Fig. 20.1
Represents the major steps in the infection of a CD4 lympocyte with HIV. Anti-retroviral drugs have been developed to target various steps in the replication of HIV
Virologic, Immunologic, and Clinical Features of HIV Disease
Early-Stage HIV Disease
Langerhans Cells as Initial Targets for HIV Following Sexual Exposure to Virus
Most HIV infections are transmitted through the mucosa. Most adults acquire the virus via vaginal, penile and rectal transmission, while most pediatric HIV infections occur through the oral ingestion of maternal fluids [19].
Langerhans cells are antigen-presenting cells found within skin and in oral, vaginal, cervical, and anal epithelial layers, and normally function as outposts of the immune system within these tissues [20–23]. Here, they capture surface antigens and emigrate from the epithelium to draining lymph nodes via afferent lymphatics. Langerhans cells then present processed antigenic peptides to T cells, thereby leading to antigen-specific T-cell activation. Intraepithelial Langerhans’ cells have been shown to be the first cells infected following vaginal exposure to simian immunodeficiency virus (SIV) in a rhesus macaque model of primary HIV infection [24]. Following infection, Langerhans’ cells are believed to migrate from mucosal surfaces to draining lymph nodes via afferent lymphatics, where they transmit HIV to paracortical activated CD4+ T cells, thus establishing infection within the lymph node compartment [25, 26].
In situ, immature Langerhans cells express CD4 and are CCR5 + CXCR4− [27–29]. Epithelial cells are CD4− and HIV co-receptor negative and are thus not predicted to be easily infected by HIV. However, they express HLA-DR, CD1a and some mannose dependent C-type lectin receptors (MCLRs) that can function as viral attachment factors [30]. The differential surface expression of CCR5 and CXCR4 may explain why macrophage-tropic, or R5 type, viruses are the dominant type of HIV to be sexually transmitted (90–95 % of cases) [31, 32]. In vitro, human immature Langerhans cells are much more easily infected by R5 viruses when compared to X4 viruses, and cells can be completely protected from infection by blocking CCR5 [33–36]. The importance of CCR5 in initiating primary HIV infection is underscored by the fact that individuals who have homozygous deletion of their CCR5 gene are relatively protected from becoming infected by HIV despite numerous exposures [37–40].
Development of Topical Microbicides to Prevent Sexual Transmission of HIV
In the absence of a prophylactic vaccine against HIV, health measures designed to limit the numbers of new cases of sexually transmitted HIV infection have included abstinence and condom use. Unfortunately, these methods can be impractical in certain countries and social situations where women are not empowered to influence decisions regarding sexual intercourse [41]. Thus, additional means to block sexual transmission of HIV are urgently needed. The use of topical microbicides, drugs or compounds that can be applied to genital tissue prior to sexual intercourse and potentially block sexual transmission of HIV, is being actively investigated [42]. Microbicide acceptability studies in populations of at-risk women have suggested that an effective topical microbicide would likely be used by women [43, 44], potentially making a major impact on improving world health.
In the past decade, several potential microbicides have been developed, many of which have reached Phase III human clinical trials. These include Nonoxynol-9 and cellulose sulfate, which failed due to inducing damage in vaginal epithelia of users thereby increasing HIV infection; and Carraguard, which failed due to lack of efficacy [45–47].
A promising microbicide currently undergoing Phase III clinical trials is tenofovir 1 % gel. In the CAPRISA 004 Phase IIb clinical trial, this gel demonstrated prophylactic efficacy against HIV acquisition [48]. Should it demonstrate efficacy, tenofovir 1 % gel will be the first, successful gel microbicide. Another highly promising potential microbicide that is currently undergoing phase III clinical trials is the dapivirine vaginal ring. Its advantages include its long-acting nature (for a month or longer), its convenient use and discrete nature, its durability and high acceptability among potential users [49]. Other new microbicides in the pipeline include vaginal tablets of tenofovir and emtricitabine [50]. Many other compounds are in the development pipeline, and the future of effective microbicides in multiple formulations to empower at-risk women to prevent themselves from acquiring HIV is promising.
