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  • Research article
  • Open Access
  • Open Peer Review

From pills to patients: an evaluation of data sources to determine the number of people living with HIV who are receiving antiretroviral therapy in Germany

  • †1Email author,
  • †1,
  • 2,
  • 3,
  • 4,
  • 5,
  • 6,
  • 7,
  • 8,
  • 9,
  • 10,
  • 11,
  • 12,
  • 13,
  • 1,
  • 1,
  • 1,
  • 1 and
†Contributed equally
BMC Public Health201515:252

https://doi.org/10.1186/s12889-015-1598-4

©  Schmidt et al.; licensee BioMed Central. 2015

  • Received: 16 January 2015
  • Accepted: 27 February 2015
  • Published:
Open Peer Review reports

Abstract

Background

This study aimed to determine the number of people living with HIV receiving antiretroviral therapy (ART) between 2006 and 2013 in Germany by using the available numbers of antiretroviral drug prescriptions and treatment data from the ClinSurv HIV cohort (CSH).

Methods

The CSH is a multi-centre, open, long-term observational cohort study with an average number of 10.400 patients in the study period 2006–2013. ART has been documented on average for 86% of those CSH patients and medication history is well documented in the CSH.

The antiretroviral prescription data (APD) are reported by billing centres for pharmacies covering >99% of nationwide pharmacy sales of all individuals with statutory health insurance (SHI) in Germany (~85%). Exactly one thiacytidine-containing medication (TCM) with either emtricitabine or lamivudine is present in all antiretroviral fixed-dose combinations (FDCs). Thus, each daily dose of TCM documented in the APD is presumed to be representative of one person per day receiving ART. The proportion of non-TCM regimen days in the CSH was used to determine the corresponding number of individuals in the APD.

Results

The proportion of CSH patients receiving TCMs increased continuously over time (from 85% to 93%; 2006–2013). In contrast, treatment interruptions declined remarkably (from 11% to 2%; 2006–2013). The total number of HIV-infected people with ART experience in Germany increased from 31,500 (95% CI 31,000-32,000) individuals to 54,000 (95% CI 53,000-55,500) over the observation period (including 16.3% without SHI and persons who had interrupted ART). An average increase of approximately 2,900 persons receiving ART was observed annually in Germany.

Conclusions

A substantial increase in the number of people receiving ART was observed from 2006 to 2013 in Germany.

Currently, the majority (93%) of antiretroviral regimens in the CSH included TCMs with ongoing use of FDCs. Based on these results, the future number of people receiving ART could be estimated by exclusively using TCM prescriptions, assuming that treatment guidelines will not change with respect to TCM use in ART regimens.

Keywords

  • HIV treatment
  • Composition of ART regimen
  • Antiretroviral drug classes
  • Health market research

Background

Combined antiretroviral therapy (ART) as a standard of care has dramatically reduced mortality and morbidity and has led to an enormous increase in quality of life among people infected with HIV [1,2]. In most patients who receive ART, progression to AIDS or death is increasingly rare [3-5], and their life expectancies have significantly improved [6-8]. However, ART is a complex and lifelong therapy that must be well monitored, coordinated and tracked. Although ART is still not available for a large number of people in need, especially in developing countries [9], the number of people living with HIV who are receiving treatment is increasing worldwide [9]. In industrialised countries, a large number of people living with HIV are under treatment [10]. As HIV has become a chronic disease, an increasing number of people must be treated for decades, making it an important economic and public health issue to gain information on this group. Information on the current number of people living with HIV receiving ART in Germany is scarce owing to a lack of data, and access to personal-level drug prescription data is forbidden because of data protection.

