High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment

Abstract

To determine the rates, reasons and predictors of treatment change of the initial antiretroviral treatment (ART) regimen in HIV-infected south Indian adults.
In this prospective cohort study, ART-naive adults initiated on generic, fixed dose combination ART as per the National AIDS Control Organization guidelines were followed up at an academic medical center. Treatment change was defined as any event which necessitated a change in or discontinuation of the initial ART regimen.
Two hundred and thirty persons with HIV infection (males 74.8% and median age 37 years) were followed up for median duration of 48 weeks. The majority (98.7%) had acquired HIV infection through the heterosexual route. Most (70.4%) had advanced IV infection (WHO clinical stage 3 or 4) and 78% had CD4+ T-lymphocyte counts below 200 cells/microL. The initial ART regimens used were: Lamivudine (3TC) with Stavudine (d4T) (in 76%) or Azidothymidine (AZT) and Nevirapine (NVP) (in 86%) or Efavirenz (EFV). The cumulative incidence of treatment change was 39.6% (91 patients). Drug toxicity (WHO grade 3 or 4) was the reason for treatment change among 62 (27%) (incidence rate 35.9/100 person-years). The most common toxicities were attributable to the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), d4T and AZT [lactic acidosis (8.7%), anemia (7%) and peripheral neuropathy (5.2%)]. The other toxicities were rash (3.9%) and hepatitis (1.3%) due to NVP. The mortality (4.6/100 person-years) and disease progression rates (4.1/100 person-years) were low.
The ART regimens used in this study were effective in decreasing disease progression and death. However, they were associated with high rates of drug toxicities, particularly those attributable to thymidine analogue NRTI. As efforts are made to improve access to ART, treatment regimens chosen should not only be potent, but also safe.

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384 © JAPI • MAY 2009 • VOL. 57
Background
Highly active antiretroviral therapy (HAART) has
dramatically reduced the morbidity and mortality
associated with human immunodeciency virus (HIV) infection,
and has improved the prognosis for people living with HIV
infection/AIDS (PLHA). About 33.2 million people worldwide
are estimated to be living with HIV infection, the large majority
of them in developing countries of Asia and Africa.1 Since 2001,
the World Health Organization (WHO) has advocated a “public
health approach” to HAART to rapidly improve access to this
life-saving intervention in resource-poor settings.2 This approach
focuses on maximizing survival at the population level through
standardized sequencing of available antiretroviral drugs,
delivered to individuals by means of simplified approaches to
clinical decision making and basic laboratory monitoring.3
The free ART initiative was launched by the Government of
India on 1 April, 2004 with a view to improve access to ART for
the estimated 2.5 million PLHA in India. Currently, the National
AIDS Control Organization (NACO) recommends the following
drugs and drug combinations for rst-line regimens:4
i. Stavudine (30 mg) + Lamivudine (150 mg)
ii. Azidothymidine (300 mg) + Lamivudine (150 mg)
iii. Stavudine (30 mg) + Lamivudine (150 mg) + Nevirapine
(200 mg)
iv. Azidothymidine (300 mg) + Lamivudine (150 mg) +
Nevirapine (200 mg)
v. Efavirenz (600 mg)
vi. Nevirapine (200 mg)
These drugs are chosen on the basis of their demonstrated
efficacy in suppressing HIV replication and improving survival
of PLHA,5 low cost and wide availability. However, concerns
have emerged about the durability, safety and tolerability of these
regimens. Lamivudine (3TC), Nevirapine (NVP) and Efavirenz
(EFV) have a low genetic barrier for emergence of resistance,6
which can potentially jeopardize the durability of these regimes.
The thymidine analogue nucleoside reverse transcriptase
inhibitors (NRTI) [Stavudine (d4T) and Azidothymidine (AZT)]
Abstract
Objectives: To determine the rates, reasons and predictors of treatment change of the initial antiretroviral
treatment (ART) regimen in HIV-infected south Indian adults.
