INFECTIONS, INFESTATIONS AND BITES SECTION 12

Cutaneous Manifestations of HIV Infection

Armin Rieger, T Minsue Chen and Clay J Cockerell
78 
was officially made by Dr Michael S Gottlieb, who reported five cases
Key features of Pneumocystis jiroveci (carinii) pneumonia in healthy young men
� Cutaneous disorders in the setting of HIV infection represent a vast from Los Angeles, California1–3. Subsequently, the major causative
spectrum of diseases. As immunity deteriorates, variable agent was identified and named human immunodeficiency virus type
presentations, opportunistic infections, mixed infections and 1 (HIV-1; hereafter referred to has HIV), and homology to an African
adverse drug reactions are increasingly likely zoonosis was demonstrated. Both blood-related and sexual transmis-
� Because the cutaneous findings often correlate with immune sion were identified, and recognition of mother-to-child transmission
status, a more focused differential diagnosis may be generated if led to specific measures for delivery and breastfeeding. Universal pre-
the viral load and CD4+ cell count are known. For example, cautions have been adopted for the handling of blood and body fluids,
seborrheic dermatitis and oral hairy leukoplakia first appear in and ART was introduced in 1996.
patients with CD4+counts >500 cells/mm3, whereas giant mollusca
and large non-healing perirectal ulcers due to herpes simplex virus
are typically seen in patients with counts of less than 50 cells/mm3 EPIDEMIOLOGY
� With the advent of antiretroviral therapy (ART; formerly referred to
as highly active antiretroviral therapy [HAART]), skin disorders such HIV infection/AIDS is a pandemic that still poses one of the greatest
as herpes zoster and Mycobacterium avium complex infection may challenges in global public health. It has disproportionately affected
become clinically apparent or worsen when the immune status resource-poor countries and disadvantaged persons, such as commer-
improves, a phenomenon known as the immune reconstitution cial sex workers, intravenous drug users and those living in poverty, as
inflammatory syndrome (IRIS) well as men who have sex with men.
Approximately 34 million people in the world are currently living
� Unusual skin eruptions, skin diseases with exaggerated with HIV infection (~22 million of whom reside in sub-Saharan Africa)
presentations (e.g. seborrheic dermatitis, molluscum contagiosum), and nearly 32 million have died since 19814. It is estimated that there
sudden acute exacerbations (e.g. psoriasis), and treatment failures are currently over 2.5 million children living with HIV infection and
(e.g. refractory dermatophyte infection) should alert the clinician 18 million children who have been orphaned because of AIDS. In 2009,
to the possibility of underlying HIV infection there were approximately 2.7 million new HIV infections (including
� Several of the medications employed in ART lead to frequent drug 390 000 children) and 1.8 million AIDS-related deaths worldwide. HIV
reactions and significant drug–drug interactions has had an especially disastrous effect in sub-Saharan Africa (Fig. 78.1).
However, in this region as well as several other areas with a high preva-
lence of HIV infection (e.g. India, Thailand and Caribbean countries),
the HIV incidence rate has decreased or stabilized over the past 5–10
INTRODUCTION years4. In contrast, the HIV infection rates in Central Asia and Eastern
Europe (particularly in the Russian Federation and Ukraine) have risen
Since the onset of the human immunodeficiency virus (HIV) pandemic substantially during the past decade, especially in high-risk groups (i.e.
in the 1980s, cutaneous disorders have been recognized as important intravenous drug users and sex workers); as a result, the prevalence of
clues to both the diagnosis of HIV infection and the existence of an HIV infection has more than doubled in this region.
associated systemic disease (including other infections). Currently, AIDS is the leading cause of death in Africa and the fourth
The epidemiology of HIV infection and its complications has changed leading cause of death in low-income countries worldwide5. On a global
in many regions of the world with the advent of antiretroviral therapy basis, access to antiretroviral drugs is still limited, although in the last
(ART; formerly referred to as highly active antiretroviral therapy few years it has improved in low- and middle-income countries. Preven-
[HAART]). Although eradication of HIV infection is not possible with tion and treatment efforts require political leadership, national
current medications, HIV infection/AIDS in the ART era has become programs and adequate funding, as well as societal awareness and
a chronic, manageable disorder. As a consequence, many of the skin response6,7.
disorders associated with HIV disease (e.g. Kaposi sarcoma) as well
as serious opportunistic infections are observed less frequently than in
the past. However, with longer survival, medical problems that previ- PATHOGENESIS
ously were less common have emerged (e.g. anal intraepithelial neopla-
HIV (including HIV-2, which is discussed separately below, as well as
sia), and ART itself has created new dermatologic challenges, including
HIV-1) is an enveloped, single-stranded RNA virus belonging to the
drug reactions, lipodystrophy and immune reconstitution inflamma-
genus Lentivirus within the family Retroviridae. HIV has substantial
tory syndrome (IRIS). While the incidence of opportunistic infections
genetic variability due to the high error rate and recombinogenicity of
has fallen in high-income countries, resurgence of risky behavior along
its reverse transcriptase as well as the very rapid turnover of the virus
with the mistaken belief that ART can “rescue and cure” infected
in infected individuals. The incubation period ranges from 3 to 6 weeks,
patients may lead to a future increase in HIV infection. Unfortunately,
but it may be shorter when it is transmitted hematogenously and/or
in low-income countries where ART is not readily available, opportun-
when the viral inoculum is large. Upon initial infection, the virion
istic infections are still common and are often the source of morbidity
binds to CD4+ T lymphocytes, monocyte-macrophages and dendritic
and mortality.
cells. Changes in conformation induce fusion of the viral envelope with
the plasma membrane. Next, its outer coat is removed and the virus
HISTORY particle is internalized (Fig. 78.2). The RNA genome is released into
the cytoplasm and transcribed by a reverse transcriptase enzyme that
June 2011 marked the thirtieth anniversary of the identification of the produces a DNA copy of the HIV RNA. The DNA copy is then inte- 1285
acquired immunodeficiency syndrome (AIDS). The first description grated into the host DNA and can be expressed as a cellular gene. As
SECTION

12 GLOBAL PREVALENCE OF HIV INFECTION, 2009

Infections, infestations and bites

No data
<0.1%
0.1–<0.5%
0.5%<1%
1%–<5%
5%–<15%
>15%–28%

Fig. 78.1  Global prevalence of HIV infection, 2009. The estimated percentage of the adult population living with HIV infection in each country is indicated. The
worldwide estimate of the number of persons living with HIV is 34 million. From the Joint United Nations Programmes on HIV/AIDS.

a result, there is transcription of viral DNA into RNA, which either widely, seeding lymphoid organs and other internal sites such as the
becomes the genome of new viral particles or is translated into viral CNS. Over time, an immunodeficient state referred to as AIDS ensues,
proteins. Cleavage of the latter into structural components of the virus complicated by opportunistic infections and neoplasms, many of which
is accomplished by proteases. Intact viruses are then produced and host have mucocutaneous manifestations10. In a person infected with HIV,
cells are destroyed. CD4+ cells are affected primarily, significantly AIDS is defined by a CD4+ cell count of <200 cells/mm3 (or CD4+ T-cell
impairing the host’s immune system, especially the cellular compo- percentage of <14) and/or the presence of an AIDS-defining condition
nent. On average, over one billion HIV particles are produced daily, (Table 78.1).
leading to a decline in the infected individual’s CD4+ cell count8. The natural history of HIV infection varies considerably. There is
In the humoral response to HIV, antibodies (IgG, IgM, IgA) directed evidence that additional acute infections (viral or non-viral) increase
against viral proteins are typically detectable within 12 weeks of infec- HIV viral load, but the significance of this phenomenon to the patient’s
tion. In the cellular response, CD8+ cytotoxic T lymphocytes (CTLs) overall course has not been established11. Some patients develop AIDS
directed against HIV begin to function within 10 days of exposure to within 2–3 years, (“rapid progressors”), whereas others remain free
viral antigens and are therefore present before seroconversion or devel- from AIDS for more than 10–15 years (“long-term non-progressors” or
opment of peak levels of viral RNA. The development of a CTL response “long-term survivors”). For untreated disease, the median time of pro-
correlates with the reduction in viremia during the acute retroviral gression to AIDS is approximately 10 years. However, institution of
syndrome and is an important factor in controlling HIV infection ART has an immense impact on the disease course. ART’s profound
throughout the disease course. In addition to their effects on viral rep- effect on HIV replication enables reconstitution of CD4+ T cells. This
lication, CTL activity (including cytokine production) has implications immune reactivation can result in a variety of inflammatory sequelae,
for the infectious, inflammatory and neoplastic complications of HIV referred to as the immune reconstitution inflammatory syndrome
infection. Although CD4+ helper T lymphocytes have a role in the (IRIS), ranging from unmasking or paradoxically “worsening” infec-
initial response to HIV infection, they become dysfunctional early in tions or neoplasms to exacerbations of inflammatory disorders (see
the disease course (even before their numbers decline). The decreased below).
ability of infected helper T lymphocytes to proliferate and produce IL-2 HIV-2 is another human retrovirus that causes immune deficiency
is central to the pathogenesis of HIV infection. Of note, infection of due to depletion of CD4+ cells. The viral structure, modes of transmis-
Langerhans cells by HIV can also affect the immune response. Despite sion, and immune deficiency syndrome it produces are virtually identi-
vigorous anti-HIV immune responses, HIV-infected individuals are not cal to those of HIV-1, and patients are commonly co-infected with
capable of clearing the infection. However, occasional patients (known HIV-112. Compared to HIV-1, HIV-2 has several distinct features,
as “long-term non-progressors”) tolerate the virus without developing including genetic differences, five- to eightfold less transmissibility, rare
significant clinical disease8,9. vertical transmission, a longer period of latency, and a slower rate of
The earliest cutaneous manifestation of HIV infection is an acute CD4+ cell count decline and clinical progression. The outcome among
1286 morbilliform exanthem that is often accompanied by fever and lymph­ HIV-2-infected patients may be slightly better, as the degree of immu-
adenopathy (see below). During this phase, the virus disseminates nodeficiency may be less. Most infections are diagnosed in endemic
 CHAPTER

THE REPLICATION OF HIV WITHIN CD4+ LYMPHOCYTE AND TARGET SITES OF ANTIRETROVIRAL DRUGS 78 

Cutaneous Manifestations of HIV Infection

HIV particle
New viral
particles
released
gp41
gp120 Fusion
inhibitors

HIV binds
to cell
HIV particle
CCR5 budding
inhibitors

CD4
Viral
CCR5 or HIV RNA assembly
CXCR4 Infected
host cell
Protease
NRTI, NtRTI and NNRTI Protease inhibitors
Reverse
(reverse transcriptase transcriptase
inhibitors)

HIV proteins

ds DNA copy
HIV
of HIV RNA Integrase Translation RNA
genome
Integrase
inhibitors
Host nucleus

