Clinico-Epidemiologic Attributes of 515 Persons Living With Human Immunodeficiency Virus Infection/Acquired Immunodeficiency Syndrome on Antiretroviral Therapy: A Cross-Sectional Study from a Tertiary Care Centre of North India.

Objectives: To study the clinico-epidemiologic attributes of persons living with HIV/AIDS on highly active antiretroviral therapy (HAART).
Methods: Clinico-epidemiological details, CD4 counts, previous illness and mucocutaneous diseases were studied in 515 persons living with HIV/AIDS on HAART.
Results: The study comprised 250 (48.5%) males and 265 (51.5%) females aged between 10 and 79 (mean 38.9) years. The 196 (38%) males were drivers, staying-alone laborers/self-employed, and 253 (49.1%) females were homemakers. All were on HAART for one month to 9 years. Heterosexual transmission was noted in 478 (92.8%) individuals. The 274 (53.5%) individuals had 200-350 CD4 cells/mm3 counts, whereas it was <200 cells/mm3 in 88 (17.2%) individuals. Candidiasis (in 48), dermatophytoses (n = 23), herpes labialis (n = 13), herpes zoster (n = 12), seborrheic dermatitis (n = 29), generalized pruritus (n = 22), and xerosis in 20 individuals were the most common dermatoses. Most dermatoses occurred with 200-350 CD4 cells/mm3. Adverse drug reactions from antiretroviral therapy (ART) and concurrent therapies also occurred. Conclusions: Although most of our patients had mild HIV-associated dermatoses while on HAART, adverse drug reactions from HAART or concurrent therapies themselves remain a potential risk. Nevertheless, knowledge of these aspects will help planning for comprehensive health care envisaged in the National AIDS Control Program phase IV. Copyright:

Human immunodeficiency virus infection (HIV)/acquired immunodeficiency syndrome (AIDS) is a significant public health problem worldwide and particularly in Africa and developing nations of South-East Asia. Although the disease prevalence is low, India still accounts for nearly the third largest HIV-infected population in the world, only next to South Africa and Nigeria. With an estimated adult (15–49 years) prevalence of 0.27% in 2015, the National AIDS Control Organization (NACO) estimates 21.17 lakhs persons living with HIV/AIDS in India.[1] The metropolitans and states such as Andhra Pradesh, Maharashtra, Orissa, Tamil Nadu, and the northeastern states share the major burden of the HIV pandemic. Himachal Pradesh, with an approximately 70-lakh population, had an estimated 5723 (approximately) persons living with HIV/AIDS in 2015 (adult prevalence 0.1%).[2] HIV infection can present with a wide variety of clinical (systemic and cutaneous) manifestations even during treatment with highly active antiretroviral therapy (HAART). HIV-related cutaneous diseases can present signs in approximately 40–96% of patients during the disease course.[345678] An increased prevalence of HIV-related mucocutaneous diseases acts as a marker of underlying alteration in immune status associated with decreasing CD4 counts.[9] These can range from common opportunistic infections to inflammatory dermatoses to drug reactions and neoplasia with varied and unusual manifestations leading to significant morbidity and poor quality of life. However, with approximately 15.8 million people having access to HAART, the quality of life has dramatically improved and prolonged the life of the HIV infected world over. Hence, adequate knowledge about the profile of HIV- or HAART-associated comorbidities is imperative for their long-term prevention and management, especially when treatment coverage is likely to increase with the current strategy of initiating HAART in all HIV-positive individuals irrespective of CD4 counts. Himachal Pradesh has low disease prevalence, with four of its 12 districts placed in category C and others in category D (low prevalence) by the NACO.[10] However, such data are lacking in this state since most studies report only HIV-related mucocutaneous diseases.[3456789] The study will help in planning comprehensive health care for affected persons envisioned in the National AIDS Control Program (NACP) phase IV.

Materials and Methods

This cross-sectional, observational study comprised 515 persons living with HIV/AIDS (old and newly diagnosed) registered at institute affiliated antiretroviral therapy (ART) center and consecutively attending the clinic for consultation/drug supply on any day between October 2016 and March 2017. After informed written consent and assuring confidentiality, their sociodemographic details, last recorded CD4 counts, and previous illness (if any) were noted from the ART record booklet after clinical history. In the case of children, the accompanying parent/guardian consented for enrollment. The patients underwent detailed clinical examination for the presence of mucocutaneous diseases attributable to underlying HIV infection or HAART. The diagnosis of various dermatoses was clinical and additional investigations such as KOH mounts, Tzanck smear and skin biopsy was performed when deemed necessary. All patients were provided standard treatment and care.

