Pedal and Lower Extremity Manifestations of HIV

KHURRAM H. KHAN

GEORGE S. ABDELMESSIEH

RIHAM M. WAHBA

Human immunodeficiency virus (HIV) has now spread to every country in the world, with a total of 33.3 million affected as per the 2009 UNAIDS global report; 189,165 cases of HIV and acquired immunodeficiency syndrome (AIDS) have been diagnosed and reported in New York City since the beginning of the epidemic. Tremendous research has been achieved on HIV over the past decade to improve health outcomes of people living with HIV. However, there has been very little written evaluating the prevalence of pedal complications of patients with HIV. The purpose of this study was to investigate pedal complications of HIV patients in an East Harlem foot clinic.

A retrospective chart review was performed for the treatment of pedal complication with the concurrence of the International Classification of Diseases, Ninth Revision (ICD-9) code 042.00; 153 HIV-infected adult patients’ medical records fit the inclusion-exclusion criteria. There were 88 females and 65 males in the 40- to 74-year age group, the average age being 55.1 years. The most common pedal complaints were onychomycosis in 107 patients (70%), neuropathy in 101 patients (66%), tyloma in 62 patients (41%), tinea pedis in 60 patients (39%), xerosis in 59 patients (39%), and longitudinal melanonychia in 10 patients (7%). The most co-common morbidity was diabetes in 37 patients (24%). Of those with neuropathy, only 18% were diagnosed with diabetes, showing that neuropathy is a significant finding in HIV+ patients on its own.

Our retrospective review sheds some light on the pedal complications in this patient population, which has not been extensively studied in the past. Further research is warranted to examine the complications more closely in a larger pool, with specific comparisons to be made between HIV neuropathy and diabetic neuropathy.

This is a literature review of PubMed and Medline with the purpose of the study to look for some of the most common pedal complications and the prevalence of each in HIV-infected persons to establish the prevalence and compare them to the results of our study performed at Foot Clinic of New York. The data of their prevalence among such high-risk group are lacking, and there is no one study that discusses the problem collectively.

Very little has been written in regard to the pedal complication in the HIV population. A wide spectrum of pedal complications are associated with HIV infection, but it is important to remember that not all are related to the infection itself and the same complications could happen in normal immune-competent persons. HIV infection can alter the clinical presentation and course of any condition, and many conditions may be more severe in an HIV-infected person. Infection should always be considered in any presentation involving the feet.

Depending on the stage of a patient’s disease, opportunistic infections (OIs) may be responsible for the pedal complications. If the CD4 count is >300 cells per µL, then an OI is less likely.

Historical Perspective

AIDS was first described in the United States in 1981. It is caused by a lentivirus (subfamily of retroviruses), the Latin word “lentus” meaning slow, denoting the long latent phase between infection and clinical presentation. Retroviruses use the enzyme reverse transcriptase to generate proviral DNA from RNA (reverse of the usual direction of genetic transcription). The term HIV was accepted in 1986 and there are two types. HIV-1 is a rapidly mutating virus that is more virulent and rapidly progressive than HIV-2, which is predominantly found in West Africa. HIV-1 is divided into three groups of M (main group), which is further subdivided into at least 11 subtypes or clades, O (outlier group) and N (new group). HIV-2 is divided into groups A to G. The most common group worldwide is HIV-1 type M.¹

A decade after the first description of AIDS, the epidemic has become a worldwide public health problem. Initially, HIV transmission occurred predominantly among homosexuals and intravenous drug users in developed countries, and among heterosexuals in developing countries.

Subsequently, HIV transmission among heterosexuals increased also in developed countries. Currently, HIV seroprevalence among heterosexuals varies from 0.1% to 1.4% in Europe and 0.3% to 0.6% in North America to as high as 39% in some regions of sub-Saharan Africa.² The majority of the 40 million people living with HIV/AIDS (of whom 70% are in sub-Saharan Africa) are young adults, but about 3 million are 50 years old or older. Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, HIV-infected patients live longer, and the proportion of deaths due to diseases of aging has increased.³ Although
men who have sex with men remain the group at highest risk in the United States, there is an increasing burden of the disease among African-Americans, heterosexual men and women, and young people.⁴

FIGURE 23-1. New HIV Diagnoses in the United States for the Most-Affected Subpopulations, 2015. (CDC. Diagnoses of HIV infection in the United States and dependent areas, 2015. HIV Surveillance Report 2016;27. Subpopulations representing 2% or less of HIV diagnoses are not reflected in this chart. Abbreviation: MSM, men who have sex with men.)

