Hindawi Publishing Corporation
AIDS Research and Treatment
Volume 2011, Article ID 621078, 7 pages
Outcomesof Universal Accessto
AntiretroviralTherapy (ART) inGeorgia
Tengiz Tsertsvadze,1,2Nikoloz Chkhartishvili,1LaliSharvadze,1,2NatiaDvali,1
Otar Chokoshvili,1PatiGabunia,1AkakiAbutidze,1KenradNelson,3Jack DeHovitz,4
andCarlos del Rio5
1Infectious Diseases, AIDS and Clinical Immunology Research Center (IDACIRC), 16 Al. Kazbegi Avenue, Tbilisi 0160, Georgia
2Faculty of Medicine, Tbilisi State University, Tbilisi, Georgia
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, W6508,
Baltimore, MD 21205, USA
4Department of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1240 Brooklyn, NY 11203, USA
5Hubert Department of Global Health, Rollins School of Public Health of Emory University, 1518 Clifton Road, NE Room 754,
Atlanta, GA 30322, USA
Correspondence should be addressed to Tengiz Tsertsvadze, email@example.com
Received 15 May 2010; Revised 7 November 2010; Accepted 8 December 2010
Academic Editor: Robin Wood
Copyright © 2011 Tengiz Tsertsvadze et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Since 2004, Georgia achieved universal access to free antiretroviral therapy (ART). A retrospective cohort study was conducted
to evaluate the outcomes of Georgia’s ART program. The study included adult patients enrolled in the ART program from 2004
through 2009. Of 752 patients, 76% were men, 60% were injection drug users (IDU), 59% had a history of an AIDS-defining
illness, and 53% were coinfected with hepatitis C. The median baseline CD4 cell count was 141cells/mm3. During followup, 152
(20%) patients died, with the majority of deaths occurring within 12 months of ART initiation. Mortality was associated with
advanced immunodeficiency or the presence of incurable disease at baseline. Among patients remaining on treatment, the median
CD4 gain was 216cell/mm3and 86% of patients had viral load <400 copies/ml at the last clinical visit. The Georgia ART program
has been successful in treating injection drug users infected with HIV.
The advent of highly active antiretroviral therapy in the
mid 1990s fundamentally altered the natural history of HIV
infection in industrialized countries, resulting in dramatic
reduction in AIDS-related morbidity and mortality [1–3].
However, for many years access to HAART in low- and
middle-income countries was limited, primarily due to the
price of antiretroviral drugs that made them beyond the
reach of most patients. The momentum generated by the
World Health Organization’s “3 by 5” strategy resulted
in considerable progress in expanding access to lifesaving
treatment in resource-limited countries . Analyses of HIV
treatment programs in low- and middle-income countries
have already shown positive outcomes in terms of response
to therapy and declining mortality [5–11].
Georgia, Armenia, and Azerbaijan make up a group
of former Soviet republics known as the South Caucasus
Republics. With the fall of the Soviet Union and the
independence of all these republics in 1991, much of the
social structure supporting health care became increasingly
dysfunctional and the system of national healthcare that held
a high standard for all Soviet citizens fell into disarray as
economies crashed and conflicts within and between the
countries disrupted services and infrastructure. Each one of
these countries has its unique set of problems and issues,
but, in general, their declining economic situations, coupled
with rising drug use and commercial sex work, and their
2 AIDS Research and Treatment
geographic proximity to Russia and Ukraine, countries with
emerging epidemics, make the South Caucasus a region ripe
for the spread of HIV.
Georgia is located at the juncture of Eastern Europe
and Western Asia and is bordered by Russia, Azerbaijan,
estimated to be 4,615,807 in a territory of 26,900sq miles.
The GDP per capita in 2009 was approximately $4,300 US
ranking 103 in the world, and the GINI coefficient was 40.8
ranking 59th in the world. Georgia regained independence
in August of 1991, followed by a two-year civil war that led
to large population migration with internal displacement,
severe poverty, a dysfunctional economy, and disruption of
many national services including healthcare. The country
was stabilized in 1995, but the dire economic position of the
Georgian government necessitated conversion of the state-
funded health care system to a market-driven system. Nearly
half of all Georgians are now forced to forego professional
medical care when sick, opting instead for advice from
friends and relatives, traditional medicine, or no care .
