HIV care in Istanbul,Turkey: How far is it from the UNAIDS 90–90

Abstract

The prevalence of human immunodeficiency virus (HIV) infection is low but it is steadily increasing in Turkey. In the current study, we aimed to assess the status of HIV infection management with the proposed 90–90–90 targets in a large HIV cohort in Istanbul, Turkey. The cohort included 2382 patients (2082 male, 300 female, mean age was 36.3 ± 11.3 years). Mean CD4 cell count was 399 cells/mm³ and HIV-RNA level was 576,235 copies/ml. According to the modeling by the Modeling tool of European Center for Diseases Control Software, 72 and 74% of all HIV patients had been diagnosed in 2016 and 2017, respectively (the first target). Among 2382 patients, 2191 (92%) were on antiretroviral therapy (the second target). The third target of virally suppressing those on treatment was achieved among 70.2% of the patients. The current study suggests that both the fraction of those living with undiagnosed HIV and the proportion of those on treatment who are virally suppressed should be targeted to sustain optimal HIV care. Efforts should continue to surpass the targets of 90–90–90.

Keywords

Human immunodeficiency virus diagnosis antiretroviral treatment 90–90–90

Introduction

Human immunodeficiency virus (HIV) infection is a global healthcare problem. International efforts aimed at reducing HIV transmission emphasize HIV testing and early initiation of antiretroviral therapy (ART). Current evidence shows that early diagnosis and ART initiation reduce morbidity and mortality and improves life expectancy¹ and quality of life² for people living with HIV (PLWH). PLWH who remain undiagnosed have a higher risk of transmission of the virus to other individuals and ART reduces HIV transmission rates.³ The concept of ‘Treatment as Prevention’ provides maximum benefits for the goals of elimination of HIV globally if PLWH are diagnosed early and retained in clinical care with effective viral suppression.⁴

Aiming to end the HIV epidemic by 2030, the Joint United Nations Programme on HIV/AIDS proposed the 90–90–90 targets which have been approved by the United Nations.^5,6 The 90–90–90 targets propose that by 2020, at least 90% of all PLWH should be diagnosed, at least 90% of those diagnosed should be on ART, and at least 90% of those on ART should be virologically suppressed, corresponding to a final target of at least 73% of all PLWH achieving virologic suppression. AIDS-related deaths are expected to decrease by 90% with full implementation of the 90–90–90 targets.

HIV infection prevalence is low but it is steadily increasing in Turkey. The first HIV/AIDS case in Turkey was described in 1985. HIV testing is performed before every surgery, blood donation, and in premarital screening for every individual and also for registered sex workers.⁷ Risk groups are sex workers, injection drug users, and men who have sex with men (MSM)^8,9 and these groups are screened routinely. HIV prevalence among MSM is high in Istanbul: a recent study reported 12.7%.¹⁰ According to the Turkish Ministry of Health (MoH), there were 18,557 cases of HIV infection and 1736 cases of AIDS out of a population of 80.81 million people in Turkey between October 1985 and December 2018.¹¹ The prevalence is highest in the age groups of 25–29 and 30–34 years. There is a male predominance (78.2%) and heterosexual intercourse is the leading cause of transmission. A multi-centered cohort study showed that 52.4% of patients were late presenters (CD4 cell count <350 cells/mm³ or presenting with an AIDS-defining event).¹²

There is an increasing trend to increase in the number of newly-diagnosed PLWH in recent years: 1083 in 2012, 1411 in 2013, 2031 in 2014, 2270 in 2015, and 2573 in 2016.

HIV care is freely available for every patient in Turkey. The drugs are reimbursed by the state. Turkey has two national guidelines. The first was produced in 2013 endorsed by the MoH and has not been updated.¹³ The second was produced in 2018 as a joint action of five HIV/AIDS societies and is used by many clinicians.¹⁴ Treatment of all PLWH regardless of the CD4 cell count was included in the recommendations of the National HIV Guidelines in 2013 and has been practiced by clinicians in Turkey since then. CD4 and viral load (VL) testing are widely available in the country.

In the current study, we aimed to summarize the preliminary results of a large HIV cohort in Turkey and assess the status of HIV infection management according to the proposed 90–90–90 targets.

