes. In recognition of this occurrence, the US CDC incorporated recurrent bacterial pneumonia in the list of AIDS-defining conditions. With some infections, such as enteritis caused by non-typhoidal salmonella, Shigella, and Campylobacter, secondary bloodstream infections may occur [126]. With the introduction and widespread use of effective cART as well as trimethoprim-sulfamethoxazole prophylaxis in patients with AIDS, the burden of bacterial infections in HIV-infected patients has decreased but remains above the risk for individuals without HIV. Therefore, surveillance for specific bacterial infections (e.g., screening for sexually transmitted diseases and tuberculosis) and institution of preventative measures where possible are important parts of the management of someone living with HIV.

Spectrum of Infection

The spectrum of bacterial infections in HIV-infected patients includes common infections such as pneumonia, bloodstream and urinary tract infections, as well as skin and soft tissue infection which are typically the most frequent presentations but also includes bacterial infections that are sexually transmitted such as syphilis, gonorrhea, and chlamydia [127, 128]. In addition to STDs, MSM can acquire proctocolitis with bacteria including Shigella, non-typhoidal salmonella and Clostridium difficile. People who inject drugs (a common comorbidity among HIV-infected cohorts) may present with skin and soft tissue infections, vascular infection (septic thrombophlebitis), and bacterial endocarditis.

Epidemiology

One study showed that bacterial infections are responsible for up to 15% of mortality among people with HIV in an urban setting [129]. The common bacterial pathogens isolated in the bloodstream of patients who present with community-acquired infections vary by region, but the most commonly reported include Streptococcus pneumoniae, the Enterobacteriaceae, Staphylococcus aureus, and coagulase-negative staphylococci (usually associated with intravascular devices) [126].

Pathogenesis

In HIV infection, there is a paradoxical B-cell hyperactivation and hyporesponsiveness [130]. This is evidenced by diminished responses to vaccines which also reflects diminished T-cell function. Similarly, cells of the innate immune system including monocyte-macrophage, natural killer cells, and dendritic cells also show some dysfunction [131, 132]. Together, this immune dysregulation increases the susceptibility of people with HIV to bacterial infections.

Clinical Presentation

The clinical presentation of bacterial infections depends on the type, but certain considerations must be included for people with HIV. Patients with AIDS may have muted or no constitutional symptoms even when they have serious infections due to immunosuppression. Leukocytosis may not be present although high normal white blood cell counts, with neutrophilia and/or bandemia, should raise concern for an infectious process. Similarly, the degree of cellular pleocytosis in bodily fluids may underrepresent the degree of inflammation in the compartment. Sweats may be a reasonable surrogate for fevers which patients may not always recognize or report, and high normal temperature should be taken seriously in the setting of immunosuppression.

Diagnosis

Diagnostic tests should be performed targeting the suspected clinical syndrome as would typically be performed in an immunocompetent host. Inflammatory markers such as ESR may be challenging to interpret as baseline levels may be elevated in people with HIV compared to healthy controls [133]. On the other hand, discriminatory tests like procalcitonin, which can help distinguish bacterial from nonbacterial infectious processes, perform well in this patient population [134, 135]. Every effort should be made to obtain relevant cultures or other diagnostic tests preferably before initiation of antibiotic therapy.

As with the clinical presentation, radiologic findings may be absent or lack prominence in patients with low CD4 counts such as a “normal-appearing” chest radiograph which may occur in a patient with pneumonia. Where clinical suspicion is high, it is advisable to obtain more sensitive imaging modalities such as a chest CT scan for a pulmonary process. Because of a typically broad differential diagnosis factoring in the host immunity, invasive diagnostic testing may be indicated so as to establish a timely diagnosis to guide appropriate management.

Treatment/Management

There are several key management principles, first of which is to maintain a high index of suspicion for infection based on clinical symptoms, derangements in vital signs, and laboratory abnormalities. Secondly, it is paramount to obtain appropriate cultures prior to initiating antibiotics, including draining accessible abscesses if present. Thirdly, initiating appropriate and timely empiric antibiotics, triaging the patient to the appropriate level of care, and considering host factors when deciding on the duration of therapy for the infection are important management principles.

Prognosis and Prevention

Because of a higher risk of secondary blood stream infections and impaired host immune responses, and occasional late recognition of sepsis by providers due to subtle presentations, bacterial infections remain a significant cause of mortality among people with HIV, especially those with AIDS [136]. Endovascular and CNS infections typically carry a worse prognosis. Pneumococcal vaccination, oral care, and medication-assisted therapy or syringe exchange programs for people who inject drugs can significantly prevent bacterial infections.

Bartonella Infections (Bacillary Angiomatosis)

Introduction

There are many Bartonella species that cause various diseases in humans, but bacillary angiomatosis in people with HIV is typically caused by Bartonella henselae and Bartonella quintana. Disseminated disease may occur, but the mortality is low.

Epidemiology

Bartonella infections have multiple modes of transmission including contact with infected animals or by arthropod vectors including cat fleas which are transmitted occasionally by a scratch by infested cat claws (B. henselae). Poor personal and environmental hygiene promotes the habitat of the human body louse, Pediculus humanus, the vector for B. quintana. As a result, homelessness and poor socioeconomic status are risk factors for infection [137]. Surprisingly, high rates of occult Bartonella bacteremia have been reported in people with HIV, with one study reporting a prevalence of 10% based on PCR surveys suggesting that it is an underrecognized disease [138].

Pathogenesis

Following inoculation in to the blood, B. henselae and B. quintana adhere to and penetrate into endothelial cells where they replicate ultimately resulting in the development of reactive vasoproliferative lesions.