Transcription

Host DNA Integrated HIV DNA

Fig. 78.2  Replication of HIV within CD4+ lymphocyte and target sites of antiretroviral drugs. CCR5, CC-chemokine receptor 5; NRTI, nucleoside reverse
transcriptase inhibitor; NtRTI, nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor.

areas (primarily West Africa); however, HIV-2 serology should not only Western blot). Primary HIV infection can be asymptomatic, but up to
be tested in individuals who are native to an endemic area, but also in 80% of newly infected individuals report a history of a “viral illness”
those who have had sex with or shared a needle with an individual (Fig. 78.3). Also referred to as “acute retroviral syndrome”, this usually
from an endemic area. occurs 2–4 weeks after HIV exposure and lasts from a few days to over
10 weeks. Reminiscent of acute mononucleosis, the most common
signs and symptoms include fever, lymphadenopathy, pharyngitis and
INFECTIOUS HIV-RELATED a morbilliform exanthem. The cutaneous eruption lasts 4–5 days and
CUTANEOUS DISORDERS is typically generalized, with most pronounced involvement on the face
and trunk (and often sparing the distal extremities). Additional mani-
Cutaneous infections associated with HIV seropositivity can be divided festations, which can include oral or anogenital ulcers, are outlined in
into five major categories: viral, bacterial, fungal, parasitic and ectopara- Figure 78.3. Due to an initial burst of HIV replication, a decline in
sitic (the latter representing infestations rather than true infections). CD4+ T cells can be observed (see Fig. 78.3), only occasionally to levels
Patients with HIV acquired via sexual contact are at increased risk of that allow the development of opportunistic infections13,14. There is
(and should be tested for) other sexually transmitted diseases, which some evidence that a more severe acute retroviral syndrome portends
are discussed in Chapter 82; the converse is also true. In addition, the a more aggressive disease course. The acute retroviral syndrome may
presence of erosions and ulcerations in the anogenital region due to be confused with a drug reaction or other infections (e.g. EBV, hepatitis
diseases such as syphilis and herpes simplex infections can increase B virus, enteroviruses, cytomegalovirus, secondary syphilis). The diag-
the risk of HIV transmission. nosis therefore requires a high degree of clinical suspicion (not just in
high-risk groups) and is confirmed by specific laboratory tests for HIV
RNA/DNA and/or p24 antigen.
Viral Infections
Exanthem of primary HIV infection (acute
retroviral syndrome) Herpes simplex virus (HSV)
The earliest cutaneous manifestation of HIV infection may be an exan- Oral, labial and genital HSV infections in relatively immunocompetent
them occurring as a manifestation of the primary infection (Table 78.2). HIV-infected individuals are typical in appearance and severity,
The latter is defined as the presence of HIV-1 in the plasma (based on with recurrence rates similar to those observed in the general popula-
detection of viral RNA or DNA by PCR and/or p24 antigen) prior to tion15. However, once significant immune suppression develops, lesions 1287
the development of HIV-1 antibodies (as determined by ELISA or may progress to chronic, non-healing, deep ulcerations that favor the
SECTION
Varicella zoster virus (VZV)
12 AIDS-DEFINING CONDITIONS IN PATIENTS INFECTED WITH HIV
In HIV-infected individuals, the spectrum of primary varicella ranges
CD4+ count <200 cell/mm3 and/or Adult or Children* from a typical course to fatal pulmonary involvement. HIV-infected
Infections, infestations and bites

adolescent patients have a 7–15 times greater relative risk of developing herpes
zoster, with reactivation of latent virus occurring as cell-mediated
Serious bacterial infections, multiple or recurrent – + immunity declines. The development of zoster in an HIV-infected
(at least two culture-confirmed infections within
individual is predictive of progression to more severe immune suppres-
a 2-year period)†
sion, especially if associated with fever20,24,25. Although the classic der-
Lymphoid interstitial pneumonitis – + matomal eruption may be seen, HIV-associated zoster can also be
Candidiasis of the esophagus, bronchi, trachea + + multidermatomal, ulcerative, chronic, verrucous and/or widely dis-
or lungs seminated with systemic involvement (see Ch. 80). Bacterial super­
Cervical cancer, invasive + + infection, acyclovir resistance, therapeutic failure, and multiple
recurrences are not uncommon25. Vasculitis with bone necrosis and
Coccidioidomycosis, disseminated or + +
exfoliation of teeth may develop if the blood supply to the mandible
extrapulmonary
and maxilla are compromised26.
Cryptococcosis, extrapulmonary + + Development of herpes zoster with an unusual presentation (e.g.
Cryptosporidiosis, chronic intestinal (>1 month + + multidermatomal, verrucous, disseminated) should prompt HIV
duration) testing. HIV-infected patients at risk for varicella who are exposed to
Cytomegalovirus disease (other than liver, spleen + + individuals who either have varicella or are recent vaccinees may require
or lymph nodes), including retinitis with loss of prophylaxis with varicella zoster immune globulin (VZIG) or acyclo-
vision vir25. Of note, herpes zoster is one of the conditions that may occur in
the immune recovery syndrome, i.e. a paradoxical worsening of clinical
Encephalopathy, HIV-related + +
status due to an increased ability to mount an inflammatory response
Herpes simplex viral infection: mucocutaneous + + (see Table 78.5), and it often appears when CD4+ cell counts rise to a
(>1 month duration), esophagitis, pneumonitis level of approximately 250 per cubic millimeter27. Treatment options
or bronchitis are outlined in Chapter 80, but in HIV-infected patients, antiviral
Histoplasmosis, disseminated or extrapulmonary + + therapy should be extended until there is clinical resolution.
Isosporiasis, chronic intestinal (>1 month + +
duration)
Kaposi sarcoma + +
Poxvirus
Molluscum contagiosum commonly affects patients with HIV infection
Lymphoma, Burkitt’s or immunoblastic + +
who have significantly reduced CD4+ cell counts28. They may develop
Lymphoma, primary, of brain + + classic dome-shaped umbilicated papules as well as larger (>1 cm),
Mycobacterium avium complex or M. kansasii, + + coalescent and disfiguring lesions that are often resistant to treatment
disseminated or extrapulmonary (Fig. 78.5). Although any part of the body can be affected, the lesions
favor the face, neck and intertriginous areas.
Mycobacterium tuberculosis, any site (pulmonary + +
or extrapulmonary) The clinical differential diagnosis includes basal cell carcinoma and
cutaneous involvement of infections with Cryptococcus spp., Histo-
Mycobacterium, other species or unidentified + + plasma capsulatum and other dimorphic fungi. Shaving in affected
species, disseminated or extrapulmonary
areas should be avoided to prevent spread via autoinoculation. Although
Pneumocystis jiroveci pneumonia + + spontaneous regression may occur with antiretroviral therapy20,24,29, the
Pneumonia, recurrent bacterial (two or more + + overall incidence of molluscum contagiosum infections remains high30.
episodes within a 1-year period) In addition to destructive modalities (e.g. curettage), imiquimod and
Progressive multifocal leukoencephalopathy + +
topical cidofovir31 have been used successfully to treat molluscum con-
tagiosum in HIV-infected patients.
Salmonella septicemia, recurrent, non-typhoid + + Vaccinia is an extremely uncommon skin disorder. Because the vac-
Toxoplasmosis of the brain + + cinia virus vaccine is live and not attenuated, persons with impaired
Wasting syndrome due to HIV + + cell-mediated immunity may develop progressive vaccinia by vaccina-
tion or by inoculation from skin lesions in a vaccinee. Currently, virtu-
*CDC criteria define children as less than 13 years of age.
†
Serious bacterial infections include: septicemia, pneumonia, meningitis, bone or joint ally all individuals who receive the vaccinia vaccine are military recruits.
infection, and an abscess of an internal organ or body cavity (excluding otitis media, Generalized vaccinia with fever and toxic symptoms typically develops
superficial skin infections, mucosal abscesses, and indwelling catheter-related infections). 6–9 days after vaccination or other exposure to the virus. Skin lesions
appear as loculated umbilicated vesicles that progress to pustules and
Table 78.1  AIDS-defining conditions in patients infected with HIV. Data from: heal with a pitted scar29.
1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS
among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17).

Human papillomavirus (HPV)

HPV is transmitted by direct person-to-person contact (which can be
perianal region (Fig. 78.4), genitalia and tongue. More frequent recur- sexual in nature) or via fomites32. HPV-induced lesions are common in
rences are also observed when the CD4+ count falls to <100 cells per the general population but even more prevalent in HIV-infected indi-
cubic millimeter16,17. viduals, and it has been demonstrated that HIV Tat protein upregulates
Orofacial lesions associated with nasogastric tube use18 and herpes the expression of HPV20. Lesions may be extensive, with multiple ver-
simplex folliculitis have been described19. Untreated ulcerative lesions rucae on the face, limbs and genitalia that coalesce into large plaques;
usually slowly enlarge and occasionally become verrucous. In suspected bowenoid papulosis can also develop (see Ch. 79). In addition, “acquired
cases, scrapings of the ulcer edge for Tzanck smear (low sensitivity in epidermodysplasia verruciformis” (AEDV) presenting with widespread
this setting), direct fluorescent antibody (DFA) assay, HSV PCR and flat warts and pityriasis versicolor-like macules due to infection with
viral culture should be performed and, if negative, a skin biopsy HPV types in the genus beta can occur (see Ch. 80). HIV-infected
performed20–22. In the setting of treatment failure, viral isolates should individuals may develop squamous cell carcinomas (SCCs) in associa-
be tested for resistance against acyclovir and related antivirals. In most tion with AEDV and other cutaneous (e.g. digital related to high-risk
instances of resistance, reduced thymidine kinase activity is detected23, HPV types) as well as anogenital warts32,33. Institution of ART does not
1288 and alternative drugs (e.g. foscarnet, cidofovir) that do not require thy- appear to result in clearance of warts and may be associated with the
midine kinase activity have to be prescribed. eruptive appearance of new lesions, sometimes in association with a
 CHAPTER

CORRELATION OF CD4+ CELL COUNT WITH SPECIFIC HIV-ASSOCIATED DISORDERS 78 

System* >500 CD4 cells/mm
+ 3
<500 CD4 cells/mm
+ 3
<250 CD4 cells/mm
+ 3
<50 CD4 cells/mm
+ 3

Cutaneous Manifestations of HIV Infection

Dermatologic Acute retroviral Oropharyngeal candidiasis Eosinophilic folliculitis Large, non-healing mucocutaneous
syndrome (thrush) Seborrheic dermatitis, refractory herpes simplex viral infections (e.g.
Oral hairy leukoplakia Herpes zoster Mollusca, extensive perianal)
Vaginal candidiasis Psoriasis, severe or refractory Bacillary angiomatosis   Papular pruritic eruption
Seborrheic dermatitis Eruptive atypical melanocytic Miliary/extrapulmonary tuberculosis Giant mollusca
nevi and melanoma Herpes simplex viral infection, disseminated Perianal ulcers due to cytomegalovirus
Kaposi sarcoma Cryptococcosis, disseminated Aspergillosis
Histoplasmosis, disseminated Acquired ichthyosis
Coccidioidomycosis, disseminated Mycobacterium avium complex
Botryomycosis infections
Non-Hodgkin lymphoma Major aphthae
Respiratory Bacterial pneumonia Pneumococcal pneumonia Pneumocystis jiroveci pneumonia (PCP) Pseudomonas spp. pneumonia
and sinusitis Pulmonary tuberculosis
Lymphocytic interstitial
pneumonia (pediatric)
Nervous Aseptic meningitis Mononeuritis multiplex HIV-associated dementia Primary CNS lymphoma
Guillain–Barré Cerebral toxoplasmosis
syndrome Peripheral neuropathy
Progressive multifocal leukoencephalopathy
Hematologic Persistent generalized Anemia Non-Hodgkin lymphoma
lymphadenopathy Idiopathic thrombocytopenic
purpura
Other Myopathy Cryptosporidiosis Esophageal candidiasis Cryptosporidiosis, refractory
Cervical/anal intraepithelial Wasting Cytomegalovirus retinitis, extraocular
neoplasia Microsporidiosis systemic cytomegalovirus infection
Cervical cancer Vacuolar myelopathy
Anal cancer Cardiomyopathy
*Diseases occur with increasing frequency and severity at lower CD4+ cell counts.