HIV treatment in Germany is characterized by a decentralised structure. Medical care is mainly provided by specialized outpatient centres and office-based HIV specialists, and unlike in many countries people can consult a doctor of their own choice at any time and anywhere in the country. Furthermore, health care in Germany is compulsory for all German citizens and legal residents and is mostly provided by statutory health insurance (SHI) or private health insurance (PHI) [11-13]. SHI occupies a central position in the German health care system. Approximately 85% of German residents are covered by SHI, and nearly 60% of the total health expenditures are borne by SHI [12]. SHI reimburses pharmacies for the prescriptions of those who are covered via specialised pharmacy billing centres. Therefore, the prescription details are electronically recorded. The recording and use of these data are regulated by the social security law (§300 SGB V). Data from health services research such as electronically recorded pharmacy data are being increasingly used for research in Germany. Nevertheless, public health studies using data representing nearly all persons covered by SHI are scarce.

The prescription data include all antiretroviral drugs, regardless of whether they are for permanent or short-term therapies, e.g., post-exposure prophylaxis (PEP). No individual information and, therefore no indications, are available. In contrast, the prospective multi-centre observational German ClinSurv HIV cohort (CSH) ongoing since 1999 is the largest available nationwide source of people infected with HIV and collects detailed information on the initiation, composition and discontinuation of individuals’ daily ART from their participating centres [14].

Since the approval of the first antiretroviral agent, at least in the industrialised world, more than 30 antiretroviral pharmaceuticals, either single-drug formulations or fixed-dose combinations, are available for the treatment of HIV infection [15]. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are still the main components of antiretroviral drug combinations [16] and are recommended as an element of any first-line antiretroviral regimen by therapy guidelines [17-19]. Currently, a combination of three antiretroviral drug classes consisting of two NRTIs and a third agent, either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor (INI), is recommended for first-line therapy [17,18]. During the last decade, it has been recommended that all first-line NRTI combinations contain an element of a thiacytidine medication (TCM), either lamivudine (3TC) or emtricitabine (FTC) [17,19,20]. The two medications are interchangeable, but because of their high antiretroviral similarity with no additional effects, concomitant use should be avoided [17]. NRTI-free regimen such as PI monotherapy are not recommended because of inferior antiviral potency [17,18,21-23]. Because standard ART consists of a combination of at least three antiretroviral drugs given in a multitude of combination regimens, it is impossible to estimate the number of people receiving ART prescriptions based on all single drugs [24]. However, virtually all ART regimens prescribed in different studies in a setting of daily clinical practice contain exactly one TCM [25-33]. Thus, each daily TCM documented in the APD may be assumed to be representative of one person per day treated with ART. It was hypothesised that the ART regimens and treatment interruptions recorded in the CSH were representative of people living with HIV under antiretroviral treatment in Germany and that the prescriptions covered by SHI were comparable with those that were not.

This study used available prescription data sources from both pharmacy billing centres and the CSH to determine the number of people living with HIV currently receiving ART, the number of HIV-infected people with ART experience, and the differences in those numbers over time between 2006 and 2013.

Methods

Data sources used for analysis

ART prescription data (APD)

ART prescription data were provided by Insight Health™ for the years 2006–2013. The data were collected on a monthly basis from billing centres that processed all reimbursed prescriptions from pharmacies based on the date of redemption at the counter. The provider claimed a coverage of >99% within the SHI prescription market. The recorded numbers of prescribed standard units (i.e., numbers of tablets) of each antiretroviral drug were used for this study.

Defined daily doses (DDDs) were determined as recommended in the treatment guidelines [17]. The number of prescribed DDDs was calculated for TCMs depending on the doses of standard units. According to our approach, a DDD that included a TCM represented one person-day, assuming that one person was treated with TCM continuously every day for a quarter, as is recommended by treatment guidelines. In the case of the prescription of a 150 mg dose of lamivudine, 2 tablets were equivalent to one DDD.

The German ClinSurv HIV cohort (CSH)

The Clinical Surveillance of HIV Disease is a nationwide multi-centre, open, long-term observational cohort study for the clinical surveillance of HIV in Germany. The CSH was initiated in 1999 as collaboration between major HIV treatment centres and the Robert Koch Institute (RKI) which serves as the coordinating institution. Anonymised data on patient demographics, detailed information on antiretroviral treatment, laboratory parameters and clinical events are collected biannually in a standardised format. The study design is described in detail elsewhere [14]. In the study period 2006–2013, an average number of 10.400 patients were observed and consecutively monitored at 15 clinical centres in various, predominantly urban areas in Germany. Antiretroviral treatment history, including any interruptions in treatment, is documented in detail in the CSH [14,24]. Treatment duration is calculated individually according to the beginning and end dates of each antiretroviral drug treatment. All ART documentation is assessed manually. Quality control algorithms are applied, and in the case of inconsistencies, the centres are requested to submit the revised data to the RKI [14].