Clinical Presentation

Fever, skin lesions resembling Kaposi sarcoma, and lymphadenopathy are the prominent symptoms of bacillary angiomatosis. The skin lesions may take the form of angiomatous nodules, papules, or plaques, which may be red, purple, or skin colored, of different sizes with smooth or eroded surfaces [139, 140, 141]. Visceral disease involving the respiratory and GI tracts, brain, bone, and lymph nodes has been described, and symptoms referable to sites may be present. Disease caused by B. quintana tends to present with more neurologic features including cranial nerve deficits and seizures, while lymphadenopathy predominates for B. henselae [137, 140]. Endocarditis may result from Bartonella infections (a leading cause of culture-negative endocarditis), but this has been rarely reported in individuals with HIV infection [142].

Diagnosis

While rare, the diagnosis of bacillary angiomatosis should be considered in a person with HIV with multiple vascular-appearing skin papules or nodules. Serology is the mainstay of diagnosis with a rise in titers over time essentially confirming the diagnosis. Histopathology of affected organs (lymph node, liver, bone marrow) may reveal the organism with specialized staining (Warthin-Starry) or by detection of the organism using PCR [137]. Bartonella species are Gram-negative bacteria, and in patients with disseminated disease, blood cultures may be positive; however, the organisms are fastidious and slow-growing, so they are not always recovered in cultures. PCR tests on blood may be more sensitive for bacteremia [143].

Treatment/Management

Doxycycline and erythromycin are the mainstay of treatment for bacillary angiomatosis, and a duration of 3 months is recommended [141, 144].

Prognosis/Prevention

With appropriate management, complete resolution of skin lesions occurs; however, relapses are common. There is no preventative vaccine.

Mycobacterial Infections (TB and MAC)

Introduction

The cellular immune defects associated with HIV create particularly vulnerability for mycobacterial infections. In areas endemic for tuberculosis (TB), it contributes significantly to morbidity and is a leading cause of mortality. Mycobacterial infections are a frequent cause of immune reconstitution inflammatory syndrome (IRIS) . In non-endemic areas, Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) are frequent opportunistic infections, the latter being more common in patients with advanced HIV disease.

Mycobacterium Tuberculosis (M.Tb)

Epidemiology

TB frequently coexists in people with HIV. In certain endemic countries, up to 70% of all TB cases occur in people with HIV. Reactivation of latent tuberculosis is very high in people with HIV, occurring at an annual rate of 1 in 10. This rate approximates the lifetime risk in an immunocompetent individual. Risk factors include male gender, low socioeconomic status, and poor living conditions [145]. People who inject drugs are a subpopulation that is also disproportionally impacted. Concurrent immunosuppressive medications or conditions further increase the risk of tuberculosis infection or reactivation.

Pathogenesis

Diminished T-cell-mediated immunity underlies the predisposition to mycobacterial infections. While pulmonary tuberculosis can occur at any CD4 count, disseminated and extrapulmonary forms of the disease occur at lower CD4 counts. The macrophage dysfunction which occurs in people with HIV is believed to contribute to the inability to confine the organism to the site of infection, allowing dissemination.

Clinical Presentation

The presentation of TB in people with HIV is similar in most respects to that of immunocompetent hosts. A chronic syndrome of fevers, malaise, night sweats, weight loss, and cough with or without hemoptysis should prompt a diagnostic evaluation for pulmonary TB. Of note, a cough of short duration (0–14 days) should not preclude a consideration of TB as studies have shown that cases may be detected in patients who report shorter cough periods [146]. In endemic areas, extrapulmonary disease occurs more frequently in people with HIV than in the general population, and clinical manifestations are typically referent to the organ system involved. More importantly, the clinician must bear in mind that TB can affect almost any organ system and that a high index of suspicion is warranted. Patients with unexplained pleural or pericardial effusions and ascites should have these serosal effusions sampled and tested for infectious etiologies including mycobacteria and for malignancy.

Diagnosis

Findings of chest radiography in people with HIV with pulmonary TB range from normal to grossly abnormal with focal or multilobar infiltrates, nodular or cavitary lesions with intrathoracic adenopathy, and pleural effusions being the most frequent disease patterns. A miliary pattern of pulmonary infiltrates suggests disseminated disease.

The diagnosis of TB typically requires isolation of the organism from tissue specimens and to differentiate it from other mimicking conditions including other mycobacterial infections. Sputum collection for acid-fast bacilli (AFB) smears for the evaluation of pulmonary disease are best collected in the morning for optimal yield, and multiple specimens may be sent to improve testing yield. “Sterile pyuria” in the setting of an epidemiologic risk for TB should prompt an evaluation for genitourinary disease. For patients with disseminated disease, bone marrow, lymph node, or liver biopsy specimens may be obtained for testing. Improved diagnostics including the GeneXpert MTB-RIF test which allow for both rapid detection of TB and rifampicin resistance, as well as liquid culture techniques such as the Mycobacterium growth indicator tube (MGIT), have led to significant shortening of the laboratory time required to diagnose TB. Furthermore, these diagnostic tests can be utilized for non-pulmonary specimens for the diagnosis of extrapulmonary disease. Genotyping of smear-positive specimens, where available, may provide useful preliminary information on the isolate’s susceptibility profile to first- and second-line medications. One important caveat patient with HIV and AFB smear-negative sputa can have culture-positive sputa and retain the potential to transmit TB to others. Where possible, all sputa should be held for culture to rule out this possibility.