Immunologic Features and Cutaneous Manifestations of Acute Primary HIV Infection
The clinical syndrome in acute HIV infection often develops within 2–4 weeks following exposure and can range from asymptomatic to a severe illness, lasting from a few days to several weeks. 50–90 % of acutely infected patients are symptomatic, often with fevers, lymphadenopathy and the nonspecific flu-like signs and symptoms outlined in Table 20.1 [51, 52]. Rash occurs in a relatively high percentage of patients (50–75 %). Lesions are described as non-pruritic erythematous macules and papules, with a predilection for the upper trunk, head, and neck (Fig. 20.2). The cutaneous eruption is probably caused by infiltration of anti–HIV-specific CD8+ cytotoxic lymphocytes, as has been shown in the skin of rhesus macaques during acute infection with SIV [53]. Painful oral ulcers are also common in primary HIV infection. Because of the nonspecific nature of these signs and symptoms, clinical diagnosis of acute HIV infection requires a high index of suspicion. Accordingly, it is now suggested that all individuals with known or suspected risk factors for acquiring HIV, who present with rash and fever, should be questioned in detail about possible HIV exposures and have laboratory tests to investigate this possibility [54].
Table 20.1
Signs and symptoms of primary HIV infection
Common | Uncommon |
|---|---|
Fever (95 %)a | Diarrhea (30 %) |
Lymphadenopathy (75 %) | Headache (30 %) |
Pharyngitis (70 %) | Nausea/vomiting (25 %) |
Rash/oral ulcers (70 %) | Hepatosplenomegaly (15 %) |
Myalgia/arthralgia (55 %) | Thrush (10 %) |
Neurologic symptoms (10 %) |
Fig. 20.2
Rash of primary HIV infection. Lesions are characteristically erythematous macules involving the head, neck, and upper trunk. Oral ulcers are also common
Characteristically, HIV plasma viremia is high during this acute syndrome, with plasma usually containing >100,000 copies of HIV RNA/mL as measured by standard viral load assays, whereas routine HIV antibody tests are negative (Fig. 20.3). The combination of a high viral load and no HIV-specific antibodies confirms the diagnosis of primary HIV infection. Signs and symptoms resolve and plasma viremia gradually drops as cellular and humoral immune responses are initiated to control initial infection. HIV antibody tests usually become positive within 3 months following infection, although this interval may be prolonged in unusual cases.
Fig. 20.3
Natural course of HIV disease. Potent highly active antiretroviral therapy (HAART) has a strong influence on this course by prolonging life for HIV-infected individuals
Most clinicians and HIV researchers promote the widespread use of antiretroviral therapy at the earliest possible time point following diagnosis of acute HIV infection [55, 56]. There are several pieces of data that support this recommendation. First, early use of cART (defined as the use of three or more HIV medications from at least two different drug classes) most likely decreases the “viral set point”—the level of plasma viremia following resolution of acute HIV infection. This level of plasma viremia is linked with the ultimate prognosis for a given HIV-infected individual [57]. Second, cART has been shown to preserve both number and function of anti–HIV-specific CD4+ and CD8+ T cells, believed to be critical in the partial, albeit incomplete, control of HIV replication. Third, early cART likely blunts loss of antigen-specific memory T cells, which are preferentially lost in early HIV disease [58]. Preservation of cellular immunity to common antigens would be predicted to prevent opportunistic infections. Fourth, early initiation of cART reduces plasma HIV-1 concentrations, and has been shown to decrease the risk of viral transmission to others [59, 60]. The drawbacks of treatment with cART in early HIV disease include the possible emergence of drug-resistant strains of HIV, the high cost of medications, drug-related side effects and chronic immune activation resulting in increased risk of several non-AIDS disorders [61, 62].
Middle Stage HIV Disease
Virologic and Immunologic Features That Determine Progression to AIDS
Following resolution of acute infection, HIV-infected individuals often go into a prolonged period without clinical symptoms of HIV disease. This is the clinical latency period. Although plasma viremia is usually low or undetectable during this asymptomatic stage, viral replication continually occurs unabated within lymph nodes and there is gradual damage to the architecture of lymph nodes and other lymphoid tissues [63]. During middle stage HIV disease, CD4+ T cell counts range between 200 and 500/μL, with a slow gradual decline often observed (Fig. 20.3).