Patients and methods

All patients diagnosed with HIV infection in all dedicated centers were recorded in a database. The study period included 1 January 2016 to 31 December 2017. The institutions included in the study were four dedicated HIV clinics of university or training hospitals in Istanbul. No specific centers (for MSM or IDUs) were available in the country; therefore the centers cared for all PLWH. The data were retrospectively collected by each attending physician and independently monitored thereafter. The data as of November 2017 were analyzed to detect the current status of HIV infection in Turkey with respect to 90–90–90 targets.

The study participants were recruited from the HIV infection in Istanbul (HIV-Ist) cohort. The cohort included longitudinal individual-level data on PLWH in the Istanbul region. It is a prospectively designed cohort study and the Strengthening the Reporting of Observational Studies in Epidemiology guideline was followed.¹⁵ The testing and ART are reimbursed at no cost and without copayments. The database captures demographics, laboratory, and clinical information of all participants.

Duplicate reports were eliminated by comparing the name codes of the patients’ given cases. Estimates of the percent of PLWH who remained undiagnosed were calculated by the modeling tool of The European Centre for Disease Prevention and Control (ECDC).¹⁶ The tool is a back-calculation model using the rate of CD4 decline and HIV notification data to estimate the diagnoses over time and produces an estimate of the percentage of undiagnosed. The model uses two methods: the London method only works for CD4 count levels below 350 cells/mm³ for which the rate of symptoms is sufficiently large. The ‘Incidence Method’ requires most data but can also provide most detailed estimates.¹⁷ This method estimates HIV incidence over time and time to diagnosis by CD4 cell count strata and then estimates the undiagnosed HIV-infected population.¹⁸

The Incidence Method uses a mathematical model to estimate the number of HIV infections in a year, the probability of HIV diagnosis based on the CD4 cell count, and the time between infection and diagnosis. The parameters of the number of HIV infections, the diagnosis probability, and the time to diagnosis are estimated by comparing expected model outcomes with observed data on HIV and AIDS diagnoses. The bestmatching set of parameters is determined by repeatedly changing the values of the unknown parameters and comparing expected model outcomes with observed data. After the number of HIV infections and the time to diagnosis has been estimated, the method calculates the number of individuals living with HIV, including those not yet diagnosed.¹⁸

The inclusion criteria consisted of all diagnosed PLWH enrolled in the HIV-Ist cohort, aged >17 years old. HIV/AIDS was defined as a confirmed HIV test positivity, a detectable VL of >50 copies/ml, or an HIV-related physician visit or hospitalization or a reported AIDS-defining disorder or the dispensation of ART.^19,20

Definition of targets

First 90, %Diagnosed: The data in the cohort were used for the currently diagnosed PLWH. To estimate the infected but undiagnosed PLWH, a simulation software, the diagnostic tool of the ECDC was used. The diagnoses of patients by years, CD4 cell count, and patients with AIDS were determined and entered into the software.

Second 90, %On ART: Among patients with PLWH, those receiving ART for at least three months within a year were calculated.^19–21

Third 90, %Suppressed: An undetectable plasma VL (<200 copies/ml) in PLWH on ART^18,19 was noted. Number on ART whose most recent HIV RNA measurement in the given year that was <200 copies/ml or below the level of detection of the assay was detected. Those who in-migrated by end of the given year were included and those who out-migrated or died by end of given year were excluded. Those with missing VL measurements in the given year were assumed to be unsuppressed.^19,20

This study was approved by the Ethics Committee of Cerrahpasa Medical School (83045809-604.01.02).

Results

First ‘90’ (proportion diagnosed)

According to the modeling by ECDC Software, 72 and 74% of all PLWH were diagnosed in 2016 and 2017, respectively (Figure 1).

Figure 1.

Diagnosed and predicted undiagnosed HIV/AIDS cases in 2016–2017 in Istanbul, Turkey.

Second ‘90’ (proportion treated)

The cohort included 2382 patients (2082 male, 87.4%; 300 female, 12.6%). Mean age was 36.3 years (standard deviation 11.3 years, range: 16–79 years). Mean CD4 cell count was 399 cells/mm³ and HIV-RNA level was 576,235 copies/ml (Table 1). All were Caucasian and 214 (9%) were foreign nationals.

Table 1.

Characteristics of all (n:2382) PLWH in the cohort.

