Epidemiology of human immunodeficiency virus (HIV) drug resistance in HIV patients with virologic failure of first-line therapy in the country of Georgia.

Human immunodeficiency virus (HIV) drug resistance is a major threat to the sustained impact of antiretroviral therapy (ART). We studied the epidemiology of drug resistance in the country of Georgia. The study included all adult patients who experienced virologic failure on first line ART and received HIV drug resistance testing between 2005 and 2016. The Stanford HIV Sequence Database was used for interpretation of the resistance data. Patient-level data were extracted from the national AIDS health information system. Of the 447 patients included, 85.5% harbored the subtype A6 virus, 8.0% - subtype B, 2.9% - subtype G, and other subtypes were <1%. The most frequent first-line regimens were Tenofovir/Emtricitabine/Efavirenz (28.4%), Zidovudine/Lamivudine/Efavirenz (28.4%), and Abacavir/Lamivudine/Efavirenz (15.9%). A total of 85.0% of the patients with treatment failure developed at least one drug resistance mutation affecting their susceptibility to ART. The most frequent nucleoside reverse transcriptase inhibitor mutations were M184V (65.3%), K65R (19.7%) and L74V (17.0%). At least three thymidine analogue mutations were detected in 6.3% of the patients. From non-nucleoside reverse transcriptase inhibitor mutations, G190S was shown to be the most prevalent (49.4%), followed by K101E (27.10%) and K103N (24.4%). G190S and K101E were more common in subtype A as compared with non-A viruses (G190S: 54.9% vs 11.3%, P < 0.0001; K101E: 29.8% vs 11.3%, P = 0.005). On the other hand, K103N was more frequent in non-A subtypes (43.4%) compared with subtype A (22.2%), P = 0.0008. A majority of persons failing on ART had HIV drug resistance. Drug resistance patterns may vary by subtype. K65R mutation remains below 20%, but given the high use of Tenofovir in the country, continuing surveillance of drug resistance is needed.

Impact of hepatitis C virus recombinant form RF1_2k/1b on treatment outcomes within the Georgian national hepatitis C elimination program.

AIM: Hepatitis C virus (HCV) recombinant form RF1_2k/1b is common in ethnic Georgians. This chimera virus contains genomic fragments of genotype 2 and genotype 1 and is misclassified as genotype 2 by standard genotyping. We aimed to identify RF1_2k/1b strains among genotype 2 patients and assess its impact on treatment outcomes. METHODS: The study included 148 patients with HCV genotype 2 as determined by 5-untranslated region/core genotyping assay. RF1_2k/1b was identified by sequencing the non-structural protein 5B region. Patients were treated within the national hepatitis C elimination program with sofosbuvir/ribavirin (SOF/RBV), interferon (IFN)/SOF/RBV, or ledipasvir (LDV)/SOF/RBV. RESULTS: Of 148 patients, 103 (69.5%) had RF1_ 2k/1b. Sustained virologic response (SVR) data was available for 136 patients (RF1_ 2k/1b, n = 103; genotype 2, n = 33). Sustained virologic response was achieved in more genotype 2 patient than in RF1_2k/1b patients (97.0% vs. 76.7%, P = 0.009). Twelve weeks of LDV/SOF/RBV treatment was highly effective (100% SVR) in both genotypes. Among RF1_2k/1b patients, LDV/SOF/RBV for 12 weeks was superior (100% SVR) to SOF/RBV for 12 weeks (56.4%, P < 0.0001) or 20 weeks (79.2%, P = 0.05). Twelve weeks of IFN/SOF/RBV also showed better response than SOF/RBV for 12 weeks (88.9% vs. 56.4%, P = 0.02) in these patients. CONCLUSIONS: High prevalence of the RF1_2k/1b strain can significantly affect treatment outcomes. Treatment with IFN/SOF/RBV and especially LDV/SOF/RBV ensured significantly higher SVR in patients infected with RF1_2k/1b strain compared to standard HCV genotype 2 treatment with SOF/RBV. There is a need to reassess existing methods for the management of HCV genotype 2 infections, especially in areas with high prevalence of the RF1_2k/1b strain.