The role of tuberculin skin tests and interferon gamma release assays in the diagnosis of active tuberculosis is limited as they do not differentiate latent from active disease. Furthermore, in people with HIV with severe CD4 depletion, or who are anergic from malnutrition or other causes, the tests may be falsely negative.

Treatment/Management

The treatment of TB depends on the site or sites of involvement and susceptibility profile of the tuberculosis isolate (see Table 13.3). CNS and osteoarticular tuberculosis and multidrug-resistant isolates require modification of the choice and duration of treatment. Adjunctive steroids may be used in patients with meningitis and pericarditis and those experiencing TB-IRIS. Drug interactions complicate the management of TB in people with HIV. The non-nucleoside reverse transcriptase inhibitor, efavirenz, and integrase inhibitors are the preferred base medications to be used in combination with rifampicin. Protease inhibitors are best avoided, and rifampicin increases their metabolism and results in subtherapeutic drug levels. Rifampicin may be substituted with rifabutin to further decrease the interaction potential [145]. Also overlapping side effects such as hepatotoxicity must be considered.
Table 13.3

Recommended treatment duration recommendations for drug-susceptible pulmonary and extrapulmonary tuberculosis (TB) (WHO guidelines 2010)

Form of tuberculosis

Recommended antitubercular drug treatment duration

Pulmonary and extrapulmonary tuberculosisa

6 months (2 months RHZE, 4 months RH)

Tuberculous meningitis

9–12 months (2 months RHZE, 7–10 months RH)

Bone and joint tuberculosis

9 months (2 months RHZE, 7 months RH)

E ethambutol, H isoniazid, R rifampicin, Z pyrazinamide

aExcept central nervous system and bone and joint tuberculosis

Following diagnosis, local health departments or other appropriate authorities should be notified of diagnosed cases to arrange for medication supervision, often referred to as directly observed therapy (DOTs), and for contact tracing as applicable.

The timing of initiation of cART following a diagnosis of TB was explored in the SAPIT trial. The study showed a mortality benefit for patients with CD4 count <50 cell/mm3 who were initiated on cART within 2 weeks of TB diagnosis and treatment compared to a group for whom cART was deferred. There was more IRIS in the early cART initiators; therefore, deferred cART for at least 4 weeks following initiation of antimycobacterial therapy may be advisable for those with CD4 count >50 cells/mm3 [147].

Infection control considerations are critical to reduce the spread of TB. Patients with suspected pulmonary TB should be immediately placed on airborne isolation to decrease risk of transmission to both healthcare workers and other hospitalized patients. Because patients with extrapulmonary disease frequently have pulmonary foci, precautions should be extended to these patients until pulmonary disease is ruled out. Isolation precautions may be lifted with documented sputum conversion and after 1–2 weeks of treatment. One important caveat is that HIV-positive patients with AFB smear-negative sputa can have culture-positive sputa and retain the potential to transmit TB to others.

Prognosis

The patient’s prognosis depends on prompt recognition of the infection, type of organ involvement, and institution of appropriate therapy with good adherence. Pleural and pericardial TB may result in long-term sequelae including trapped lung and constrictive pericarditis. Individuals with TB meningitis may have residual neurologic disability. Severe bony destruction by Pott’s disease may require surgical stabilization.

TB can be prevented by intensive case finding (to address community-based transmission), isoniazid prevention therapy (for individuals with latent infection), and observance of infection control precautions. The BCG vaccine reduces the incidence of tuberculosis in infants and children.

Mycobacterium Avium Complex (MAC)

Introduction

Mycobacterium avium complex is a ubiquitous organism that is a common cause of infection in people with AIDS, typically manifesting as disseminated disease and is a frequent cause of IRIS.

Epidemiology

In the pre-cART era, the prevalence of MAC among AIDS patients was as high as 40% and is a marker of mortality [148]. Mycobacterium avium is the principal disease-causing species. The organism is acquired primarily by inhalation, but ingestion is also a significant means of infection. Risk factors for disease include CD4 count <50 cells/mm3 and previous colonization with MAC.

Pathogenesis

As described for TB, diminished cellular immunity, as well as impairment in macrophage function, is the immunologic basis for increased susceptibility to MAC infection in people with HIV. Certain primary immune deficiencies have been also implicated in increased susceptibility to mycobacterial infections [149].

Clinical Presentation

With cART , isolated organ involvement has been reported including isolated pulmonary disease and may reflect the impact of cART on host immunologic status [150]. The clinical presentation of disseminated MAC (dMAC) is nonspecific; however, in patients with advanced HIV infection (e.g., CD4 <50/mm3), constitutional symptoms of weight loss, fatigue, intermittent fevers, night sweats, as well as organ-centered symptoms, such as diarrhea, lymphadenitis, and/or abdominal pain, should prompt the clinician to include a workup for MAC. Hepatosplenomegaly and lymphadenopathy may also be present.

Diagnosis

The diagnosis of MAC can be made by isolating the organism in blood (by culture) or by a biopsy of affected tissue including the bone marrow and/or liver in disseminated disease. While blood culture has reasonable sensitivity, the results do not return quickly enough, typically taking 2–4 weeks to grow in culture. If there is pulmonary involvement, multiple sputa may be sent for AFB smear and culture but interpreted with caution as MAC is an occasional contaminant of respiratory specimens. When AFB are identified in clinical specimens, rapid PCR tests may detect MAC shortening the time-specific species identification, which, in the past, had to be identified only after growth in culture. Certain laboratory abnormalities such as cytopenias (suggesting bone marrow involvement) and elevated liver transaminase or alkaline phosphatase (suggesting liver involvement) in the context of a compatible syndrome favor MAC as the etiology.