As mentioned earlier, three strains of HIV can be classified based on their cellular tropism: (1) macrophage-tropic (R5) strains that preferentially infect peripheral mononuclear cells, monocytes and macrophages via the co-receptor CCR5; (2) T-cell line tropic (X4) strains that preferentially infect T cell lines via the CXCR4 co-receptor; and (3) Dual-tropic (R5X4) strains that infect macrophage and T cell lines using both receptors. R5 strains are present in all stages of HIV. During the middle stage of HIV, there is a gradual increase of X4 strains, which are more cytopathic to CD4+ T cells leading to their gradual decline in numbers.
The V3 loop of the gp120 viral protein determines the viral phenotype (R5, X4 or R5X4). It is thought that mutations in gp120 lead to more X4 viruses, which in turn deplete CD4+ T causing the progression to AIDS [64]. However, it should be noted that even individuals with predominant R5 or R5X4 strains still develop AIDS; only at a much slower rate, since the R5 strains are still able to deplete T cells [65].
Deletions or polymorphisms in genes encoding HIV co-receptors (i.e., chemokine receptors) and their ligands (i.e., chemokines) have been associated with delayed HIV disease progression. For example, individuals with a particular polymorphism in their SDF-1 gene, the gene that encodes for the natural chemokine ligand of CXCR4, progress to AIDS less quickly than individuals without this particular polymorphism [66]. Functional studies on the two forms of SDF-1 protein suggest that the variant form is degraded less rapidly than the wild-type form, and would therefore be predicted to have more prolonged binding periods with CXCR4. In addition, heterozygous mutations of the CCR5 gene or its promoters as well as gene duplications in CCR5 ligands prolong the onset of AIDS, presumably by limiting infection and spread of macrophage-tropic viruses early in HIV disease [67–69].
Cutaneous Manifestations of Middle-Stage HIV Disease
Human immunodeficiency virus–infected individuals with CD4+ T-cell counts in the 200 to 500/μL range are mostly asymptomatic, although this certainly is not always true. Signs and symptoms that belie underlying HIV infection often manifest as cutaneous diseases during this phase [70]. In particular, herpes zoster and treatment-resistant seborrheic dermatitis in young persons should alert clinicians to the possibility of coexisting HIV infection and lead to questioning about known HIV risk factors. Zoster involving multiple dermatomes, zoster involving the head and neck, and prolonged healing of lesions are distinct clues to possible underlying immunosuppression, and thus are more common in HIV-infected individuals [71]. Subtle loss of antigen-specific cell-mediated immunity is believed to be the mechanism by which these diseases occur. Although not limited to patients with particular CD4+ T-cell counts, diagnosis of any sexually transmitted disease (syphilis, condyloma, herpes simplex, etc.) should also prompt questioning about possible concomitant HIV infection. Additionally, there is an increase in Staphylococcus aureus colonization and infections in HIV infected people, especially in the middle and late stages of the disease [72].
Acute illnesses, such as herpes simplex reactivation and herpes zoster, lead to tissue inflammation, immune activation, and increases in HIV plasma viremia. The basis for increased plasma viremia is most likely multifactorial. Inflammatory cytokines released during acute inflammation or infection can directly lead to enhanced viral replication within HIV-infected cells. As well, immune activation and cytokine production can stimulate HIV infection of previously uninfected CD4+ T cells. Thus, there is a strong basis for both preventing and aggressively treating all acute infections and illnesses in HIV-infected individuals. Of note, immunizations, which lead to transient activation of the immune system, also trigger transient increases in HIV plasma viremia [73]. The benefits, however, of protecting against future illnesses accorded by immunizations outweigh any potential harm caused by them.
Late Stage HIV Disease, or AIDS
Virologic and Immunologic Features of AIDS
Viruses of all types (T-cell-tropic, macrophage-tropic, dual-tropic) can be isolated from most AIDS patients [64]. Plasma viremia is also usually high in untreated patients (Fig. 20.3). In addition, destruction of lymph node architecture also contributes to high viral loads in blood. This occurs because many infectious HIV virions previously trapped by follicular dendritic cells are released into blood following breakdown of lymphoid tissue [63]. Viral loads can drop dramatically in AIDS patients who are placed on cART for the first time, although it can be difficult for AIDS patients to get to the point where plasma viremia is undetectable [74].
