|Ahead of print publication
“A randomized controlled single blind clinical trial to evaluate effectiveness of empirical treatment with albendazole in delaying disease progression among human immunodeficiency virus positive antiretroviral therapy naïve patients at an antiretroviral therapy center of a tertiary care hospital”
Apoorva Sindhu1, TS Ramakrishnan1, VK Sashindran2, Anurag Khera1
1 Department of Community Medicine, AFMC, Pune, Maharashtra, India
2 Department of Medicine, AFMC, Pune, Maharashtra, India
|Date of Submission||11-Jul-2019|
|Date of Decision||22-Aug-2019|
|Date of Acceptance||27-Aug-2020|
|Date of Web Publication||01-Apr-2021|
Graded Spl (PSM), DADH, HQ 19 Inf Div, C/O 56 APO, Pin 908419
Source of Support: None, Conflict of Interest: None
Introduction: Parasitic opportunistic infections are widely accepted to accelerate the progression of human immunodeficiency virus (HIV) infection to acquired immunodeficiency syndrome. A large number of interventions are needed to delay HIV progression and improve the health status of HIV patients. The cheapest, simplistic, and practical intervention in a resource-limited setting like India, where HIV and helminth co-infection is common, is deworming. Methodology: The participants were assesses for their eligibility and recruited into two study arms. Both groups were followed for 1 year. CD4 count was assessed at baseline, 6 months, and 12 months. Study participants assigned to the treatment group were treated at 0, 3, 6, and 9 months with tablet Albendazole (400 mg) for 3 days. Study participants assigned to the control arm were given Placebo (Tablet Calcium 500 mg) for 3 days at 0, 3, 6, and 9 months. Results: In both treatment group and the placebo control group, the mean CD4 count was found to be declining. The mean decline in CD4 count of the intervention group was 72 cells/mm3 at 6 months and 85 cells/mm3 at 1 year. Similarly, the mean decline of CD4 count in the control group was 94 cells/mm3 at 6 months and 120 cells/mm3 at 1 year. We found that the mean difference in CD4 count between the intervention group and control group was −31.66 cells/mm3, −9.98 cells/mm3 and 24.87 cells/mm3 at baseline, 6 months, and 1 year, respectively. Our results are consistent with various other studies conducted in Uganda and Africa, as well as Cochrane systematic review. Conclusion: We conclude that empirical treatment with Albendazole in HIV-positive antiretroviral therapy naïve patients has no significant influence on delaying the progression of HIV disease.
Keywords: Helminths, human immunodeficiency virus, human immunodeficiency virus helminthic co-infection, randomized controlled trial
|How to cite this URL:|
Sindhu A, Ramakrishnan T S, Sashindran V K, Khera A. “A randomized controlled single blind clinical trial to evaluate effectiveness of empirical treatment with albendazole in delaying disease progression among human immunodeficiency virus positive antiretroviral therapy naïve patients at an antiretroviral therapy center of a tertiary care hospital”. J Mar Med Soc [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=312888
| Introduction|| |
The prevalence of human immunodeficiency virus (HIV) in India is >20.89 lakh people. As per the estimates, >10 lakh people are co-infected with helminths. The helminthic infection causes considerable immune system stimulation. Increased levels of eosinophilia and immunoglobulins are a common feature of helminthic infection. Hence, the hypothesis that co-infection with HIV and helminths may have a role in pathogenesis and HIV disease progression. Findings from several studies have shown that the treatment of opportunistic infections associated with HIV disease might delay HIV disease progression. Therefor this in this study we tried to see the Effectiveness of Empirical Treatment with Albendazole in Delaying Disease Progression among HIV Positive ART Naïve Patients by means of RCT.
To measure HIV disease progression in terms of mean difference in CD4 count between HIV positive antiretroviral therapy (ART) naïve patients on empirical treatment with Albendazole as compared to HIV-positive ART naïve patients on placebo.