Table 78.2  Correlation of CD4+ cell count with specific HIV-associated disorders.

clinically evident inflammatory response (i.e. a form of IRIS; see prevent (and even stimulate immune responses against existing) genital
below)34,35. warts, dysplasias and cancer.
Furthermore, HIV-infected patients have a higher risk of developing
cervical intraepithelial neoplasia (CIN) and anal intraepithelial neo-
plasia (AIN), with the latter affecting approximately three-quarters of Epstein–Barr virus (EBV)
HIV-infected men who have sex with men (MSM)36. Immunosup- Oral hairy leukoplakia is an EBV-associated mucosal condition that
pression, as evidenced by depressed CD4+ cell counts, is associated represents an early sign of HIV infection. It develops in up to 25% of
with more rapid progression from low-grade to high-grade premalig- HIV-infected individuals24 but can also occur in patients with other
nant lesions. ART-induced immune reconstitution does not appear to forms of immunosuppression (e.g. in organ transplant recipients).
prevent high-grade CIN or AIN from progressing to cancer, and Development of oral hairy leukoplakia predicts disease progression if
longer survival due to ART has been associated with an increase in ART is not administered41. Lesions are usually asymptomatic and
the incidence of anal cancer in HIV-infected individuals37,38. Anal appear as corrugated white plaques with hair-like projections along the
cancer developed in 3% of HIV-infected MSM over a 5-year period in lateral aspect of the tongue (Fig. 78.6). There is no association with
one prospective study36, and the overall rate is >50-fold higher than malignant degeneration. Although treatment is usually not necessary,
in the general population39; a ~5-fold increased risk of penile cancer topical or oral antiviral agents, podophyllin resin or gentian violet can
has also been documented. Monitoring should include serial physical be of benefit. Antiretroviral therapy may also lead to regression of the
examinations of the anogenital area, colposcopy/proctoscopy, cervical plaques41.
and anal HPV determination and cytology (utilizing the Papanicolaou
[Pap] smear), followed by histologic confirmation when indicated;
sensitivity can be increased by repetitive examinations40. Of note, Cytomegalovirus (CMV)
recurrence rates of cervical cancer following standard therapy are sig- Despite ART, CMV remains an important cause of serious opportunis-
nificantly higher in HIV-infected women than in HIV-negative tic infections in patients with advanced AIDS. Common clinical mani-
women. festations include retinitis, esophagitis and colitis. Despite the high
Treatment decisions for cutaneous and anogenital warts in the setting frequency of CMV viremia, cutaneous disease is relatively uncommon;
of HIV infection depend upon the size and location of the lesions as presentations include ulcers (especially in the anogenital area), verru-
well as the presence or absence of histologic atypia; the threshold for cous or hyperpigmented plaques, purpuric papules, vesicles and morbil-
biopsy should be low, and several sites may need to be sampled to liform eruptions20,42. Ulcers may develop on any mucosal surface and
exclude SCC. Therapeutic options for warts include standard cytotoxic/ are usually a sign of disseminated disease. Demonstration of intranu-
destructive and immunomodulatory (e.g. topical imiquimod) approaches clear CMV inclusions within dermal endothelial cells usually proves to
as well as alternative modalities such as topical or intralesional cido- be a more sensitive assay than viral cultures (see Fig. 80.23). Of note,
fovir. However, treatment is often challenging and relapse rates are because many of the ulcerative lesions are co-infected with HSV or
high. Of note, the quadrivalent HPV vaccine (Gardasil™) was recently VZV, and CMV can also be detected in non-lesional skin, a primary
found to be safe and immunogenic in HIV-infected children; hopefully, role for CMV in the pathogenesis of these lesions has been 1289
use of HPV vaccines in young HIV-infected individuals will help to questioned43.
SECTION

12 KINETICS OF VIRAL LOAD AND IMMUNE RESPONSE DURING THE PHASES OF HIV-1 INFECTION
Infections, infestations and bites

Levels of viral
load and Negative Positive
immune Peak
serology serology
response viremia
for HIV for HIV

HIV-1
exposure

2–4 weeks 5–10 years 2–3 years

Acute retroviral syndrome Phase of clinical latency Overt AIDS

Symptoms % of patients Severe constitutional

Late appearance of constitutional symptoms
Fever 80–90 symptoms Opportunistic infections
Fatigue 70–90
Rash 40–80 Neoplasms
Headache 30–70
Lymphadenopathy 40–70
Pharyngitis 50–70
Arthralgia 50–70 Viral load in
Plasma viremia
Myalgia 50–70 lymphoid tissue
Night sweats 50
Gastrointestinal symptoms 30–60 Immune response (HIV-1-specific CD4+ T lymphocyte
Aseptic meningitis 25 cytotoxic lymphocytes) count
Oral or genital ulcers 5–20

Fig. 78.3  Kinetics of viral load and immune response during the phases of HIV-1 infection. After HIV-1 exposure, initial virus replication and spread occur in the
lymphoid organs, and systemic dissemination of HIV-1 is reflected by the peak of plasma viremia. A clinical syndrome of varying severity is associated with this
phase of primary HIV-1 infection in up to 80% of HIV-1-infected persons. Down-regulation of viremia during the transition from the primary to the early chronic
phase coincides with the appearance of HIV-1-specific cytotoxic T lymphocytes and with the progressive resolution of the clinical syndrome. The long phase of
clinical latency is associated with active virus replication, particularly in the lymphoid tissue. During the clinically latent period, CD4+ T-lymphocyte counts slowly
decrease, as does the HIV-1-specific immune response. When CD4+ T-lymphocyte counts decrease below 200 cells/ml (i.e. when overt AIDS occurs), the clinical
picture is characterized by severe constitutional symptoms and by the possible development of opportunistic infections and/or neoplasms. Adapted with permission of
Elsevier from Bart PA, Pantaleo G. The immunopathogenesis of HIV-1 infection. In: Cohen J, Powderly WG (eds). Infectious Diseases. Edinburgh: Mosby, 2004.

Fig. 78.4  Chronic

ulcerative herpes
simplex viral infection in
an HIV-infected patient.
Slowly enlarging ulcers
of the buttocks and
perianal area. Note the
scalloping of the border.

Fig. 78.5  Molluscum contagiosum. Large lesions with coalescence in an

HIV-infected patient.

1290
 CHAPTER
antimicrobial treatment has yet to be defined, but a minimum of 2
months is recommended. If left untreated, death may ensue from pul- 78 
monary or hepatic failure42.

Cutaneous Manifestations of HIV Infection

Mycobacteria
Cutaneous tuberculosis can develop during advanced stages of HIV
infection. Other mycobacteria such as Mycobacterium avium complex,
M. kansasii, M. haemophilum and M. fortuitum may also produce skin
lesions. Erythematous papules and nodules, ulcers, verrucous plaques
and deep nodules can all be observed. Pruritus is generally absent and
patients may be febrile. The common practice of prophylaxis with
antimycobacterial medications as well as the use of ART has led to a
decrease in the frequency of this complication20.

