A Prospective Study on Impact of Early Initiation of Antiretroviral Therapy in Human Immunodeficiency Virus-Positive Adults on Immunological Status and Adverse Events.

INTRODUCTION: Antiretroviral therapy (ART) is a lifelong commitment for human immunodeficiency virus infection (HIV)-positive patients. The patients may develop early adverse drug reactions (ADRs) during the first 3 months of treatment, especially when they have advanced HIV disease with low CD4 counts.
MATERIALS AND METHODS: The present study was a prospective observational study that took place from January 2017 to July 2017 at ART center, Government Medical College, Amritsar, Punjab, India. The primary objective of the study was to evaluate ADRs to ART and immunological status in HIV-positive patients. The patients received ART regimens as per the National AIDS Control Organization guidelines. The sample included both ART-naïve and ART-experienced HIV-positive patients. The causality of reported ADRs assessed according to the World Health Organization guidelines. The study was conducted after taking approval from the Institutional Ethics Committee, Government Medical College, Amritsar, and informed consent from the patients. Data were analyzed statistically using Chi-square test, and P < 0.05 was considered statistically significant.
RESULTS: Out of total 350 patients screened during study period, 84 patients reported with confirmed ADRs. The most widely used treatment regimen was tenofovir + lamivudine + efavirenz (59.52%). Central nervous system (19.05%)-, renal (14.29%)-, and immune reconstitution inflammatory syndrome (14.29%)-related ADRs were mostly reported. The causality assessment revealed insignificant P value (Chi-square = 8.656 and P = 0.07), with 19.05% probable and 80.95% possible ADRs.
CONCLUSIONS: The CD4 count <200/μl at the initiation of ART and treatment duration <1 year proved to be predictors for ADRs. Early initiation of ART in HIV-positive patients can improve immunological status and decrease in the incidence of ADRs.

INTRODUCTION

Combination antiretroviral therapy (ART), also known as highly active ART, is the mainstay of management of patients with human immunodeficiency virus (HIV) infection.[1] Antiretroviral (ARV) therapy is potent, convenient, and usually well tolerated, capable of reducing HIV blood concentration to undetectable values within a few weeks from treatment initiation and of inducing a robust and sustained CD4 T-cell gain.[2] At present, all international guidelines recommend treatment of all HIV-positive patients irrespective of their CD4 count.[3456] According to latest recommendations, early initiation of antiretroviral therapy (ART) is needed to reduce morbidity and mortality from HIV infection and to reduce HIV transmission.[7] It is now strongly evident from various randomized control trials that initiating ART at higher CD4 count entails individual benefit in addition to population benefit by preventing HIV transmission to non-HIV-infected partners.[89] The major challenge to the success of therapy is the emergence of adverse drug reactions (ADRs) related to ART that lead to modification of ART and also affect treatment adherence.[10111213] ART-associated ADRs may range from acute and potentially life threatening to chronic and insidious conditions. Serious life-threatening reactions such as hypersensitivity reaction, symptomatic hepatotoxicity, and severe cutaneous drug reactions warrant immediate discontinuation of ARV drugs and switching over to alternative regimen without overlapping toxicities. The non-life-threatening toxicities such as urolithiasis and renal tubulopathy are addressed by substituting the presumed causative ARV agent without interrupting the ART. For chronic non-life-threatening adverse events such as dyslipidemia, either switching the potentially causative ARV with another ARV agent or managing the adverse event by pharmacological or nonpharmacological interventions is done. These management strategies for adverse events must be individualized for a specific patient.[14] The goal of the present study was to evaluate the frequency and nature of adverse events in HIV-positive patients undergoing ART at ART center in Government Medical College, Amritsar.