Treatment/Management

The anchor for the treatment of MAC is the macrolides: clarithromycin or azithromycin. These have excellent penetration into the intracellular compartment which makes them ideal for treating MAC, an intracellular pathogen. Combination therapy is the norm for the dual benefit of synergistic bactericidal activity and to prevent the emergence of drug resistance. Clarithromycin appears to be superior to azithromycin with regard to microbiologic clearance of the organism. Rifabutin and ethambutol are typically used in addition to a macrolide offering the advantage in clinical trials of improving clinical cure rates with less relapse. Aminoglycosides can be added for severe disease although long-term use carries the risk of renal and hearing complications. As with the treatment of TB, the use of rifabutin and clarithromycin raises risk of drug-drug interactions including with cART . Treatment for dMAC should be continued for at least 1 year and/or for 3–6 months after CD4 stays above 100 cells/mm3, whichever is longer.

Prognosis

To the extent that MAC in patients with AIDS reflects severely impaired immune status, it has been shown in multiple studies to correlate with an increased risk of mortality. Prevention may take the form of primary prophylaxis with intermittent azithromycin for HIV patients at risk for dMAC. For individuals with a past episode, secondary prophylaxis with azithromycin or clarithromycin should be given until sufficient immune recovery (>100 cells/mm3).

Parasitic Infection

Toxoplasmosis

Introduction

Toxoplasmosis is a common protozoal infection that afflicts people with AIDS who have more advanced HIV infection (i.e., CD4 <50 cells/mm3), typically occurring as reactivation of prior infection in the setting of being severely immunocompromised.

Epidemiology

Toxoplasma gondii, an obligate intracellular protozoan and the causative organism of toxoplasmosis, is acquired via ingestion of raw/undercooked meats or contact with cats and their feces containing oocysts. Vertical transmission of tachyzoites can occur and is the only form of person-to-person transmission known to occur. The incubation period is 10–23 days. Seroprevalence rates of 10–90% have been reported, with higher rates observed in certain European and developing countries [151].

Pathogenesis

When Toxoplasma cysts or oocysts are ingested, bradyzoites or sporozoites are released, respectively, and penetrate the lining of the gastrointestinal tract where they are transported via lymphatics and are subsequently disseminated through the bloodstream. At the tissue level, the organism proliferates, producing necrotic foci. In severely immunodeficient individuals, this process can progress without disruption, leading to clinically overt disease.

Clinical Presentation

In people with AIDS, the most common presentation of toxoplasmosis is cerebral disease which typically manifests as multiple ring-enhancing lesions on CT scan and MRI brain imaging [152]. Seizures, fevers, altered mentation, and focal neurologic deficits are frequent findings. Rarely, dissemination may occur with rash. Ocular, cardiac, and pulmonary disease can occur but are also uncommon.

Diagnosis

Exposure to Toxoplasma gondii can be determined by the detection of IgG antibodies; however, the test does not distinguish active infection from past exposure. A negative IgG test makes toxoplasmosis unlikely. Toxoplasma PCR may be assessed in various body fluids or tissue specimens but has suboptimal sensitivity. Biopsies may be attempted on involved organs to enable detection of the organism; however, for the brain, risks may outweigh benefits. As such, a therapeutic trial of agents known to be active against the protozoan may first be attempted, and, if there is no improvement in 1–2 weeks, invasive diagnostic testing will then be justified. This usually results in the diagnosis of an alternate etiology of the brain lesion.

Treatment/Management

The standard of care for toxoplasmosis is combination treatment with pyrimethamine with leucovorin and sulfadiazine. High-dose trimethoprim-sulfamethoxazole is an alternative. A combination of pyrimethamine and leucovorin with clindamycin or atovaquone is appropriate for patients with allergies to sulfa-containing medications. Steroids may be used for severe brain swelling with mass effect. A 6-week treatment course is recommended followed by secondary prophylaxis in people with HIV until the CD4 count remains above 200 cells/mm3 for 3–6 months. Antiepileptic medications may be required if the patient presents with seizures.

Prognosis

With prompt and appropriate treatment, toxoplasmosis usually responds to appropriate therapy; however, neurologic deficits may persist.

Fungal Infections

General Introduction

Certain fungal infections are particularly common in people with HIV: these include cutaneous infections, Pneumocystis jirovecii pneumonia, endemic mycoses, cryptococcal disease, and mucocutaneous candidiasis. Filamentous fungal infections such as aspergillosis and mucormycoses are less common, for unclear reasons, unless related to other immunocompromising conditions such as receipt of cancer chemotherapy, posttransplant, steroid use, or poorly controlled diabetes mellitus. This section will discuss common fungal infections in people living with HIV.

Oropharyngeal Candidiasis

Introduction

Candidiasis is the most frequent opportunistic fungal infection observed in people with HIV. Oral candidiasis is a reliable marker of severe immune deficiency and heralds the susceptibility to other opportunistic infections if the individual remains untreated. Esophageal candidiasis and candidiasis of the upper airway tract are designated as AIDS-defining conditions.

Epidemiology

Colonization with Candida occurs in up to 65% of adults [153]. There are no differences in colonization rates between people with and without HIV. Risk factors for clinical disease include smoking, dentures, use of inhaled or systemic steroids or other immunosuppressant medications, xerostomia, and exposure to broad spectrum antibiotics [153]. The most common species causing disease in people with HIV is Candida albicans. Other species that cause disease include C. glabrata and C. krusei, which may be the predominant species in patients receiving fluconazole. C. glabrata is variably fluconazole-sensitive, while C. krusei is fluconazole-resistant. Invasive visceral candidiasis and bloodstream infections may occur in people with HIV with other comorbidities, such as cancer chemotherapy-associated mucositis and neutropenia and indwelling vascular devices.