	Baseline	Week 48
Age (years)	36.3 ± 11.3
CD4 cell count (cells/mm³)	399 ± 272	497 ± 248
HIV-RNA (copies/ml)	576,235 ± 1,241,053	13,289 ± 17,185

Among 2382 patients, 2191 (92%) were on ART, while 191 (8%) were not on treatment (Figure 2). This figure shows that PLWH receiving ART among those who presented to the hospitals included in the study have met the target of providing ART to at least 90% of those diagnosed.

Figure 2.

Flowchart of the patients diagnosed, given antiretroviral therapy (ART), and those available for viral suppression analysis. ART: antiretroviral therapy.

Third ‘90’ (proportion virally suppressed)

The third goal of virally suppressing 90% of the PLWH was determined in 2191 patients on treatment. Due to several reasons (182 patients lost to follow-up after initial visit without any virologic test, 51 patients died, and 104 patients out-migrated), 337 patients were excluded and 2047 patients remained available for virologic suppression analysis. Among them, 1436 achieved virologic suppression (70.2%) (Figure 2).

Tables 1 and 2 show characteristics of all the patients in the cohort and those given treatment, respectively. Decrease in HIV-RNA level and increase in CD4+ cell count are statistically significant during the 48 weeks of the treatment period (p < 0.0001 for both) (Table 2 and Figure 3).

Figure 3.

HIV RNA levels and CD4 cell count at baseline and treatment weeks 24 and 48.

Table 2.

Characteristics of 2047 PLWH with treatment data in the cohort.

	Baseline	Week 48	P*
Age (years)	38.4 ± 13.6
CD4 cell count (cells/mm³)	293 ± 252	472 ± 202	<0.0001
HIV-RNA (copies/ml)	872,767 ± 3,370,435	22,770 ± 315,223	<0.0001

*Repeated measures t test.

On treatment, it appears that 1436 out of 2047 (70.2%) patients had viral loads < 200 copies/ml.

Discussion

The concept of 90–90–90 enables us to look at the continuum in HIV care and estimates the gaps in management, and thus gives a future perspective for HIV care in a given country. Based on observed data and ECDC modeling, we estimate that 72–74% of the PLWH were diagnosed, 92% were given ART, and 70.2% had sustained a virologic response.

Substantial numbers of patients were lost at step 1 and 3 and this relatively poor outcome emphasizes the holistic role of HIV care in maintaining viral suppression in the country. The low diagnosis rate remains a challenge because of the high transmission rate of undiagnosed patients and their late admission with advanced disease since they are mostly asymptomatic.²² There is a need especially for sustained HIV screening and high treatment coverage to reduce HIV incidence significantly. This cohort includes 2382 patients. The number of patients reported by the Ministry of Health from 1985 to 2017 (13,158 cases of HIV infection and 1537 cases of AIDS) is cumulative and includes 15% of foreign nationals. The cohort includes 13% of the currently diagnosed patients in the country. Analysis of the data from the Ministry of Health and from the cohort suggests that the diagnosis rate is lower than the UNAIDS target of 90%.

Almost half of the patients in the country are diagnosed during a diagnostic work-up for medical conditions/illnesses.^13,14 The percentage diagnosed by screening for blood donation or presurgical screening is low (17–20%). The cases presenting with a sexually transmitted infection or with an AIDS-defining disorder represent a late presentation, challenging for both transmission to other individuals and response to ART.²³ Among those diagnosed, ¾ are in the age group of 20–45 years and the main route of transmission is heterosexual intercourse. We estimate that this age group also has the highest prevalence of undiagnosed cases and screening strategies should target this age group.

The rate of patients on ART is relatively better than other steps of HIV care in the country. Adherence to ART seems high, reaching 85%.²⁴ In an adherence study, we detected that during ART, 90% reported no missed doses in the past four days and 78% reported no missed doses in the past month.²⁴ However, the adherence rates depend on self-report questionnaire and the relatively low rate of viral suppression at week 48 may be linked to adherence problems. This was supported by lack of resistance in patients with still high levels of VL at week 24 or week 48 in some patients.