Results

The studied 515 individuals comprised 250 (48.5%) males and 265 (51.5%) females aged between 10 and 79 (mean 38.9) years [Table 1]. The majority (420 (81.6%)) individuals were aged 20–50 years and 480 (93.2%) individuals were ruralites. Three hundred forty-six (67.2%) individuals were either illiterate, under matric, or school dropouts. The majority 196 (38%) individuals were drivers, staying-alone laborers, and self-employed among males, whereas 253 (49.1%) females were homemakers. Heterosexual contact was the mode of infection in 478 (92.8%) individuals, and all females had acquired the disease from infected spouses. Disease acquisition from other modes was blood transfusion (n = 6) or injection (n = 1). Thirty (5.8%) children/adolescents (18 boys and 12 girls) aged between 10 and 19 years were students and infected from the vertical transmission. All individuals were on regular ART for one month to 9 (mean 3.5) years. Records of last CD4 cell counts were available for 512 individuals, and levels ranged from 9 to 1254 cells/mm3. The majority 274 (53.5%) individuals had CD4 counts of 200–350 cells/mm3, whereas CD4 counts were <200 cells/mm3 in 88 (17.2%) individuals. Four persons (CD4 counts <200, mean 111 cells/mm3) had received treatment for pulmonary tuberculosis in the past. In 359 (69.7%) individuals, the CD4 cell count varied between 11 and 1136 (mean 386.4) cells/mm3.

Table 1

Baseline characteristics of patients

Baseline Characteristics			Number of patients n=515 (%)
Gender		Males	250 (48.5)
		Females	265 (51.5)
		Male:Female	1:1.04
Age		<20 years	30 (5.8)
Range (Mean)		20-50 years	420 (81.6)
10-79 (38.97) years		>50 years	65 (12.6)
Social background		Rural	480 (93.2)
		Urban	35 (6.8)
Education status		Under 10th standard/School drop outs/Illiterates	346 (67.2)
		10th standard or more	169 (32.8)
Occupation	Males	Drivers	106 (20.6)
		Laborers	38 (7.4)
		Self employed	52 (10.1)
		Govt. employed	29 (5.6)
		Defense personnel	07 (1.4)
		Students	18 (3.5)
	Females	House makers	253 (49.1)
		Students	12 (2.3)
Mode of disease acquisition		Heterosexual	478 (92.8)
		Mother to child (Vertical)	30 (5.8)
		Blood transfusion	06 (1.7)
		Injections	01 (0.2)
CD4 cell counts n=512		>500 cells/mm3	150 (29.3)
Range 6-1254 cells/mm3		499-350 cells/mm3	129 (25.2)
		349-200 cells/mm3	145 (28.3)
		<200 cells/mm3	88 (17.2)
Mucocutaneous manifestations		Present	156 (30.3)
		Absent	359 (69.7)

There were 292, both infective and non-infective, mucocutaneous manifestations observed in 156 (30.3%) individuals (average 1.9 dermatoses per person); 82 (52.6%) patients had more than one dermatoses, and two of the three patients with unrecorded CD4 cell counts also showed infective or non-infective dermatosis [Table 2]. The various mucocutaneous manifestations according to CD4 cell counts among these individuals are depicted in Table 3. Overall, a greater number of dermatoses were observed with the decreasing CD4 counts; 117 dermatoses (infective, n = 64; non-infective, n = 53) were seen with <200 cells/mm3 CD4 counts versus 34 (infective, n = 14; non-infective, n = 20 dermatoses) occurring in persons with >500 cells/mm3 CD4 counts.

Table 2

CD4 cell counts and number of patients with or without associated dermatoses

CD4 cell count (cells/mm3) and Number of patients (%)	Number of patients with associated dermatoses n=156 (30.3%)*			No. of patients with no associated dermatoses n=359
	Number of patients with Infective dermatoses	Number of patients with Non-infective dermatoses	Number of patients with infective and non-infective dermatoses
>500 n=150 (29.1)	3	6	17	124
499–350 n=129 (25.0)	3	7	11	108
349-200 n=145 (28.2)	11	18	16	100
<200 n=88 (17.1)	29	17	16	26
Not recorded n=3 (0.6)	1	1	0	1
n=515 (%)	47 (9.1)	49 (9.5)	60 (11.7)	359 (69.7)