Late presentation of HIV infection in the country of Georgia: 2012-2015.

Late presentation for HIV care has important individual and population implications. The objective of this study was to explore the problem of late presentation in the country of Georgia. Data on adult persons newly diagnosed with HIV in Georgia between 2012 and 2015 were extracted from the national AIDS Health Information System. Late presenter was defined as a person diagnosed with HIV with a CD4 cell count <350 cells/mm3 or an AIDS defining illness regardless of the CD4 cell count in the six months after HIV diagnosis. Late presenter with advanced disease was defined as a person diagnosed with HIV with a CD4 cell count <200 cells/mm3 or an AIDS defining illness, regardless of CD4 cell count in the six months after HIV diagnosis. Among 2267 adults diagnosed with HIV in Georgia in 2012-2015, 1987 (87.6%) had CD4 cell count measured within 6 months of HIV diagnosis and were included in the analysis. Among them 1260 (63.4%) patients were classified as late presenters and 870 (43.8%) as late presenters with advanced disease. The proportion of late presenters declined from 71.1% in 2012 to 55.5% in 2015 (p<0.0001), while presentation late with advanced disease decreased from 56.6% in 2012 to 34.5% in 2015 (p<0.0001). Late presentation was most common among people who inject drugs (77.7%). Overall 186 patients died over the studied period. Mortality was higher both among late presenters (6.74 per 100 person-years vs. 1.08 per 100 person-years, p<0.0001) and late presenters with advanced disease (8.93 per 100 person-years vs. 1.34 per 100 person-years, p<0.0001). High prevalence of late presentation in Georgia reflects insufficiency in HIV testing services. Better testing strategies are needed to improve earlier diagnosis and disease outcomes.

Progress Toward Achieving the UNAIDS 90-90-90 Goals in HIV Care From Diagnosis to Durable Viral Suppression in the Country of Georgia.

Successful engagement in HIV care is required to reach UNAIDS targets of 90-90-90. We analyzed routine programmatic data to quantify losses along the HIV care continuum in the country of Georgia. Analysis was limited to diagnosed persons and did not include estimated number of HIV-infected persons. Cascade of HIV care continuum was constructed for adult (age ≥18 years) HIV-infected persons newly diagnosed in Georgia in 2008-2012. Data were extracted from the national AIDS Health Information System as of June 30, 2014. Among 1,931 patients included, the median age was 37 years, 72% were men, and 40.7% had CD4 count <200 cells/mm3. A total of 1,711 (88.6%) were linked to care, 1,333 (69.0%) ever started antiretroviral therapy (ART), 1,044 (54.1%) ever achieved viral suppression, and 792 (41.0%) maintained viral suppression till the end of follow-up. Overall, 1,139 patients were lost from HIV diagnosis to maintaining viral suppression, including 761 (66.8%) patients who remained alive and 378 (33.2%) patients who died. Among 378 deceased patients, 324 (85.7%) died before achieving viral suppression after the median 3.5 months since diagnosis and 54 (14.3%) died after achieving viral suppression after the median 21.2 months since diagnosis. Among 761 alive patients without viral suppression, 297 (39.0%) were fully disengaged, 144 (18.9%) had never been prescribed ART, 161 (21.2) either never achieved suppression or discontinued ART, and 159 (20.9%) experienced rebound while on ART. Efforts are needed to improve earlier HIV diagnosis, to reduce the number of patients not in care, and to extend durability of viral suppression.

Significant Improvements Are Needed in HIV Care Continuum to Meet 90-90-90 Targets in Georgia.

The objective of this report was to assess Georgia's progress toward Joint United Nations Programme on HIV/AIDS 90-90-90 targets over the period between 2011 and 2015. The number of HIV-positive persons was estimated using Spectrum software. Number of persons diagnosed, on antiretroviral therapy (ART) and virally suppressed were quantified using data from the national AIDS health information system. By the end of 2015, out of the estimated 7100 persons living with HIV, 62% were diagnosed, 38% were on ART, and 32% were virally suppressed. There were improvements in each stage of cascade from 2011 to 2015: the proportion of diagnosed persons increased from 46% to 61%, ART coverage among diagnosed persons increased from 46% to 62%, and the proportion of virally suppressed patients among those on ART increased from 74% to 85%. Despite the progress, additional efforts are needed to reach the 90-90-90 targets. Reducing the number of people living with undiagnosed HIV will be critical for achieving goals.

