|Ahead of print publication
Outcomes in HIV patients on two different protease inhibitors on second-line antiretroviral therapy: An observational study
Kuldeep Kumar Ashta1, Sumit Arora2, Niket Verma2
1 Department of General Medicine, Army Base Hospital and Army College of Medical Sciences, New Delhi, India
2 Department of General Medicine, Army College of Medical Sciences, New Delhi, India
|Date of Submission||20-Feb-2021|
|Date of Decision||24-May-2021|
|Date of Acceptance||24-May-2021|
|Date of Web Publication||01-Apr-2022|
Department of General Medicine, Army College of Medical Sciences, Delhi Cantt, New Delhi - 110 010
Source of Support: None, Conflict of Interest: None
Introduction: There were 38 million people living with HIV in the world in 2019, out of which 5.8 million were living within the Asia-Pacific region. Globally, 67% (25.4 million) and within the Asia-Pacific region, 60% (3.5 million) of the individuals living with HIV were accessing anti-retroviral therapy (ART) respectively. Approximately 4% of the patients on ART are on second-line therapy. The aim of this research was to analyze the difference in efficacy and tolerance of boosted lopinavir and boosted atazanavir as part of second-line ART regimens and factors associated with the difference. Materials and Methods: The observational study was conducted at a referral ART clinic of a tertiary care hospital in North India. This was an ambispective study on patients under evaluation for first-line treatment failure. One hundred and fifteen and sixty patients were recruited to lopinavir and atazanavir study groups, respectively. Efficacy was assessed by adequate suppression of plasma viral loads 12 months after starting therapy with protease inhibitors. Results: Both the regimens are highly effective in reducing viral loads. Regarding adverse drug reactions (ADRs), hyperlipidemia and abnormal liver function test (transaminitis) were the most common ADRs in the lopinavir study group, whereas nausea, fever, and indirect hyperbilirubinemia were the most common ADRs in the atazanavir study group. Conclusions: Lopinavir and atazanavir are both highly effective in reducing viral loads and produced comparable CD4 levels post 1-year follow-up.
Keywords: Acquired immunodeficiency syndrome, atazanavir sulfate, lopinavir, protease inhibitors, viral load
| Introduction|| |
There were 38 million people living with HIV (PLH) in the world in 2019, out of which 5.8 million were living within the Asia-Pacific region. Globally, 67% of the individuals living with HIV (25.4 million) were accessing antiretroviral therapy (ART), whereas in the Asia-Pacific region, 60% of the individuals living with HIV (3.5 million) were accessing ART. Roughly 4% of the patients on ART are on second-line therapy.
The WHO advises that second-line ART should consist of a boosted protease inhibitor (PI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs), with at least one of these NRTIs being new to the patient; the second-line ART should consist of the most active drugs available which should be decided on the basis of genotype analysis, treatment history, adverse event history as well as the availability of any additional classes of drugs. PIs, such as ritonavir (RTV)-boosted lopinavir (LPV/r) and RTV-boosted atazanavir (ATV/r), have been available across the Asian region for more than a decade, but there is a little evidence regarding the outcomes of second-line ART in patients who fail to respond to the recommended first-line treatment.
In addition, the recommendations for these drugs are based on the evidence gathered from studies conducted in resource-rich settings which have access to resistance testing that helps in determining the most efficacious second-line regimens. The aim of this research was to analyze the difference in efficacy and tolerance of boosted lopinavir and boosted atazanavir in the Indian setting among patients on the second-line ART regimens as well as analyze the factors associated with treatment outcomes in both the groups. The results from this study will aid caregivers in selecting an effective ART regimen and in clinical decision-making for patients who develop adverse drug reactions (ADRs).
| Materials and Methods|| |
This observational study was conducted from January 1, 2017, to March 2020 on a cohort of PLH/AIDS (PLH/A) under evaluation for first-line treatment failure at a referral ART clinic of a tertiary care hospital in North India. All eligible patients currently being treated with boosted lopinavir and boosted atazanavir were included in the study. Institute ethical committee clearance was obtained before beginning the study. Informed written consent was obtained from all the participants.
Study participants included PLH/A on regular follow-up with a failure of first-line ART in spite of adequate adherence counseling and as far as possible at least two serial plasma viral loads >1000 copies/ml 3 months apart.
