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A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan

1 Department of Medicine, ART Centre, SMS Medical College, Jaipur, Rajasthan, India
2 Department of Pharmacology, SMS Medical College, Jaipur, Rajasthan, India
3 Department of Medicine, SMS Medical College, Jaipur, Rajasthan, India
4 Department of Medicine, RUHS College of Medical Sciences, Jaipur, Rajasthan, India
5 ART Centre, SMS Hospital, Jaipur, Rajasthan, India

Date of Submission06-Jun-2021
Date of Decision03-Jul-2021
Date of Acceptance30-Jul-2021
Date of Web Publication11-Jan-2022

Correspondence Address:
Charu Jain,
A-2, New Heera Bagh Doctors Flats, Near Kalyan Dharamshala, Jaipur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/picr.PICR_117_21


Introduction: Second-line antiretroviral therapy (ART) regimens are used when patients develop treatment failure from first-line drug regimens. The present study is aimed to compare treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in human immunodeficiency virus (HIV) patients, switched to various second-line ART regimens and to assess adverse drug reactions (ADRs).
Materials and Methods: A longitudinal observational study was conducted at ART center, SMS Hospital, Jaipur, after approval from Institutional Research Review Board. One hundred HIV positive patients, resistant to first line ART, switched to either of the 2 s line ART regimens were followed for 1 year for early treatment outcomes and any ADRs.
Results: Out of 97 patients enrolled 65 patients received Tenofovir and 32 patients received Zidovudine (ZDV) along with lamivudine and Atazanavir/ritonavir. There was significant increment in CD4 count from the baseline value (202.51–438.52 cells/mm3) after 12 months of therapy. On comparison, CD4 cell rise was not significantly different between the two groups. However, Plasma viral load suppression was achieved insignificantly more number of patients in ZDV group than in tenofovir group: 31 (96.9%) versus 57 (87.7%), respectively. Opportunistic infections (OI) were seen in 21.5% and 28.1% patients respectively at the time of switching of second-line ART. Out of 59 ADRs reported, nausea, vomiting, diarrhea, hyperbilirubinemia, dyslipidemia, and anemia were most common.
Conclusion: Nonadherence, drug resistance, and treatment failure are the major challenges in controlling HIV disease. Our study shows that both the second-line regimens were comparable in improvement in CD4 count and viral load suppression with 1 year success rate of 90.7%.

Keywords: CD4 count, drug resistance, protease inhibitor-based antiretroviral therapy, second-line antiretroviral therapy, viral load

How to cite this URL:
Agrawal A, Jain C, Kumar D, Kumar M, Sharma L, Advani U, Soni DC. A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan. Perspect Clin Res [Epub ahead of print] [cited 2022 Dec 8]. Available from: http://www.picronline.org/preprintarticle.asp?id=335579

   Introduction Top

Prevention of the emergence of human immunodeficiency virus drug resistance (HIV DR), is the key for success of the national antiretroviral Therapy (ART) program and prevention of transmission of resistant virus. The global target of ending acquired immunodeficiency syndrome (AIDS) is by 2030. To meet this goal, Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90[1] was targeted, which refers to 90% People living with HIV (PLHIV) to be tested and aware of their status, 90% of those to be on ART and of those, 90% to be virologically suppressed by the end of year 2020 but as per critics, it was overemphasized so UNAIDS set a revised target for 2025 which calls for 95% testing, treatment and viral suppression of PLHIV. As well as 95% access to combination prevention services; 95% access to sexual reproductive health services; and 95% coverage of prevention of mother-to-child transmission services along with removal of societal and legal barriers of HIV services.[2]

Conventionally, ART consists of the use of a combination of at least three ART drugs from different classes to inhibit the replication of HIV and reduce viremia to undetectable levels. Continued suppression of viral replication leads to the restoration of immune response, reflected by an increase in the CD4 count. This leads to slowing of the disease progression, reduced frequency of opportunistic infections (OI), improvement in the quality of life and increased longevity.[2]

