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Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
15
Original Article
Antiretroviral Therapy for HIV Infection:
Time to Switch to Once-Daily Regimens?
Raman Gaikwad1, Ram Gopalakrishnan2, Sheela Nagusah1, D Sureshkumar3,
V Ramasubramanian 2
Abstract
Editorial Viewpoint
Background: Data is scarce regarding virologic and immunologic
outcomes and the side-effect profile of antiretroviral therapy in the
private health sector in India.
• Single pill therapy for
HIV/AIDS has improved
compliance and in
turn virological and
immunological response.
Methods: We retrospectively reviewed the case records of 250 HIV
infected individuals being followed up at a private sector hospital, with
emphasis on the nature of antiretroviral regimens prescribed, virologic
and immunologic response to therapy and the side-effect profile of
medications.
Results: Once daily co-formulated tenofovir-emtricitabine-efavirenz
was the most commonly used antiretroviral regimen (58% of patients).
Virologic suppression (HIV RNA quantitative RT-PCR <200 copies/ml) was
achieved in 79% of patients at 6 months, 81% patients at 1 year and 87%
at 5 years. The mean CD4 count at treatment initiation was 191 cells/
µl, and increased to 359 cells/µl after 1 year and to 521 cells /µl after
5 years. Stavudine was stopped in 16.7% due to side-effects, abacavir
associated hypersensitivity reactions developed in 13%, zidovudine
associated anemia developed in 5.2% and tenofovir was discontinued
due to nephrotoxicity in 1.4%. Serum LDL, fasting blood glucose and
serum creatinine did not significantly change over time in our patient
population.
Conclusions: In a private sector setting, ART with co-formulated single
tablet TDF/FTC/EFV resulted in excellent virologic suppression and
immune reconstitution and had few adverse effects over a follow up
period of almost 5 years. Nephrotoxicity was not a major concern and it
may not be necessary to monitor blood glucose and lipid profiles on this
regimen. Based upon our results and WHO guidelines, we recommend
that the public sector ART program adopt annual virologic monitoring
and switch to single pill once daily relatively non-toxic formulations as
first-line regimens.
Introduction
T
he prevalence of HIV in India
is estimated to be 0.31%,
corresponding to 2.39 million
people infected with HIV. 1 While
approximately 486,000 people
were receiving care in the public
healt hcare sect or in 2012, 2 the
number of those treated in the
private sector remains unknown.
Although private healthcare
practices account for 80% of
• Co-formulated tenofoviremtricitabine-efavirenz is
most commonly used.
• T e n o f o v i r - i n d u c e d
nephrotoxicity is the
major adverse event.
outpatient visits and 60% of
inpatient care overall, 3 there is
considerable heterogeneity in
available resources and quality of
care. Data regarding antiretroviral
therapy outcomes in this setting is
scarce. While regimens containing
stavudine, zidovudine and
nevirapine (all of which are twice
daily regimens with multiple daily
pills) are usually used in the public
sector, 4 the WHO recommended
co-formulated regimen of TDF/
FTC/EFV5 is often used in the
private sector. We conducted a
retrospective review of patients
on longitudinal follow up for
HIV infection in a private sector
hospital.
Material and Methods
We analyzed the case records
of 250 patients attending the
Infectious Diseases Clinic at a
1
Infectious Diseases Fellow, 2Consultant in Infectious Diseases, 3Associate Consultant, Department of Infectious
Diseases, Apollo Hospitals, Chennai, Tamil Nadu
Received: 03.04.2014; Revised: 15.07.2014; Accepted: 07.08.2014
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Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
Table 1: Baseline clinical characteristics
N (denominator )
*
Age (in years)
Male gender
Married
Persons with HIV positive spouses
Women with HIV positive children
HIV II infection
Males reporting MSM behaviour
Prior blood transfusions
WHO stage I disease
WHO stage II disease
WHO stage III disease
WHO stage IV disease
Tuberculosis
Extrapulmonary tuberculosis
Pulmonary tuberculosis
Cryptococcal Meningitis
Pneumocystis jirovecii pneumonia
Diabetes
Hypertension
Chronic kidney disease
Hepatitis B
Hepatitis C
*
160
222
86 (135)
11 (90)
4
4 (160)
31
67 (227)
33 (227)
18 (227)
99 (227)
123
107
16
6
24
35
18
6
7
2
Percent value
(95% confidence intervals)
41 (40.5-43.4)
64 (57.9-69.7)
88.8 (84.3-92.3)
63.7 (56.8-72.7)
8.9 (4.5-16.5)
1.6 (0.6-4.0)
2.5 (0.9-6.2)
12.4 (8.8-17.0)
30.9 (25.1-37.3)
15.2 (11.0-20.6)
8.3(5.3-12.7)
45.6(39.1-52.2)
49.2 (43.1-55.4)
42.6 (36.8-49.0)
6.4 (4.0-10.1)
2.4 (1.1-5.1)
9.6 (6.9-13.9)
14 (10.2-18.8)
7.2 (4.6-11.1)
2.4 (1.1-5.1)
2.8 (1.4-5.7)
0.8 (0.2-2.8)
If not specified, denominator is 250 patients
private sector tertiary care referral
hospital. Patients above the age of
18 years with a positive HIV ELISA
test were included in the study.