Patients with poor adherence to therapy (<80% adherence to the prescribed drug regimens) and those who had been exposed to both zidovudine and tenofovir for a significant duration as part of first-line therapy (as this might compromise the NRTI backbone in second-line therapy and affect outcomes independent of the PI used) were excluded from the study. Patients with other major comorbidities such as coexisting chronic kidney/liver disease or other organ dysfunctions which may affect outcomes adversely and patients with absolute contraindications to use of either drug under evaluation were also excluded.
A total of 115 and 60 patients met the inclusion criteria over the given time period and were recruited to the lopinavir and atazanavir study groups, respectively.
The two primary outcomes were the efficacy of each regimen (calculated as the percentage of patients who achieved target viral load by 12 months after starting therapy with the PI-based therapy, i.e., plasma levels of HIV RNA <1000 copies/ml) and major adverse effects in the two groups requiring drug substitution. The secondary outcomes were the minor adverse effects not requiring drug substitution but affecting quality of life.
Means and proportions were calculated for continuous and categorical variables, respectively. P <0.05 was considered statistically significant. Data entry was carried out using MS Excel 2013 and data analysis was done using SPSS Inc. IBM, 2009.
| Results|| |
No significant difference was observed in distribution of patients based on age and study groups (P = 0.179). Significantly higher proportions of males were in the lopinavir group as compared to that of the atazanavir group (P = 0.006) [Table 1].
No significant differences were observed in the study groups with respect to duration of illness (P = 0.131).
The distribution of the study groups based on mean baseline CD4 count and mean CD4 count at follow-up is presented in [Table 2], and the distribution of the study groups based on mean baseline HIV RNA and mean HIV RNA at follow-up is presented in [Table 3].
|Table 2: Distribution of study groups based on mean baseline CD4 count and CD4 count at follow-up (n=175)|
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|Table 3: Distribution of study groups based on baseline HIV ribonucleic acid and mean HIV ribonucleic acid at follow-up (n=175)|
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Seventy-three percent of the patients in the lopinavir group and 81.7% of the patients in the atazanavir group achieved target HIV RNA copies after follow-up [Table 4].
|Table 4: Distribution of study groups based on target HIV ribonucleic acid copies after follow-up (n=175)|
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The distribution of the study groups based on difference in CD4 count and HIV RNA at baseline and follow-up is presented in [Table 5].
|Table 5: Distribution of study groups based on difference in CD4 count and HIV ribonucleic acid at baseline and follow-up (n=175)|
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With regard to ADRs, hyperlipidemia and abnormal liver function test (LFT) in the form of transaminitis were the most common ADRs noted in patients in the lopinavir study group, whereas nausea, fever, and indirect hyperbilirubinemia were the most common ADRs noted in the atazanavir study group. A significantly higher proportion of patients in the lopinavir group had abnormal transaminases and neutropenia (mild, not requiring intervention), whereas dermatological manifestations were higher in the atazanavir group [Table 6]. Two patients (1.73%) on lopinavir required drug substitution due to persistent diarrhea and none for transaminitis as it was always lesser than 2.5 times the upper limit of normal. Two patients (3.33%) required substitution in the atazanavir group, of which one patient required substitution for indirect hyperbilirubinemia. This patient had compensated (Child A) cirrhosis and was apprehensive about rising bilirubin and requested to be switched to an alternate drug. The other patient on atazanavir had to be substituted with an alternative drug due to persistent gastritis and frequent use of proton-pump inhibitors risking the efficacy of atazanavir.
|Table 6: Distribution of study groups based on adverse drug reactions (n=175)|
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| Discussion|| |
PIs are potent antiretroviral drugs which are recommended as part of the “preferred second-line regimen” for patients with retroviral disease. PIs inhibit the HIV protease enzyme which results in the production of noninfectious viral particles. Although RTV was also developed as a PI, its main utility lies in its ability to inhibit cytochrome P450-3A4, an enzyme that metabolizes the PIs. Addition of RTV, therefore, boosts the pharmacokinetic parameters of the second PI and also helps in reducing the frequency of dosing, thereby improving treatment compliance.
The present study was carried out with an aim to analyze the efficacy and tolerance of boosted lopinavir and atazanavir in patient subsets as part of second-line ART regimens. One hundred and seventy-five PLH/A who were undergoing ART in the study hospital comprised the study population. Both the study groups were comparable in terms of demographic distribution (age and gender). The number of patients achieving target RNA copies (73% in the lopinavir group and 81.7% in the atazanavir group) was significantly higher than the number of patients who did not achieve target RNA copies in both the study groups (P < 0.0001).