Syphilis
Syphilis is caused by Treponema pallidum (see Ch. 82). Although
classic papulosquamous secondary lesions are often seen, unusual pres-
entations may be observed in hosts with HIV infection, including a
Fig. 78.6  Oral hairy leukoplakia. Shaggy white keratotic plaques along the noduloulcerative form, papular eruptions that mimic molluscum con-
lateral aspect of the tongue. A corrugated pattern is often seen. Courtesy, Charles
Camisa, MD. tagiosum, syphilitic palmoplantar keratoderma and lues maligna42.
Lues maligna is an aggressive, widespread variant of secondary syphilis
with a prodrome of fever, headaches and myalgia followed by an erup-
Bacterial Infections tion of papulopustular or necrotic lesions47. CNS involvement occurs
The immunosuppression of HIV infection predisposes affected indi- more frequently and with greater severity in individuals with HIV infec-
viduals to recurrent and potentially severe cutaneous bacterial infec- tion, and neurosyphilis should be considered in HIV-infected patients
tions, which can be localized or widespread and sometimes have with neurologic symptoms. All patients with HIV infection should be
unusual clinical appearances. Indwelling venous catheters, excoriations tested for syphilis, and vice versa.
and ulcers with non-bacterial etiologies in HIV-infected individuals
impair cutaneous barrier function and further increase the risk of bacte- Fungal Infections
rial infections. In addition to the entities discussed below, cutaneous
bacterial infections that can occur in association with HIV infection Cutaneous presentations of fungal infections in HIV-infected individu-
include necrotizing fasciitis, nocardiosis, malacoplakia and pseudo­ als range from localized superficial skin lesions to a manifestation of
monal “hot tub” folliculitis, “malignant” otitis externa and ecthyma disseminated multiple-organ disease, and clinical morphologies may be
gangrenosum. atypical. Implementation of ART has significantly decreased the inci-
dence of cutaneous fungal infections in this patient population48.
Staphylococcus aureus
Staphylococcus aureus is the most common bacterial pathogen in
Candidiasis
patients infected with HIV, with common presentations including Candidiasis is the fungal infection most frequently encountered in
impetigo, folliculitis, furunculosis and cellulitis. The incidence of soft association with HIV infection, and its incidence correlates with lower
tissue infections with methicillin-resistant S. aureus (MRSA) is over CD4+ cell counts49. Ninety percent of patients with AIDS develop can-
sixfold higher in HIV-infected individuals that in those without HIV- didiasis of the oropharynx41. Perlèche with painful fissures at the oral
infection. Pyogenic bacterial infections generally respond to treatment commissures and persistent candidal infections of intertriginous zones
with antibiotics to which they are susceptible and/or (for furunculosis) are also commonly seen in HIV-infected individuals42. Other signs sug-
incision and drainage, but unusual presentations (e.g. botryomycosis) gesting immune suppression include chronic paronychia, onychodys-
may be refractory to therapy. Use of intranasal mupirocin and skin trophy and refractory vaginal candidiasis. Disseminated candidiasis has
cleansers containing chlorhexidine gluconate can temporarily eradicate been reported and may be fatal in those with HIV infection20.
bacterial colonization (which is especially common among HIV-infected Antiretroviral therapy has a beneficial effect on candidiasis, decreas-
individuals), but it usually recurs. ing the prevalence of oral lesions and reducing the oral candidal load50.
Conventional therapy (e.g. oral fluconazole) is indicated when the
Bacillary angiomatosis patient is symptomatic42; however, persons with CD4+ counts <50 cells/
mm3 should be advised that excessive antifungal use can promote
Bacillary angiomatosis is a bacterial infection that can affect virtually
resistance.
any body site, but it favors the skin and subcutaneous tissue. Lesions
of variable size and shape may be seen, including red to purple “vascular-
appearing” papules or nodules and ulcers (see Ch. 74). The number of
Dermatophytoses
lesions ranges from one to more than hundreds. It has been postulated The severity of dermatophyte infections is increased in immunosup-
that a vasoproliferative factor may lead to their formation. pressed hosts (see Ch. 77). In such patients, even minor infections can
Gram-negative bacilli in the genus Bartonella are responsible for this serve as a source of morbidity by providing portals of entry for serious
disease, specifically B. henselae (associated with cat scratches/bites and bacterial pathogens. Cutaneous involvement can be atypical in appear-
exposure to cat fleas) and B. quintana (associated with poverty and poor ance, and lesions may be more widespread and resistant to therapy.
hygiene)44. B. quintana may be transmitted from human to human by Spread of interdigital tinea pedis onto the dorsal foot, Majocchi’s granu-
the body louse, Pediculus humanus var. corporis, although other as yet loma (a deep folliculitis with rupture of the follicle wall) and proximal
unidentified vectors may be also involved. Cutaneous lesions induced white onychomycosis have all been associated with HIV infection21,24.
by B. henselae and B. quintana are indistinguishable, but the extracu- The goals are to eradicate the infection as well as to prevent recurrence.
taneous manifestations differ. Subcutaneous and osseous involvement The latter includes local measures such as absorbent powders24.
is associated with B. quintana infections, whereas visceral disease is
seen more often with B. henselae infections. Diagnosis is usually based Systemic fungal infections
on histologic features, i.e. characteristic vascular proliferation and Cryptococcosis and any of the dimorphic fungal infections (including
numerous bacilli visualized by Warthin–Starry staining. Culture of histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioid-
Bartonella spp. and detection via PCR of the blood and/or tissue may omycosis, sporotrichosis and penicilliosis) can lead to disseminated
also be helpful45. disease in HIV-infected patients. Disseminated cryptococcosis (Fig.
Resolution usually occurs with institution of appropriate antibiotic 78.7) and histoplasmosis are seen most commonly, followed by coccidi- 1291
therapy (e.g. macrolides or tetracyclines)20,46. Optimal duration of oidomycosis and sporotrichosis51. In affected individuals, the CD4+
SECTION

12 DIFFERENTIAL DIAGNOSIS OF ORAL EROSIONS AND ULCERS IN

HIV-INFECTED PATIENTS
Infections, infestations and bites

INFLAMMATORY
Aphthae, major and minor (Fig. 78.8)
Stevens–Johnson syndrome, toxic epidermal necrolysis
INFECTIOUS
Herpes simplex and herpes zoster viral infections, acute and chronic
Cytomegalovirus (often component of co-infection with above)
Dimorphic or opportunistic fungal infections, e.g. histoplasmosis, cryptococcosis
Extragenital chancre
Mucous patches of secondary syphilis
Mycobacterial infections (tuberculosis and mycobacteria other than tuberculosis)
Necrotizing ulcerative gingivitis/periodontitis
NEOPLASTIC
Squamous cell carcinoma
Kaposi sarcoma
Lymphoma

A Table 78.3  Differential diagnosis of oral erosions and ulcers in HIV-infected

patients.

Fig. 78.7  Disseminated

cryptococcosis in
the setting of AIDS. Fig 78.8  Major aphthae
A Several ulcers in a patient with AIDS.
with rolled borders.   Resolution of these
B Numerous molluscum lesions may require
contagiosum-like lesions. thalidomide.
Microscopic examination
and culture of either
dermal scrapings or a
biopsy specimen confirm
the diagnosis.

counts are usually <250 cells/mm3 (see Table 78.2). These infections infection may produce an unfavorable environment in the lung, leading
present with a wide range of morphologies, including pustules, crusted to retrograde spread of the organism through the eustachian tubes.
papules, papulonodules, verrucous plaques and mucocutaneous Standard therapy such as intravenous trimethoprim–sulfamethoxazole
ulcerations51. (TMP-SMX) or pentamidine is given for disseminated Pneumocystis
In addition to signs of CNS involvement (e.g. meningitis), dissemi- infection in the setting of HIV infection20,42. Pulmonary prophylaxis
nated cryptococcosis may be associated with translucent dome-shaped with oral TMP-SMX or aerosolized pentamidine is recommended when
papules with central umbilication (often on the face) that resemble the CD4+ count is <200 cells/mm3. Prophylactic treatment can be dis-
mollusca contagiosa (see Fig. 78.7B)52. Cutaneous lesions of histoplas- continued when, in the course of ART, CD4+ counts have risen to >200
mosis and coccidioidomycosis can also appear on the face, and oral cells/mm3 for >3 months54.
ulcerations are commonly seen in disseminated histoplasmosis (Table
78.3)24. Widely distributed crusted cutaneous ulcers have been reported Other fungal infections
in sporotrichosis42. Skin biopsy and culture of dermal tissue should be In addition to those described above, a number of other fungal
performed for any new, unexplained or unusual lesion where the dif- infections have occasionally been reported in patients with HIV
ferential diagnosis includes a disseminated bacterial, mycobacterial or disease. These include disseminated infections with Scedosporium/
fungal infection. Detection of cryptococcal antigen in the serum or Pseudallescheria spp. and primary cutaneous (e.g. ass­ociated with
cerebrospinal fluid (CSF) may be helpful in the diagnosis of systemic an intravenous catheter site) as well as disseminated zygomycosis
disease. Although intravenous amphotericin B remains a primary form or aspergillosis20. Prototheca are achlorophyllic algae that occasionally
of therapy, other antifungal agents (e.g. itraconazole, fluconazole, vori- cause cutaneous lesions (e.g. plaques, nodules, ulcers) in individuals
conazole, posaconazole, caspofungin) may prove useful (see Ch. 76). with HIV, usually following skin trauma and/or exposure to contami-
Unfortunately, these fungal infections are difficult to eradicate and nated water.
relapses are common.

Pneumocystis jiroveci Parasitic Infections

P. jiroveci (formerly P. carinii) is now categorized as fungal organism Leishmaniasis
rather than a protozoan (see Ch. 77). Pneumocystis pneumonia (referred Leishmaniasis is a protozoal infection transmitted primarily by sand
to as PCP) is by far the most frequent form of infection. Disseminated flies and is due to organisms of the genus Leishmania (see Ch. 83).
cutaneous P. jiroveci infection is extremely rare and may appear as HIV-associated leishmaniasis may occur in both endemic and non-
molluscum contagiosum-like papules, bluish cellulitic plaques, and/or endemic regions of the world. Endemic areas include the Mediterranean
1292 deeply seated abscesses in the external auditory canal or nares53. It is basin, India, east Africa, Sudan and Brazil. Individuals who were born
theorized that aerosolized pentamidine administered for pulmonary in or once traveled to endemic areas may also develop disease, pointing
 CHAPTER

78 
to recrudescence of a previously controlled latent infection. A decrease Fig. 78.9  Crusted
in the incidence of visceral leishmaniasis after the introduction of ART (Norwegian) scabies in
has been observed in several Mediterranean countries. the setting of HIV
infection. Crusted and

Cutaneous Manifestations of HIV Infection

Multiple organs may be parasitized, and, when the skin is involved,
keratotic plaque on the
the lesions typically present as ulcerated nodules or plaques (up to 2 cm
elbow that is teeming
in diameter) that favor the extremities. Atypical presentations in HIV- with mites.
infected patients include disseminated lesions, diffuse erythema and
induration, and large necrotic ulcerations55. Erosions and ulcerations
of the lips, palate and nasal mucosa can be seen in mucocutaneous
forms. If left untreated, destruction of cartilaginous structures may
result in disfigurement. Fever, hepatosplenomegaly and varying degrees
of pancytopenia may also be present.
The diagnosis of cutaneous leishmaniasis is established via micro­
scopy, in vitro culture or PCR of lesional tissue. In HIV-infected
patients, amphotericin B (which acts by T-cell-independent mecha-
nisms) typically has better efficacy than pentavalent antimonials42,56.
In a randomized open-label study, oral miltefosine (phosphocholine
hexyl ester) and amphotericin B had similar cure rates57.

Strongyloidiasis
Strongyloides stercoralis is an intestinal helminth endemic to tropical
and subtropical regions. In the US, it is endemic in the rural Southeast
and Appalachia. HIV-associated cutaneous strongyloidiasis may be with standard therapies (e.g. topical permethrin; see Ch. 84), but they
caused by larval penetration of the skin and superficial veins giving rise may require multiple courses. Treatment with oral ivermectin is also
to the migrating serpiginous urticarial eruption known as larva currens. highly effective and is generally used in those who do not respond to
Dissemination (i.e. hyperinfection) may occur in immunosuppressed standard regimens. Mites under the nails, failure to treat contacts
individuals58, and, when the skin is affected, lesions can mimic a and failure to dry laundered bed linens and clothing at high tempera-
number of other conditions such as urticaria and livedo reticularis; on tures are common causes of reinfestation. Scale-crusts often serve as
the lower trunk, they may resemble purpuric “thumbprints” (see Ch. reservoirs for mites, and keratolytic agents such as 6% salicylic acid
83). Eosinophil counts are commonly elevated. Identification of larvae ointment can facilitate exfoliation as well as penetration of topical
in biopsy specimens as well as sputum, duodenal or gastric contents, medications.
or CSF confirms the diagnosis, as does identification of eggs in stool
specimens. S. stercoralis hyperinfection is almost universally fatal, with
poor response to treatment with ivermectin or thiabendazole20,59. Demodicosis
Demodicosis is caused by the mites Demodex folliculorum and D.
Acanthamebiasis brevis and has been reported in association with HIV infection. Rosacea-
like demodicosis may be more frequent in HIV-positive patients. These
In acanthamebiasis, dissemination to the skin and CNS can occur in
eruptions, usually affecting the head and neck region, are similar in
profoundly immunocompromised patients60; the usual cause is Acan-
morphology to, and must be differentiated from, other pruritic papular
thamoeba castellani, a microorganism that is part of the normal oral
eruptions (see below)63. Microscopic examination of skin scrapings
flora. Necrotic nodules and painful ulcerations on the trunk and
placed in mineral oil demonstrates multiple mites. Demodex infection
extremities develop in these patients. Careful inspection on tissue sec-
usually responds to treatment with topical permethrin, gamma benzene
tions will reveal amebic cysts, trophozoites and histiocyte-like cells
hexachloride or metronidazole, or with oral metronidazole20,24,42; refrac-
with erythrophagocytosis. The infection is reported to respond to
tory cases may require ivermectin.
metronidazole20.