High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment.

AIM: The first hepatitis C virus (HCV) recombinant, RF2k/1b, was initially described from Russia and has since then been identified from patients in Ireland, Estonia, Uzbekistan and Cyprus. Many of these patients originated from Georgia; however, there is no information on its prevalence in Georgia or its susceptibility to antiviral treatment. METHODS: We retrospectively sequenced the non-structural region 5B (NS5B) of the HCV genome in samples from 72 Georgian patients, 36 of whom had been treated with pegylated interferon and ribavirin. RESULTS: The HCV genotype was determined using the Versant HCV Genotype v2 kit. Based on this typing, 32 patients (44.4%) were infected with genotype 1, 21 (29.1%) genotype 2 and 19 (26.3%) genotype 3. Partial NS5B of these strains was sequenced and analyzed for type, with concordant genotype results for all type 1 and 3 strains. Discrepant results were observed for genotyped 2 strains, with 16 (76%) having NS5B of subtype 1b. On phylogenetic analysis, 15 NS5B sequences of these strains were found in a clade formed by recombinant RF2k/1b strains. The remaining discordant sequence was found within a clade formed by 1b strains. CONCLUSION: Our findings show that the RF2k/1b recombinant strain is common among Georgian patients previously assumed to be infected with genotype 2. Because genotyping is mainly performed to decide treatment strategies, there is a need to determine the genotype by analysis of at least two genomic regions in strains from Georgian patients considered infected with genotype 2 based on standard HCV genotyping methods.

Etiologic agents of central nervous system infections among febrile hospitalized patients in the country of Georgia.

OBJECTIVES: There is a large spectrum of viral, bacterial, fungal, and prion pathogens that cause central nervous system (CNS) infections. As such, identification of the etiological agent requires multiple laboratory tests and accurate diagnosis requires clinical and epidemiological information. This hospital-based study aimed to determine the main causes of acute meningitis and encephalitis and enhance laboratory capacity for CNS infection diagnosis. METHODS: Children and adults patients clinically diagnosed with meningitis or encephalitis were enrolled at four reference health centers. Cerebrospinal fluid (CSF) was collected for bacterial culture, and in-house and multiplex RT-PCR testing was conducted for herpes simplex virus (HSV) types 1 and 2, mumps virus, enterovirus, varicella zoster virus (VZV), Streptococcus pneumoniae, HiB and Neisseria meningitidis. RESULTS: Out of 140 enrolled patients, the mean age was 23.9 years, and 58% were children. Bacterial or viral etiologies were determined in 51% of patients. Five Streptococcus pneumoniae cultures were isolated from CSF. Based on in-house PCR analysis, 25 patients were positive for S. pneumoniae, 6 for N. meningitidis, and 1 for H. influenzae. Viral multiplex PCR identified infections with enterovirus (n = 26), VZV (n = 4), and HSV-1 (n = 2). No patient was positive for mumps or HSV-2. CONCLUSIONS: Study findings indicate that S. pneumoniae and enteroviruses are the main etiologies in this patient cohort. The utility of molecular diagnostics for pathogen identification combined with the knowledge provided by the investigation may improve health outcomes of CNS infection cases in Georgia.

Virologic outcomes of second-line antiretroviral therapy in Eastern European country of Georgia.