Methods: In this prospective cohort study, ART-naïve adults initiated on generic, fixed dose combination ART as
per the National AIDS Control Organization guidelines were followed up at an academic medical center. Treatment
change was defined as any event which necessitated a change in or discontinuation of the initial ART regimen.
Results: Two hundred and thirty persons with HIV infection (males 74.8% and median age 37 years) were followed
up for median duration of 48 weeks. The majority (98.7%) had acquired HIV infection through the heterosexual
route. Most (70.4%) had advanced HIV infection (WHO clinical stage 3 or 4) and 78% had CD4+ T-lymphocyte
counts below 200 cells/µL. The initial ART regimens used were: Lamivudine (3TC) with Stavudine (d4T ) (in
76%) or Azidothymidine (AZT) and Nevirapine (NVP) (in 86%) or Efavirenz (EFV). The cumulative incidence
of treatment change was 39.6% (91 patients). Drug toxicity (WHO grade 3 or 4) was the reason for treatment
change among 62 (27%) (incidence rate 35.9/100 person-years). The most common toxicities were attributable to
the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), d4T and AZT [lactic acidosis (8.7%),
anemia (7%) and peripheral neuropathy (5.2%)]. The other toxicities were rash (3.9%) and hepatitis (1.3%) due to
NVP. The mortality (4.6/100 person-years) and disease progression rates (4.1/100 person-years) were low.
Conclusions: The ART regimens used in this study were effective in decreasing disease progression and death.
However, they were associated with high rates of drug toxicities, particularly those attributable to thymidine
analogue NRTI. As efforts are made to improve access to ART, treatment regimens chosen should not only be
potent, but also safe.
Original Article
1Departments of Medicine Unit 1 & Infectious Diseases, 2Dermatology
and 3Clinical Virology, Christian Medical College, Vellore.
Received : 28.05.2008; Accepted : 02.03.2009
High Rates of Regimen Change due to Drug Toxicity
Among a Cohort of South Indian Adults with HIV
Infection Initiated on Generic, First-Line Antiretroviral
Treatment
Ajith Sivadasan1, OC Abraham1, Priscilla Rupali1, Susanne A Pulimood2, Joyce Rajan1,
S Rajkumar1, Anand Zachariah1, Rajesh Kannangai3, Abraham Joseph Kandathil3, G Sridharan3,
Dilip Mathai1

© JAPI • MAY 2009 • VOL. 57 385
and the non-nucleoside reverse transcriptase inhibitor (NNRTI)
NVP are associated with several toxicities, which have led to
the complete omission of d4T in treatment guidelines from
industrialized countries.7 With the scaling up access to ART in
our country, there is an opportunity to better understand the
benefits and drawbacks of these regimens. Hence this study
was conducted to determine the incidence and determinants of
initial HAART regimen change in these patients.
Methods
This prospective cohort study was conducted at the Christian
Medical College, Vellore, a 2200 bedded academic medical center
in south India. Eligible subjects were recruited from the ‘Infectious
Diseases Clinic’ (ID Clinic) which is a dedicated outpatient
service for PLHA manned by staff from the departments
of General Medicine and Infectious Diseases, Dermatology
and Venereology, Child Health, Obstetrics and Gynecology,
Psychiatry, medical social workers and a pharmacist. The ID
Clinic provides generic, xed-dose combination of anti-retroviral
drugs at subsidized rates to patients.
The subjects were residents of southern Indian states (Tamil
Nadu, Andhra Pradesh, Kerala and Karnataka). The diagnosis
of HIV infection was confirmed by two serially reactive ELISA
tests in symptomatic individuals and three tests in asymptomatic
individuals.4 All subjects satisfied the medical eligibility for
initiation of antiretroviral therapy [WHO clinical stage 3/4 or
WHO clinical stage 1/2 with CD4+ T-lymphocyte (CD4 cell)
counts less than 200 cells/µL].4 The subjects were ART-naive
(defined as having received less than 4 weeks of ART prior to
enrolment). Patients who were pregnant, breast-feeding and
younger than 13 years were not included.