Pathogenesis

Candida species are common commensals of the human gastrointestinal tract. Candida species possess enzymes known as secreted aspartyl proteases (SAPs), which facilitate adherence and damage to epithelial surfaces [154]. These SAPs degrade host epithelial cell-mediated anticandidal immune responses which play a role in suppressing the development of clinical disease. On the other hand, protease inhibitors used in the treatment of HIV may impede adherence mechanisms of Candida as HIV protease has homology with Candida SAPs [153, 154]. CD4 cells, through expression of TH-17 cytokines , also participate in the defense against Candida infection [154].

Clinical Presentation

Oropharyngeal candidiasis in HIV patients manifests as three forms: (1) white dense plaques, semi-adherent to the buccal mucosa, palate, gingivae, tongue, or throat, (2) erythematous patches at the same sites, and (3) hyperplastic firmly adherent plaques on the buccal mucosa, palate, and tongue that may mimic oral hairy leukoplakia [153]. Dysphagia in the setting of oral candidiasis usually implies esophageal involvement. Odynophagia is unusual and should raise concern for ulcerative disease, most frequently caused by HSV or CMV. Severe disease can impair taste sensation and, in patients with dysphagia, impair nutrition and the ability to take oral medications.

Diagnosis

The diagnosis can be made by its characteristic clinical appearance and confirmed by resolution with antifungal therapy. Oral swabs for fungal stains and culture are indicated in patients who do not respond to treatment and may reveal species that are resistant to the chosen therapy, for example, Candida krusei in patient who is treated with fluconazole. Esophageal candidiasis is easily visualized and identified by upper endoscopy; however, the invasive test is not warranted in all cases.

Treatment/Management

Spontaneous resolution of candidiasis is uncommon in adults with HIV, and treatment is generally indicated. Topical therapies with clotrimazole or nystatin are effective treatments. Gentian violet has been shown to be a lower-cost and equally effective alternative to oral nystatin for the treatment of oropharyngeal candidiasis [155]. Oral azoles allow for systemic treatment with higher efficacy than nystatin [156]. Azole-resistant Candida species, however, will require treatment with an intravenous echinocandin or an amphotericin B formulation. Treatment duration of 14 days is recommended and relapses are common.

Prognosis/Prevention

Candidiasis responds quickly to antifungal drugs and typically resolves within a week. Candida vaccines are in early phase development [157].

Pneumocystis jirovecii Pneumonia (PJP)

Introduction

Pneumocystis jirovecii pneumonia (PJP) was one of the opportunistic infections that drew attention to the AIDS epidemic. It remains one of the most common opportunistic infections, irrespective of setting, reflecting the global distribution of the causative organism. An improved understanding of the natural history and pathogenesis of disease caused by the organism has led to advancements in its management, which has translated into improved treatment outcomes for patients.

Epidemiology

Pneumocystis jirovecii (formerly P. carinii) is acquired via inhalation. The organism has a predilection for the lungs where the trophic form predominates over the cystic stage of the fungus. Colonization without clinical disease is well described, and human-to-human transmission can occur [158]. Before cART , up to 80% of people with AIDS developed disease associated with the organism. Since cART and widespread use of antimicrobial prophylaxis, the incidence has dramatically declined.

Pathogenesis

Alveolar macrophages are thought to be the primary host defense against Pneumocystis [159]. Immunoglobulins (IgG) and other opsonins are also involved with the macrocytic phagocytosis of invading organisms. CD4 T-cells produce cytokines in response to Pneumocystis, which facilitate recruitment of neutrophils and macrophages to the lung but also mediate tissue damage [159]. Thereby, tissue damage occurs from the immune response to the organism rather than the organism itself.

Clinical Presentation

Patients with PJP typically report a subacute syndrome of dyspnea that is worse on exertion, dry cough, low-grade fever, and malaise. While tachypnea and exertional hypoxia are common, cyanosis is rare. Lung exam may be normal or demonstrate diffuse dry crackles. There is usually no wheezing. Extrapulmonary pneumocytosis (liver, spleen, brain, retina, or kidney) is rare.

Diagnosis

The typical radiographic appearance of PJP is that of bilateral ground-glass opacities more easily identified on a high-resolution chest CT than X-ray. In patients who received inhaled pentamidine for prophylaxis, upper lobe disease alone may occur. Focal consolidation, pleural effusions, or intrathoracic adenopathy is unusual and should prompt search for an alternate primary or concurrent etiology. Granulomatous disease manifesting as nodular opacities on chest imaging has also been reported in a minority of patients with PJP [160]. The definitive diagnosis of PJP requires visualization of the teacup-shaped fungal forms in respiratory secretions including induced sputum or bronchoalveolar lavage, the latter specimen being more sensitive. While transbronchial biopsies are very helpful from a diagnostic standpoint, the risk of pneumothorax is high and may not justify the invasive procedure. A surrogate marker of the fungus, 1 → 3 beta-D-glucan, may be useful where bronchoscopy is not available and has a sensitivity of 92% and a specificity of 65% [161, 162]. The low specificity, however, reflects the cross-reaction with other fungi such as Candida, Aspergillus, and Histoplasma which is a significant limitation. Although frequently used historically, the utility of an elevated LDH as a screening test to assess the likelihood of PJP is problematic as it has suboptimal sensitivity and specificity [163].