BACKGROUND: Data on the effectiveness of second-line antiretroviral therapy (ART) in resource-limited countries of Eastern Europe is limited. Objective of this study was to evaluate virological outcomes of second-line ART in Georgia. METHODS: We conducted retrospective analysis using routinely available program data. Study included adult HIV-infected patients with confirmed HIV drug resistance, who were switched to second-line ART from August 2005 to December 2010. Patients were followed until July 1, 2011. Primary outcome was achievement of viral suppression. Demographic, clinical, laboratory and adherence data were abstracted from medical and program records. Adherence was expressed as percentage based on medication refill data, and was calculated as days supply of medications dispensed divided by days between prescription fills. Predictors of primary outcome were assessed in modified Poisson regression analysis. RESULTS: A total of 84 patients were included in the study. Among them 71.4% were men and 62% had history of IDU. All patients were receiving non-nucleoside reverse transcriptase based regimen as initial ART. The mean 6-month adherence prior to virologic failure was 75%, with 31% of patients showing 100% adherence. All patients were switched to protease inhibitor based regimens. Patients were followed for median 27 months. Over this period 9 (10.7%) patients died. Among 80 patients remaining alive at least 6 month after ART regimen switch, 72 (90%) patients ever reached undetectable viral load. The mean first 6-month adherence on second-line treatment was 81%, with 47.5% of patients showing 100% adherence. The proportion of patients achieving viral suppression after 6, 12, 24 and 36 months of second-line ART did not vary significantly ranging from 79 to 83%. Percentage of IDUs achieving viral suppression ranged from 75% and 83%. Factors associated with failure to achieve viral suppression at 6-months of second-line ART were: adherence <80% (Risk ratio [RR] 5.09, 95% CI: 1.89-13.70) and viral load >100,000 at the time of treatment failure (RR 3.39, 95% CI: 1.46-7.89). CONCLUSIONS: The study demonstrated favourable virological outcomes of the second-line ART in Georgia. Majority of patients, including IDUs, achieved sustained virological response over 36 month period. The findings highlight the need of improving adherence.

Estimating HIV incidence in eastern European country of Georgia: 2010-2012.

The knowledge of HIV incidence is essential to better understand patterns of HIV transmission. We estimated HIV incidence over 2010-2012 in the eastern European country of Georgia. Mathematical modeling using Spectrum software and assay-based recent infection testing algorithm were applied. The study included 1155 HIV patients newly diagnosed in 2010-2012 (84% of total diagnoses). Of them, 231 were determined to be recently infected on the recent infection testing algorithm. The proportion of recent cases did not differ between 2010, 2011 and 2012 (20.4% vs. 19.4% vs. 20.2%, p = 0.94). Both study methods derived comparable estimates ranging from 0.2 to 0.3%, which is up to twice as high as rates of new diagnosis reported in the same period. Despite the relatively stable HIV incidence over 2010-2012, the epidemic continues to grow because of the increasing gap between HIV-infected and diagnosed persons. Increased efforts are needed to reduce the number of people with undiagnosed HIV.

Poor agreement between interferon-gamma release assays and the tuberculin skin test among HIV-infected individuals in the country of Georgia.

BACKGROUND: Improved tests to diagnose latent TB infection (LTBI) are needed. We sought to evaluate the performance of two commercially available interferon-gamma release assays (IGRAs) compared to the tuberculin skin test (TST) for the diagnosis of LTBI and to identify risk factors for LTBI among HIV-infected individuals in Georgia, a country with high rates of TB. METHODS: HIV-patients were enrolled from the National AIDS Center in Tbilisi, Georgia. After providing informed consent, each participant completed a questionnaire, had blood drawn for QuantiFERON-TB Gold in-Tube (QFT-GIT) and T-SPOT.TB testing and had a TST placed. The TST was read at 48-72 hrs with ≥ 5 mm induration considered positive. RESULTS: Between 2009-2011, 240 HIV-infected persons (66% male) with a median age of 38 years and a median CD4 count of 255 cells/µl (IQR: 124-412) had diagnostic testing for LTBI performed. 94% had visible evidence of a BCG scar. The TST was positive in 41 (17%) patients; QFT-GIT in 70 (29%); and T-SPOT.TB in 56 (24%). At least one diagnostic test was positive in 109 (45%) patients and only among 13 (5%) patients were all three tests positive. Three (1%) QFT-GIT and 19 (8%) T-SPOT.TB test results were indeterminate. The agreement among all pairs of tests was poor: QFT-GIT vs. T-SPOT.TB (κ = 0.18, 95% CI .07-.30), QFT-GIT vs. TST (κ = 0.29, 95% CI .16-.42), and TST vs. T-SPOT.TB (κ = 0.22, 95% CI .07-.29). Risk factors for LTBI varied by diagnostic test and none showed associations between positive test results and well-known risk factors for TB, such as imprisonment, drug abuse and immunological status. CONCLUSIONS: A high proportion of HIV patients had at least one positive diagnostic test for LTBI; however, there was very poor agreement among all tests. This lack of agreement makes it difficult to know which test is superior and most appropriate for LTBI testing among HIV-infected patients. While further follow-up studies will help determine the predictive ability of different LTBI tests, improved modalities are needed for accurate detection of LTBI and assessment of risk of developing active TB among HIV-infected patients.