MATERIALS AND METHODS

This was a prospective observational cohort study conducted at ART center, Government Medical College, Amritsar. The study was conducted from January 2017 to July 2017. The cohort included both ART-naïve and ART-experienced HIV-positive patients undergoing treatment at ART center. The sample size was determined by the prevalence of ADRs due to ART in a study conducted at a tertiary care center in East India, by taking critical value at 95% confidence interval and degree of precision 0.05.[15] The data were collected from the HIV-positive patients reporting to ART center. ADRs were diagnosed and classified as per the National AIDS Control Organization (NACO) guidelines, based on clinical presentations and laboratory investigations. Among all patients who received ART regimens and followed up as per the NACO guidelines, those presented with confirmed ADRs diagnosed on the basis of clinical examinations and laboratory investigations were consecutively recruited in the study. Patients were followed up monthly as a part of regular treatment.

The primary outcome of the study was to assess the frequency and nature of adverse events in HIV-positive patients undergoing ART. Immunological status was assessed by CD4 counts. Informed consent was taken from each patient enrolled in the study, and approval from the Institutional Ethics Committee, Government Medical College, Amritsar, was obtained.

Inclusion criteria

To assess the ART-related side effects, all HIV male, female, and transgender participants above 18 years were included in the study. Both ART-naïve and ART-experienced patients currently undergoing treatment were recruited. Only those patients with ADR confirmed based on clinical presentation and diagnostic parameters were considered for recruitment in the study.

Exclusion criteria

All HIV-positive patients <18 years were excluded from the study. Current pregnancy or lactating females were not included in the study. The HIV-positive patients not taking ART were not included in the study.

The diagnosis of HIV positivity was based on serological test and enzyme-linked immunosorbent assay, by detecting HIV-specific antibody. The patients were assessed for clinical signs and symptoms of ADRs by taking history and performing complete physical examination. Patients were further categorized according to the World Health Organization (WHO) clinical staging [Annexure 1]. The laboratory parameters considered for the evaluation of ADRs were complete blood count, liver function test, renal function test, lipid profile, urine routine and microscopic examination, and CD4 count to assess the immunological status of the patients. Some imaging tools such as chest X-ray and ultrasound whole abdomen were considered to assess the findings, when needed. The causality of reported ADRs assessed according to the WHO guidelines.

RESULTS

The present study enrolled 350 HIV-positive patients who presented to ART center from January 2017 to July 2017. Out of 350 patients, 84 with confirmed ADRs who met inclusion and exclusion criteria were considered for final analysis. Out of 84 HIV-positive patients recruited, 45 and 39 were male and female, respectively [Figure 1].

Figure 1

Gender distribution

Patients who presented with ADRs were on one of the four ART regimens: tenofovir + lamivudine + efavirenz (TLE), zidovudine + lamivudine + nevirapine (ZLN), zidovudine + lamivudine + atazanavir (ZL + ATZr), tenofovir + lamivudine + atazanavir (TL + ATZr), and zidovudine + lamivudine + efavirenz (ZLE). Patients who developed ADR were mostly on TLE regimen (59.52%) [Figure 2].

Figure 2

Antiretroviral therapy regimens

Central nervous system (CNS) (19.05%)-, renal (14.29%)-, and immune reconstitution inflammatory syndrome (IRIS) (14.29%)-related ADRs were mostly reported. Other ADRs included drug-induced hyperbilirubinemia (9.52%), anemia (8.33%), peripheral neuropathy (8.33%), skin reactions (7.14%), lipodystrophy (4.76%), hepatitis (4.76%), gynecomastia (3.57%), osteoporosis (2.38%), myalgia (1.19%), atypical diarrhea (1.19%), and joint pain (1.19%) [Figure 3].

Figure 3

Adverse drug reaction reported

Severity of ADRs was assessed as 73.81% mild, 11.90% moderate, and 14.29% severe grades [Figure 4].

Figure 4

Severity of adverse drug reactions

The causality assessment according to the WHO guidelines revealed 19.05% probable and 80.95% possible ADR categories [Figure 5], with chi-square = 8.656 and P = 0.07 [Table 1].