The first case of HIV in Georgia was reported in 1989.
As of December 31, 2009 a cumulative 2,236 HIV cases had
been reported. Among them 1,151 persons developed AIDS
and 479 died. Males constitute the majority (74%), of the
reported HIV/AIDS cases with injection drug use (IDU)
responsible for HIV acquisition among nearly 60% of all
reported cases. The estimated HIV prevalence in Georgia
is less than 0.1%. Antiretroviral drugs have been available
in the country since 1990s, but the access was limited only
to those able to afford them. Since 2004, through support
from the Global Fund, Georgia became the first country
to achieve universal access to antiretroviral therapy (ART).
This major achievement has been acknowledged in the joint
WHI/UNAIDS/UNICEF report on universal access . ART
coverage estimation is based on standard WHO method-
ology using SPECTRUM projection software. According to
this report, Georgia is among few low- and middle-income
countries with highest attainable coverage. The objective of
this study is to evaluate outcomes of Georgia’s free ART
2.1. Study Design. A retrospective cohort study was con-
ducted at the Infectious Diseases, AIDS and Clinical
Immunology Research Center (IDACIRC), in Tbilisi, Geor-
gia, which is the country’s referral institution for HIV/AIDS
diagnosis, treatment, and care. The study population
programfrom2004 throughSeptember 302009, whostarted
therapy for at least six month prior to April 1, 2010.
viral drugs are dispensed in the IDACIRC clinic in the
capital city of Tbilisi as well as at three affiliated regional
centers in the cities of Kutaisi, Batumi, and Zugdidi. HIV
infected persons are identified through state and donor
funded HIV testing and counseling (HTC) services and
screening programs. All persons with positive screening test
results are referred to IDACIRC for confirmatory testing
and if confirmed are initially assessed at IDACIRC. Patients
have the option to continue clinical care either at central or
Provision of therapy is governed by the National
HIV/AIDS Treatment and Care guidelines developed based
on the protocols of WHO as well as the guidelines of major
Western countries [13–16]. The first guidelines were devel-
oped in 2004 and have been regularly updated thereafter.
At the time that the patients included in this analysis were
started on ART, treatment was recommended when the CD4
cell count was ≤200/mm3or if the patient had an AIDS
defining illness. ART was also recommended at CD4 cell
count of ≤350/mm3, based on the CD4 cell decline rate, a
high HIV-1 viral load, and coinfection with viral hepatitis.
Currently, steps are being taken towards implementation of
the recommendation to initiate treatment in all patients with
CD4 cell count of ≤350/mm3.
Identification of patients in need of treatment is based
on following those who don’t qualify for therapy every 3-4
months and monitoring the CD4 cell count and HIV viral
The recommended initial regimen consists of two nucle-
oside reverse transcriptase inhibitors (NRTI) and one non-
nucleoside reverse transcriptase inhibitor (NNRTI). A rito-
navir (r) boosted protease inhibitor (PI) is recommended
in cases when an NNRTI cannot be prescribed. Currently
tenofovir (TDF) + emtricitabine (FTC), zidvudine (AZT), or
abacavir (ABC) + lamivudine (3TC) are used for the NRTI
component of initial regimen. Stavidine (d4T) is no longer
when AZT, ABC, or TDF cannot be used because of severe
toxicity. Since 2008, patients are tested for HLA B ∗ 5701
before starting on an ABC-containing regimen. Efavirenz
(EFV) is the preferred NNRTI with nevirapine (NVP) being
recommended as an alternative to EFV.
experienced patients is based on the drug resistance profile
with the goal of providing patients with at least two, and
preferably three, fully active drugs. In addition to boosted
PIs (ATV/r, DRV/r, FPV/r, LPV/r), new classes of drugs
are also now available for highly treatment-experienced
patients, such as the integrase strand transfer inhibitor
raltegravir (RAL), the fusion inhibitor enfuvirtide (ENF),
and the CCR5 antagonist maraviroc (MVC). Recently, the
new NNRTI etravirine (ETV) has also become available.