Characterization of HIV-1 subtypes and drug resistance mutations among individuals infected with HIV in Georgia.

In order to describe HIV-1 subtypes and drug resistance mutations in Georgia, blood samples from 153 patients infected with HIV-1 collected from 2006 to 2008 were genotyped. Of these, 126 samples were from newly diagnosed, antiretroviral (ARV)-naïve patients and 27 from ARV-treated patients. Partial pol region sequences were used to identify drug resistance mutations and to conduct phylogenetic analysis for subtype determination. The results indicated that 138 (90.2%) patients harbored subtype A viruses, 11 (7.2%) carried subtype B virus, two subtype G (1.3%), one (0.6%) subtype F and one (0.6%) 03_AB recombinant. All subtype A strains clustered with the Former Soviet Union A (A FSU) subtype. Among patients with no prior exposure to ARVs, mutations associated with resistance were detected in five patients: three (2.4%) patients had reverse transcriptase (RT) inhibitor mutations and two other patients had the protease (PI) inhibitor associated mutation M46I. PI mutation V77I was found in 42 of subtype A isolates. Of 27 ARV-treated patients, 22 (81.5%) harbored at least one nucleoside reverse transcriptase inhibitors (NRTI), a non-NRTI (NNRTI) and/or a PI mutation. The most common NRTI resistance mutation was M184V/I (74.1%). Frequency of thymidine analog mutations was relatively low (25.9%). With regard to NNRTI mutations, G190S/A was the most frequent mutation, which might be a preferred mutations for subtype A. Georgia's HIV epidemic continues to be dominated by Subtype A FSU. The prevalence of transmitted drug resistance is low, but has the potential to increase with increasing use of ARVs.

IL28B favorable genotype and ultrarapid viral response as the earliest treatment predictors of a sustained viral response in a Georgian cohort infected with the hepatitis C genotype 1.

OBJECTIVES: The early identification of factors contributing to the successful treatment of hepatitis C infection is important for researchers and clinicians. Studies carried out on the role of an ultrarapid viral response (URVR) for the prediction of a sustained viral response (SVR) have shown its high positive predictive value (PPV). However, data on the combined effect of URVR with IL28B genotypes for the prediction of SVR are lacking. Our aim was to study the role of URVR and IL28B genotypes in the prediction of SVR among patients in Georgia infected with genotype 1. METHODS: Of a total of 156 patients enrolled in the study, 143 were included in the final analyses. Viral load testing for monitoring the viral response was carried out at 3, 24, 48, and 72 h and at 1, 2, and 4 weeks after the initiation of treatment. IL28B single nucleotide polymorphisms in rs12979860 were genotyped using real-time PCR methods. RESULTS: Our study showed that URVR was the earliest treatment predictor among genotype 1 patients harboring the IL28B C/C genotype (PPV-100%). Moreover, the C/C genotype was found to have a high PPV among genotype 1 patients without URVR or a rapid viral response, unlike patients infected with genotype 2 or 3. URVR and IL28B C/C genotypes were not as predictive of an SVR among genotype 2 and 3 patients; however, rapid viral responses were highly predictive of an SVR in these patients. CONCLUSION: Our results suggest that testing for IL28B genotypes and viral load at weeks 1 and 2 may improve the ability to predict an SVR among hepatitis C virus genotype 1 patients; this information may be useful to ensure patient compliance with treatment.