Figure 5

World Health Organization causality assessment

Table 1

WHO causality assessment

WHO causality categories	WHO causality assessment						Percentage	χ2, P
	TLE	ZLN	ZL + ATZr	TL + ATZr	ZLE	Total
Probable	7	3	1	3	2	16	19.05	8.656, 0.07
Possible	43	17	0	4	4	68	80.95

TLE: Tenofovir + lamivudine + efavirenz, ZLN: Zidovudine + lamivudine + nevirapine, ZL + ATZr: Zidovudine + Lamivudine + Atazanavir, TL + ATZr: Tenofovir + Lamivudine + Atazanavir, ZLE: Zidovudine + Lamivudine + Efavirenz, WHO: World Health Organization

Among these patients, majority had CD4 count < 200/μl (47.62%) at the initiation of ART and between 200 and 499/μl when they reported with ADRs. Most of the patients were asymptomatic and found to be in the WHO clinical stage I at the initiation of ART (51.19%). Patients were mostly observed to be in WHO clinical stage I even when they developed ADRs (77.38%). However, P values for CD4 count and WHO clinical stage, at baseline and during episode of ADRs, were insignificant [Table 2]. Most of the patients required no post-ADR intervention (73.81%). However, 15.48% required substitution of therapy [Table 2].

Table 2

Patients characteristics in different treatment groups

Patients characteristics	Treatment regimen (TLE)	Treatment regimen (ZLN)	Treatment regimen (ZL + ATZr)	Treatment regimen (TL + ATZr)	Treatment regimen (ZLE)	Percentage	χ2, P
Number of patients	50	20	1	7	6
Gender
Male	24	13	0	3	5	53.57	5.29, 0.259
Female	26	7	1	4	1	46.43
CD4 cell count categories (baseline)
>500	4	1	0	0	1	7.14	8.208, 0.413
200-499	27	6	0	2	3	45.24
<200	19	13	1	5	2	47.62
CD4 cell count categories (at ADR)
>500	11	5	0	0	1	20.24	8.502, 0.386
200-499	24	13	1	5	5	57.14
<200	15	2	0	2	0	22.62
WHO clinical stage (baseline)
I	27	7	0	4	5	51.19	14.590, 0.265
II	3	4	0	0	0	8.33
III	13	8	1	3	0	29.76
IV	7	1	0	0	1	10.71
WHO clinical stage (at ADR)
I	34	19	0	6	6	77.38	20.738, 0.054
II	7	0	1	0	0	9.52
III	3	1	0	1	0	5.95
IV	6	0	0	0	0	7.14
Types of ADRs
Anemia	0	3	0	1	3	8.33
Atypical diarrhea	1	0	0	0	0	1.19
CNS-related side effects	15	1	0	0	0	19.05
Drug-induced hyperbilirubinemia	0	2	1	3	2	9.52
Gynecomastia	2	0	0	0	1	3.57
Hepatitis	2	2	0	0	0	4.76
IRIS	11	1	0	0	0	14.29
Joint pain	1	0	0	0	0	1.19
Lipodystrophy	0	4	0	0	0	4.76
Myalgia	1	0	0	0	0	1.19
Osteoporosis	2	0	0	0	0	2.38
Peripheral neuropathy	1	6	0	0	0	8.33
Renal derangement	9	1	0	2	0	14.29
Skin reaction	5	0	0	1	0	7.14
Severity of ADRs
Mild	40	16	0	3	3	73.81	15.106, 0.057
Moderate	6	2	0	1	1	11.90
Severe	4	2	1	3	2	14.29
Post-ADR intervention
None	40	16	0	3	3	73.81
Dose modify	4	0	0	0	0	4.76
Substitute	4	4	1	1	3	15.48
Switch	1	0	0	1	0	2.38
Stop	1	0	0	2	0	3.57

ADRs: Adverse drug reactions, CNS: Central nervous system, IRIS: Immune reconstitution inflammatory syndrome, WHO: World Health Organization, TLE: Tenofovir + lamivudine + efavirenz, ZLN: Zidovudine + lamivudine + nevirapine, ZL + ATZr: Zidovudine + Lamivudine + Atazanavir, TL + ATZr: Tenofovir + Lamivudine + Atazanavir, ZLE: Zidovudine + Lamivudine + Efavirenz