All subjects had a detailed symptom-directed clin ica l
evaluation to rule out any active opportunistic infections prior
to initiation of HAART. Baseline anthropometric data including
weight, height and body mass index (BMI), complete blood
counts (CBC), biochemical tests (blood glucose, liver and renal
function tests) and CD4 counts were obtained. All subjects had
several (three to four) counseling sessions before initiation
of HAART to assess treatment readiness and educate them
regarding the need for life-long treatment, stringent adherence
to therapy and potential side eects of the drugs.
All patients received a combination of two NRTI (either AZT
300 mg twice daily or d4T 30 mg twice daily with 3TC 150 mg
twice daily) and an NNRTI (either NVP 200 mg once daily for 14
days followed by 200 mg twice daily or EFV 600 mg once daily at
bed time). All the drugs were generic, xed-dose combinations
(AZT 300 mg + 3TC 150 mg, d4T 30mg + 3TC 150 mg, AZT 300
mg + 3TC 150 mg + NVP 200 mg, d4T 30mg + 3TC 150 mg + NVP
200 mg) procured from the same pharmaceutical manufacturing
rm (CIPLA Ltd., Mumbai).
Follow up clinical assessments were done at two weeks, one
month and subsequently once every 3 months after enrolment.
Cohort surveillance was mainly passive. Patients had open access
to the study clinic and were encouraged to attend whenever ill.
Each episode of illness was investigated and managed according
to established protocols. At each follow-up visit, the body
weight was recorded, and each patient had a symptom-directed
evaluation to assess any new events indicating treatment failure
or drug toxicity.3 Follow-up CD4 cell count estimation was
scheduled at 6 months after initiation of HAART, and every 6
to 12 months thereafter. Adherence was assessed by patient self
report, and veried by pill count.
The primary outcome was the incidence of t rea tme nt
change, defined as any event which necessitated a change
or discontinuation of the initial HAART regimen, excluding
dosage change or interruption of a drug for less than 14 days.
The reasons for treatment change included:
1. Death (from any cause)
2. Treatment failure defined as a new or recurrent AIDS-
defining illness diagnosed at least six months after the
initiation of HAART
3. Non-adherence to therapy dened as ingestion of less than
90% of the prescribed doses of drugs. Patients who did not
return for follow-up after ini tiation of HAART were also
considered to be non-adherent.
4. Drug toxicity (WHO Grade 3 and 4) requiring substitution
or immediate discontinuation of the oending drug3
Statistical methods: Statistical Package for the Social Sciences
(SPSS) software package (version 11.0) was used for data analysis.
Rate of HAART regimen change was calculated as the number
of events over the person-years follow-up. The time to change
was estimated using Kaplan-Meier method. Determinants of
treatment change were assessed by constructing univariate
logistic regression models with “HAART regimen change” as
the dependent variable. Odds ratio (OR) and condence intervals
(CI) were calculated and a two-sided ‘p’ value less than 0.05
was considered statistically significant. Baseline parameters
considered as possible determinants of treatment change were
age, sex, duration of HIV infection (from the time of diagnosis
to initiation of HAART), WHO clinical stage, BMI, alanine
aminotransferase (ALT) and aspartate aminotransferase (AST)
> 40 IU/ml, baseline CD4 cell counts, and HAART regimen
used.
The study was approved by the institutional review board of
Christian Medical College, Vellore, and written informed consent
was obtained from all participants.
Results
Baseline characteristics (Table 1): Subjects were enrolled
between March 2004 and May 2006. A total of 230 consecutive
ART-naive patients were followed up for a median period of 48
weeks. The majority (74.8%) were males and the median age of
the study population was 37 years [inter-quartile range (IQR), 34
to 44; mean (+ S.D), 38.9 (+ 8.4) years]. The route of acquisition
of HIV infection was heterosexual contact in the majority
(98.7%). Two patients had acquired the infection through blood
transfusion, and one through homosexual contact. Majority (70.4
%) of the patients had advanced stages of HIV infection (WHO
clinical stage 3 or 4). The median CD4 cell count at baseline was
112.5 cells/µL (IQR: 57 to 190 cells/µL; mean (+ S.D) 127.7 (+
81.06) cells/µL.