Patients had entered clinical care
from January 2001 to July 2013 and
remained on follow-up since.
Demographic data included
gender, age at entry into clinical
care, marital status and partner
HIV status, WHO clinical stage at
diagnosis, prior history of blood
transfusions, self-reported MSM
and intravenous drug abuse.
Opportunistic infections during the
course of illness, their prophylaxis
and treatment, vaccinations
received and co-morbid illnesses
(diabetes, hypertension, coronary
artery disease, hepatitis B infection,
hepatitis C infection, chronic
kidney or liver disease, syphilis)
were analyzed.
The details of antiretroviral
r e g i m e n s r e c e i ve d , s e r i a l C D 4
cell counts and HIV viral loads,
significant drug toxicities,
metabolic parameters and other
major clinical events were recorded.
Results
Demographic Features
The average age at patient entry
into clinical care was 41 years and
average duration of follow up was
4.8 years. Males comprised 64% of
the patients. The HIV status of the
spouse was known for 135 patients:
36.3% (n=49) of these were serodiscordant. Four patients were
infected with HIV-II virus. Four of
160 males (2.5%) reported having
male sexual partners.
Clinical Characteristics
The commonest opportunistic
infection diagnosed was
tuberculosis (49%). Other clinical
characteristics are summarized in
Table 1.
Baseline CD4+ Lymphocyte Counts and
HIV Viral Loads
The mean CD4+ lymphocyte
count at entry into care was 259
(95% CI 231-288) cells/ µl. Patients
with CD4+ counts of more than
500 cells/µl accounted for 15.3%
of patients, while 49.5% had a
CD4+ count less than 200 cells/
µl. The mean CD4+ count at the
time of initiation of ART was 191
cells/µl. The mean log10 viral
load (copies/ml) at entry into
care was 4.78 (95% CI 4.62-4.94),
corresponding to 60,255 copies/ml.
Fifty three percent of patients had
a viral load >100,000 copies/ml at
study entry.
Vaccinations
Influenza and pneumococcal
(either polysaccharide or conjugate)
vaccines were administered in 74%
and 77% patients, respectively.
54.8% patients received hepatitis
B vaccine.
Antiretroviral Regimens (Table 2)
NNRTI based ART regimens
were used as the first-line regimen
in 96% (n=216). The most frequently
e m p l o ye d i n i t i a l r e g i m e n wa s
co-formulated single pill once
daily tenofovir, emtricitabine and
efavirenz in 58.6% (n=132). Protease
inhibitor based regimens were used
in 29 patients, of whom 19 patients
(8.4% of 225) received them as
second-line regimens after failure
of NNRTI based regimens.
Response to ART (Table 3)
HIV Viral Loads
At 6 months after initiation of
treatment, 79% of 62 patients (in
whom data was available) had
a viral load <200 copies/ml with
58% having <40 copies/ml. At 1
year after treatment initiation,
81% of 105 patients (in whom data
was available) had a viral load
<200 copies/ml with 75% having
<40 copies/ml. Among patients
receiving co-formulated TDF/FTC/
EFV, 79% and 84% patients had a
viral load less than 200 copies/ml at
6 months and 1 year respectively.