At the end of 2013, an estimated 1.2 million persons aged 13 and older were living with HIV infection in the United States, including an estimated 161,200 (13%) persons whose infections had not been diagnosed.⁵

The Centers for Disease Control and Prevention (CDC) reports in 2015 that 39,513 people were diagnosed with HIV infection in the United States and estimates 265,330 new infections could occur in the next five years, if current testing, treatment, and pre-exposure prophylaxis (PrEP) trends remain the same (Fig. 23-1).

To remedy this situation, the CDC currently recommends voluntary “opt-out” HIV screening at health care centers, which means that HIV testing is performed unless the patient declines.⁷

Etiology and Pathogenesis

HIV is an RNA virus (retrovirus) that binds to the CD4 antigen, mainly expressed on the surface of helper T lymphocytes and dendritic cells, including Langerhans cells. Coreceptors for HIV are the chemokine receptors CCR5 and CXCR4. Viral RNA undergoes reverse transcription to DNA, which is incorporated into the host DNA. Viral replication occurs by transcription of proviral DNA into viral mRNA, which is associated with a decline in the CD4 cell count and consequently impaired cellular immunity. After initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection. This leaves a window of opportunity for postexposure prophylaxis (PEP) using antiretroviral drugs to block replication of HIV.⁸

HIV is transmitted through blood, semen, vaginal secretions, and breast milk. The virus has also been isolated from saliva, tears, urine, amniotic fluid, and cerebrospinal fluid.⁷,⁹ The routes of HIV transmission are sexual intercourse, sharing infected needles or syringes, transfusion of blood or blood products, from mother to baby during birth or breast-feeding, and occupational exposure of health care professionals. The approximate risks of infection are listed in Table 23-1.

In comparison to the risks shown in the table, the average transmission risk after percutaneous exposure of a health care professional is 6% to 30% for hepatitis B virus (HBV) and 2% for hepatitis C virus (HCV). To minimize the risk of blood-borne pathogen transmission from patients, all health care professionals should adhere to standard precautions, including hand washing, protective barriers, and care in the use and disposal of needles and sharp instruments.¹⁰ Semen represents the main vector for HIV dissemination. HIV-1 replication may occur in macrophages in the testis and/or prostate, which may constitute pharmacologic sanctuaries protecting the virus against HAART. Persistence of virus release into the semen may occur despite an undetectable blood viral load (BVL).¹¹ Vertical transmission of HIV from mother to baby is increased with CD4 counts <500 cells per µL, intrapartum use of invasive procedures, rupture of membranes >6 hours, and labor >5 hours. HAART reduces the risk of mother to baby transmission from about 18% to less than 1%.¹² HIV infection is usually diagnosed by detecting antibodies in a serum sample. There is a delay (window period) between infection and a positive HIV antibody test, varying from 2 to 6 weeks and up to 3 months. During this time, the person is often very infectious with a high viral load, but antibody tests may be false-negative. Therefore, plasma should be tested for HIV p24 antigen and RNA by a technique such as polymerase chain reaction.¹

Table 23-1. Approximate HIV Transmission Risk Following a Single Exposure to HIV Infection

		% Risk
Vaginal or anal insertive intercourse		0.03-0.09
Vaginal or anal receptive intercourse		0.1-3
Oral (fellatio)		0.04
Occupational:
	Mucous membrane contact	0.1
	Needle-stick injury	0.3
	Transfusion of 1 unit of blood	90-100
(Data from Pattman R, Snow M, Handy P, et al. Oxford Handbook of Genitourinary Medicine, HIV, and AIDS. Oxford, UK: Oxford University Press; 2008:345-548.)

When the CD4 counts are <200 cells per µL certain AIDS defining illnesses, such as OTs, can develop (Appendix 1) (see Table 23-2).