Immune defects in advanced-stage HIV disease are profound. Due to chronic immune activation from persistent viral antigens, both the innate and adaptive immune systems develop immune exhaustion: a state of relative unresponsiveness to the persistent pathogen [75]. T cell exhaustion is weak or absent virus-specific T cell reactivity characterized by impaired cytokine production (such as the loss of interleukin-2 production, a key cytokine involved in normal T-cell function), decreased T cell proliferation, poor effector cytotoxic activity, and sustained expression of inhibitory receptors – such as PD-1, LAG-3, CTLA4, and Tim-3 [76, 77]. Eventually, this results in apoptosis of T cells – preferentially the memory subset of T cells – leads to AIDS. By definition, patients with AIDS have CD4+ T-cell counts less than 200/μL.
B cell exhaustion is also seen in AIDS, characterized by hypergammaglobulinemia, decreased sub-populations of memory B cells, over-representation of exhausted B cells that have decreased capacity to proliferate in response to de novo stimuli, and increased numbers of aberrant naïve B cell subsets – many of which express increased inhibitory receptors [78, 79]. Macrophages also demonstrate numerous defects in AIDS and may also display immune exhaustion, although the mechanism of this is less well understood. Surprisingly, most studies show that dendritic cell function, including epidermal Langerhans cell function, remains relatively intact, even in late-stage AIDS patients [33, 80, 81].
In conclusion, due to immune exhaustion, HIV-infected individuals develop loss of antigen-specific cell-mediated immunity and are susceptible to opportunistic infections. Early initiation of cART is important in reducing viral loads and preventing T-cell exhaustion. Use of cART often leads to increases in CD4+ T-cell counts for AIDS patients [82]. Additionally, new approaches to combating immune exhaustion are being explored such as the development of molecules that block inhibitory ligand-receptor interactions, leading to the rescue of exhausted T cells. Immunotherapy targeting the inhibition of inhibitory receptors (PD-1, CTLA-4, Tim-3, LAG-3) is not only being studied in chronic viral infections such as Hepatitis C and HIV, but also in fields like oncology in which PD-1 blockage has been used to target tumors in humans [83].
Cutaneous Manifestations of AIDS
In patients with AIDS, especially those that are not on anti-retroviral therapy, the most cutaneous manifestations of their disease are opportunistic infections, which can be viral, bacterial, fungal, parasitic and ectoparasitic (infestations). Additionally, they develop neoplasms such as Kaposi’s Sarcoma, lymphomas, non-melanoma skin cancers, and other cutaneous neoplasms. They also develop forms of non-infectious dermatoses such as papular pruritic eruption of AIDS and severe ichthyosis. They are susceptible to many severe drug-reactions such as toxic epidermal necrolysis. Due to AIDS and the initiation of anti-retroviral drugs, they develop metabolic changes such as HIV/ART-associated lipodystrophy. Finally, patients with AIDS who then receive anti-retroviral therapy may develop the immune reconstitution inflammatory syndrome (IRIS), which is the paradoxical worsening of pre-existing infections after initiation of cART due to inflammatory sequelae that result when the immune response to those pathogens is enhanced [84]. These cutaneous manifestations of AIDS are discussed in more detail below.
Kaposi’s Sarcoma
Kaposi’s sarcoma (KS) is the most common neoplasm in HIV-infected individuals [85]. However, due to more widespread use of anti-retroviral therapy, its incidence is declining, except in resource-poor settings where cART is not readily available. Most investigators now believe KS is not a true malignancy, but rather a multicentric proliferative process driven by inflammation and immune dysregulation. In a landmark study from 1994, the KS-associated herpesvirus (KSHV) – now more commonly referred to as human herpesvirus 8 (HHV-8) – was discovered within lesions of AIDS-associated KS [86]. HHV-8 is transmitted sexually and also through saliva and blood, and it infects endothelial and spindle cells [87]. Factors that play a role in the pathogenesis of KS include loss of HHV-8-specific cell-mediated immune immunity and inflammatory cytokines [88]. Only a small number of cells (<2 %) within KS tumors are productively infected with HHV-8 and produce virions. The remaining cells are latently infected with virus [89]. It is thought that the viral genes expressed in latently infected cells contribute to the abnormal spindle cell growth observed in KS lesions [90, 91].