Treatment/Management

Trimethoprim/sulfamethoxazole (15–20/75–100 mg/kg/day) [Bactrim] is the mainstay of therapy. This may be given orally in mild to moderate disease, while IV is used for severe disease. Individuals unable to tolerate Bactrim can take atovaquone for mild to moderate disease. In severe disease, IV pentamidine or IV clindamycin + primaquine are reasonable options, although with significant toxicities. A 21-day treatment duration is recommended and is usually successful for the vast majority of patients. For individuals with a paO2 <70 mmHg or A-a gradient >35 mmHg, the use of a tapering course of adjunctive steroids confers a mortality benefit and decreases the probability of requiring mechanical ventilator support. After treatment is completed, people with HIV should be placed on prophylaxis until the CD4 count recovers to above 200 cell/mm3 for at least 3 months.

Prognosis

The mortality rate from PJP is about 10–20% in people with HIV [159].

Histoplasmosis

Introduction

Histoplasmosis is a significant cause of morbidity and mortality among people with HIV, especially individuals living in areas endemic to the fungus. Its presentation may mimic mycobacterial disease and limited diagnostics, especially in resource-limited settings, and may lead to delayed recognition of the disease. A synopsis of the epidemiology, clinical presentation, management, and prevention is presented below.

Epidemiology

The causative organism of histoplasmosis, Histoplasma capsulatum, has a worldwide distribution and may be isolated in soil, bird, and bat droppings [164]. Three varieties of the fungus have been described with regional differences in distribution: H. capsulatum var. duboisii being found in Africa (African histoplasmosis), H. capsulatum var. capsulatum in the Americas, and H. capsulatum var. farciminosum, which causes disease in animals in Africa and the Middle East [164]. African histoplasmosis is reported to occur very rarely in people with HIV [165]. In the United States, the Ohio and Mississippi valley regions are endemic for histoplasmosis. Two to 25% of people with HIV living in endemic areas develop clinical disease [164]. Exposure to birds including chickens and low baseline CD4 counts (<150 cells/mm3) have been identified as risk factors for the disease [166].

Pathogenesis

Histoplasma, a dimorphic fungus, exists in its yeast form at body temperature and as a mold at cooler temperatures. Humans become infected through inhalation of its micronidia or hyphal forms, and in the lungs, the organism is ingested by phagocytic cells of the innate immune system (macrophages, neutrophils, and dendritic cells), which also facilitate its dissemination to mediastinal and hilar lymph nodes and organs of the reticuloendothelial system [164]. When cell mediated immunity is depressed, clinical disease is more likely; otherwise, a latent, asymptomatic infection typically results following exposure.

Clinical Presentation

In people with HIV, clinical disease may result from acute infection or reactivation of latent foci. Clinical syndromes of histoplasmosis include acute and chronic pulmonary infection. Disseminated disease is the most common presentation in people living with AIDS. Less common presentations include pericardial, cutaneous, gastrointestinal, ocular, musculoskeletal, central nervous system, and rheumatologic disease [167]. Disseminated histoplasmosis may involve any organ.

Patients with histoplasmosis typically present with nonspecific chronic symptoms of fatigue, fever, headache, and weight loss. Those with pulmonary disease may report cough and dyspnea and may be found to be hypoxic. Individuals with esophageal disease may report dysphagia or odynophagia, and diarrhea may be a marker of bowel involvement. Examination may reveal hepatic or splenic enlargement, peripheral lymphadenopathy, and a skin rash particularly in patients with disseminated infection [164]. Patients with CNS disease may present with neurologic symptoms including deficits attributable to a space-occupying lesion (histoplasmoma).

Diagnosis

Patients with pulmonary disease may have a myriad of findings: diffuse interstitial infiltrates and miliary and cavitary lung disease associated with mediastinal or hilar adenopathy. The presence of calcified granulomata may signify past exposure. An elevated LDH level is frequently observed, and pancytopenia suggests bone marrow involvement. Histoplasma antigen detection tests are a useful diagnostic marker with variable sensitivity (42–100%), depending on the test and specimen used. Serum and urine antigen testing is a very useful test for detection of systemic histoplasmosis. The test cross-reacts with other fungal infections such as blastomycosis, coccidioidomycosis, and aspergillosis [168]. Blood cultures may be useful in patients with disseminated disease. Fungal stains and cultures should be performed on all tissue specimens with bone marrow specimens offering the highest yield, but cultures may take up to 6 weeks to yield positive results. PCR tests are a helpful adjunct test that may be performed on tissue specimens with the advantage of more rapid diagnosis, though sensitivity remains suboptimal [168]. Seroconversion following exposure to Histoplasma capsulatum typically occurs 4 weeks following exposure. Antibodies do not distinguish latent from active infection, though a negative test makes chronic infection less likely. In addition, antibody testing has a limitation of lower sensitivity in people with HIV (90%) [167].

Treatment/Management

For patients with severe or disseminated histoplasmosis, intravenous liposomal amphotericin B as induction therapy for at least 2 weeks (or 4–6 weeks for patients with CNS disease) followed by oral itraconazole for 1 year is the recommended treatment [169]. As there are significant drug interactions between itraconazole and antiretroviral drugs including efavirenz and protease inhibitors, adjustments may have to be made to HIV therapy. Fluconazole is less effective than itraconazole for the treatment of histoplasmosis [164].