Ectoparasitic Infestations Insect bite reactions

Insect bite reactions can be severe in HIV-infected patients and should
Scabies be differentiated from other causes of pruritus, including non-infectious
Scabies, an infestation with the mite Sarcoptes scabiei var. hominis, is papular pruritic disorders associated with HIV infection.
the most common ectoparasitic skin infestation in HIV-infected
patients (see Ch. 84). Severe infestation may develop as a consequence
of diminished cell-mediated immunity. Cutaneous lesions vary from
the “classic” crusted papules to pruritic dermatitis to keratotic and
NON-INFECTIOUS HIV-RELATED
crusted plaques61 (Fig. 78.9); the latter may or may not be pruritic. CUTANEOUS DISORDERS
Burrows, commonly found on the hands, wrists, ankles and interdigital
areas, are less apparent in HIV-infected patients62. Also, the ears, face A number of non-infectious dermatoses have been described in associa-
and scalp (sites not usually affected in immunocompetent adults) are tion with HIV infection. The development of inflammatory disorders
commonly involved in immunosuppressed patients. In crusted (Nor- that are characteristic of HIV infection or unusual presentations (e.g.
wegian) scabies, hyperkeratotic lesions may be generalized with subun- increased severity, eruptive onset or atypical morphology) of other
gual debris and marked nail thickening due to an extraordinary mite inflammatory conditions should alert the clinician to consider HIV
load; thousands to millions may be present on a single patient. Second- infection as a possible underlying factor.
ary infection with bacteremia and fatal septicemia has been reported
in HIV-infected patients with scabies62. Papulosquamous Disorders
Crusted scabies, in particular, is extremely contagious. In any itchy
HIV-infected patient, there should be a high index of suspicion for Seborrheic dermatitis
scabies. Persistent scaly or crusted eruptions should be scraped and Seborrheic dermatitis is the most common skin disorder to affect HIV-
examined for mites, and dermoscopic evaluation may also be useful in infected individuals (up to 85%) and is seen in all stages of the disease
identifying mites. The hyponychium is a protected area, and, if scraped, (see Table 78.2)20. Clinical findings may be similar to those seen in the
can be a high-yield site for mites62. general population, i.e. erythema and yellowish, greasy scale on the
Therapy for scabies is aimed at eliminating the causative ectoparasite scalp and face as well as involvement of other locations such as the
and providing symptomatic relief with topical and systemic antiprurit- central chest and inguinal creases. However, exaggerated presentations 1293
ics21. HIV-infected individuals with scabies are usually treated initially with exuberant facial plaques can also occur and should raise
SECTION
Non-infectious papular pruritic disorders
12 the possibility of HIV infection, as should a sudden onset or acute
worsening of seborrheic dermatitis. The disease may be more difficult
Papular pruritic disorders are common in HIV infection, and the
to control with conventional therapy, including that aimed against
extreme itch can be debilitating. The pathogenesis of these pruritic
Infections, infestations and bites

Malassezia spp. (see Ch. 13).

dermatoses is not entirely clear20. Hypersensitivity reactions to drugs
or parasites, peripheral eosinophilia with increased levels of IgE, “hyper-
Psoriasis reactive” basophils and mast cells, and circulating pruritogens associ-
The overall incidence of psoriasis is probably not increased in the ated with systemic disorders (e.g. hepatobiliary disease, renal disease,
setting of HIV infection, although its clinical presentation tends to be lymphoma) can contribute to the development of these conditions.
more severe. It may develop at any stage of HIV infection64; as with Neural irritation related to HIV infection as well as autonomic dysfunc-
seborrheic dermatitis, a rapid onset of “eruptive” psoriasis can serve as tion with diminished sweating and sebaceous gland secretion may also
a clue to an underlying HIV infection, and psoriasis tends to worsen contribute to the pruritus.
with declining immune status. Two clinical subgroups have been The differential diagnosis of itchy papules is extensive. Underlying
described: (1) patients with a personal and/or family history of psoriasis, infections/infestations and systemic etiologies must be excluded, par-
in whom chronic plaque psoriasis is the most common clinical pres- ticularly scabies and adverse drug reactions. In some instances, primary
entation; and (2) those who develop psoriasis after becoming infected lesions are absent, and prurigo nodularis or lichen simplex chronicus
with HIV and more commonly have palmoplantar involvement and may be the only finding. Knowledge of the patient’s medications, expo-
psoriatic arthritis. An “inverse” distribution involving inguinal creases sures, travel history and prior treatments can aid in diagnosis, and
and genitalia may also occur22. The psoriasis is often extensive (Fig. histologic evaluation may also be helpful.
78.10) or erythrodermic, and exudative crusting or exacerbation with
staphylococcal or streptococcal infections may be observed65. It can be Papular pruritic eruption of AIDS
associated with significant nail dystrophy, arthritis and reactive arthri- Papular pruritic eruption (PPE) of AIDS is characterized by marked
tis (formerly Reiter’s disease)65. pruritus and greater involvement of the extremities than the trunk or
For HIV-associated psoriasis that is refractory to topical therapies, face. It is more prevalent in Africa than in North America or Europe.
phototherapy and systemic retinoids represent first- and second-line Some authors believe that PPE represents a spectrum of pruritic disor-
treatments, respectively65–67. Immunosuppressive agents such as meth- ders, including eosinophilic folliculitis64, while others have suggested
otrexate, cyclosporine and tumor necrosis factor-α (TNF-α) inhibitors that it is an exaggerated response to arthropod antigens69. Clinically,
should be used with caution in HIV-infected patients. A beneficial effect the lesions are symmetrically distributed, non-follicular papules, often
of zidovudine on HIV-associated psoriasis (independent of CD4+ cell with secondary changes (e.g. excoriations, formation of prurigo
counts) has been described65. However, worsening of psoriasis following nodularis).
ART-associated elevation in CD4+ counts has been reported.
Eosinophilic folliculitis
Reactive arthritis (formerly Reiter’s disease) Eosinophilic folliculitis (see Ch. 38) is one of the most characteristic
and common pruritic dermatoses associated with HIV disease, usually
All patients with newly diagnosed reactive arthritis should undergo HIV
occurring in patients with CD4+ counts <200 cells/mm3. One theory is
testing, as the association between the two conditions is strong21. In
that it results from an exaggerated reaction to Malassezia yeast or other
HIV-infected patients with HLA-B27, reactive arthritis commonly
organisms normally present within the follicular infundibula and is a
occurs after genitourinary or gastrointestinal infections. Treatment of
reflection of immune dysregulation leading to a Th2-predominant
cutaneous lesions is similar to that for psoriasis24.
immune response. Excoriated follicular papules and rare intact pustules
are found primarily on the face and upper trunk64 (Fig. 78.11). Cultures
Other papulosquamous dermatoses
are negative and peripheral eosinophilia may be present24.
Generalized xerosis can be seen in HIV-infected patients and may be Eosinophilic folliculitis associated with HIV infection differs from
associated with refractory pruritus. When the CD4+ count drops Ofuji’s disease in its intense pruritus but lack of circinate or palmo-
below 50 cells/mm3, acquired ichthyosis with large plate-like scales plantar lesions. In addition to infectious causes of folliculitis (e.g.
may develop, beginning on the legs and often becoming widespread.
Atopic dermatitis is a frequent problem in children with AIDS and is
often difficult to control with conventional therapy24,68 (see Ch. 12).
Fig. 78.11  Eosinophilic
Pityriasis rubra pilaris (PRP) can develop in conjunction with HIV
folliculitis. Due to
infection (referred to as type VI PRP; see Ch. 9). In this setting, PRP associated pruritus,
is typically generalized and may occur together with follicular spines, follicular papules are
acne conglobata and hidradenitis suppurativa (HIV-associated follicu- often excoriated; lesions
lar syndrome). favor the head and
upper torso.

Fig. 78.10  Severe

psoriasis in a patient
with AIDS. Both sudden
acute exacerbations and
treatment resistance can
be observed.

1294
 CHAPTER
Pityrosporum, Demodex) , acne vulgaris, rosacea and drug reactions
should be excluded70. Although topical corticosteroids, topical tac-
immune complex-mediated disease as well as direct vessel wall damage
by infectious agents. Treatable infectious causes should always be 78 
rolimus, topical permethrin, UVB phototherapy, systemic antibiotics, sought, e.g. hepatitis C and hepatitis B viruses, HSV, CMV, Toxoplasma,