Apart from these OIs, other AIDS defining conditions include CD4 count <200 cells per mm³, non-Hodgkin lymphoma (NHL), Kaposi sarcoma (KS), invasive cervical cancer, HIV encephalopathy, and wasting syndrome due to HIV. If untreated, the average time between HIV infection and AIDS is about 10 years. BVL predicts the likely rate of disease progression and indicates response to therapy. BVL <5,000 copies per mL generally suggests a low rate of progression in the next 5 years and >55,000 copies per mL is associated with increased progression. HIV-associated OIs can affect virtually any organ or system, and are caused by organisms those are rarely pathogenic if the cellular immune system is intact.

APPENDIX 1:

Organisms Causing Opportunistic Infections in HIV+ Patients

Bacteria: Salmonella, Mycobacteria (M. tuberculosis, M. kansasii, M. avium-intracellulare complex, M. genavense, M. simiae, M. celatum), Bartonella henselae, and B. quintana
Viruses: Herpes simplex, Cytomegalovirus, Varicella zoster virus, Human papillomavirus, Epstein-Barr virus, Hepatitis B, Hepatitis C, Polyoma virus, Pox virus, Parvovirus, Adenovirus, Erythrovirus B19
Fungi: Candida, Pneumocystis jiroveci (carinii), Cryptococcus neoformans, Histoplasma capsulatum, Aspergillus species, Coccidioides immitis, Penicillium marneffei, Blastomyces
Protozoa/Parasites: Cryptosporidiosis, Microsporidiosis, Isospora belli, Strongyloides stercoralis, Toxoplasma gondii, Leishmaniasis

Table 23-2. CD4⁺ Count and Opportunistic Conditions in HIV Infection

CD4⁺ Count (cells/mm³)	Infectious Complications	Noninfectious Complications
>500	Acute retroviral syndrome Candidal vaginitis	Persistent generalized lymphadenopathy Guillain-Barré syndrome Myopathy Aseptic meningitis
200-500	Pneumococcal and other bacterial pneumonias Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis Kaposi sarcoma Oral hairy leukoplakia	Cervical neoplasia and cancer B-cell lymphoma Anemia Mononeuropathy multiplex Idiopathic thrombocytopenic purpura Hodgkin lymphoma Lymphocytic interstitial pneumonia
<200	Pneumocystis pneumonia Disseminated histoplasmosis and coccidioidomycosis Miliary and extrapulmonary tuberculosis Progressive multifocal leukoencephalopathy	Wasting Peripheral neuropathy HIV-associated dementia Cardiomyopathy Vacuolar myelopathy Progressive polyradiculopathy Non-Hodgkin lymphoma
<100	Disseminated herpes simplex Toxoplasmosis Cryptococcosis Cryptosporidiosis, chronic Microsporidiosis Candidal esophagitis
<50	Disseminated cytomegalovirus Disseminated Mycobacterium avium complex
(Data from Refs. 8, 12-15.)

Infection

Since the introduction of HAART in the mid-1990s, there has been a dramatic decrease in the incidence of OIs in HIV-infected subjects.¹³ This decrease is due to restoration of cell-mediated immunity induced by HAART, whereas protease inhibitors used during HAART may have a direct effect against the proteases of parasites.¹⁶ However, patients remain vulnerable to OIs for approximately 2 months after starting HAART. Sometimes OIs occur despite increased CD4 counts because of impaired functioning of CD4 effector memory T cells and deregulation of B cells that may persist despite changes in the CD4 count.¹⁷

The resurgence of tuberculosis (TB) in the United States is largely linked to the HIV epidemic. Multidrug-resistant (MDR)-TB and extensive drug-resistant TB have emerged as threats to TB control. HIV infection may be associated with primary MDR-TB, possibly by causing malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TB have increased mortality.¹⁸

Prophylaxis against disseminated Mycobacterium avium-intracellulare complex infection with azithromycin or clarithromycin is recommended for all patients with CD4 counts <50 cells per µL.