According to the current recommendation of the National AIDS Control Programme phase IV (NACP-IV), in case of failure of first line NNRTI-based ART regimen and if adherence to treatment is adequate, the patient is switched to second-line protease inhibitor (PI)-based ART. Second-line drugs consist of Ritonavir boosted PI, Atazanavir/ritonavir (ATV/r) or Lopinavir/ritonavir (LPV/r) in combination with lamivudine and one new and previously unused nucleoside reverse transcriptase inhibitor, Zidovudine (ZDV) or Tenofovir. In some situations alternative drug from the class, integrase inhibitor (Raltegravir or Dolutegravir) has to be prescribed, only after approval from concerned Centre of excellence affiliated to the ART center. PIs act at the late step in HIV replication, i.e. maturation of new virus particles when the RNA genome acquires the core proteins and enzymes so they are effective in both newly as well as chronically infected cells.[3]

Although there has been a rapid decline in the HIV related mortality and morbidity due to the wider availability of Antiretroviral (ARV) drugs over the last two decades. However, all standard ART can attribute to diverse range of unwelcoming adverse drug reactions (ADRs) which can lead to interruptions in the treatment, therefore, it is critical to anticipate, recognize, and manage these adverse reactions.

PIs can attribute to class specific side-effects such as hyperglycemia, fat maldistribution, hyperlipidemia and increased bleeding episodes in hemophiliacs more commonly seen with Ritonavir boosted regimes. While ATV was found associated with unique side-effects of indirect hyperbilirubinemia (presents as yellow discoloration of eyes), skin rash, nephrolithiasis and prolongation of P-R and Q-Tc interval in the electrocardiogram.[4]

By early detection of the virological failure and timely switching to second-line ART might decrease accumulation of DR at individual and community level. Further, it is essential to evaluate early treatment outcome associated with second-line ART in context with routine patient care. The data on Indian patients regarding the efficacy and side effect profile of second-line regimens of ART compared to its first-line counterpart is very scanty and this study will definitely add to the existing knowledge in this field. Under this background, the present study was conducted with the aim and objectives of evaluation and comparison of treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in HIV patients who were switched to PI based second-line ART at our center and also to access ADR profile of second-line ART in these patients.

   Materials And Methods Top

A hospital-based longitudinal observational study was conducted at ART center in the department of medicine, SMS Hospital from May 2019 to October 2020 after due approval from Institutional Research Review Board (25/MC/EC/2020 dated January 29, 2021). ART plus center of Sawai Man Singh Hospital, Jaipur, was founded on 5/05/05 and has dedicated an area of 2750 yards with complete diagnostic (hematological, radiological) work up facilities. The center provides counseling services and ARV drugs (first line, second line, and third line) as well as drugs for managing all OI free of cost. A total of 15,460 HIV + ve adult patients and 976 children are registered till October 2020 with an average OPD of about 250–290 patients per day. The selection of patients for the study was done as per inclusion and exclusion criteria. All HIV positive patients resistant to first line ART, switched to second-line ART regimen and of age >18 years were included in the study while patients with preexisting renal and liver dysfunction, severally anemic patients (Hb < 8 gm%) and pregnant women were excluded from the study.

Criteria of treatment failure in HIV patients are well defined. This in turn can be measured in three ways: clinical and/or immunological and/or virological failure. As per NACP, the patient is qualified for second-line ART if he had received 6 month or more of standard first line ART and still demonstrated treatment failure. This can be demarcated by:

CD4 decline to pre ART values, CD4 drop to < 50% of peak on-treatment value or failure to achieve CD4 > 100 cells/mm3 (immunologic failure), or developed a new WHO stage III/IV AIDS defining illness (Clinical failure) or those with HIV RNA 1000 copies/ml or greater (virological failure) after optimal (>95%) adherence is ensured.[5]


Sample size calculation

The sample size calculated was 82 HIV positive patients on second-line ART as per previous studies showing the prevalence of good outcome after 1 year of ART that is 82%. To assume dropout of 20%, the total 100 patients were planned to be taken in study for 95% confidence limit, 80% power, and 8.5% relative error.[6]

Data collection

A total of 100 HIV-positive patients resistant to first-line ART and who were switched to either of the two second-line ART regimens:

Regimen 1: Fixed dose combination of tablet Tenofovir 300 mg + Lamivudine 300 mg (TL) once daily along with Tablet ATV 300 mg + Ritonavir 100 mg. Each tablet to be taken once daily simultaneously (TL/ATV/r)

Regimen II: Fixed dose combination of Tab. ZDV 300 mg + Lamivudine 300 mg (ZL) once daily along with Tablet. ATV 300 mg + Ritonavir 100 mg. Each Tablet to be taken once daily simultaneously.(ZL/ATV/r).