*Overall 82 (52.6%) patients had two or more dermatoses

Table 3

Muco-cutaneous manifestations in 156 patients according to CD4 counts

Muco-cutaneous manifestations (number of associated dermatoses)	Number of patients with dermatoses according to CD4 counts (cells/mm3)				Total (%)	Mean CD4 cell count (cells/mm3)	Treatment given
	>500 n=150	499-350 n=129	349-200 n=145	<200 n=88
Infective Dermatoses (n=164)
Candidiasis	3	9	13	24	49 (29.8)	248.1	FCZ
Dermatophytosis*	3	3	14	9	26 (15.9)	394.7	TBF
Pyodermas	1	1	8	10	20 (12.2)	217.4	AmC
Herpes labialis	2	1	5	6	14 (8.3)	384.9	Acyclovir
Herpes Zoster	1	2	6	4	13 (7.9)	356.5	Acyclovir
Common Warts	1	3	4	3	11 (6.7)	408.8	Paring + TCA touch
Scabies	1	2	4	2	9 (5.5)	336.4	Ivermectin
Molluscum Contagiosum	-	1	4	3	8 (4.9)	256.7	Extirpation, TCA cautery
Pityriasis Versicolor	2	1	3	1	7 (4.3)	409.2	FCZ
BT Leprosy	-	-	2	-	2 (1.2)	331	WHO MDT-MB
Oral Hairy Leukoplakia	-	-	-	1	1 (0.6)	36	Acyclovir
Disseminated Histoplasmosis	-	-	-	1	1 (0.6)	33	Amph-B, I.V. f/b ITZ
Total number of infective dermatoses (%)	14 (8.5)	23 (14.1)	63 (38.4)	64 (39)	164 (100)	-	-
Non-Infective Dermatoses (n=128)
Seborrhea or Seborrhoeic dermatitis	5	2	8	13	28 (21.9)	336.9	KTZ 2% shampoo, lotion
Generalized Pruritus	1	4	8	9	22 (17.9)	397.4	Cetirizine
Xerosis	4	5	4	7	20 (15.6)	477.3	Emollients
Hair Loss	1	2	5	4	12 (9.4)	287.4	-
Drug Reactions	1	1	2	5	9 (7.0)	248.9	Change of drug and Treated as per IADVL protocol for ADRs#
PPE	1	1	2	4	8 (6.2)	306.4	Cetirizine
Oral Aphthae	1	1	-	3	5 (3.9)	324.7
Hyper-pigmentation	1	-	2	2	5 (3.9)	454.3	-
Psoriasis	2	1	-	1	4 (3.1)	484.5	CT + SA oint
Dermatitis	1	-	2	1	4 (3.1)	361.2	Topical BMD
Nail Pigmentation	1	-	-	2	3 (2.3)	250.9	-
PLE	-	2	-	-	2 (1.6)	414	Calamine lotion
Trichomegaly of eyelashes			1		1 (0.8)	248	-
Lipoatrophy	1	-	-	-	1 (0.8)	822	-
DLE	-	1	-	-	1 (0.8)	362	Topical BMD
Canities	-	1	-	-	1 (0.8)	437	-
LSC	-	-	-	1	1 (0.8)	39	Topical BMD
PPK	-	-	-	1	1 (0.8)	75	SA3% oint
Total number of non-infective dermatoses (%)	20 (15.6)	21 (16.4)	34 (26.6)	53 (43.8)	128 (100)	-	-
Total number of dermatoses observed in 156 (30.3%) patients	34	44	97	117	292	-	-

Foot Notes: 82 (52.6%) patients had two or more dermatoses. *Dermatophytosis comprised 19 patients with widespread superficial fungal infection and four patients with Tinea unguium. f/b- followed by; PPE – Pruritic papular eruption; DLE – Discoid lupus erythematous; PLE – Polymorphic light eruption; LSC – Lichen simplex chronicus; PPK– Palmoplantar keratoderma. FCZ – fluconazole 200 mg/d x 10 day for candidiasis, 400 mg two doses at 1 week interval for pityriasis versicolor; TBF – terbinafine 250 mg twice daily for 6-8 weeks; AmC –Amoxiclavunate 625 mg 2-3 times daily x 5-7 days; Acyclovir 400 mg thrice daily for herpes simplex and oral hairy Leukoplakia, 800 mg 5 times daily for Herpes zoster x 5–7 days; TCA – trichloroacetic acid 40%; Ivermectin- 200 mcg/kg body weight two doses at 1 week interval in addition to cetirizine 10 mg/day; Amph B, I.V.+ITZ - Amphotericin B (1 mg/kg/d) for 14 days f/b itraconazole (200 mg twice/d) for life. KTZ- ketoconazole; Emollients- Liquid paraffin was prescribed for topical application for xerosis; Cetirizine was prescribed in 10 mg/d dose when needed; CT+SA oint- Coal tar 5% + salicylic acid 3% in ointment; BMD – betamethasone dipropionate 0.05% cream. # Adverse drug reactions were treated as per Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) guidelines[11]