Malignancy

HIV-1 may contribute to the development of malignancy through several mechanisms, including infection by oncogenic viruses, impaired immune surveillance, or imbalance between cellular proliferation and differentiation.¹⁴

The incidence of certain malignancies is increased with impaired cellular immunity. The AIDS defining cancers (ADCs) are KS, NHL, and cervical carcinoma, which are associated with DNA viruses, namely KS-associated herpes virus, Epstein-Barr virus, and human papillomavirus (HPV), respectively.¹⁹

In the pre-HAART era, approximately 10% of HIV-infected persons had cancer. HAART has dramatically reduced the incidence and mortality of KS and NHL, but has not significantly decreased the incidence of cervical or anal cancer. Although reduced, the incidence of KS and NHL remains higher in HIV-infected than noninfected patients.¹²,¹⁹,²⁰

Since the introduction of HAART, rates of non-ADCs have increased and they currently comprise about 70% of cancers in HIV-infected people.²¹ Non-ADCs include carcinoma of the anus, lung, breast, skin, conjunctiva, head and neck, liver, testis and prostate, Hodgkin lymphoma, plasma-cell neoplasia, multiple myeloma, leukemia, melanoma, and leiomyosarcoma.²²,²³ The risk of HPV-associated cancers of the anus, cervix, oropharynx, penis, vagina, and vulva is increased among HIV-infected persons. The risk increases with advancing immunosuppression, reflecting gradual loss of control over HPV-infected keratinocytes. Infection with oncogenic HPV may facilitate HIV acquisition.²⁴,²⁵

Currently, malignancies are the most frequent cause of death (around a third) of HIV-infected patients. Non-ADC accounts for more morbidity and mortality than ADC in the HAART era. The reasons include the decreased occurrence of OIs and ADCs, longer survival of HIV-infected patients, and the possible oncogenic role of HIV itself. The use of HAART is associated with lower rates of non-ADCs.²⁶

Treating cancer in HIV-infected patients remains a challenge because of late presentation, immunosuppression, drug interactions, compounded side effects, and the potential effect of chemotherapy on CD4 count³ and HIV-1 viral load.¹⁷ Nonetheless, HIV-infected patients with cancer should receive the same treatment as HIV-uninfected patients.²⁷

Current Therapy

Since the approval of zidovudine as the first anti-HIV drug two decades ago, remarkable advances in the understanding of HIV/AIDS pathogenesis and drug development have led to the current availability of more than 30 drugs and fixed dose combinations to treat HIV infection (Appendices 2 and 3).

The median survival after AIDS diagnosis has increased significantly during the HAART era, which has transformed HIV from an almost uniformly fatal condition to a chronic disease. Other benefits of HAART include potential reduction of HIV transmission among adults and decrease of mother to child transmission.

However, in countries where early access to HAART is not readily available, death is still most often due to AIDS-related disorders such as OIs and advanced AIDS status.²⁸

HIV drug resistance may be intrinsic or acquired as a result of mutations in viral proteins. The overall prevalence of baseline genotypic resistance is about 30%. Resistance is disseminated by transmission of resistant mutations selected during therapy. To minimize the development of drug resistance, a combination of at least three drugs from at least two different classes should be used (Appendices 4 and 5) (see Table 23-3).⁷

The benefits of beginning HAART at CD4 counts <200 cells per µL are well documented. Recent studies
have suggested that 350 cells per µL should be the minimum threshold for initiation of HAART.²⁸,²⁹

Table 23-3. Recommendations for Initiation of HAART in Treatment-naïve, Nonpregnant Adults

Patient Status^a	Recommendation
Symptomatic HIV disease	HAART recommended
CD4⁺ T-cell count ≤200	HAART recommended
CD4⁺ T-cell count <350 but >200	Consider HAART, individualize to patient
CD4⁺ T-cell count ≥350 but ≤500	HAART generally not recommended (see text)
CD4⁺ T-cell count >500	HAART generally not recommended
HAART, highly active antiretroviral therapy.
^aCD4⁺ T-cell counts in cells/mm³. The closer the CD4⁺ T-cell count is to 200, the stronger the recommendation, particularly if the plasma HIV RNA level is high (>100,000/mL) or the CD4⁺ T-cell count is declining rapidly (>100 cells/mm³/yr). (Data from Refs. 8, 12-15.)