Outcomes of Universal Access to Antiretroviral Therapy (ART) in Georgia.

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 141 cells/mm(3). 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 216 cell/mm(3) and 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.

Experience of antiretroviral treatment in Georgia.

INTRODUCTION: HIV infection is the major public health, social and economic problem in Georgia. Although the HIV epidemic is in its nascent phase in the country, the potential risk for development of a wide spread HIV epidemic is very high. The aim of this study is to evaluate the effectiveness of ARV treatment principles in Georgia, including treatment and monitoring methods. MATERIALS AND METHODS: The study included 985 people living with HIV/AIDS in Georgia registered at Infectious Disease, AIDS and Clinical Immunology Research Center since 2004. To ensure universal access to ARV therapy all HIV/AIDS individuals included in the study were investigated by special algorithm, all identified patients requiring ARV therapy were offered treatment and monitored during therapy on treatment effectiveness and side effects. HIV-1 RNA in plasma was measured by quantitative Polymerase Chain Reaction. For determination of percentages and absolute count of T-lymphocyte subpopulations single-platform immunophenotyping technique using the Becton-Dickinson FACSCalibur flow cytometer was applied. For resistance testing TRUGENE HIV-1 Genotyping Kit with the OpenGene DNA Sequencing System (Siemens) was used. Reasons of treatment failure and mortality rate among ARV treated patients were analyzed. RESULTS AND CONCLUSIONS: Treatment was offered to 398 HIV/AIDS patients. 397 patients started treatment, 1 patient refused. Out of 397 HIV/AIDS patients treated 21 patients discontinued, 54 patients died and 322 patients are currently on ARV treatment. Out of the treated patients 281 adults and 11 children are receiving first-line treatment, 27 adults and 2 children are on second-line treatment and 1 adult is receiving salvage regimen. Treatment failure was defined in 52 cases. Among them immunological failure was observed in 7 cases, clinical failure in 1 case and virologic failure in 44 cases. Prevalence of drug resistance among virologic failure cases accounted for 73% and inadequate adherence for 27% cases. Out of drug resistance cases 3% has three-class drug resistance, 84%--two-class drug resistance and 13% found to be resistant to one class. In ARV naive patients the prevalence of drug resistance to any class was 4.33%. The majority of death cases among ARV treated patients was due to non-AIDS related or incurable conditions, while deaths due to AIDS related conditions were mainly associated with delayed referral of patients in already advanced stage of disease. It's worth to mention that the highest number of death cases was due to liver failure in HIV/HCV and/or HBV co-infected patients.

Prevalence of drug-resistant and nonsubtype B HIV strains in antiretroviral-naïve, HIV-infected individuals in New York State.

The duration of HIV infection is usually unknown for most patients entering into HIV care. Data on the frequency at which resistance mutations are detected in these patients are needed to support practical guidance on the use of resistance testing in this clinical situation. Furthermore, little is known about HIV subtype diversity in much of the United States. Therefore, we analyzed the prevalence of drug resistance mutations and nonsubtype B strains of HIV among antiretroviral-naïve individuals presenting for HIV care in New York State between September 2000 and January 2004. Sequences were obtained using a commercial HIV genotyping assay. Seventeen of 151 subjects (11.3%; 95% confidence interval 7.2%-17.3%) had at least one drug-resistance mutation, including 5 subjects with fewer than 200 CD4(+) T cells, indicative of advanced infection. Nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, and protease inhibitor resistance mutations were detected in 6.6%, 5.3%, and 0.7% of subjects, respectively. Subjects from New York City-based clinics were less likely to have resistant virus than subjects from clinics elsewhere in New York State. Nonsubtype B strains of HIV were detected in 9 (6.0%) individuals and were associated with heterosexual contact. Two nonsubtype B strains from this cohort also carried drug-resistance mutations. These data indicate that drug-resistant virus is frequently detected in antiretroviral-naïve individuals entering HIV care in New York State. Furthermore, a diverse set of nonsubtype B strains were identified and evidence suggests that nonsubtype B strains, including those carrying drug-resistance mutations, are being transmitted in New York State.