HAART regimens used (Figure 1): Sixty eight percent of
the patients initiated treatment with a combination of d4T +
3TC + NVP. Stavudine was part of the NRTI backbone in 76%
of the patients. Nevirapine was the NNRTI used in 86% of the
patients. Twenty six (11.3 %) patients received concomitant anti-
tuberculous therapy. All patients also received trimethoprim-
sulfamethoxazole (TMP-SMX) prophylaxis (except one who
received dapsone due to TMP-SMX allergy).
Primary outcome (Figure 2): Total follow-up time was
approximately 173 person-years, with a median duration of
follow-up of 48 weeks (IQR, 16 to 52 weeks; mean (+S.D), 39
(±24.2) weeks). The cumulative incidence of treatment change of

386 © JAPI • MAY 2009 • VOL. 57
the initial HAART regimen was 39.6% (91 patients). The median
time to treatment regimen change was 12 weeks.
Reasons for initial HAART regimen change (Table 2):
1. Deaths: Eight (3.5%) subjects died during follow up. The
mortality rate was 4.6/100 person-years. Five deaths
were due to related causes; two patients died due to drug
toxicities (one had toxic epidermal necrolysis and the other
lactic acidosis), and three due to treatment failure.
2. Drug toxicity: WHO Grade 3 or 4 toxicities occurred in 62
patients (27%) and were the commonest reason for treatment
change. The incidence rate for drug toxicity was 35.9/100
person-years.
3. Non-adherence: Nineteen patients (8.3%) were non-adherent
(incidence rate 11/100 person-years).
4. Treatment failure: Seven patients (3%) developed new or
recurrent AIDS-defining illnesses during the follow-up
period, an incidence rate of 4.1/100 person years. The
events were disseminated tuberculosis (seven patients)
and cytomegalovirus retinitis (one patient). Four among
these also had oropharyngeal candidiasis. Three patients
eventually succumbed to these illnesses.
Drug toxicity (Table 3): The commonest drug toxicities we
observed were lactic acidosis (LA), anemia and peripheral
neuropathy. All of these were attributable to the thymidine
analogue NRTI (d4T and AZT).
Table 1 : Baseline characteristics of subjects initiated on
HAART (N = 230)
Characteristic
Age (years)
Median
Interquartile range
37
34 - 44
Male sex (%) 74.8
Route of acquisition
Heterosexual (%) 98.7
WHO Clinical Stage
1
2
3
4
8 (3.5%)
60 (26.5%0
104 (45.2%)
58 (25.2%)
Hemoglobin (g/dL)
Median
Interquartile range
11.75
10.25 - 13
Serum creatinine (mg/dL)
Median
Interquartile range
0.9
0.8 – 1.1
CD4 cell counts (cells/µL)*
Median (IQR)
Mean (±SD)
< 50
50 – 200
> 200
112.5 (57 – 190)
127.7 (±81.06)
42 (21%)
113 (56.5%)
45 (22.5%)
* Missing values = 30
Fig. 1 : Initial HAART regimes
d4T + 3TC + NVP,
157, 68%
AZT + 3TC + NVP,
41, 18%
d4T + 3TC + EFV,
18, 8%
AZT + 3TC + EFV,
14, 6%
Fig. 2 : Kaplan-Meier analysis for cumulative incidence of treatment
change
Proportion of
patients
remaining
on initial
HAART
regimen
Time (in weeks)
1.0
.9
.8
.7
.6
.5
.4
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Table 2 : Reasons for treatment change of the initial HAART
regimen
Event Frequency (%) Incidence rate
(per 100 person-years)
Drug toxicity 62 (68.1) 35.9
Non-adherence 19 (20.9) 11.0
Treatment failure 7 (7.7 ) 4.1
Deaths#3 (3.3) 2.4
Total 91 (100)
#Eight patients died during the follow-up (incidence rate 4.6/100
person-years). Three of them were attributed to treatment failure, two
to drug toxicity, and three were due to unrelated (accident / suicide)
causes.