Cutaneous Manifestations of HIV Infection

itraconazole, dapsone and oral retinoids (e.g. isotretinoin) have each Pneumocystis, Salmonella, M. tuberculosis and Mycobacterium leprae.
shown some efficacy24,71, HIV-associated eosinophilic folliculitis may Polyarteritis nodosa-like vasculitis with peripheral neuropathy or
prove recalcitrant to therapy. The impact of ART varies, with anecdotal digital ischemia occasionally occurs in HIV-infected individuals. Unlike
reports of beneficial effects72 as well as flares shortly after its classic polyarteritis nodosa, multisystem involvement is often absent.
institution73,74. Usually there is no evidence of hepatitis B viral infection. As expected,
cutaneous small vessel vasculitis usually presents as palpable
Hair and Nail Disorders purpura78,79. Erythema elevatum diutinum, a chronic form of cutaneous
A variety of disorders of the hair and nails have been recognized in leukocytoclastic vasculitis, has also been reported when CD4+ counts
HIV-infected individuals. Alopecia can occur due to infectious etiolo- are <200 cells per cubic millimeter80. Clinically, the skin lesions are
gies such as severe tinea capitis or secondary syphilis, and serious similar to those seen in non-HIV-infected individuals and appear as
systemic infections can trigger telogen effluvium. Although alopecia in persistent erythematous papules and nodules that favor extensor sur-
association with nucleoside analogue treatment has been reported (see faces; failure to respond to dapsone has been reported in some patients.
Table 78.4), hair regrowth has also been observed after initiating zido-
vudine therapy75. Photosensitivity Reactions
The hair of HIV-infected patients may spontaneously straighten and UV light hypersensitivity
become softer and more silky, or it can become lusterless and dull75.
Sudden graying of the hair has been observed with HIV infection, and UV light “hypersensitivity” may be a presentation of HIV disease or
it may develop via mechanisms similar to those of alopecia areata or related to photosensitizing medications such as sulfonamides. Cutane-
AIDS-related vitiligo75. Trichomegaly of the eyelashes, a sign of pro- ous lesions are characteristically pruritic, lichenoid, violaceous plaques
longed anagen phase, has also been noted in AIDS patients, including in sun-exposed areas24, i.e. a photolichenoid reaction.
those receiving interferon-α and zidovudine20,76. The causes of these
phenomena remain unknown and may be related to HIV infection of Porphyria cutanea tarda
the hair follicle or concomitant nutritional deficiencies. The acquired form of porphyria cutanea tarda (see Ch. 49) is not
Nail disorders also commonly develop in HIV-positive patients. Prox- uncommonly observed in the setting of HIV infection. When phle-
imal subungual onychomycosis, the least common of the three forms botomy proves difficult because of coexistent anemia, low-dose antima-
of onychomycosis, is often a reflection of immunosuppression, includ- larial therapy (e.g. hydroxychloroquine three times weekly) should be
ing HIV infection (see Ch. 77). Chronic candidiasis with paronychia considered. Avoidance of triggering factors such as alcohol and sunlight
and nail ridging can be seen, as can nail infections with Scopulariopsis can be helpful, and serum ferritin levels and hepatitis C serologies
brevicaulis and Alternaria spp. Patients receiving zidovudine may should be obtained81,82.
develop hyperpigmentation of the nail plates as a reflection of increased
melanin within melanocytes and dermal melanophages (Fig. 78.12). Chronic actinic dermatitis
Protease inhibitors, especially indinavir, have been associated with
paronychia and ingrown toenails77. Beau’s lines (transverse ridging 2–3 Chronic actinic dermatitis (see Ch. 87) may also be associated with
months after serious physiologic stress), psoriatic nail pitting and ony- HIV infection, presenting as chronic, scaly, erythematous plaques24.
cholysis may also be seen75. There is usually evidence of photosensitivity, which often extends into
the visible light range. Sometimes it may represent evolution of a per-
sistent photodrug eruption.
Vasculitis
Systemic vasculitis should be considered if an HIV-infected patient has Metabolic Changes
fever of unknown origin or unexplained multisystem disease. Causes
of vasculitis in the setting of HIV infection range from systemic infec- HIV/ART-associated lipodystrophy
tions to drug reactions to inflammatory disease. Arteries and veins of Changes in body fat distribution are commonly observed in HIV-
all sizes can be involved and any organ, including the brain, skin and infected patients receiving ART, and this is referred to as HIV/ART-
neuromuscular tissues, may be affected. The pathogenesis includes associated lipodystrophy or fat redistribution syndrome83. Patients may
present with various constellations of findings, including lipoatrophy
of the face, limbs and buttocks (see Ch. 101); central obesity (“protease
pouch”, “crix belly”); dorsocervical lipomatosis (“buffalo hump”); and
breast hypertrophy. Hypertriglyceridemia and insulin resistance are also
commonly observed. On the face, the lipoatrophy occurs predominantly
on the cheek, temples and periorbitally. The resultant clinical appear-
ance is highly characteristic and stigmatizing, potentially causing not
only psychosocial stress but also decreased adherence to the antiretro-
viral medication regimen.
Proposed mechanisms for the lipoatrophy component include the
following effects of antiretroviral drugs: (1) impaired differentiation and
increased apoptosis of adipocytes; (2) increased lipolysis and decreased
lipogenesis; and (3) mitochondrial toxicity84,85. While lipoatrophy and
visceral obesity do share several risk factors (e.g. age, viral load, dura-
tion of therapy, CD4+ count), lipoatrophy is associated with being
Caucasian and exposure to and duration of treatment with nucleoside
reverse transcriptase inhibitors (especially stavudine)86, whereas vis-
ceral obesity/abnormal fat accumulation is associated with female sex
and protease inhibitor use. Thus, the possibility has been raised that
these two findings reflect separate pathophysiologic processes.
Although substituting non-nucleoside reverse transcriptase inhibitors
for the protease inhibitor in a given regimen does not change the likeli-
hood of lipodystrophy, substitution of non-thymidine analogues for
Fig. 78.12  Zidovudine-associated melanonychia. Patients receiving stavudine (a thymidine analogue) can lead to a gradual improvement
zidovudine may develop longitudinal streaks, horizontal bands and diffuse of peripheral lipoatrophy as well as dyslipidemia87. Other pharmacologi- 1295
hyperpigmentation. cal interventions, such as administration of pravastatin, pioglitazone
SECTION

12 and uridine, can result in fat gain in areas of peripheral lipoatrophy88.

In contrast to the small and gradual benefits of pharmacologic treat-
immune suppression with CD4+ counts <200 cells/mm3. Clinically,
pink to violaceous papules and nodules are usually seen; the lesions
ments for lipoatrophy, surgical interventions are often successful and often ulcerate and sometimes simulate panniculitis20. HIV infection-
Infections, infestations and bites

can provide almost immediate improvement in appearance. Surgical associated lymphomas are most often non-Hodgkin B-cell type and
approaches for lipoatrophy include autologous fat transplants89 and high or intermediate grade. Additional differences from lymphomas in
injection of degradable or non-degradable synthetic fillers, such as poly- the general population include a younger age of onset, more advanced
L-lactic acid90 or silicone. stages and extranodal involvement (especially of the CNS, intestine and
Tesamorelin, an injectable growth hormone-releasing factor ana- skin) at presentation24. Approximately one-half of non-Hodgkin lym-
logue, was recently approved by the US Food and Drug Administration phomas in HIV-infected patients are associated with EBV infection.
(FDA) as a treatment to reduce excess visceral abdominal fat in patients A decrease in the incidence of all types of lymphoma in HIV-infected
with HIV/ART-associated lipodystrophy91. Lifestyle modification and individuals has been noted since the introduction of ART. Antiretroviral
other pharmacologic interventions, such as the use of metformin92, therapy also significantly improves the clinical outcome and overall
may also help to decrease truncal and visceral fat. Cosmetic surgery survival of patients with AIDS-related lymphoma. A prior diagnosis of
(e.g. liposuction) is an option for the management of large dorsocervical AIDS (see Table 78.1) and bone marrow involvement are associated
lipomatosis, although the risk of recurrence exists. with an unfavorable prognosis100.
Cutaneous T-cell lymphoma, in particular the mycosis fungoides
Malnutrition variant, and T-cell lymphoproliferative disorders (which can mimic
Decreased appetite and reduced intake of food along with nausea and mycosis fungoides clinically) can occur in patients with HIV infec-
malabsorption are common in HIV-infected patients, and they often tion20,24,42,98, albeit much less frequently than B-cell lymphomas. The
suffer from gastrointestinal side effects of medications and infectious possibility of adult T-cell leukemia and lymphoma caused by human
diarrhea. Cutaneous manifestations of malnutrition may be encoun- T-cell leukemia/lymphotropic virus type I (HTLV-1) needs to be con-
tered, including those associated with kwashiorkor and deficiencies of sidered and excluded.
vitamins B12 and A93,94 (see Ch. 51). Nutritional replacement should be
initiated once the deficiency is recognized, as severe malnutrition can Kaposi Sarcoma
be life-threatening93,95. The neoplasm most closely associated with HIV infection is Kaposi
sarcoma (KS)101. With the widespread use of ART, the incidence of HIV-
Miscellaneous Conditions related KS has declined significantly in high-income countries. However,
Primary cutaneous mucinoses have been linked to HIV infection (see elsewhere it remains a significant source of morbidity, especially in
Ch. 46). Most commonly, localized lichen myxedematosus or acral sub-Saharan Africa. The etiologic agent, human herpesvirus type 8
persistent papular mucinosis occurs in an individual with a relatively (HHV-8), can be transmitted via exposure to the semen or saliva of
advanced stage of HIV infection. Granuloma annulare is also occasion- infected individuals24,99 (see Ch. 80). It is estimated that KS comprises
ally observed in HIV-infected patients, and the lesions may be widely 20% of childhood malignancies in African countries.
disseminated or have an atypical distribution pattern. Major aphthae Clinically, skin lesions vary from small violaceous papules to large
(especially oral lesions; see Ch. 72) can represent a therapeutic chal- plaques to ulcerated nodules42 (Fig. 78.13). The upper body is typically
lenge in HIV-infected individuals. After excluding infectious etiologies involved, often along skin lines in a pityriasis rosea-like pattern and at
(see Table 78.3), systemic therapy (e.g. thalidomide) is often required. sites of local trauma20,24. Lesions also develop on the face, in particular
Additional findings that are occasionally observed in individuals with the nose, and on oral mucosal surfaces, including the gingiva and hard
HIV infection include hyperpigmentation (in addition to that related to palate20. Internal involvement is common in HIV-related KS, most
photosensitivity, systemic drugs or adrenal insufficiency), especially of often affecting the lymph nodes (potentially leading to lymphedema),
the face, and linear telangiectasias on the chest. gastrointestinal tract and lungs.
Several treatment options exist and should be selected according to
the stage of HIV disease, the extent of KS involvement, comorbidities,
NEOPLASTIC HIV-RELATED CUTANEOUS and the likelihood of receiving effective ART. Regression may be
observed with reversal of immune suppression by ART, and for patients
DISORDERS with less extensive disease, it may be reasonable to start ART alone
and monitor the response. However, flares of KS can also occur as a
A number of different cutaneous neoplasms may develop in patients
manifestation of immune reconstitution following initiation of ART.
with HIV infection. Diagnosis is established primarily by clinical
HIV-associated KS responds fairly well to local destruction, e.g. cryo-
assessment and histologic examination. Aggressive treatment and
therapy, topical alitretinoin (9-cis-retinoic acid) gel, superficial radio-
heightened awareness are imperative for improving prognosis.
therapy, intralesional vinblastine or interferon, and intravenous
liposomally encapsulated doxorubicin, daunorubicin or pacli­
Squamous and Basal Cell Carcinomas taxel24,102,103. Radiotherapy is contraindicated for oral lesions, as AIDS
As in immunocompetent individuals, fair skin and sun exposure patients are more likely to develop severe radiation-associated mucosal
(cumulative and intense intermittent) are risk factors for the develop- ulcers and stomatitis.
ment of basal cell carcinoma (BCC) and SCC96. Compared with the
general population, HIV-infected individuals have a three- to fivefold Other Cutaneous Neoplasms
higher risk of developing these non-melanoma skin cancers, which tend
Eruptive atypical nevi have been described in HIV-positive patients42.
to appear at a younger age and are more often multifocal and located
Melanoma has been reported in association with HIV infection, but the
on the trunk and extremities20,96–98. Cutaneous SCCs in HIV-infected
prognosis (based on AJCC staging) is similar to that seen in immuno-
individuals have a high risk of recurrence and metastasis. Although
competent hosts21. Cutaneous smooth muscle tumors, including leio-
BCC metastases have been reported, overall, BCCs do not behave more
myomas and leiomyosarcoma, occur more frequently in HIV-infected
aggressively in patients with HIV infection20. As discussed above, HPV
pediatric patients and may be associated with EBV infection24,104.
infection (in particular, high-risk genital and genus beta types) increases
the risk of anogenital, oral, digital and EDV-associated cutaneous SCCs
in HIV-infected individuals37–39, and aggressive treatment is often
required to prevent recurrences and metastases20. Monitoring strategies DIFFERENTIAL DIAGNOSIS AND DIAGNOSIS
for HPV-associated AIN, CIN and SCC are outlined in the section on
HPV (see above). Differential Diagnosis of HIV-associated
Skin Conditions
Lymphomas As noted above, HIV-infected individuals can develop a wide variety of
1296 Cutaneous lymphomas of B- or T-cell lineage may develop in HIV- infectious, inflammatory and neoplastic disorders of the skin, many of
infected adults and children98,99, often in the setting of significant which have overlapping clinical features. Cutaneous eruptions range
 CHAPTER