Clinically, KS patients present with violaceous lesions ranging from small papules to large plaques and ulcerated nodules. It typically affects the upper body, usually along the skin-lines. It has a predilection for the face, especially around the nose and oral mucosa. KS can also affect internal organs such as the lymph nodes, gastrointestinal tract and lungs. Multiple treatments exist for KS depending on the stage of HIV, extent of KS and other patient comorbidities. Most patients on cART note regression of their disease: most likely due to improved HHV-8-specific immune function and decreases in HIV-associated inflammatory cytokines that directly stimulate KS spindle cell growth [92]. However, patients on cART may develop KS flares due to immune reconstitution inflammatory syndrome (IRIS). Other options include local destruction (for example cryotherapy), laser therapy, topical alitretinoin, radiotherapy, and intralesional chemotherapy (for example vinblastine). Systemic therapies for disseminated KS include IV liposomally encapsulated doxorubicin, duanorubicin and paclitaxel [93].
Other Viral Infections
Loss of cell-mediated immunity predisposes to viral infections. Infection with herpes simplex virus types 1 and 2 in AIDS patients often results in slow-healing, painful cutaneous ulcerations in the perianal region, genitalia and tongue. These lesions can get large and verrucous, and often take longer to respond to treatment. Varicella zoster virus (VZV) in AIDS patients is usually multidermatomal, and lesions can be chronic, verrucous, ulcerative and widely disseminated with systemic involvement [70]. Treatment and prophylaxis with acyclovir or one of its derivatives is indicated, although clinicians should be wary of the development of acyclovir-resistant strains of both HSV and VZV in the setting of AIDS.
Lytic replication of Epstein-Barr virus within lingual epithelial cells produces oral hairy leukoplakia. This manifests as white corrugated adherent plaques on the lateral aspects of the tongue. CMV viremia can rarely lead to cutaneous diseases, such as ulcers in the anogenital area [94]. Human papillomavirus and molluscum contagiosum virus infections can be particularly aggressive and treatment-resistant in individuals with AIDS. Giant mollusca are seen, and the lesions of HPV can also be quite extensive. Of note, anogenital cancer, like cervical cancer, has been linked to human papilloma virus infection and occurs more commonly in HIV- infected persons compared to the general population [95].
Cutaneous viral infections, like all other cutaneous manifestations of HIV disease, are best treated by first ensuring that patients are on proper cART, which completely suppresses HIV plasma viremia. Second, specific treatment as dictated by the clinical disease, biopsy findings, and culture results should be instituted. As learned in the era prior to cART, specific treatment of AIDS- associated dermatoses is unlikely to be optimally effective in face of uncontrolled HIV plasma viremia and continued destruction of the immune system.
Fungal Infections
Loss of cell-mediated immunity also predisposes to fungal infections. Candidiasis is the most common mucocutaneous manifestation of AIDS, often presenting as friable non-adherent white plaques within oral and vaginal mucosa. Esophageal candidiasis is a particularly painful complication and can lead to impaired swallowing. Treatment and prophylaxis with systemic antifungals is often indicated. Dermatophytosis can also be particularly widespread and difficult to treat.
Systemic fungal infections are also seen in AIDS, with the most common being cryptococcosis and histoplasmosis, where up to 10–15 % of patients have cutaneous involvement. Cutaneous cryptococcosis in AIDS usually presents as papules and nodules with central umbilication (i.e., molluscum-like) or necrosis. Histoplasmosis can present with acneiform papules and pustules, which often involve the face. Other systemic fungal diseases that can affect the skin when they are disseminated include coccidioidomycosis, blastomycosis, paracoccidioidomycosis, sporotrichosis, penicilliosis and aspergillosis [96]. Fungal infections in AIDS are best managed by optimizing cART, making accurate diagnoses, and instituting specific antifungal therapy.
Bacterial Infections
Bacillary angiomatosis is caused by gram-negative Bartonella bacteria (specifically B. henselae and B. quintana species), and is thought to be a reactive, vasoproliferative condition. Lesions affect any body site and present as red-purple vascular papules, nodules and ulcers. Staphylococcal infections in AIDS present as impetigo, folliculitis, furunculosis, botryomycosis and cellulitis and tend to be more refractory to therapy. Mycobacterial infections such as cutaneous tuberculosis are seen in AIDS. Other mycobacteria that produce cutaneous lesions include: Mycobacterium avium complex, M. kansasii, M. haemophilum and M. fortuitum.