Retention of PLWH in care is critical for effective HIV management. Movement of the patients from one HIV clinic to another is frequent in the country and this may underestimate retention rates. Although switching of the patients between centers included in the study was easily noted, switching to other centers could not be noted and recorded as lost to follow-up. In the cohort, 70.2% of the patients sustained viral suppression (<200 copies/ml). However, this figure represents the percentage of those with data available for virologic suppression, not for those who are on ART. This rate is comparable to those observed in the studies of antiretroviral-naive, HIV-1-infected adults.^25–28 In another Turkish cohort, at week 48, HIV-RNA was <50 copies/ml in 82% of 311 patients.¹²

The first limitation of the study is that the estimates are based on a large cohort, but it represents only 13% of PLWH in the country. It may not represent the whole country since it includes hospitals only from Istanbul. Since the Ministry of Health’s data did not include CD4 cell count, HIV-RNA levels, treatment information, and retention rates, it could not be used to estimate the undiagnosed in the country. The second limitaiton is the centers included in the cohort are dedicated, experienced centers for HIV care and the data represent the dedicated centers’ care. In the other hospitals, rates of patients on ART, retention rates, and viral suppression rates may not be as high, and suboptimal management of side effects and failing regimens might directly affect retention rates. On the other hand, dedicated centers in the other parts of the county may have provided better figures.

The third limitation concerns the target of virologic outcome searched among 2047 out of 2191 patients. Among them, 1218 patients had a 48-week virologic study result. For the remaining 829, by definition, their most recent virologic study was used and those with missing VL measurements in the given year were assumed to be unsuppressed. Although overall virologic suppression rate is 1436/2047 (70.2%), it is 85% among those with a 48-week virologic outcome and 48.3% for the remaining subpopulation. This suggests that viral suppression is underestimated among those without a 48-week virologic result. Loss to follow-up or lack of adherence to clinical visits leads to an assumption of being unsuppressed and may lower the overall virologic suppression rates.

The number of PLWH has steadily increased in the last decade. The diagnosis rate has increased as well though with a slower pace. The centers caring for PLWH have increased and PLWH dying of AIDS have decreased. However, the current study suggests that only 73% of PLWH have been diagnosed and only 70% of the treated patients achieve sustained viral suppression. The fraction of the undiagnosed should be targeted to sustain greater access to HIV testing. Efforts should continue to surpass the targets of 90–90–90 and should primarily focus on the detection of undiagnosed PLWH in Turkey. Nevertheless, it should be realized that this is a theoretical study and further research is warranted to validate the findings.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Wandeler

Johnson

Egger

Trends in life expectancy of HIV-positive adults on antiretroviral therapy across the globe: comparisons with general population. Curr Opin HIV AIDS 2016; 11: 492–500.

Lifson

Grund

Gardner

, et al. Improved quality of life with immediate versus deferred initiation of antiretroviral therapy in early asymptomatic HIV infection. AIDS 2017; 31: 953–963.

Mayer

Gazzard

Zuniga

, et al. Controlling the HIV epidemic with antiretrovirals: IAPAC consensus statement on treatment as prevention and preexposure prophylaxis. J Int Assoc Provid AIDS Care 2013; 12: 208–216.

Gardner

McLees

Steiner

, et al. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis 2011; 52: 793–800.

The Joint United Nations Programme on HIV/AIDS (UNAIDS). The gap report Geneva. Geneva: UNAIDS, http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/unaidspublication/2014/UNAIDS_Gap_report_en.pdf (2014, accessed 23 February 2018).

United Nations General Assembly. Resolution No. A/RES/70/266, political declaration on HIV and AIDS: on the fast-track to accelerate the fight against HIV and to end the AIDS epidemic by 2030, https://www.unaids.org/sites/default/files/media_asset/2016-political-declaration-HIV-AIDS_en.pdf (2016, accessed 23 February 2018).

Gokengin

Oprea

Begovac

, et al. HIV care in Central and Eastern Europe: how close are we to the target? Int J Infect Dis 2018; 70: 121–130.

Alaei

Waye

, et al. Hepatitis C infection and other drug-related harms among inpatients who injected drugs in Turkey. J Viral Hepat 2017; 24: 496–505.

Ertunc

Kaya

Koksal

Clinico-epidemiological analysis of HIV/AIDS patients. Eurasian J Med 2016; 48: 157–161.

10.

Sargin

Goktas

HIV prevalence among men who have sex with men in Istanbul. Int J Infect Dis 2017; 54: 58–61.

11.