| Methodology|| |
A total of 437 ART naïve adults who were enrolled at ART center were assessed for their CD4 count and clinical staging. Two hundred and fifty-four patients met the inclusion criteria and 174 patients were excluded because of low CD4 count and 09 patients were excluded because they refused to participate. Eligible participants were enrolled in the study if they provided informed consent, if they were serologically confirmed cases of HIV, if the participants were >18 years of age and if the participants had a CD4 count of ≥500 cells/μL. Individuals were excluded if they had any opportunistic infection. Individuals were also excluded if they presented with advanced stages of HIV disease, which is defined as stage 3 or 4 of the revised World Health Organization criteria. Sample size was calculated using Power of study 80%, α error 5%, standard deviation (SD) σ = 92 (treatment group) and 78 (control group), Effect size d = 35 (mean difference in CD4 count between the intervention group and study group). Based on the above, the sample size was calculated to be n = 73 in each arm. Adding 10% loss to follow-up, 80 participants were enrolled in each arm. Study participants were selected using simple random sampling. [Figure 1] shows complete Consort chart depicting enrollment, allocation, follow-up and analysis of study participants. The sampling frame was obtained from the database of the ART center where the study was conducted. All HIV-positive patients with CD4 count >500 cells/mm3 and satisfied the inclusion criteria were included in the sampling frame. Out of the 254 eligible participants, a random sample of 160 ART naïve patients were selected using computer generated random numbers between 1 and 254, and the first 160 were included in the study. Computer generated random number table containing numbers from 1 to 160 was used for randomization. We included even numbers in the intervention group and odd numbers in the control group. The study was single-blind trial with participants blind to group allocation. We used opaque envelopes to hide the randomization sequence and prevent allocation bias.
Participants who were found to be eligible were recruited into the treatment group and the placebo group. Both treatment and placebo groups were followed for 1 year. CD4 count was assessed at baseline, 6 months, and 12 months. Participants in the treatment group were treated with a 3 days course of Tablet Albendazole (400 mg) at 0, 3, 6, and 9 months. Participants in the placebo group were given placebo (Tablet Calcium 500 mg) for 3 days at 0.3, 6, and 9 months. Consumption of the first dose was directly observed by the investigator, and adherence to the treatment regimen was assessed by participant interviews. All participants recruited into the study were clinically examined at each scheduled visit and requisite primary medical care was given as indicated. As the participants were being recruited, sociodemographic, behavioral, and medical data were collected using a structured interview and by obtaining information through the patient card. During the follow-up visits, participants were evaluated for disease progression by using basic clinical and laboratory parameters. The analysis was carried out as per intention to treat analysis, i.e., analysis was carried out by assigning all participants as per the study arm to which they originally belonged. The baseline characteristics between participants who received Tablet Albendazole and those who received placebo during the study period were compared. Chi-square test was applied to compare the categorical variables between the two study groups. Continuous variables assessed in the study were compared between the two groups using Students t-test for data, which were normally distributed, and Mann–Whitney U-test for data which were not normally distributed. Ethical clearance was obtained from the institutional ethical committee for all study procedures. Consistent with national guidelines, the study was registered with the Clinical Trials Registry of India. Registration number is CTRI/2018/05/014237.
| Results|| |
The data entry was carried out using Microsoft excel. Analysis was carried out by using SPSS version 20 statistical software SPSS Statistics for Windows, version 22.0 (SPSS Inc., Chicago, Ill., USA).
Mean CD4 count at enrolment and at follow-up of 6 months and 1 year are shown in [Table 1]
The distribution of categorical variables was assessed using Chi-square test between the groups. The difference between the intervention group and control group with respect to age, marital status, place of residence, education, occupation, income, or socioeconomic status was not found to be statistically significant. Data are shown in [Table 2].
|Table 2: Comparison of various baseline characteristics between intervention and control group|
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Chi-square test was used to determine the distribution of characteristics influencing intestinal helminthic infestation between the groups. There was no significant difference between the intervention group and control group with respect to the type of house, location of toilet, type of toilet, and source of water. Data are shown in [Table 3].
|Table 3: Comparison of characteristics influencing intestinal helminthic infestation in intervention and control group|
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The distribution of risk factors associated with HIV infection between the treatment groups and control group was determined by using Chi-square test. The difference between the intervention group and control group with respect to the history of high-risk behavior, history of blood transfusion at any time during the entire life span, history of HIV in family, and history of tattoo was not found to be statistically significant. Data are shown in [Table 4].
|Table 4: Comparison of characteristics influencing HIV infection in intervention and control group|
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Unpaired t-test was used to determine the distribution of continuous variable between the intervention group and control group. There was no significant difference between the intervention and control group with respect to age, BMI, income, and duration since diagnosis of HIV in months. The mean difference of various variables is shown in [Table 5].