As per the Georgian National guidelines, the standard
of ART monitoring relies upon laboratory monitoring of
CD4 count, HIV-1 viral load, and development of resistance
based on a resistance-genotype detection when indicated.
>400copies/ml 6 months after starting therapy or plasma
HIV-1 RNA >50copies/ml 12 months after starting therapy
in a patient who is on potent ART.
AIDS Research and Treatment3
Georgia was the first NIS country to introduce genotypic
resistance testing in 2005 into routine clinical practice. HIV
drug resistance testing is used to guide treatment decisions
during virologic failure and to make decisions as to the most
effective subsequent regimen.
Special attention is paid to adherence to therapy as an
important determinant of treatment success. A program to
promote and maintain antiretroviral adherence has been
developed that includes maintenance of an adherence diary,
pill identification by shape and color, patient self-report
about the medication intake in the preceding 3- to 7-day
period and medication refill using pharmacy records. In
addition, to improve adherence, mobile units to deliver
home-based adherence support operate countrywide.
2.3. Laboratory Assays. Plasma HIV-1 RNA levels were ini-
tially measured using Amplicor HIV-1 Monitor test, version
1.5 (Roche Molecular Diagnostics, Germany), with lower
limit of detection of 400copies/ml. Since 2006, the real-time
PCR assay COBAS TaqMan HIV-1 test (Roche Molecular
Diagnostics, Germany) has been in use with a lower limit of
detection of 40copies/ml.
Determination of CD4+ cell count is based on the
single-platform immunophenotyping technique using the
FACSCalibur flow cytometer (Becton-Dickinson, USA) with
four-color direct immunofluorescence reagent MultiTEST
For genotypic resistance testing, the TruGene HIV-1
Genotyping Kit was employed according to the manu-
facturer’s instructions using OpenGene DNA Sequencing
System (Siemens Medical Solutions Diagnostics, Germany).
The Guidelines Rules version 14.0 and Stanford University
algorithm (http://hivdb.stanford.edu/) were used for resis-
tance interpretation. Mutations listed by the International
AIDS Society-USA Panel were considered .
2.4. Statistical Analysis. Data were obtained from the
National HIV/AIDS electronic database, operated by
HIV cases, including demographic, epidemiological, clinical,
and laboratory data. Information on all patients initi-ating
HAART from 2004 through 2009 was extracted. Obser-
vations were censored as of April 1, 2010. Descriptive
statistics were performed to assess distribution of covariates.
Normality of continuous variables was evaluated using Q-Q
plots. Kaplan-Meier product-limit estimator method was
used to assess probability of survival and probability of
virological failure. Predictors of mortality were evaluated
in multivariate Cox proportional hazards model. The
proportional hazards assumption was tested and was met
for the final model. All tests were two-sided at a significance
level of 0.05. Statistical analyses were performed using SAS v
9.2 (SAS Institute, Cary, NC, USA).
2.5. Ethical Approval. Study was approved by Institutional
Review Board (IRB) of the Infectious Diseases, AIDS and
Clinical Immunology Research Center. The study was based
on information routinely collected as part of the standard of
clinical care of HIV infected individuals.
841 patients started on ART
from 2004 through 2009
152 patients died
566 patients remaining on
therapy as of April 1, 2010
752 patients started on ART for
>6 months prior to inclusion in
lost to followup
Figure 1: Cohort profile.
Since 2004, over 1,800 patients have been seen for HIV
clinical care at the IDACIRC and of these, 841 adults met
the treatment initiation criteria and were enrolled in the
HAART program (through December 2009). This analysis
includes 752 adult patients who had started therapy at least
six months prior to inclusion in the study (Figure 1).
Table 1 summarizes the baseline characteristics of these
752 patients. Their median age was 37 years (Interquartile
range [IQR] 33–43), and 75% were men. The most common
mode of HIV transmission was injection drug use (IDU)-
60%, followed by heterosexual contact (35%). The median
CD4 cell count at treatment initiation was 141cells/mm3
(IQR 76–208), with approximately one third of patients
having a CD4 cell count less than 100cells/mm3. Median
viral load was 5.4 log10 copies per ml (IQR 4.8–5.8).