In general, 30 dermatoses (infective, n = 12; non-infective, n = 18) were observed. Superficial fungal infections such as oral or vaginal candidiasis (n = 49), dermatophytoses (n = 26), and pityriasis versicolor (seven individuals) were the most common. Severe hyperplastic oral candidiasis [Figure 1] and widespread tinea corporis occurred in one individual each with <200 CD4 cells/mm3. Viral infections herpes labialis (n = 14), herpes zoster (n = 13), common warts (n = 11) [Figure 2] and molluscum contagiosum (n = 8) were next in order of frequency. Pyoderma in 20 individuals and borderline tuberculoid leprosy (n = 2) were observed. One person each (< 200 CD4 cells/mm3) had oral hairy leukoplakia and disseminated histoplasmosis [Figure 3].

Figure 1

Severe hyperplastic oral candidiasis in a patient with CD4 counts of 72 cells/mm3

Figure 2

Multiple common warts in a patient having CD4 counts of 154 cells/mm3

Figure 3

Disseminated histoplasmosis in a patient having CD4 counts of 53 cells/mm3

Seborrheic dermatitis (n = 28), generalized pruritus (n = 22), and xerosis (n = 20) were the predominant non-infective dermatoses. Hair loss/canities (n = 13) and drug reactions (n = 9) were the other manifestations. Hypersensitivity (Stevens-Johnson syndrome) to nevirapine (n = 3, CD4 counts of 316,168 and 341 cells/mm3) [Figure 4] or tenofovir, cotrimoxazole and isoniazid (n = 1, each with CD4 counts of 563,132 and 351 cells/mm3), mild maculopapular rash (n = 1, CD4 counts 143 cells/mm3) and fixed drug eruption (n = 2, CD4 counts of 157 and 189 cells/mm3) from analgesics were common adverse drug reactions [Table 3]. All these patients recovered well following the immediate withdrawal of the offending drug and oral prednisolone 40 mg/d in tapering doses as per the Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) guidelines.[11] Fixed drug reaction was managed symptomatically with topical betamethasone dipropionate 0.05% cream and oral levocetirizine 5 mg/d. They were advised strict avoidance of the offending drugs in the future. Other disorders attributable to HIV infection were pruritic papular eruptions, cutaneous or nail hyperpigmentation, oral aphthae, lipoatrophy, trichomegaly of eyelashes [Figure 5] and palmoplantar keratoderma [Figure 6]. None had immune reconstitution inflammatory syndrome. HAART led to a good therapeutic outcome in all patients from prescribed treatments.

Figure 4

Nevirapine hypersensitivity syndrome (Stevens-Johnson syndrome) in a patient with CD4 counts of 168 cells/mm3

Figure 5

Trichomegaly of eyelashes

Figure 6

Palmoplantar keratoderma possibly from retention hyperkeratosis

Discussion

The demographic profile of our patients was similar as reported previously.[1213] Slight over-representation of females perhaps reflects their proxy visits during the study period or survival over spouses. The 480 (93.2%) individuals from the rural background reflect the actual demography of 95% rural population and conform with the epidemiological shift of disease to the rural population. Infective and non-infective dermatoses affecting 156 (30.3%) individuals are common among persons living with HIV/AIDS and occur in 40–96% as presenting signs or anytime during the course of disease irrespective of ART.[34567814] However, a higher number of dermatoses were observed with the decreasing CD4 counts; 117 dermatoses were seen with <200 CD4 cells/mm3, and 34 dermatoses occurring with >500 CD4 cells/mm3 was reflective of their altered immune status.[8] Candidiasis observed in our 49 (29.8%) individuals remains the most common infective mucocutaneous manifestation corroborating its reported prevalence of 16–36% among these patients.[345] Severe oral candidiasis in one of our patients was correlating with decreasing CD4 cell counts, as has been suggested previously by Josephine et al.[15] Similarly, increased incidence of widespread dermatophytoses in our patients suggests underlying HIV disease progression and decreasing CD4 cell counts.[516] With declining CD4 cell counts and immunity, herpes simplex infection will manifest with chronic, persistent, tender ulcerations of the lips, perineum or genitalia, whereas herpes zoster will usually be severe, have atypical lesions (necrotic, disseminated), multidermatomal and have prolonged clinical course. Multiple common warts, especially of the periungual variety, may constitute an early sign of immune suppression in HIV infection and so is the presence of numerous facial/atypical/giant molluscum contagiosum lesions persisting for months to years. However, these viral infections in our cases with 200–350 CD4 cells/mm3 and no atypical presentation indicated no significant immune suppression in them. On the other hand, oral hairy leukoplakia (Epstein–Barr virus infection) and disseminated histoplasmosis (Histoplasma capsulatum infection) in one individual each with CD4 counts 36 and 33 cells/mm3, respectively, reflects declining CD4 counts/immunity in them conforming to previous observations.[1718]