Prognosis/Prevention

Severe fatal forms of histoplasmosis have been described that present as severe sepsis with multi-organ failure and may occur in 10–20% of people with HIV with mortality rates as high as 70% [164]. People with HIV living in endemic areas should be considered for itraconazole prophylaxis (200 mg/day) when CD4 counts fall below 150 cell/mm3. Secondary prophylaxis should be continued until CD4 counts >150 cells/mm3 for 6 months on cART and after they have received at least 12 months of antifungal therapy with negative fungal blood cultures and with a serum Histoplasma antigen <2 ng/mL [169].

Cryptococcal Infection

Introduction

Central nervous system (CNS) disease associated with cryptococcal infection is a major cause of morbidity in people with HIV/AIDS with a significant mortality rate in spite of optimal management. As with other opportunistic infections, the availability of cART has led to decreased incidence of this serious condition.

Epidemiology

Cryptococcal disease in HIV-infected patients is primarily caused by two species of Cryptococcus, Cryptococcus neoformans and Cryptococcus gattii. The latter organism has a predilection for forming cryptococcomas in the CNS, causing disease in immunocompetent individuals, and some strains have a high fluconazole minimum inhibitory concentration [170]. C. neoformans is globally distributed, although with significant variation in the prevalence of species and molecular types. The yeast has been isolated from tree hollows, soil, and bird droppings [170, 171]. The prevalence of cryptococcal infection among people with HIV ranges from 5% to 8% in developed countries but is higher in developing countries. The portal of entry is likely inhalation of yeasts. In people with HIV, the most common presentation of cryptococcal infection is meningitis; however, pulmonary, lymph node, and musculoskeletal can occur. Skin disease is often a marker of dissemination [171]. The incubation period is not well defined and ranges from 1 to 110 months [170].

Pathogenesis

Following inhalation, cryptococcal organisms invade lung tissue and subsequently disseminate through the blood stream. The polysaccharide capsule of the yeast enables it to evade or suppress host immune responses, and enzymes like urease promote its ability to penetrate human tissue. Defective neutrophil, natural killer (NK), dendritic cell, and monocyte-macrophage function have been shown, primarily in animal models, to be associated with susceptibility to cryptococcal disease [172, 173, 174, 175]. In humans, impaired cellular immunity is the major risk factor for C. neoformans meningitis. In cryptococcal meningitis, the organism can obstruct CSF drainage through the arachnoid granulations, commonly leading to hydrocephalus which is a life-threatening complication of the disease [176].

Clinical Presentation

Generalized and nonspecific symptoms of cryptococcal disease include fevers with chills and/or sweats and weight loss. Individuals with CNS disease may have a headache as their solitary symptom, nuchal rigidity, photophobia, and other classical signs of meningismus are frequently absent. Abnormal mentation, blurring of vision, focal neurologic deficits with cranial nerve VI involvement being the most common, and seizures may occur especially if there are concurrent brain space-occupying lesions (cryptococcomas). Cognitive impairment, gait ataxia, urinary incontinence, and/or vomiting should raise concerns for raised intracranial pressure associated with CNS disease [177]. Cryptococcal pneumonia typically manifests with cough with or without hemoptysis, dyspnea, and pleuritic chest pain. Skin lesions of Cryptococcus may be nodular or exhibit the characteristic central umbilication resembling Molluscum contagiosum lesions; however, cryptococcal lesions are typically larger. Biopsies are required to establish the diagnosis.

Diagnosis

In patients with cryptococcal meningitis, head imaging may reveal ventriculitis with or without ventricular dilatation, and focal nodules or cystic lesions may be demonstrated [171]. CSF analysis typically reveals a lymphocytic predominance of white blood cells, with high protein and low glucose. Characteristically, opening pressures are elevated in patients with cryptococcal meningitis. Organisms may be rapidly identified by the use of India ink stain (sensitivity of 70–90%). Otherwise cultures of CSF or other specimens (e.g., blood or tissue) are very sensitive and typically yield growth of the organism within 2–5 days. Cryptococcus will grow on most standard blood culture media and fungal media including Sabouraud Dextrose Agar. Cryptococcal antigen tests have the advantage of rapid diagnosis with a titer of >1:4 having >90% sensitivity for detection of disease [177]. Chest imaging may reveal focal infiltrates, nodules, and/or cavitary disease. Large lesions mimicking malignancy may occur. Biopsies of the skin, lymph node, bone marrow, lungs, and brain or other tissue specimens, when performed, allow for direct visualization of the organisms in tissue with specialized stains.

Treatment/Management

Treatment of CNS cryptococcosis occurs in three phases: induction, consolidation, and maintenance. There is robust evidence showing that induction treatment with amphotericin B and flucytosine confers a morbidity and mortality benefit [178]. Liposomal amphotericin offers the advantage of better CNS penetration and less nephrotoxicity than conventional amphotericin B. In areas where flucytosine is unavailable, fluconazole may be used as a substitute in combination with amphotericin, but studies have shown lack of a mortality benefit compared to amphotericin alone [178]. Induction phase of treatment should be for 2 weeks or until CSF cultures are negative, whichever comes last. In patients with cryptococcomas, prolonged induction phases up to 6 weeks are recommended by the Infectious Diseases Society of America (IDSA) [179]. Consolidation phase consists of fluconazole 400–800 mg once daily for an 8-week period and then maintenance therapy (or secondary prophylaxis) with fluconazole 200 mg once daily until CD4 counts are above 100 cells/mm3 for >3 months. The use of adjunctive steroids has not been shown to impact mortality and leads to higher adverse effects and disability in patients with AIDS-associated cryptococcal meningitis [180]. Recent clinical trials have shown that sertraline may be a reasonable substitute for fluconazole for the treatment of cryptococcal meningitis [181, 182].