Fifty-nine percent of patients had a history of an AIDS
defining illness (ADI), with 32.4% having a history of active
tuberculosis. More than half of the patients had antibodies
of chronic Hepatitis B infection, and 6% had dual infection
with HCV and HBV. Fourteen percent of patients had
cirrhosis. Almost 3% of patients had a malignancy.
All but 5 patients were started on an NNRTI-based
regimen, most frequently with EFV (82.9%). AZT + 3TC
was the most common NRTI component of the first ART
regimen (53.0%), followed by ABC + 3TC (27.2%) and
d4T + 3TC (18.3%). After the 2007 revision of the national
HIV/AIDS Treatment and Care guidelines, all patients on
d4T were switched to AZT, ABC, or TDF.
The median duration of followup was 24 months (IQR
10–45 months). During followup, 152 (20.2%) patients died
4 AIDS Research and Treatment
Table 1: Baseline characteristics.
Age, median years (IQR)
Gender, n (%)
Mode of transmission, n (%)
Injection drug use
CD4 cell count, median cells/mm3(IQR)
HIV RNA load, median log10copies/ml (IQR)
AIDS defining illness, n (%)
Malignancy, n (%)
Liver related diseases, n (%)
Initial HAART regimen, n (%)
AZT + 3TC + EFV
AZT + 3TC + NVP
AZT + 3TC + LPV/r
ABC + 3TC + EFV
ABC + 3TC + NVP
ABC + 3TC + LPV/r
TDF + FTC + EFV
TDF + FTC + NVP
d4T + 3TC + EFV
d4T + 3TC + NVP
n = 752
and 34 (4.5%) patients self-discontinued ART/were lost to
follow-up, with overall retention rate of 84%.
Kaplan-Meier estimates of survival probability were 0.84
(95% CI: 0.82–0.87), 0.80 (95% CI: 0.77–0.83), 0.78 (95%
CI: 0.75–0.81), and 0.77 (95% CI: 0.74–0.80) at 12, 24, 36,
and 48 months, respectively (Figure 2). Of 152 patients, 115
(75%) died within 12 months of HAART initiation. Median
time to death was 3 months (IQR 1–10). Most common
causes of death were tuberculosis (34 cases, 22%) and end
stage liver disease (29 cases, 19%). Eleven percent of patients
died due to incurable malignancies at baseline, including
Kaposi’s sarcoma, HIV-related lymphomas, invasive cervical
cancer, lung cancer, and breast cancer. Other causes of death
included cryptococcal meningitis, cardiovascular diseases,
wasting syndrome, and infectious diseases of unknown
Factors associated with mortality were assessed in a
multivariate Cox proportional hazards model. The following
baseline factors were associated with death: male gender
(Hazard ratio [HR] 1.96, 95% CI 1.19–3.24), CD4 cell count
Table 2: Cox proportional hazards model analysis of factors
associated with death.
HR (95% CI)
HR (95% CI)
AIDS defining illness
HR = Hazard ratio, CI = Confidence interval, NS = Not significant.
2.14 (1.38–2.32)1.96 (1.19–3.24)
2.50 (1.82–3.45)2.06 (1.48–2.87)
1.67 (1.15–2.45) NS
2.69 (1.90–3.81)2.01 (1.36–2.96)
1.40 (1.01–1.93) NS
2.05 (1.24–3.40)1.95 (1.36–2.81)
<100cells/mm3(HR 2.06, 95% CI 1.48–2.87), history of an
AIDS-definingillness(HR2.01,95% CI1.36–2.96), cirrhosis
(HR 1.95, 95% CI 1.36–2.81). Other covariates did not
Presence of active TB was fitted into the multivariate model
independently from other ADIs; it showed only active TB to
be marginally significant with an HR of 1.40 (95% CI 1.01–
Among 566 patients still on ART, the median gain
of CD4 cells was 216cells/mm3(IQR 112–348) and 487
(86%) patients had an HIV-1 viral load measurement of
<400copies/ml at their last clinical visit. Data on medication
refill adherence were available starting from 2007; the refill
adherence rates were 85% in 2007, 83% in 2008, and 92% in
Eighty-two patients (10.9%) experienced virological fail-
ure. All of them have been tested for the presence of drug
resistance virus while on a failing regimen. Median time
to virologic failure was 16 months (IQR: 10–28 months).