78 

Cutaneous Manifestations of HIV Infection

A B C

Fig. 78.13  Kaposi sarcoma in the setting of HIV infection. Violaceous papules
and plaques on the face (A), palate (B), trunk (C) and extremity (D). Oral
candidiasis is also seen (B). Some of the lesions on the back follow cleavage lines
(C). D, Courtesy, Thomas Horn, MD.

from “textbook” classic forms to bizarre variants that present a diag- HTLV-1, the absolute CD4+ cell count may not be as reliable as in
nostic challenge. Serious and potentially fatal diseases must be consid- others with regard to immune status11. The HTVL-1-related diseases
ered and distinguished first and foremost. In particular, disseminated infective dermatitis and adult T-cell leukemia/lymphoma are discussed
fungal infections and adverse drug reactions (see below) may be life- in Chapters 13 and 120, respectively.
threatening and require early intervention with systemic antifungal
agents or withdrawal of the offending medication, respectively. Diagnosis of HIV-associated Skin Conditions
The spectrum of cutaneous diseases tends to correlate with the
immune status of the HIV-infected patient. Although HIV-1 RNA and HIV Infection
(copies/ml plasma) is a marker for disease progression, levels vary In HIV-infected patients, the diagnosis of cutaneous disorders is estab-
during acute infection and no defined relationship between viral load lished based on the clinical appearance coupled with confirmatory
and opportunistic infections exists. However, an association between studies such as scrapings, cultures, biopsies and serologic assays. Given
HIV-related disease incidence and the CD4+ cell count has been estab- their immunocompromised state, patients often have mixed infections
lished105 (see Table 78.2), and this allows for a more focused differential (Fig. 78.14) or combination infectious–neoplastic or inflammatory–
diagnosis. In general, disseminated and extensive disease presentations neoplastic lesions. Other factors such as age, sex and anatomic distribu-
occur with increasing frequency at lower CD4+ cell counts. tion assist in narrowing the differential diagnosis.
Although it does not induce an immunodeficiency syndrome, HTLV-1 Virtually any cutaneous lesion in an HIV-infected patient may be
primarily infects CD4+ lymphocytes in a mechanism similar to that of caused by a potentially treatable infectious agent. Histologic examina-
HIV-1 and HIV-2. HTLV-1 is endemic primarily in the Caribbean tion and culture of biopsy specimens may be required for diagnosis.
basin, southern Japan, northern Iran, Papua New Guinea and some Additional evaluation with special stains and serologic or molecular
parts of Africa and also exhibits vertical (mother-to-child) transmission. tests may be necessary. Special growth requirements for fastidious
Co-infections with HIV and HTLV-1 have generated substantial inter- opportunistic organisms need to be anticipated. It should be remem-
est. The incidence ranges from 3% to 25% of HIV-infected individuals. bered that mixed infections may also be present12.
It has been postulated that an HTLV-1 protein acts indirectly on HIV serologic testing should be performed in any patient who requests
the long terminal repeat (LTR) region of both HTLV-1 and HIV-1, it. Testing is recommended for individuals in high-risk groups (e.g. men
inducing interleukin-2 (IL-2) and IL-2 receptors that accelerate HIV-1 who have sex with men, intravenous drug users, commercial sex
proliferation and subsequent T-cell death. Interestingly, co-infection is workers) and those who have sexually transmitted infections, active
associated with higher CD4+ cell counts (by 75–80%). However, the tuberculosis or are pregnant. Atypical herpes zoster (especially in a
lymphocyte proliferation is nonspecific and does not appear to provide young person), chronic HSV infection, refractory mucocutaneous can- 1297
immunologic benefit. Thus, in patients co-infected with HIV-1 and didiasis, generalized lymphadenopathy, extranodal lymphoma or the
SECTION

12
Fig. 78.14  Oral herpes
simplex viral infection
and oral candidiasis.
Infections, infestations and bites

This combined infection

was in an otherwise
healthy young man who
proved to be
HIV-positive.

Fig. 78.15  Exacerbation of leprosy due to immune reconstitution

inflammatory syndrome following institution of ART therapy. Courtesy, Beatriz
Trope, MD PhD.

occurrence of generalized pruritus, dementia, aseptic meningitis,

peripheral neuropathy, fever, diarrhea or weight loss with unknown
etiology should prompt testing for HIV.
HIV seroconversion usually occurs 6 weeks after initial infection.
Currently, first-line initial ART includes two N(t)RTIs (typically teno-
Criteria for HIV seropositivity include positive ELISA results confirmed
fovir and emtricitabine) and one NNRTI (usually efavirenz). The Inter-
by a positive Western blot study (usually requiring reactivity against at
national AIDS Society–USA 2010 guidelines for adults with HIV
least two of the viral protein markers p24, gp41 or gp120/160). Non-
infection recommend introduction of ART for symptomatic patients
reactive results are obtained during a seronegative “window” that can
and asymptomatic patients with a CD4+ cell count ≤500 cells/mm3 or
last up to 3 months after the initial infection. Thus, if HIV infection
certain conditions/comorbidities (e.g. HIV RNA >100 000 copies/ml,
is strongly suspected, methods for detection of viral antigens or nucleic
decline in the CD4+ cell count of >100 cells/mm3/year, pregnancy, active
acid rather than anti-HIV antibodies need to be employed. Fourth-
hepatitis B or C viral infection, cardiovascular disease, a serodiscordant
generation HIV screening assays have been developed that attempt to
partner)107. Important factors to consider include viral resistance,
shorten the seronegative window by simultaneous detection of anti-
patient adherence, potential adverse effects and drug interactions.
HIV antibodies and p24 antigen.
Response to therapy is monitored by quantitative HIV RNA PCR (as
Early (i.e. in the process of seroconversion) or advanced HIV disease,
plasma viremia is a strong prognostic indicator of HIV disease progres-
HIV-2 infection, the presence of alloantibodies (seen with pregnancy,
sion)108. Suppression of HIV replication to below the limit of quantifica-
blood transfusions or organ transplantation) or autoantibodies (seen in
tion for as long as possible is therefore a critical goal of ART. When
autoimmune connective tissue diseases, other autoimmune diseases or
HIV replication is adequately suppressed (i.e. below 50 copies/ml
malignancy) may lead to an indeterminate test result in which both
plasma), evolution of viral resistance to antiretroviral drugs is minimal.
the ELISA and Western blot studies are positive but with reactivity
However, continuous replication in the presence of antiretroviral drugs,
against only one protein marker present. Repeat tests should be per-
whether due to patient non-adherence, pre-existent drug resistance and/
formed in 2–6 months for confirmation. Individuals with an indeter-
or low drug levels, can rapidly exhaust currently available treatment
minate test result who are in the process of seroconverting will usually
options.
become seropositive within 1 month.
In addition to increasing life expectancy in those with HIV infection,
If necessary, HIV RNA or DNA PCR and/or isolation of the virus by
ART has resulted in a significant decrease in the incidence of several
culture can be used to confirm the diagnosis in questionable cases.
of its cutaneous manifestations, including candidiasis, KS, eosinophilic
However, the specificity of a single plasma viral load test is only about
folliculitis, opportunistic mycoses/mycobacterioses, and oral hairy leu-
97% and false-positive results, particularly in the range of <5000 copies/
koplakia. However, the prevalence of HPV and poxvirus infections and
ml, have been described106. Importantly, HIV postexposure prophylaxis
incidence of anal cancer have actually increased30. It is possible that
may hamper detection of the virus by culture or PCR and delay
other cutaneous neoplasms will be seen with greater frequency as
seroconversion.
patients survive longer. While in developed countries the spectrum of
concerns related to HIV has shifted from opportunistic infections to
TREATMENT long-term complications (e.g. cancer, co-infection with other viruses
such as hepatitis C, and the metabolic effects of ART), patients in
developing countries continue to be ravaged by HIV infection, with high
Antiretroviral Therapy (ART) treatment costs and underdeveloped infrastructure continuing to be
Fifteen years ago, the treatment of HIV infection was revolutionized by major obstacles.
the development of combination ART regimens (previously known as
HAART). The different classes of antiretroviral agents target various Immune Reconstitution Inflammatory
aspects of the HIV life cycle (see Fig. 78.2): (1) nucleoside (including
zidovudine [AZT], the first agent developed [in 1987]), nucleotide and Syndrome (IRIS)
non-nucleoside reverse transcriptase inhibitors (NRTIs, NtRTIs and Paradoxically, exacerbations of the clinical manifestations of infectious
NNRTIs, respectively) terminate viral DNA chain synthesis; (2) the and neoplastic (due to inflammatory immune reactions) as well as
integrase inhibitor prevents integration of viral DNA into the host inflammatory diseases have been observed following institution of
genome; (3) protease inhibitors abrogate viral processing and assembly; ART, especially when CD4+ cell counts rise at least twofold from
(4) the CC-chemokine receptor 5 (CCR5) inhibitor blocks binding of depressed levels (usually <50 cells/mm3). Examples include herpes
viral particles to the CCR5 co-receptor on host cells (with a host rather zoster, leprosy (Fig. 78.15), and disseminated Mycobacterium avium
than viral target); and (5) the fusion inhibitor disrupts fusion of the complex and CMV infections. This phenomenon has been referred to
viral envelope with the cell membrane (Table 78.4). ART can pro- by various names, including IRIS, immune reconstitution-associated
foundly suppress viral propagation, leading to the reconstitution of disease (IRAD) and immune reconstitution/recovery/restoration
CD4+ lymphocyte counts and a dramatic decrease in disease-related disease/syndrome. Distinguishing IRIS-associated flares of inflamma-
1298 morbidity and mortality. As a consequence, the annual mortality from tion from active opportunistic infections or drug reactions may be
AIDS has declined by >75% since 1995 in high-income countries. difficult27,109. The majority of patients with IRIS have cutaneous
 CHAPTER