|Table 5: Mean difference between continuous variables in the intervention and control group|
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Mann–Whitney U-test was used to determine the mean difference in CD4 count at enrolment and at follow-up of 6 months and 1 year. The difference between the two groups for mean CD4 count was not statistically significant. Mean difference of CD4 count is shown in [Table 6].
|Table 6: Mean difference between CD4 count at enrolment and follow-up of intervention and control group|
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| Discussion|| |
The mean age of study participants was 36.63 ± 10.84 in intervention group and 32.83 ± 9.66 in the control group. This finding was similar to various studies conducted throughout the country as well as in Ethiopia.,,,, The findings of our study are similar to data as published by the National Acquired Immunodeficiency Syndrome Control Organization , which has reported that 89% of the cases were also in the age group of 15–44 years as per the national statistics.
Majority of the participants in our study, 36.3% in intervention group and 31.3% in control group, had education up to high school and 21.3% in intervention group and 23.8% in control group were illiterate. According to a study conducted in Mangalore shows that 18.62% were illiterate and 81.37% were literate. As per the data, we can come to this conclusion that individuals with higher education have some protection against HIV owing to better awareness and practices. An individual who is educated below the secondary education level or who is illiterate may not have adequate knowledge regarding the prevention of HIV.
Majority of the participants in the study belonged to the lower middle class. 57.5% of the patients in the intervention group and 50% of the patients in the control group belonged to the lower middle class as per the Kuppuswamy scale. These findings were the same as a study conducted in Maharashtra where 35.58% of the individuals belonged to the lower middle class. This shows that when individuals in the reproductive age group are affected, it increases the economic burden, decreases the standard of living, and affects the overall development of the individual, family, community, and the country.
In our study, 10% of the participants in the intervention group and 8.8% of the participants in the control group gave a history of blood transfusion at any time during their lifetime. This was found to be higher than that seen in various other studies conducted throughout the country.,,, This difference might be because of better awareness from being in the urban locality or because of differences in the sample size. However, the difference in the distribution of this risk factor between the two groups was not statistically significant.
In this study, we found that the mean difference in CD4 count between the intervention group and control group was −31.66 cells/mm3, −9.98 cells/mm3, and 24.87 cells/mm3 at baseline, 6 months and 1 year, respectively.
The results of our study were similar to other studies conducted in Africa. As per a prospective cohort study done in Uganda by Brown et al., there was a mean decrease of CD4 count by 45.7 cells per cu mm (SD 129.7 cells per cu mm). The study conducted by Brown et al. evaluated the effects of antihelminthic on the course of HIV infection. The assessment of the difference in CD4 count and the difference in HIV RNA in HIV infected individuals who either had helminthic co-infection or did not have helminthic co-infection over a span of 6 months was the primary objective of this study. As per a study conducted by Lankowski et al. on Ugandan patients, treatment with antihelminthic medication did not result in any statistical difference in CD4 cell count during the follow-up period of 1st year on ART (b = 42.8; 95% confidence interval [CI], 22.1–87.7) or after the follow-up period of 1st year of ART (b = 29.9; 95% CI, 224.1-4.4) The study results showed that treatment with antihelminthic medication has no significant benefit in improving the CD4 count subsequently. A multicentric randomized controlled trial (RCT) conducted in Africa suggests that there is no effect of empirical deworming in delaying HIV disease progression in adults. As per a Cochrane systematic review done by Walson et al., treating helminthic infection has no significant effect on fall in CD4 count, clinical staging of HIV disease, or the mortality due to HIV infection.
Another randomized control study conducted by Walson et al. in Kenya showed an increase in mean CD4 count of + 109 cells per cu mm (95% CI + 38.9 to + 179.0) and P value of 0.003. However, the study was done by predetermining the HIV and soil-transmitted helminthic infection in the participants and follow-up period was 12 weeks. As per a meta-analysis conducted by Walson et al., treating helminth infection in HIV infected individuals had beneficial effects on the markers of HIV disease progression. The primary objective of this study was to determine if treating helminths infection in individuals who are infected with HIV can prolong the progression of HIV, which was determined by changes in CD4 cell count, viral load, or clinical disease progression. Three RCTs were included in the study. All three trials showed that treating helminth infection had beneficial effects on markers of HIV disease progression. When data from these trials were pooled, the analysis demonstrated a significant benefit of deworming on both plasma HIV RNA and CD4 counts. However, similar beneficial effects of empirical deworming were not found in our study.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]