In the study by Molina et al., it was observed that of 883 patients enrolled, 440 were randomized to atazanavir/RTV and 443 to lopinavir/RTV. On completion of 96 weeks, more patients receiving atazanavir/RTV achieved HIV RNA <50 copies/mL (74% vs. 68%, P < 0.05). This is similar to the results of our study. Molina et al. reported that on both the regimens, 7% of the patients were virologic failures at 96 weeks. Although the difference in Viral Load of the above study posttreatment with PIs was found significant, the difference does not seem clinically significant.
Laker et al. in their study documented that 90% of the study patients on atazanavir and 83% of the study patients on lopinavir had a viral load <1000 copies/ml on follow-up. The odds of achieving viral load suppression between the two groups was not statistically significant after stratifying for duration of ART (P = 0.09). In a multivariate analysis, the type of PI used was not a predictor of virological outcome (P = 0.60). These results of the above study were similar to that of the present study observations.
In their study, Johnson et al. reported that over a period of 96 weeks, the boosted atazanavir regimen demonstrated a similar efficacy in viral load suppression as compared to the boosted lopinavir regimen. The mean reductions from baseline in HIV RNA were −2.29 and −2.08 log10 copies/ml, respectively (Time Averaged Difference [97.5% confidence interval]: 0.14 log10 copies/ml [−0.13, 0.41]). The above findings were concordant with that of the present study observations with respect to viral load.
Cohen et al. noted that among 290 patients (144 on atazanavir and 146 on lopinavir/RTV), boosted lopinavir resulted in significantly greater reduction in viral loads than atazanavir (P < 0.001) at 48 weeks. Secondary efficacy endpoints also favored lopinavir/RTV; the differences in efficacy between regimens were also observed in secondary analyses comparing those patients who were susceptible and those patients who were resistant to their respective PIs at baseline. However, both the regimens were equally effective in patients who had no baseline NRTI mutations. The study results were in agreement with that of the findings noted in the present study also.
A significant number of PI-associated lipid abnormalities have been reported, although the pathogenesis is not fully understood. Molina et al. reported a higher incidence of gastrointestinal side effects in patients taking lopinavir/RTV. At week 96, the mean changes from baseline of total cholesterol levels, nonhigh-density lipoprotein cholesterol levels, and triglyceride levels were significantly higher in patients taking boosted lopinavir (P < 0.0001). Identical ADRs were noted in the present study also, where hyperlipidemia and abnormal LFT in the form of transaminitis were the most common ADRs noted in the lopinavir group.
Johnson et al. observed that the boosted lopinavir regimen resulted in a significant increase in the total cholesterol and fasting triglycerides levels as compared to the boosted atazanavir regimen, which demonstrated a decrease in these parameters. Grade 2–4 diarrhea occurred less frequently in patients taking atazanavir (3%) as compared to lopinavir (13%) (P < 0.01). Elevation in bilirubin levels was more common in ATV/RTV patients (53%) than LPV/RTV patients (<1%) (P < 0.0001). A similar proportion of patients had lipid profile derangements and gastrointestinal system involving ADRs in the present study also.
Cohen et al. reported that from baseline to week 48, atazanavir resulted in either no change or decrease in fasting LDL cholesterol, total cholesterol, and triglyceride levels (–6%, –2%, and +1%), whereas lopinavir/RTV resulted in an increase in the levels of all three parameters (+3%, +12%, and +53%) (P < 0.05). Fewer patients were administered lipid-lowering therapy in the atazanavir group (6%) as compared to the lopinavir group (20%). Both the regimens were safe and well tolerated. The results of the above study were comparable to that of the ADRs reported in the present study.
One limitation of the ambispective study design was that no sample size was calculated and convenient nonprobability sampling was used to select study participants. Furthermore, the authors have not compared the efficacy of the two drug regimens. Both the regimens are standard regimens followed across the world, but there is a lack of data in the Indian context, which the authors have tried to supplement with the data presented in the current study.
| Conclusions|| |
Lopinavir (in combination with RTV) and atazanavir (in combination with RTV) are highly effective in reducing viral load and produced comparable CD4 levels post 1-year follow-up. Hyperlipidemia and mild transaminitis were the most common ADRs noted with lopinavir, whereas nausea, indirect hyperbilirubinemia, and fever were the most common ADRs noted in the atazanavir study group.
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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]