The mean treatment duration for the development of ADRs was 2.6 ± 2.88 (mean ± standard deviation) years. Most of the patients developed ADRs within 1 year of treatment (45.24%) [Table 3]. The mean treatment duration for development of ADRs for the patients on TLE, ZLN, ZL + ATZr, TL + ATZr, and ZLE was 1.23 ± 1.87, 4.33 ± 2.58, 2.60 ± 1.83, 6.96 ± 3.55, and 5.80 ± 0.00 years, respectively. P values for treatment duration for the development of ADRs were significant except for patients on ZLE regimen [Table 4].

Table 3

Mean treatment duration at ADRs

Treatment duration (year)	Number of patients	Percentage of patients	Mean treatment duration at ADRs (mean±SD)
≤1	38	45.24	2.6±2.88
>1-≤5	29	34.52
>5-≥10	16	19.05
>10	1	1.19

ADRs: Adverse drug reactions, SD: Standard deviation

Table 4

Mean treatment duration in different treatment groups

Treatment duration (year)	Treatment regimen (TLE)	Treatment regimen (ZLN)	Treatment regimen (ZL + ATZr)	Treatment regimen (TL + ATZr)	Treatment regimen (ZLE)
Mean±SD	1.23±1.87	4.33±2.58	2.60±1.83	6.96±3.55	5.80±0.00
P	0.000	0.000	0.021	0.019	Nonsignificant

TLE: Tenofovir + lamivudine+efavirenz, ZLN: Zidovudine + lamivudine + nevirapine, ZL + ATZr: Zidovudine + Lamivudine + Atazanavir, TL + ATZr: Tenofovir + Lamivudine + Atazanavir, ZLE: Zidovudine + Lamivudine + Efavirenz, SD: Standard deviation

DISCUSSION

According to the WHO, almost 20.9 million people were receiving ART by the mid-2017.[16] ADRs have been reported with all ARV drugs; however, overall benefits of viral suppression and improved immune function far outweigh the risk.[17] In the present study, 84 HIV-positive patients on ART reported with ADRs during the study period of 7 months. ADRs reported in the present study are less as compared to previous studies.[1318] This shows that newer ART regimens are associated with fewer and less ADRs as compared to the past.[17]

In the present study, maximum ADRs were experienced by the patients on TLE regimen, which may be attributed to larger number of patients receiving this combination as first-line therapy.[19] ADRs related to CNS (19.05%), renal (14.29%), and IRIS (14.29%) were mostly reported. Other system-related ADRs found were drug-induced hyperbilirubinemia (9.52%), anemia (8.33%), peripheral neuropathy (8.33%), skin reaction (7.14%), lipodystrophy (4.76%), hepatitis (4.76%), gynecomastia (3.57%), osteoporosis (2.38%), myalgia (1.19%), atypical diarrhea (1.19%), and joint pain (1.19%), as found in a prospective observational study conducted for 6 months to study ADRs in 235 AIDS patients on ART, though incidence of ADRs reported was less in this study.[13]

Patients mostly experienced CNS-related ADRs such as vivid dreams, insomnia, and mild depression as most of them were on TLE regimen. Efavirenz is documented for causing CNS-related ADRs.[17] In a retrospective cross-sectional observational study, conducted for 18 months to study type of ADRs and causality, severity and preventability assessment of 197 spontaneously reported ADRs found neuropsychiatric (29.44%)-related ADRs as most common followed by gastrointestinal-hepatobiliary-related ADRs (24.87%).[20]

Most of the ADRs reported were of mild grade (73.81%), which required no post-ADR interventions in the form of discontinuation of therapy, dose modification, drug substitution, or switch to other regimens.[21] However, moderate (11.90%) and severe grade (14.29%) ADRs required post-ADR interventions as per the NACO guidelines.[21]

According to the WHO causality assessment, mostly ADRs were possible (80.95%) and rest were probable (19.05%). However, P value was insignificant for ADR categories. Similar results on causality assessment were obtained in a prospective observational study, conducted for a period of 6 months to study type and risk factors for ADRs due to ART in 158 patients evaluated.[22]

The present study did not show any association between CD4 count and clinical staging with ADRs, while other studies have associated low CD4 count as risk factor for ADRs.[2324] However, majority of the patients had CD4 count <200/μl (47.62%) at the initiation of ART and between 200 and 499/μl when they reported with ADRs.