Of those followed up for more than
5 years, 87% of 66 patients had
a viral load less than 200 copies/
ml. Virologic suppression (<200
copies/ml) was achieved in 90%
and 74% of patients receiving TDF
and non-TDF based regimens after
1 year of treatment (p=0.10, Fischer
Exact Probability Test).
CD4+ Counts
O n e ye a r a f t e r i n i t i a t i o n o f
treatment, the mean CD4 count
Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
Table 2: Initial antiretroviral therapy
Table 3: Response to ART
Total 225 patients
TDF+FTC+EFV
ZDV+3TC+EFV
ZDV+3TC+NVP
D4T+3TC+EFV
D4T+3TC+NVP
TDF+3TC+EFV
Virologic and
value
immunologic
(95% confidence
parameters (n) [units]
intervals)
CD4 count (cells/µl)
At entry into care (n=241) 259 (231-188)
At ART initiation (n=171) 191.8 (167-216)
n (%)
132 (58.7)
26 (11.6)
22 (9.8)
12 (5.3)
6 (2.7)
5 (2.5)
rose to 358 (95% CI 325-392) cells/
µl. At this stage, 20% patients had
a CD4 count <200 cells/μL. There
was no significant difference in the
CD4 count increment after 1 year
of treatment between patients who
were started on zidovudine-based
regimens compared to those started
on tenofovir based regimens (212
vs 208 cells/µl, p=0.91, Wilcoxon
Rank-Sum Test).
Toxicity of Antiretroviral Therapy
Stavudine was stopped in
16.7% (6 of 36 patients) due to
lactic acidosis, steato-hepatitis or
peripheral neuropathy. Abacavir
associated hypersensitivity
developed in 13% (three of 22
patients); HLA-B 5701 typing
prior to abacavir initiation was not
performed. Zidovudine-associated
anemia developed in 5.2% (4
o f 7 6 p a t i e n t s ) . Te n o f o v i r wa s
discontinued due to nephrotoxicity
in 1.4% (3 of 211 patients). Efavirenz
was discontinued in 1 patient due
to neuropsychiatric symptoms.
Metabolic Changes (Table 4)
Patients on antiretroviral
therapy did not have increased
mean fasting blood glucose levels
compared to baseline (117 vs
111 mg/dl, p=0.69). The serum
creatinine tended to be higher in
these patients (0.99 vs 0.90 mg/dl);
however the difference was not
statistically significant (p=0.097).
Though serum total cholesterol rose
After 1 year of ART
359 (325-392)
(n=122)
After 5 years of ART
521 (450-592)
(n=46)
Viral load (log10 copies/ml)
At entry into care (n=159) 4.78 (4.62-4.94)
After 6 months of ART
1.34 (0.95-1.72)
(n=62)
After 1 year of ART
0.96 (0.63-1.28)
(n=107)
After 5 years of ART
0.70 (0.35-1.05)
(n=66)
Viral load (less than 200 copies/ml)
At 6 months of ART
79%
At 1 year of ART
81.3%
At 5 years of ART
87.9%
significantly from 157 mg/dl to 190
mg/dl (p=0.009), LDL cholesterol
was not significantly increased
(101 vs 101 mg/dl, p=0.97). HDL
cholesterol was significantly higher
in treated patients (51 vs 39 mg/
dl, p=0.014). Serum triglycerides
were also unchanged (165 vs 173,
p=0.25).
Discussion
We hereby describe a cohort of
HIV positive patients undergoing
c a r e i n a p r i va t e h o s p i t a l i n
India who were managed with
n e we r a n t i r e t r o v i r a l r e g i m e n s
in accordance with the WHO /
US DHHS guidelines. Although
mean CD4 count at entry into care
was generally higher than seen
in public hospital settings, 6 about
half of our pat ient s present ed
w i t h a d va n c e d d i s e a s e ( W H O
stage 3 or 4). Tuberculosis was
the commonest opportunistic
Table 4: Metabolic changes
Metabolic parameters
Fasting blood glucose
Serum creatinine
Serum total cholesterol
Serum HDL cholesterol
Serum LDL cholesterol
Serum triglycerides
*
ART Naïve
117 [98-135]
0.90 [0.85-0.94]
157 [135-180]
39 [32-47]
101 [84-117]
165 [101-229]
After 5 years of ART; +Wilcoxon rank sums
With ART*
111 [97-126]
0.99 [0.91-1.06]
190 [179-200]
51 [46-57]
101 [93-109]
173 [146-200]
P value+
0.694
0.097
0.009
0.014
0.973
0.254
17
infection with almost half of our
patients developing the disease. 7
The prevalence of hepatitis B (2.8%)
and C (0.8%) was generally similar
to those in other HIV cohorts in
India.8,9 We also achieved high rates
of pneumococcal and influenza
vaccination, a practice that is not
commonly followed in developing
countries.