Data regarding patient's demographics and clinical information were collected by investigators and recorded on a predesigned study pro forma. For the analysis of early outcome of two ART regimes clinical details were noted down including duration of illness, clinical signs and symptoms, WHO staging of the disease,[7] presence of OI and concomitant treatment with anti-tubercular therapy. Laboratory investigations were also done such as complete blood counts, blood sugar, renal and liver function, lipid profile, hepatitis markers, VDRL, urine routine microscopy, and Chest radiograph. Other parameters of early outcome were periodic CD4 count (every 6 months) which was used as the marker of immunological recovery and plasma viral load (PVL) suppression (<1000 copies/mL)[8] as a virological marker. Patients were followed every month for 1 year and at every visit thorough history and clinical examination was done targeting the occurrence of any adverse effects or new OI.

Statistical analysis

Qualitative data are presented as percentage of proportion. Quantitative data are presented as mean and standard deviation. Significance of difference in proportion was inferred by Chi-square test. Significance of difference in mean was inferred by Unpaired t-test. The level of significance was kept at 95% for all statistical analysis. P <0.05 was taken as significant.

   Results Top

For the purpose of the study, 100 consecutive HIV patients who were started on second-line ART were selected. Out of total 100 patients 54 were males and 42 females. Three Patients were excluded due to suboptimal adherence (<95%) to the treatment. Among the study population, 65 patients received regimen 1 (TL/ATV/r) and 32 patients received regimen II (ZL/ATV/r). Most of the patients were from 40 to 60 years of age group. Immunological assessment of the patients was done by comparing the value of CD4 count at 6th month and 12th month of the treatment with the base line value at the start of second-line treatment in between the two groups [Figure 1]. There was statistically significant increment in CD4 count (P > 0.001) in the entire study population as well as in the two groups. However, on comparison, the difference of the CD4 cell rise was not significant (P > 0.001) between the two study groups.
Figure 1: Comparison of mean CD4 count among study groups

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The evaluation of virological effectiveness was done after 1 year of therapy. It was found that 57 (87.7%) patients on regimen 1 while 31 (96.9%) patients on regimen II achieved PVL value to < 1000 copies/ml. Although the proportion of viral suppression was higher in ZL/ATV/r than in TL/ATV/r group but the difference was statistically nonsignificant (P < 0.001).

The occurrence of OI in the study population shows that 21.5% patients on regimen1 and 28.1%on regimen II were having OI at the time of switching over to second-line ART. Tuberculosis followed by oral candidiasis and skin infection in the form of herpes, psoriasis, and shingles were the most common OIs. These cases were recovered during the 12 months of observation period and after taking definitive treatment for OIs. Patients were in WHO clinical stage 1 and 2 in both the groups.

Laboratory parameters including serum hemoglobin, serum bilirubin, urea, creatinine, and cholesterol were monitored at different time intervals for the assessment of ADRs due to ART [Table 1]. Total number of ADRs was counted to be 59 in 97 patients under study. Among the most common ADRs were from Gastrointestinal system-30 (nausea, vomitings, diarrhea, and hyperbilirubinemia), metabolic-14 (weight gain, hypercholesterolemia) and haematological-15 (anemia). Anemia was seen mostly in ZLATV/r group. ADR profile is shown in [Table 2]. The pill count showed that most patients on both the regimens (98.8% and 98.2%) on second-line ART were adherent to the treatment except the three patients who were excluded from calculations as these patients stopped treatment due to intolerability to ART.
Table 1: Comparison of mean CD4 count, hemoglobin, serum bilirubin, serum urea, serum creatinine, serum cholesterol at different time interval in study population

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Table 2: Adverse drug reactions profile of antiretroviral therapy drugs among human immunodeficiency virus patients

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   Discussion Top

This study designates the early treatment outcomes (at one year) of 100 patients switched from first line ART to second-line ATV/r-based ART regimens who were followed for 12 months at ART center of SMS Hospital, Jaipur, India.[8]

Male preponderance was observed in our study (55%). A study done by Jha DK, et al.[9] also found the male predominance (78%) indicating high HIV prevalence among males. The mean age of patients in our study was comparable (41.02 ± 9.90 years) to study done by Patel et al.[10] (39.6 years) and Jha, et al. (36.7 ± 8.7 years).