Table 3 : Incidence of drug toxicity
Drug toxicity Frequency
(Cumulative
incidence)
Incidence rate (per
100 person-years)
Lactic acidosis 20 (8.7%) 11.6
Severe anemia 16 (7.0%) 9.3
Peripheral
neuropathy
12 (5.2%) 7.0
Severe drug rash 9 (3.9%) 5.2
Hepatitis 3 (1.3 %) 1.7
Others (pancreatitis) 2 (0.9 %) 1.1
Total 62 (27%) 35.9

© JAPI • MAY 2009 • VOL. 57 387
LA was diagnosed in 20 (8.7%) patients, an incidence rate
of 11.6/100 person-years. All these patients were on d4T. The
median time to diagnosis of LA was 42 weeks (range 24 to 67
weeks). The mean (±SD) venous bicarbonate and anion gap levels
in these patients were 15 (±5.3) mmol/L and 22.5 (±6.4) mmol/L
respectively. The mean level of venous lactate in these patients
was 3.7 mmol/L. One patient died due to severe metabolic
acidosis. Severe anemia (WHO Grade 3 or 4) was diagnosed
in 16 (7.0%) patients (incidence rate 9.3/100 person-years). The
median time to diagnosis of anemia was 8 weeks (range 3 to 36
weeks). Severe, symptomatic peripheral neuropathy was the
reason for treatment change in 12 (5.2%) patients (incidence
rate 7/100 person-years). The median time to development of
peripheral neuropathy was 32 weeks (range 20 to 56 weeks).
Severe rash [Stevens-Johnson syndrome or toxic epidermal
necrolysis (TEN)] occurred in 9 (3.9%) patients, and one patient
who had TEN died. The median time to treatment change due
to drug rash was 2 (range 2 to 6) weeks.
Predictors of treatment change: A univariate logistic
regression analysis showed the following factors to be signicant
predictors of treatment regimen change:
1. Advanced HIV infection (WHO clinical stage 3, 4) [OR, 1.59;
95% CI, 1.38 to 1.88].
2. Duration of HIV infection (from the time of diagnosis to
initiation of HAART) more than 3 months [OR, 1.22; 95%
CI, 1.04 to 1.44].
3. Current smoking [OR, 2.16; 95% CI, 1.52 to 3.06].
4. BMI > 25 kg/m2 [OR, 1.56; 95% CI, 1.18 to 2.06].
5. AST levels > 40 U/L [OR, 2.26; 95% CI, 1.47 to 3.47]
6. ALT levels > 40 U/L [OR, 4.07; 95% CI, 2.36 to 6.99]
In the multivariate model, advanced HIV infection (OR, 1.39;
95% CI, 1.21 to 1.61; p <0.001), current smoking (OR, 1.51; 95%
CI, 1.08 to 2.18; p <0.02), BMI more than 25 kg/m2 (OR, 1.68; 95%
CI, 1.29 to 2.18; p <0.001) and baseline elevated ALT (OR, 2.48;
95% CI, 1.60 to 3.49; p 0.001) remained predictors of treatment
regimen change. Age, sex, route of HIV acquisition, CD4 cell
counts and individual regimens were not associated with the
HAART regimen change.
Discussion
We analyzed the outcome of generic, xed-dose combination
ART regimens recommended by NACO in 230 ART-naïve adult
PLHA followed up at a tertiary care teaching hospital in south
India. The majority of patients had advanced HIV infection
(WHO clinical stage 3 or 4 and CD4 cell count less than 200 cells/
µL). The cumulative incidence of treatment regimen change in
this cohort was 39.6%. The incidence of mortality (4.6 per 100
person-years) and disease progression (4.1 per 100 person-years)
was low and drug toxicity was the most important reason
(35.9 per 100 person-years) for treatment change. This rate of
treatment change is signicantly higher than hitherto reported
from India. Kumarasamy et al8 reported that 20% of their patients
had modied their rst-line HAART regimen, most often due to
adverse events. In the TREAT Asia HIV Observational Database,
the overall rate of treatment change among patients starting rst-
line triple combination antiretroviral treatment was 29 per 100
person-years, adverse events again being the commonest reason.9
Possible reasons for our nding include the advanced stage of
immunosuppression of our patients and intensive monitoring
for adverse drug reactions.