However, the costs and possible side effects of HAART are important considerations in the debate about the indications for initiating therapy (see Tables 23-4, 23-5 and 23-6).

Table 23-4. Side Effects, Contraindications, and Interactions of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Agent	Common Side Effects	Serious Side Effects	Contraindications	Interactions	Comments
Abacavir (ABC)	Hypersensitivity (5%-8%) with morbilliform rash; GI complaints; fever, dyspnea, cough, malaise, usually in first 6 weeks, may be confused with influenza or other intercurrent illnesses; nausea, vomiting; headache	Life-threatening systemic hypersensitivity reaction if rechallenged after developing hypersensitivity (usually within hours of restarting dose)	History of ABC hypersensitivity; avoid with endstage liver disease	Overlapping resistance with ddI, insufficient data for recommendation	Hepatic metabolism
Didanosine (ddI)	Nausea	Pancreatitis, lactic acidosis, peripheral neuropathy	Use with ribavirin contraindicated because of increased toxicity	TDF increases ddI concentration, is antagonistic, and inhibits T-cell recovery; avoid combination or dose reduce ddI; D4T increases risk of pancreatitis and lactic, avoid coadministration	Renal elimination, do not take with food
Emtricitabine (FTC)	Minimal; occasional hyperpigmentation of palms and soles, especially in dark-skinned persons	None	None	3TC has similar action and resistance profile, avoid coadministration	Renal elimination
Lamivudine (3TC)	Minimal	None	None	FTC has similar action and resistance profile; avoid coadministration	Renal elimination
Stavudine (D4T)	Headache, nausea (uncommon)	Lactic acidosis and hepatic steatosis, pancreatitis, lipodystrophy, peripheral neuropathy	Avoid in patients with neuropathy, lipoatrophy, previous NRTI-associated lactic acidosis	Antagonism with AZT, increased pancreatitis and lactic acidosis with ddI, avoid coadministration	Renal elimination
Tenofovir (TDF)	Minimal	Nephrotoxicity, especially in patients with preexisting renal disease	None	ddI: avoid coadministration or use reduced dose of ddI; ATV must be boosted with ritonavir (300/100 qd); caution when used in patients with underlying renal disease	Renal elimination
Zidovudine (AZT, ZDV)	Headache, nausea, malaise, macrocytosis; within 4 wk after start of therapy, nearly all pts have MCV >100 µm³	Bone marrow suppression with anemia or neutropenia, lactic acidosis and hepatic steatosis, lipoatrophy, myopathy (leg pain, increased CPK)	Avoid in patients with anemia	D4T: antagonism avoid coadministration, Ribavirin: increased risk for anemia Methadone: increases AZT levels	Dose adjustment needed with renal impairment
CPK, creatine phosphokinase; MCV, mean corpuscular volume; NRTI, nucleoside reverse transcriptase inhibitors.
(Data from Refs. 8, 12-15.)

Table 23-5. Side Effects, Contraindications, and Interactions of Nonnucleoside Reverse Transcriptase Inhibitors

Agent	Serious Side Effects	Contraindications	Interactions^a
Delavirdine (DLV)	Hepatotoxicity, Stevens-Johnson syndrome	Not recommended for use in pregnancy	Cytochrome P450 metabolites
Efavirenz (EFV)	Hepatotoxicity	Not recommended for use in pregnancy; can cause neural tube defects	Cytochrome P450 metabolites
Nevirapine (NVP)	Severe hepatotoxicity and/or rash, including Stevens-Johnson syndrome	Do not start in women with CD4 > 250 or men with CD4 > 400 because of risk of fulminant hepatic necrosis	Cytochrome P450 metabolites
^aNNRTIs decrease PI concentrations; PI dose adjustment needed with many PIs (FPV, ATV, LPV); discontinuation of NNRTI-based regimens may lead to NNRTI resistance because of long half-life; consider step-wise discontinuation or substitution of PI.

HAART in individuals with an OI increases the risks of subtherapeutic antiretroviral exposure and the development of resistance, or supratherapeutic levels resulting in adverse effects. Recommendations advise starting HAART 2 to 4 weeks after initiating treatment of the OI.³⁰

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