We m e a s u r e d v i r a l l o a d s a t
baseline and on follow up visits for
the majority of patients and showed
a 6 month virologic suppression of
almost 80%, comparable to other
cohorts. 10 Our 5 year virologic
s u p p r e s s i o n r a t e o f 8 7 % wa s
also comparable to other studies
and probably due to the efficacy
and tolerability of once daily
T D F / F T C / E F V. 1 1 T h e r e wa s n o
difference between virologic and
immunologic outcomes at one
year between TDF-based regimens
and other regimens. We suggest
that virologic monitoring at least
annually be routinely incorporated
into public sector programs as per
recent WHO guidelines. 12
Significant progress has been
made in increasing access to
antiretroviral therapy in the public
sector and the cost of generic
antiretroviral drugs has fallen
over time. However many patients
seek care in the private sector and
pay for antiretroviral therapy: coformulated TDF/FTC/EFV costing
approximately 1700 INR (~30 USD)
per month was the most commonly
used regimen in our cohort of
patients. This is in contrast to
the public sector program where
nevirapine and zidovudine are used
as part of twice daily multiple pill
initial regimens and TDF/FTC/EFV
is considered an alternative firstline regimen. 4 Co-formulated TDF/
FTC/EFV had a one year virologic
suppression rate of 90% and was
well tolerated with low rates of
a d ve r s e e f f e c t d r i ve n r e g i m e n
change (mostly due to tenofovir
associated renal dysfunction in
1.4%). Renal function also did not
deteriorate significantly over time;
this was reassuring and suggested
18
Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
that tenofovir nephrotoxicity was
not a major issue, similar to other
studies. 13 In contrast, patients who
received zidovudine, stavudine
or abacavir (without prior HLA
B5701 testing) had a high incidence
of drug toxicities and resultant
regimen changes.
Antiretroviral therapy has been
associated with hyperlipidemia
and hyperglycemia, especially
when older NRTI or PI based
regimens are used. 14 We found
no evidence that our patients had
adverse lipid profiles or impaired
glucose tolerance over time while
on ART. Fasting blood glucose,
LDL cholesterol, and triglycerides
did not change significantly and
HDL cholesterol actually rose over
5 years of follow-up. We attribute
this to the generally favorable
metabolic side effect profile of
TDF/FTC/EFV, which most of our
patients were on. We suggest that
lipid and blood glucose monitoring
need not be performed annually
as recommended in guidelines, in
view of our findings of minimal
toxicity.
Our results demonstrate that
patients receiving antiretroviral
therapy in a private sector setting
in a developing country are able
t o a c h i e ve d u r a b l e v i r o l o g i c a l
suppression and a sustained rise in
CD4 count with minimal toxicity,
despite paying for the care. We
believe adherence was the key,
facilitated by once a day therapy
with a single pill with minimal side
effects. A progressively smaller
fraction of HIV infected patients
are diagnosed, are prescribed
antiretroviral regimens, maintain
drug adherence and achieve
virologic suppression. Therefore,
it is important to mitigate the
barriers along the road to virologic
suppression. 15 To facilitate this
goal, we recommend that public
sector HIV clinics in India adopt
WH O guidelines such as viral
load testing at least annually after
commencing ART and use of once
a day co-formulated TDF/FTC/
EFV or similar regimens in place
of older and more toxic regimens.
Abbreviations
ART – Antiretroviral Therapy,
NNRTI- Non-nucleoside reverse
transcriptase inhibitor, FTC –
Emtricitabine, EFV – Efavirenz, TDF
– Tenofovir, WHO – World Health
Organisation, US DHHS – United
States Department of Health and
Human Services, NACO – National
AIDS Control Organisation.
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