The initial choice of HAART regimen offers the best chance
to control HIV replication. Potency of the regimen is the rst line
of defense against the development of resistance. Other factors
that aect resistance development include tolerability, potential
for optimum adherence, and genetic and pharmacologic
barriers to development of resistance. The cumulative rate of
treatment failure among adults in a large government funded
ART programme at the largest HIV care center in India10 was
3.9% (95% CI, 2.9 to 4.9%). This finding, very similar to ours, is
an indication of the potency of the first-line HAART regimens
recommended by WHO and NACO. However, we observed
that tolerability was poor. Forty percent of our patients had to
change their regimen by 48 weeks. This could adversely impact
adherence and lead to emergence of resistance and eventually
treatment failure.
The most common drug toxicities we observed (lactic acidosis,
anemia and peripheral neuropathy) were all caused by the
thymidine-analogue NRTI, stavudine and azidothymidine.
Lactic acidosis is due to the inhibition of mitochondrial DNA
polymerase by the NRTI. Among the NRTI, stavudine and
didanosine are much more likely to cause this complication
than tenofovir or abacavir. Risk factors for this potentially life-
threatening condition include simultaneous use of stavudine
and didanosine, long duration of NRTI use, female gender and
high baseline BMI. The clinical manifestations of this disorder
(which occurs several months after starting HAART) are quite
non-specic, and the diagnosis is conrmed by demonstration of
metabolic acidosis with elevated anion gap, and elevated venous
lactate levels. Any delay in diagnosis due to a lack of awareness
of the manifestations or laboratory infrastructure may lead to
avoidable mortality due to severe metabolic acidosis. Signicant
anemia, which occurs most commonly 4 to 6 weeks after
starting treatment, is due to inhibition of erythropoiesis by AZT.
Therefore, routine monitoring of hemoglobin is recommended
during the initial 4 weeks after starting AZT-based regimen.3;4
Drug toxicity may be life-threatening, disfiguring or
distressing, thus adversely aecting quality of life and potential
for optimum adherence. Lack of adherence ultimately leads
emergence of resistance to antiretroviral drugs and treatment
failure. Serious toxicities occurred as early as 2 weeks (drug rash)
or as late as 42 weeks (lactic acidosis) in our cohort, emphasizing
the need for continued vigilance for months after initiation of
HAART. There is also a need for intense laboratory monitoring to
diagnose drug toxicity early (anemia while on AZT and hepatitis
while on NVP). This is bound to put an enormous strain on the
healthcare infrastructure providing HAART to large number
of PLHA. Therefore, there is an urgent need to provide drug
regimes which are potent, efficacious, safe and tolerable and
require only a minimum of laboratory monitoring.
Patients with advanced HIV infection were more likely to
change the initial HAART regimen. This nding underscores the
need for improved case nding, routine monitoring of CD4 cell
counts and treatment initiation before patients develop severe
immunodeciency.
Our study has several possible limitations. Cohort surveillance
was not active. Plasma viral load testing was not performed at
follow-up visits. Therefore we may have underestimated the
proportion of subjects with treatment failure. Our patients might
not be completely representative of HIV-infected patients in
India. We studied patients who were followed-up at a medical
college. Therefore, care should be taken in extrapolating these
results.

388 © JAPI • MAY 2009 • VOL. 57
In conclusion, the currently recommended first-line HAART
regimens have achieved their primary objective of reducing
HIV related morbidity and mortality. They are however, poorly
tolerated due to several short-term and long-term toxicities.
There is an urgent need to introduce HAART regimens which
are potent, safe, well tolerated and convenient.
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