Kaplan-Meier probability of failure at 12, 24, 36, and
AIDS Research and Treatment5
Survival time (months)
012 24 36 48
At 12 month 0.84
(95% CI: 0.82 – 0.87)
At 24 month 0.8
(95% CI: 0.77 – 0.83)
At 36 month 0.78
(95% CI: 0.75 – 0.81)
At 48 month 0.77
(95% CI: 0.74 – 0.8)
Figure 2: Kaplan-Meier curve of survival probability.
Probability of failure
0 1224 36 48
Time on HAART (months)
At 12 months 0.03
At 24 months 0.11 At 36 months 0.16
At 48 months 0.19
Figure 3: Kaplan-Meier curve of virological failure probability.
48 months were 0.04, 0.11, 0.16, and 0.19, respectively
(Figure 3). Of 82 patients, 65 (79.3%) had mutations con-
sistent with antiretroviral resistance. Resistance to a single
drug class (NRTI or NNRTI) was found in 4 (4.9%) patients;
dual-class drug resistance to NRTI and NNRTI occurred in
61 (74.4%) patients.
The frequency of drug resistance mutations in the
reverse-transcriptase (RT) gene is shown in Figure 4. The
most commonly detected NRTI mutation was M184V/I
(63.4%). The frequency of thymidine analogue muta-
tion (TAM) (M41L, D67N, K70R, L210W, T215Y/F, and
K219Q/E) was relatively low, with only 14 (17.1%) patients
having virus with any TAM. Only five (6.1%) patients had
viruses with ≥3 TAMs. G190S/A was the most frequent
NNRTI mutation (40.2%), followed by K103N (28.1%). No
major PI mutations were detected.
All patients with drug resistant viruses were switched
to second line regimens with boosted PIs. At present, of
56 patients remaining on second-line therapy, 61%, 21%,
11%, and 7% receive LPV/r, ATV/r, DRV/r, and FPV/r
based regimens respectively. Three patients are on salvage
regimens, consisting of ENF plus optimized background
1020 30 40
(a) NRTI Mutations
10 20 3040
(b) NNRTI Mutations
Figure 4: Frequency of resistant mutations in reverse transcriptase
We report the outcomesof the universal ART accessprogram
in Georgia. The program builds upon the successful training
of young clinicians and scientists who started in their train-
ing in the care of HIV/AIDS patients in the 1990s with the
that promotes research. The capacity to provide universal
access to ART has been further strengthened through the
support of the Global Fund. Under this framework, the
approach to ART provision taken by Georgia has been
designed to maximize effectiveness of the intervention.
The IDACIRC mandate—as the lead agency for the
provision of all HIV care activities in the country—ensures
universal access and high retention on therapy, with less than
5% drop-out rate. In addition, a coordinated approach to
ART monitoring, including availability of laboratory moni-
toring (CD4 cell counts, HIV-1 viral load and HIV genotypic
resistance testing), and adherence counseling contributes
to the achievement of optimal outcomes. Establishment of
mobile units for providing home-based adherence support
and monitoring resulted in improvement of medication
refill adherence from 83% in 2008 to 92% in 2009. Good
immunological and virologic responses seen in our cohort
also serve as an evidence of good overall adherence.
6AIDS Research and Treatment
The probability of virological failure in our study was
similar to that reported from developed countries [18,
19]. In contrast to most other resource-limited countries,
where treatment monitoring is limited to clinical findings
and changes in CD4 cell counts , viral load and drug
resistance testing are performed in Georgia as part of the
standard of care. Earlier, we have shown feasibility and
effectiveness of routine use of these laboratory tools in early
identification of patient failing on ART and in improving
clinical outcomes in patients with drug resistant viruses .