Our study displays that at the time of initiation of second-line ART regimen, the CD4 count (202.51) was lower and PVL (326274.23 copies/ml) was higher. It was found in our study that both the PI-based regimens were comparable in improvement in CD4 count and viral load suppression with 90.7% success rate of second-line ART drug regimens. Our results were in concordance with one previously done study[9] where a total of 100 patients who were switched either of two2ndline regimens (ZDV + lamivudine [3TC] + tenofovir [TDF] + boosted LPV [LPV/r]) or (3TC + TDF + LPV/r) and was concluded that on comparing the CD4 count level at 6th month and 12th month with the base line value, statistically significant (P < 0.001) results were seen in both the groups. On analysis of mean PVL 55 patients achieved virological suppression (PVL < 400 copies/ml) at 6 months and 45 patients at 12 months. Further analysis exhibited 45 patients achieved virological suppression at 6 months and rest 25 at 12 months, 10 patients achieved virological suppression at 6 months and rest 20 at 12 months with both the regimen, respectively.[9] Results of another study[10] were comparable to our study where early treatment outcome with second-line ART (TLZ/LPV/r and TL/LPV/r) was good but the success rate (82%) was found lower than our study.

A study done by Cao et al.[11] shows that HIV-infected patients had viral load ≥ 1000 copies/mL at the time of regimen switch after a long duration of first-line therapy had good virological responses to second-line regimens. It has been recommended by Ajose et al.[12] to initiate second-line ART as soon as the PVL is more than 400 copies/ml in second-line ART programs.[13]

Alene et al.[13] suggested that the rate of second-line treatment failure was higher for patients who did not change drug regimens, who had poor ART adherence, and who were taking isoniazid for the treatment of tuberculosis, these findings were in concordance with our study.

A significant proportion (26.80%) of patients in our study developed ADRs on 2nd line regimens. Out of them ten patients established multiple ADRs. According to WHO UMC Causality assessment scale[14] 70% ADRs were possible, 30% ADRs were probable in nature and none were certain. However, most of them were mild in severity as they were self-limiting while ten ADRs required treatment discontinuation or regimen change, in these patients, symptomatic treatment was not enough and they were switched to alternative 2nd line or 3rd line ART. According to Hartwig severity assessment scale[15] 80% ADRs were mild and 16.67% were moderate in severity.

In patients with abdominal discomfort which seemed within a week of therapy, antacids were prescribed. Four patients developed dyslipidemia induced by PIs after 3–6 months of therapy. Atorvastatin was given in these patients as they are at risk of cardiac events. In our study, hepatotoxicity in form of hyperbilirubinemia was found in nine patients, 9 the probable ADR was due to ATV/r. Among them two patients who developed hepatic enlargement and raised serum transaminases > 5 times of upper limit of normal value required treatment discontinuation. In these patients, ATV/r was replaced by LPV/r. It was found that risk factors for the development of acute hepatitis were advance HIV disease, presence of OI, baseline CD4 count < 200 cells/mm3 and concomitant drug therapy like cotrimoxazole or ATT. A study done by Jha et al.[16] highlighted the similar risk factors. Only one patient suffered from severe anemia with ZDV (Hb < 6 g/dl) required change of therapy to dolutegravir-based dual drug regimen. One postmenopausal woman developed lower backache after 4–5 months of therapy, probably enhanced due to tenofovir. Severe osteoporosis (T score <−2.5) was noted in this woman. The adherence of both the regimen was > 95%, so both the regimens were well tolerated.

The earlier study done by Jha, et al.[6] recognized that out of 100 patients on second-line ART, 53 patients presented with a total number of 74 ADRs. Most common was anemia followed by rash. Anemia was more commonly seen due to ZDV. While a et al. former study[10] detected 83 ADRs in 69 patients out of 126. Dyslipidemia (57) and anemia (9) were the common ADRs observed in the study.

Strength of the study

The various strengths of the study are adequate sample size, proper follow-up and data collection. The study used surrogate markers for examining association of the variables which were easy to analyze.