Parasitic and Ectoparasitic Infestations
Scabies, caused by infestation with the Sarcoptes scabiei var. hominis mite is the most common ectoparasitic skin infestation patients with AIDS. Lesions range from the usual burrows, vesicles and papules – to a widespread dermatitis of thickened, dry, scaly hyperkeratotic eruption called crusted scabies in which thousands to millions of mites may be present on an individual. Demodicosis is also frequent in AIDS. Parasites such as leishmaniasis, acanthamebiasis and strongyloidiasis are also seen in AIDS. In patients with disseminated strongyloidiasis, thumb-print purpura on the lower trunk may be seen.
Neoplastic Cutaneous Disorders in AIDS
In addition to Kaposi’s Sarcoma (which is considered both infectious and neoplastic), other neoplastic disorders that may develop in AIDS include lymphomas such as non-Hodgkin B-cell and T cell lymphomas. The lymphomas usually present as violaceous papules and nodules that sometimes ulcerate and resemble panniculitis. Roughly half of non-Hodgkin lymphomas in HIV are associated with EBV infection. Cutaneous T cell lymphomas, squamous cell carcinomas and basal cell carcinomas are also seen in not only AIDS, but also patients with higher CD4 counts. HPV-induced genital SCCs – such as vaginal, cervical, penile and anal SCC – occur at increased frequency and with more rapid progression in HIV-infected individuals.
Other Cutaneous Diseases
Eosinophilic folliculitis is an extremely common cutaneous manifestation of AIDS. Patients present with intensely pruritic urticarial papules surmounted by tiny central vesicles usually on the face and upper trunk [97]. This morphology may not be preserved at the time of presentation due to scratching of lesions, in which case the lesions appear as excoriated papules or small round scars (Fig. 20.4). Lesions are distributed on the face, neck, and upper chest and back. In early nonexcoriated lesions, Demodex mites are observed within hair follicles at the center of heavy eosinophilic infiltrates [81]. Eosinophilic folliculitis is thought to be an aberrant immune response directed against Demodex mites or Malassezia yeast. Treatment options for eosinophilic folliculitis – which is often refractory to therapy – include topical permethrin, topical corticosteroids, topical tacrolimus, UVB phototherapy, systemic antibiotics, itraconazole, dapsone and oral retinoids [98]. Papular pruritic eruption (PPE) of AIDS is believed to be in the same spectrum of pruritic disorders as eosinophilic folliculitis. It primarily affects the extremities more than the trunk and face [99].
Fig. 20.4
(a) Typical urticarial papules of eosinophilic folliculitis. (b) High-power histologic view of an early lesion of eosinophilic folliculitis. Demodex mites are characteristically seen within centers of affected hair follicles surrounded by sheets of eosinophils. Excoriated or older lesions show a mixed infiltrate and will not demonstrate mites
Other non-infectious cutaneous disorders seen in AIDS include an acquired ichthyosis with generalized dryness and scaling of skin, refractory seborrheic dermatitis, severe psoriasis, development of refractory oral aphthae, and photosensitive dermatoses such as chronic actinic dermatitis and generalized UV light sensitivity (often with a photolichenoid reaction) [100].
Drug Reactions in AIDS
Drug reactions are common in advanced- stage HIV disease, particularly severe reactions, like Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrosis (TEN), which occur with increased frequency in these patients [101]. The most common drug eruptions in AIDS are morbilliform eruptions. Others include urticarial eruptions, vasculitis, exfoliative erythrodermas, photodermatitis and SJS/TEN. Common triggers of AIDS-associated drug reactions include medications like trimethoprim-sulfamethoxazole and the antiretroviral drug nevirapine. Up to 8 % of patients treated with nevirapine develop Steven Johnson’s syndrome [102]. Additionally, patients taking protease inhibitors may develop a syndrome with clinical features resembling Cushing’s disease. These individuals have central fat deposition (“buffalo humps,” protuberant abdomens, gynecomastia), wasting of facial fat and peripheral fat of the arms and legs, hypertriglyceridemia, glucose intolerance, and increased risk for myocardial infarction (Fig. 22.6) [103]. Unlike in Cushing’s disease, the pituitary axis is unaffected. Facial wasting may be treated by switching drug regimens that have less lipodystrophic effects and by injection of filler substances [104, 105]. Other cART-associated cutaneous drug reactions have also been reported, including abacavir hypersensitivity, zidovudine-associated hyperpigmentation of the nails, and retinoid-like effects due to protease inhibitors (Table 20.2) [106]. The pathogenic basis for all of these drug reactions occurring in HIV-infected individuals is unclear (Figs. 20.5 and 20.6).