ADVERSE REACTIONS TO DRUGS USED TO TREAT HIV INFECTION 78 

Drug (abbreviation, trade name) Important adverse reactions/interactions

Cutaneous Manifestations of HIV Infection

Mucocutaneous Other
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
Abacavir (ABC, Ziagen®) • Hypersensitivity syndrome*, Sweet’s syndrome (rare) • Hypersensitivity syndrome*,†
Didanosine (ddl, Videx®) • Xerostomia, alopecia • Pancreatitis, optic neuritis, peripheral
• Lipodystrophy neuropathy, lactic acidosis, hepatic steatosis
• Small vessel vasculitis (rare)
Emtricitabine (FTC, Emtriva®) • Xerosis, “rash” (morbilliform, pustular, urticaria), palmoplantar †

hyperpigmentation
Lamivudine (3TC, Epivir®) • Paronychia, alopecia, “rash”, pruritus • Pancreatitis (pediatric patients)†
Stavudine (d4T, Zerit®) • Lipodystrophy • Peripheral neuropathy, pancreatitis, muscle
• Peripheral edema weakness, lactic acidosis, hepatic steatosis
Tenofovir (TDF, Viread®) • Morbilliform, vesicular and urticarial eruptions • Renal impairment, hypophosphatemia
Zalcitabine (ddC, Hivid®) ‡
• Macular eruption, urticaria, oral/esophageal ulcers • Pancreatitis, peripheral neuropathy†
Zidovudine (AZT, Retrovir®) • Blue–brown pigmentation of nails and mucosae, cutaneous • Bone marrow suppression, increased MCV,
hyperpigmentation thrombocytopenia, nausea, dilated
• Urticaria, morbilliform eruption, small vessel vasculitis, cardiomyopathy, myopathy, lactic acidosis,
anaphylaxis hepatic steatosis
• Lipodystrophy
• Acral/periarticular reticulate erythema
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Delavirdine (DLV, Rescriptor®) • Morbilliform eruption (usually within first 3–6 weeks), SJS, • Hepatotoxicity
Efavirenz (EFV, Sustiva®) TEN, DRESS • CNS symptoms
Etravirine (ETR, Intelence®) • In the case of nevirapine, higher incidence (especially in • Delaviridine inhibits CYP450 3A4, nevirapine
Nevirapine (NVP, Viramune®) women), which may be reduced by dose escalation; also oral induces CYP450 3A4
Rilpivirine (RPV, Edurant®) ulcers
INTEGRASE INHIBITOR
Raltegravir (RAL, Isentress®) • “Rash”, SJS, TEN, DRESS • Myopathy, rhabdomyolysis
PROTEASE INHIBITORS
Amprenavir (APV, Agenerase®)‡ • Morbilliform eruption, generalized erythema, SJS • Hyperlipidemia, insulin resistance
Atazanavir (ATV, Reyataz®) • Lipodystrophy syndrome, striae formation • Increased risk of cardiovascular disease with
Darunavir (Prezista®) • Paronychia, ingrown toenails long-term exposure
Fosamprenavir (FPV, Lexiva®) • Pruritus, xerosis • Spontaneous bleeding in hemophiliacs
Indinavir (IDV, Crixivan®) • Desquamative cheilitis, oral numbness • Avascular necrosis of the hip
Lopinavir/Ritonavir (Kaletra®) • Icterus, esp. atazanavir • Hepatotoxicity
Nelfinavir (NFV, Viracept®) • Metallic taste, esp. indinavir
Ritonavir (RTV, Norvir®) • Inhibit CYP450 3A4, esp. ritonavir
Saquinavir (SQV, Invirase®)
Tipranavir (TPV, Aptivus®)
CC-CHEMOKINE RECEPTOR 5 (CCR5) INHIBITOR
Maraviroc (MVC, Selzentry®) §
• “Rash” • Hepatotoxicity with allergic features
• May increase risk of myocardial ischemia
• Postural hypotension
FUSION INHIBITOR
Enfuvirtide (T-20, Fuzeon®) • Injection site reactions (granulomatous inflammation) • Frequency of painful injection site reactions and
• Morbilliform eruption high cost limit use
COMBINATIONS
Abacavir/Lamivudine (ABC/3TC, Epzicom®) See above See above
Efavirenz/Emtricitabine/Tenofovir (EFV/FTC/
TDF, Atripla®)
Emtricitabine/Tenofovir (FTC/TDF, Truvada®)
Emtricitabine/rilpivirine/tenofovir DF (FTC/
RPV/TDF, Complera®)
Lamivudine/Zidovudine (3TC/AZT, Combivir®)
Abacavir/Lamivudine/Zidovudine (ABC/3TC/
AZT, Trizivir®)
*Includes fever, malaise, gastrointestinal symptoms and sometimes a cutaneous eruption; occurs in 5–8% of patients within the first 8 weeks of receiving abacavir and is an absolute
contraindication for repeat administration; associated with HLA-B*5701 allele, screening for which is commercially available and recommended prior to initiating/reinitiating therapy.
†
Uncommonly lactic acidosis and hepatic steatosis.
‡
No longer available in the US.
§
Requires an assay to screen for co-receptor tropism, since this drug is only active in patients who do not have virions that use CXCR4 for cell entry; has an immunomodulatory effect that is
independent of its effect on HIV replication.

Table 78.4  Adverse reactions to drugs used to treat HIV infection. CY, cytochrome; DRESS, drug rash with eosinophilia and systemic symptoms; MCV, mean
corpuscular volume; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

1299
SECTION

12 CUTANEOUS DISEASES THAT CAN “FLARE” DUE TO THE IMMUNE

RECONSTITUTION INFLAMMATORY SYNDROME
Drug Eruptions
Adverse cutaneous reactions to drugs can range from extremely mild
to life-threatening, and they may be caused by either a single drug or
Infections, infestations and bites

INFECTIONS drug combinations110,113,114. Unfortunately, drug eruptions are common

Mycobacterium tuberculosis in HIV-infected individuals, likely reflecting underlying immune dys-
Mycobacterium leprae regulation, and represent a frequent source of morbidity. Because these
Mycobacterium avium complex and other species patients typically take multiple medications, identification of the causal
Herpes simplex virus 1 and 2 agent or combination of agents is often a complex and frustrating
Varicella–zoster virus process (see Ch. 21).
EBV (e.g. oral hairy leukoplakia) Morbilliform drug eruptions are the most common presentation of
Cytomegalovirus
drug hypersensitivity, and the incidence is significantly higher in HIV-
Human papillomavirus
Molluscum contagiosum virus
infected patients than in the general population. Patients may also
Candida spp. present with urticaria, pruritus, vasculitis, exfoliative erythroderma,
Dermatophytes photodermatitis, Stevens–Johnson syndrome and toxic epidermal
Cryptococcus spp. necrolysis. An adverse drug reaction should be high on the differential
Histoplasma capsulatum, Penicillium marneffei diagnosis list when a patient taking several medications develops a
Demodex, Malassezia spp. (e.g. folliculitis) cutaneous eruption.
Leishmania spp. Protease inhibitors may cause retinoid-like effects, including parony-
INFLAMMATORY DISORDERS chia, ingrown toenails, desquamative cheilitis and xerosis77. Lipodys-
Psoriasis, seborrheic dermatitis trophy syndrome, as described previously, may also develop. Oral
Sarcoidosis numbness has been observed, especially with therapeutic doses of riton-
Foreign body reactions (granulomatous) avir115. The major cutaneous and extracutaneous side effects of the
Eosinophilic folliculitis other classes of antiretroviral drugs are outlined in Table 78.4.
Acne vulgaris, rosacea Trimethoprim–sulfamethoxazole (TMP-SMX) is the most common
Papular pruritic eruption drug to cause a cutaneous reaction in HIV-infected patients20. Often
Lupus erythematosus (systemic, discoid, tumid), relapsing polychondritis taken for prophylaxis or treatment of Pneumocystis jiroveci pneumonia
Alopecia areata or toxoplasmosis, TMP-SMX leads to an exanthematous eruption and
Dyshidrotic eczema
fever in 50–60% of HIV-infected patients treated intravenously with
NEOPLASMS this agent (typically 8–12 days after initiating therapy). This occurrence
Kaposi sarcoma is 10 times more frequent than in the general population66. Stevens–
Non-Hodgkin lymphoma Johnson syndrome and toxic epidermal necrolysis can also occur sec-
Multiple eruptive dermatofibromas ondary to TMP-SMX.
Table 78.5  Cutaneous diseases that can “flare” due to the immune Although close observation and documentation is often adequate as
reconstitution inflammatory syndrome (IRIS). most cutaneous drug eruptions regress (especially the morbilliform
type), if systemic signs such as fever develop or epidermal detachment
is observed, the suspected offending agent(s) should be withdrawn
immediately as this may herald a more serious, possibly life-threatening,
complication. With some drugs such as zidovudine, sulfonamides and
manifestations, and skin diseases that can be exacerbated by IRIS are
dapsone, patients may be successfully desensitized after an adverse drug
listed in Table 78.5110.
reaction66. Drug rechallenge should be done under controlled circum-
stances. Rechallenge is contraindicated for abacavir and is not recom-
Drug–Drug Interactions mended for NNRTIs.
Knowledge of potential drug interactions is necessary to prevent adverse
reactions and therapeutic failures. The human cytochrome P450
system metabolizes a number of drugs used to treat HIV infection and CONCLUSIONS
associated complications. Cytochrome P450 3A4 inhibitors, which
include most of the protease inhibitors and delavirdine, impair drug The number and variety of cutaneous manifestations of HIV infection
metabolism, leading to accumulation of drugs that share the same are greater than those in any other organ. These complications are a
metabolic pathway (see Ch. 131). Cytochrome P450 3A4 mixed source of significant morbidity and, in some cases, mortality. Although
inducers/inhibitors and inducers (e.g. efavirenz and nevirapine, respec- ART has decreased the incidence of many opportunistic infections,
tively) may accelerate clearance of other medications and may neces- other adverse sequelae such as IRIS, drug reactions, metabolic distur-
sitate dose adjustments. Cytochrome P450-independent interactions bances, HPV infections and SCCs remain common and may even be
include: (1) an increase in intracellular drug levels and toxicity of dida- increasing in incidence due to longer survival of HIV-infected individu-
nosine when used in combination with ribavirin and/or tenofovir111; als. By recognizing the spectrum of skin conditions associated with HIV
and (2) a decrease in atazanavir concentration when coadministered infection and performing appropriate diagnostic tests, treatment can be
with tenofovir112. administered in a timely fashion and outcomes optimized.

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