HIV-AIDS Statistics. Turkish Ministry of Health, Public Health Department, 2017. https://hsgm.saglik.gov.tr/tr/bulasici-hastaliklar/862-hivaids/1135-h%C4%B1v-aids-istatislik.html (accessed 27 May 2019).

12.

Korten

Gökengin

Fincanci

, et al. Outcomes of initial antiretroviral treatment (ART) among recently diagnosed HIV patients in HIV-TR cohort, 2011–2012. J Int AIDS Soc 2014; 17: 19678.

13.

Buzgan

Torunoğlu

Gökengin

(eds). HIV/AIDS tanı tedavi rehberi . Ankara: T.C. Sağlık Bakanlığı Türkiye Halk Sağlığı Kurumu, 2013, https://dosyaism.saglik.gov.tr/Eklenti/29508,hiv-aids-tani-tedavi-rehberi-1pdf.pdf?0 (accessed 27 May 2019).

14.

Gökengin

Kurtaran

Korten

, et al. (eds). HIV/AIDS Tanı İzlem ve Tedavi El Kitabı. Türk HIV/AIDS Platformu, https://www.klimik.org.tr/wp-content/uploads/2018/11/HIV_AIDS-El-Kitabı.pdf (2018, accessed 27 May 2019).

15.

Vandenbroucke

von Elm

Altman

, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med 2007; 147: W163–W194.

16.

European Centre for Disease Prevention and Control, HIV modelling tool, 2015. https://ecdc.europa.eu/en/publications-data/hiv-modelling-tool (accessed 31 March 2018).

17.

van Sighem

Nakagawa

De Angelis

, et al. Estimating HIV incidence, time to diagnosis, and the undiagnosed HIV epidemic using routine surveillance data. Epidemiology 2015; 26: 653–660.

18.

HIV Modelling Tool User Manual version 1.0.0. European Centre for Disease Prevention and Control, https://ecdc.europa.eu/sites/portal/files/media/en/healthtopics/aids/Documents/hivmodelling- tool-manual-version1.pdf (2015, accessed 29 October 2018).

19.

UNAIDS Guidance. Global AIDS monitoring 2019. Indicators for monitoring the 2016 political declaration on ending AIDS. Geneva, UNAIDS, 2018.

20.

Gourlay

Pharris

Noori

, et al. Towards standardized definitions for monitoring the continuum of HIV care in Europe. AIDS 2017; 31: 2053–2058.

21.

Heath

Samji

Nosyk

, et al. Cohort profile: seek and treat for the optimal prevention of HIV/AIDS in British Columbia (STOP HIV/AIDS BC). Int J Epidemiol 2014; 43: 1073–1081.

22.

Chkhartishvili

Sharavdze

Chokoshvili

, et al. The cascade of care in the Eastern European country of Georgia. HIV Med 2015; 16: 62–66.

23.

Yemisen

Aydın

Gunduz

, et al. Epidemiological profile of naive HIV-1/AIDS patients in Istanbul: the largest case series from Turkey. Curr HIV Res 2014; 12: 60–64.

24.

Yildiz Sevgi

Gunduz

Altuntas Aydin

, et al. Adherence to antiretroviral therapy in Turkey: results from the ACTHIV-IST study group. AIDS Res Hum Retroviruses 2017; 33: 1192–1198.

25.

Swartz

Vandekerckhove

Ammerlaan

, et al. European Society for translational Antiviral Research (ESAR). Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe. J Antimicrob Chemother 2015; 70: 1850–1857.

26.

Post

Moyle

Stellbrink

, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr 2010; 55: 49–57.

27.

Cohen

Wohl

Arribas

, et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS 2014; 28: 989–997.

28.

Charpentier

Choquet

Joly

, et al. Virological outcome at week 48 of three recommended first-line regimens using ultrasensitive viral load and plasma drug assay. J Antimicrob Chemother 2014; 69: 2819–2825.

HIV care in Istanbul,Turkey: How far is it from the UNAIDS 90–90–90 targets?

Abstract

Keywords

Introduction

Patients and methods

Definition of targets

Results

First ‘90’ (proportion diagnosed)

Second ‘90’ (proportion treated)

Third ‘90’ (proportion virally suppressed)

Discussion

Footnotes

Declaration of conflicting interests

Funding

References