An important component of managing cryptococcal meningitis is the monitoring of electrolytes. Amphotericin B causes electrolyte wasting, and hypokalemia and hypomagnesemia are serious risks during treatment, as well as acute kidney injury, and significant renal impairment can increase flucytosine levels, leading to marrow and gastrointestinal toxicity. Also, ongoing monitoring of intracranial pressure is critical with changes in clinical status such as worsening headache, vomiting, and new or evolving neurologic deficits. Spinal taps may be required daily until pressure normalizes. In a minority of patients, an external ventricular drain or a ventriculoperitoneal shunt may be placed to provide relief of spinal fluid pressure. Patients with seizures in the setting of CNS lesions require antiepileptics.

Another important consideration in patients with cryptococcal meningitis is the timing of antiretroviral therapy for patients who are cART naïve. Studies show higher mortality in patients who receive cART within 2 weeks of the diagnosis and treatment compared to deferred therapy (after 4–5 weeks) [183]. Initiation of cART at four or more weeks into treatment of cryptococcal meningitis is recommended.

In isolated pulmonary, lymph node, or skin disease, fluconazole alone may be an adequate treatment.

Prognosis

Mortality from cryptococcal meningitis ranges from 5.5% to 25% with survivors also experiencing residual neurologic and intellectual disability. Outcomes are worse in resource-limited settings. Predictors of mortality include a low CSF WBC count (<20 cells per high-power field), altered mental status, high fungal burden, and older age (>50 years), and slow rate of clearance of CSF infection have been associated with increased mortality [184]. The development of immune reconstitution inflammatory syndrome (IRIS) with introduction of cART may mimic disease progression or relapse and can pose a great challenge to the clinician to differentiate them. IRIS can lead to increased morbidity and mortality.

The best way to prevent cryptococcal meningitis is the maintenance of a robust CD4 count with cART . Studies do support the use of fluconazole prophylaxis for patients with asymptomatic cryptococcal antigenemia for the prevention of end-organ disease [185].

Immune Reconstitution Inflammatory Syndrome (IRIS )

HIV-infected patients initiated on cART and who achieve viral suppression typically experience improvements in immune responses demonstrated by a rise in CD4 counts. This phenomenon may result in inflammatory responses to an existing opportunistic pathogen manifesting as a new manifestation of a previously undiagnosed subclinical infection (unmasking IRIS) or worsening of an already diagnosed infection (paradoxical IRIS) typically occurring 3–6 months following initiation of cART [186]. However, shorter periods of occurrence of IRIS of under a week or longer period of months to years have been reported. Patients on the integrase strand transfer inhibitor class of antiretrovirals, which cause steep virologic decay, experience disproportionately higher rates of IRIS compared to other classes of antiretrovirals [186]. Other risk factors for IRIS include a low CD4 count and high HIV viral load at treatment initiation [187].

The presentation of IRIS is nonspecific but is attributable to an inflammatory response to the infecting pathogen, and symptoms or signs are manifest at sites where the organism is present. For example, a patient with Pneumocystis jirovecii pneumonia may develop adult respiratory distress syndrome with worsening hypoxia, or a patient with cerebral toxoplasmosis may have worsening brain edema around a focal brain lesion and/or manifest new (previously undetected) lesions on imaging with worsening neurologic signs. For patients with CNS OIs, development of IRIS may be catastrophic and lead to mortality.

While IRIS is a clinical diagnosis, a thorough diagnostic evaluation targeted at the patient’s signs and symptoms is prudent and may include a thorough physical exam (such as eye exams for CMV retinitis); blood tests including cultures for bacteria, acid-fast bacilli, and fungi; cerebrospinal fluid examination; imaging; and tissue biopsies. As IRIS may mimic disease progression, consideration should be given to possible resistance of the pathogen to the therapy administered prior to the event.

As a rule, the management of IRIS should not include discontinuation of antiretroviral except in very extreme cases that are life-threatening. Anti-inflammatory medications such as aspirin and nonsteroidal anti-inflammatory drugs may be used to provide symptom relief. The use of steroids should be done very judiciously as it may cause more harm than benefit except for well-defined syndromes such as TB-IRIS where it has been shown to decrease length of hospitalization and improve patients’ quality of life [188].

Due to concerns for paradoxical IRIS, delaying initiation of cART for no more than a 2-week period from the initiation of treatment of most OIs may prevent its occurrence, but delayed cART initiation beyond the 2-week timeframe may also result in adverse consequences [189]. One OI for which this recommendation does not apply is cryptococcal meningitis where early cART initiation (<4 weeks) may lead to increased mortality [183].

Future Directions

For the HIV-infected patient, improving rates of early diagnosis as well as access to and utilization of effective cART is the most important factor that has and will continue to lead to a decline in the incidence of OIs [11, 190]. However, achieving those goals is particularly difficult for low-resource settings, such as sub-Saharan Africa that have been disproportionately impacted by the HIV epidemic. In recent years, better diagnostics have led to faster and more accurate identification of OIs, and these are expected to continue to evolve positively. For treatment of OIs, it is hoped that future studies will inform better ways to utilize or administer existing treatments or evaluate new treatments that should result in improved management and outcomes of patients with HIV-associated OIs.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Section of Infectious DiseasesYale University School of MedicineNew HavenUSA
  2. 2.Yale University School of Medicine, Cornell Scott-Hill Health CenterNew HavenUSA

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