Our current analysis corroborates previous findings: overall
the small number of mutations and low frequency of TAMs
is suggestive of shorter exposures to failing regimens among
our patients, thus preventing the opportunity for mutations
Interestingly, the most common NNRTI mutation
detected in our study was G190S/A but not K103N. It is
possible that G190S/A is the favoured NNRTI mutation in
HIV subtype A1—which is the most common circulating
strain in Georgia . Further investigation of clade-specific
resistance pathways is needed to provide more detailed
picture, which may have important implications for the
clinical management of infection with HIV subtype A1.
An important challenge that remains to be addressed
and that has been identified through this study is the early
mortality of patients who start ART in Georgia. As shown
in our analysis, the highest mortality rate was observed
within the first year of ART initiation, with 75% of all
deaths occurring in the first 12 months. Our results are
consistent with findings from other resource-constrained
countries reporting increased risk of mortality early after
starting ART [23–26]. In our study, the majority of deaths
were due to either advanced HIV disease, as evidenced by
severe immunodeficiency due to the history of an ADI or
the presence of incurable non-AIDS defining conditions. At
present a large proportion of persons in Georgia continue
to enter health care very late in the course of their chronic
HIV infection, often resulting from missed opportunities to
among male IDUs, whose HIV disease is further complicated
the twofold increased risk of dying in men compared to
and treatment initiation.
The most common causes of death in our cohort were
TB and end stage liver disease, together accounting for more
than 40% of all deaths. Multivariate analysis showed a strong
association between cirrhosis and death, emphasizing the
problem of coinfection with viral hepatitis, especially with
hepatitis C. Dually infected patients virtually have no access
to this fact, HIV/HCV coinfected patients die from hepatic
disease despite the successful antiretroviral therapy. The high
prevalence of coinfection with HCV among patients with
HIV in Georgia may prevent the full realization of the
benefits of ART, and may compromise the cost-effectiveness
of ART. Recent studies have shown that the availability of
ART does not decrease the risk of mortality among patients
with a dual infection with HIV and HCV . Moreover,
HIV/HCV coinfected IDUs have been shown to be at 7-fold
increased risk of dying from end stage liver disease compared
to HCV monoinfected IDUs .
Another important challenge is HIV/TB coinfection.
The high prevalence of this coinfection in our cohort was
not a surprise given the overall high burden of TB in the
country . However, the high mortality from TB is of
particular concern. Collaboration between the HIV/AIDS
and TB services in Georgia is excellent, and all patients have
free access to both TB treatment and ART. However, it is
clear that the outcomes are not as good as we would have
predicted. One possible challenge is limited information on
TB drug susceptibility as these data were only available for
very few patients. Taking into account the high prevalence of
multidrug resistant TB in Georgia (7% in newly diagnosed
and 27% in previously treated patients ), TB drug
resistance may have contributed to excess death from TB
similar to that experienced in other countries .
As with all studies, limitations should be mentioned.
First, the study was based on data available in national
HIV/AIDS database. Adverse events of ART are carefully
monitored, the data are not entered into electronic database,
and therefore we were not able to determine contribution of
adverse events to outcomes of interest. A further limitation
is that the only baseline information on drug abuse was
available and this precluded us from assessing the impact of
current drug use on outcomes.
In summary, the HIV epidemic in Georgia has entered
a new phase. ART has been successfully introduced in
Georgia, including in IDU population. The next stage is to
maximize and sustain the benefits of ART. Mortality can
be substantially reduced by improving earlier HIV diagnosis
and initiation of ART. The comprehensive program for the
identification and treatment of patients with HIV/AIDS in
Georgia, a relatively low income country, has been quite suc-
cessful in limiting premature mortality and morbidity from
this epidemic disease. Increased efforts and new strategies
HIV/HCV epidemics and their resulting mortality.
This study was supported in part by the NIH/FIC (Emory
AIDS International Training and Research Program, grant
#D43 TW01042 and the New York State International
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