Although a good number of patients on second-line ART were followed up for 12 months. Yet it was an observational, single centric study. We suggest, a multicenter study with more number of subjects is required to improve the accuracy of the results.

   Conclusion Top

Despite rapidly declining mortality and morbidity among HIV patients due to the wider availability of Antiretroviral (ARV) drugs, nonadherence, DR, and treatment failure are creating a significant challenge in controlling HIV disease. The study provided important information about efficacy and tolerability of two PI-based NACO regimens in Indian HIV patients. The success rate of second-line ART drug regimens were 90.7% in our study. Second, both the PI-based regimens were comparable in improvement in CD4 count and viral load suppression. However, PVL suppression was achieved insignificantly more number of patients in ZDV group than tenofovir group. The study reports GI side effects, hyperbilirubinemia, dyslipidemia, and anemia were most common ADRs.

Consent of the patient

Written informed consent was obtained from all the patients.

Ethical approval

Ethical approval was obtained from institutional research review board (25/MC/EC/2020 dated 29/1/21).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

UNAIDS. Global Report: UNAIDS Report on the Global AIDS Epidemic. Geneva: Joint United Nations Programme on HIV/AIDS (UNAIDS); 2020.  Back to cited text no. 1
Tanwar S, Rewari BB, Rao CD, Seguy N. India's HIV programme: Successes and challenges. J Virus Erad 2016;2:15-9.  Back to cited text no. 2
Global Information and Education on HIV and AIDS. Available from: https://www.avert.org/global-hiv-targets. [Last assessed on 2021 May 24].  Back to cited text no. 3
Tripathi KD.Antiretroviral drugs. In: Essentials of Medical Pharmacology. 8th ed. New Delhi: Jaypee Publications; 2019. p. 860-72.  Back to cited text no. 4
National AIDS Control Organisation. Operational Guidelines on HIV Sentinel Surveillance. New Delhi: Ministry of Health and Family Welfare, Government of India; 2017.  Back to cited text no. 5
Hagos L, Fessehaye S, Anand IS. Nature and prevalence of adverse drug reaction of antiretroviral medications in Halibet National Referral Hospital: A retrospective study. BMC Pharmacol Toxicol 2019;20:112-8.  Back to cited text no. 6
Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd edition. Geneva: World Health Organization; 2016. ANNEX 10, WHO clinical staging of HIV disease in adults, adolescents and children. Available from: https://www.ncbi.nlm.nih.gov/books/NBK374293. [Last assessed on 2020 Aug 08].  Back to cited text no. 7
NACO. National Guidelines on Second Line ART. New Delhi: Ministry of Health and Family Welfare, Government of India; 2018.  Back to cited text no. 8
Jha DK, Ojha UK, Jha AK. Treatment outcome of second line anti-retroviral therapy in HIV positive patients over one year period. Int J Contemp Med Res 2018;5:I1-4.  Back to cited text no. 9
Patel D, Desai M, Shah AN, Dikshit RK. Early outcome of second line antiretroviral therapy in treatment-experienced human immunodeficiency virus positive patients. Perspect Clin Res 2013;4:215-20.  Back to cited text no. 10
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Cao P, Su B, Wu J, Wang Z, Yan J, Song C, et al. Treatment outcomes and HIV drug resistance of patients switching to second-line regimens after long-term first-line antiretroviral therapy: An observational cohort study. Medicine 2018;97:e11463.  Back to cited text no. 11
Ajose O, Mookerjee S, Mills EJ, Boulle A, Ford N. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: A systematic review and meta-analysis. AIDS 2012;26:929-38.  Back to cited text no. 12
Alene M, Awoke T, Yenit MK, Tsegaye AT. Incidence and predictors of second-line antiretroviral treatment failure among adults living with HIV in Amhara region: A multi-centered retrospective follow-up study. BMC Infect Dis 2019;19:599.  Back to cited text no. 13
The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2016 May 21].  Back to cited text no. 14
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 15
Jha AK, Gadgade A, Shenoy AK, Chowta MN, Ramapuram JT. Evaluation of adverse drug reactions in HIV positive patients in a tertiary care hospital. Perspect Clin Res 2015;6:34-8.  Back to cited text no. 16
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