Most of the patients developed ADRs early in course of treatment. Treatment duration was significantly associated with ADRs in the present study, except for the patients on ZLE. In a prospective observational study conducted for a period of 1 year in 280 patients, to monitor ADRs associated with various ART regimens, most of the ADRs were observed within 6 months of initiation of therapy.[25]

Limitations

The present study was conducted for a short period at a single center with a small sample size. Moreover, data for adherence were lacking that could affect ADRs due to inadequate treatment uptake. Detailed investigations could not be ordered other than routine one due to limited resource setting.

CONCLUSIONS

Effective ART is required for viral suppression and improvement of immune status, but risk of ADRs is also associated with it. ADRs in HIV-positive patients on ART possess a huge challenge in lifelong continuation of therapy. Regular monitoring of ADRs is important for early detection and prevention of ADRs. Low CD4 count <200/μl at the initiation of ART and treatment duration <1 year was found to be a predictor for ADRs. Early initiation of ART led to an improvement in immunological status, slowed progression to AIDS, and decrease in the incidence of ADRs.

Financial support and sponsorship

Department of Health Research (Ministry of Health and Family Welfare), Indian Council of Medical Research (ICMR), New Delhi.

Conflicts of interest

There are no conflicts of interest.

Annexure 1

World Health Organization clinical staging of Human immunodeficiency virus disease in adults and adolescentsa

WHO staging	Clinical features
Clinical Stage 1	AsymptomaticPersistent generalized lymphadenopathy
Clinical Stage 2	Moderate unexplained weight loss (<10% of presumed or measured body weight)Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, and pharyngitis)Herpes zosterAngular cheilitisRecurrent oral ulcerationPapular pruritic eruptionFungal nail infectionsSeborrheic dermatitis
Clinical Stage 3	Unexplained severe weight loss (>10% of presumed or measured body weight)Unexplained chronic diarrhea for longer than 1 monthUnexplained persistent fever (intermittent or constant for longer than 1 month)Persistent oral candidiasisOral hairy leukoplakiaPulmonary tuberculosisSevere bacterial infections (such as pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, and bacteremia)Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitisUnexplained anemia (<8 g/dl), neutropenia (<0.5×109/l), and/or chronic thrombocytopenia (<50×109/l)
Clinical Stage 4	HIV wasting syndromePneumocystis jirovecii pneumoniaRecurrent severe bacterial pneumoniaChronic herpes simplex infection (orolabial,genital, or anorectal of>1-month duration or visceral at any site)Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs)Extrapulmonary tuberculosisKaposi sarcomaCytomegalovirus infection (retinitis or infection of other organs)Central nervous system toxoplasmosisHIV encephalopathyExtrapulmonary cryptococcosis, including meningitisDisseminated nontuberculous mycobacterial infectionProgressive multifocal leukoencephalopathyChronic cryptosporidiosisChronic isosporiasisDisseminated mycosis (extrapulmonary histoplasmosis and coccidioidomycosis)Lymphoma (cerebral or B-cell non-Hodgkin)Symptomatic HIV-associated nephropathy or cardiomyopathyRecurrent septicemia (including nontyphoidal Salmonella)Invasive cervical carcinomaAtypical disseminated leishmaniasis

Source: Adapted from the WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children. Geneva: World Health Organization; 2007. Available from: http://www.who.int/hiv/pub/guidelines/arv2013/annexes/WHO_CG_annex_1.pdf. aIn the development of this table, adolescents were defined as 15 years or older. HIV: Human immunodeficiency virus, WHO: World Health Organization