A high incidence of seborrheic dermatitis correlated with declining immunity/CD4 cells and was seen in our 28 (21.9%) individuals having <350 CD4 cells/mm3 and corroborated its reported prevalence of 4–83% in Indian studies.[3481920] Severe, intractable, non-responsive pruritus in HIV-seropositive individuals is attributed to impaired immune response due to altered cytokine increased interleukin (IL)‒4 and IL‒5 and decreased interferon-gamma production.[21] It was a common presentation in 45% of 201 HIV-affected persons with severe impairment of quality of life in a study.[15] Similarly, intractable generalized pruritus in our 22 (17.9%) persons and the majority having <350 CD4 cells/mm3 was the second common non-infectious dermatosis. HIV-associated xerosis, attributed to the depletion of the peptidergic innervations affecting the nutrient supply of the upper dermis and diminished substance P innervations of the sweat glands affecting their secretory activity was noted in our 20 (15.6%) individuals corroborating its reported prevalence of 5–75%.[52223] Trichomegaly of eyelashes and palmoplantar keratoderma observed by us are infrequent findings.

Mild-to-severe adverse drug reactions (lichenoid rash, erythema multiforme major, Stevens-Johnsons syndrome and drug reaction, eosinophilia and systemic symptoms (DRESS) from nevirapine, cotrimoxazole and tenofovir among HIV-affected attributed to altered drug metabolism/immune function and polypharmacotherapy are not uncommon and were also noted in our nine (7%) individuals particularly those having <350 CD4 cells/mm3.[23] Lipoatrophy in one of our cases (CD4 >822 cells/mm3) could be from ART rather than the HIV disease per se. Oral aphthae are usually recurrent and more severe in HIV-affected individuals. In our study, they were non-recurrent and less severe, perhaps due to their coincidental occurrence or beneficial effect of HAART, as has been suggested previously.[24] We did not observe Kaposi's sarcoma in any of our patients. The presence of other dermatoses with usual clinical presentations appears fortuitous in our patients.

Limitations

It was a limited period cross-sectional study and included persons registered with only one ART center and visited the center during the study period. This ART center also caters to persons living with HIV/AIDS from adjoining districts. Hence, the study sample is not representative of their actual numbers in the state/district. Demographic data for the state and the district are from the last held 2011 census. Treatment and follow-up were not a part of the study.

Conclusions

Clinico-epidemiologic profile of persons living with HIV/AIDS on ART in this study appears similar to that of newly diagnosed cases. Although most of our patients had mild HIV-associated dermatoses while on HAART, adverse drug reactions from HAART or concurrent therapies themselves remain a potential risk. Nevertheless, knowledge of these aspects will help in planning for comprehensive health care and measures to prevent morbidity/mortality and disease transmission to susceptible uninfected individuals envisaged in NACP phase IV.

Contributor's statement

VKM conceptualized, analyzed, interpreted data, and designed, drafted, and critically evaluated the manuscript for important intellectual content. MG conceptualized, collected, analyzed and interpreted the data and helped in preparing the manuscript draft. RS, ST, SG and RR helped in data collection/compiling and interpretation of clinical data, and literature search. All authors were involved in the preparation and revision of the draft manuscript and have agreed to the final content.

Statement of ethics

The study (Protocol number 20/2016) was approved by Institutional Scientific Protocol Review Committee and Institutional Ethics Committee (Registration number: ECR/490/Inst/HP/2013/RR-16) on May 11, 2016, vide their letter number HFW-HDRPGMC/Ethics/2016. Informed consent was obtained from the patients for enrolment and publication of the clinical material in a scientific journal with the understanding that names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. All patients were provided standard medical treatment and counselling.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.