The Robert Koch Institute is the German national public health institute, therefore the Federal Commissioner for Data Protection is the responsible entity for studies which are conducted by the Robert Koch Institute. Information on HIV infection collected in ClinSurv corresponds to the data reported to the RKI according to legal requirements implemented by the national Protection against Infection act (IfSG) of 2001. All patient data collected in ClinSurv are generated during routine care. The German Federal Commissioner for Data Protection therefore waived the need for ethical approval for the ClinSurv study. No written informed consent is required from patients.

The overall person-days observed from persons receiving any antiretroviral treatment between 2006 and 2013 in the CSH were analysed and categorised into three groups: medications that contained approved drugs, medications that contained at least one non-approved drug, and interrupted therapy. In the first group, we distinguished between regimens that did include a TCM and those without TCM. The numbers of all of these groups were calculated quarterly. Treatment interruption was defined as any observation time between therapy initiation and latest observed event with documented treatment discontinuation.

For the analysis of ART regimen in the CSH we separated mainly used regimens and minor regimens. Mainly used regimens were either defined as ART regimen containing two or three NRTIs and another drug class (NNRTIs, PIs, INIs) or two or three NRTIs exclusively. Minor regimens were those including more than three NRTIs and NRTI-free regimen.

Combination of data sources

Determining the number of people living with HIV receiving ART

The number of prescribed DDDs of TCMs derived from ART prescription data was used to determine the number of people living with HIV receiving quarterly SHI-covered TCM containing ART in Germany. The proportion of persons covered by SHI was calculated for each federal state based on the number of persons with SHI and the population number of the respective state. To account for patients without SHI (including those privately insured, uninsured, or receiving free medical care) whose prescriptions were not covered in the APD, the number of patients was raised in average by a weighted factor of 16.3% [34]. By adding the numbers of person-days of non-TCM ART segments derived from the CSH, we determined the total number of people living with HIV receiving quarterly ART in Germany. In addition, considering the proportion of person-days with treatment interruption seen in the CSH yielded the number of patients in Germany with ART experience. For an overview of the investigated data sources, see Figures 1 and 2.
Figure 1
Figure 1

Schematic overview of subpopulations and available data sources in Germany. Approximately 85% of the population in Germany is covered by statutory health insurance (SHI), most of the remainder are covered by private health insurance (PHI) and a small proportion are uninsured (exact number unknown). For persons covered by the SHI, antiretroviral prescriptions are recorded and reported through antiretroviral prescription data (APD). The German ClinSurv HIV cohort (CSH) contains detailed ART history data on approximately 20% of people living with HIV in Germany receiving ART, both those who are covered by SHI and those who are not. This schematic is not to scale.

Figure 2
Figure 2

Process diagram of used data sources and calculation steps proceeded.

The estimated number of HIV-infected persons with ART experience was smoothed using a negative binomial regression with quadratic time trend in the period of 2006 to 2013. The statistical errors of these numbers were assumed to be independent. The independent variables considered in the negative binomial regression were the time - measured in quarters since the first quarter in year 2006 - and the square of this time. The latter variable allowed us to adjust for a slowing down of the exponentially increasing trend in the recent years.

Results

ClinSurv HIV cohort (CSH)

The proportion of person-days with TCM-containing regimens reported in the CSH increased continuously over the study period, from 85% in 2006/I to 93% in 2013/IV. In contrast, the proportion of person-days with any observed treatment interruption declined from 11% in 2006/I to 2% in 2013/IV. The proportion of person-days with an antiretroviral regimen that contained non-approved drugs decreased from 6% in 2006/I to 2% in 2013/IV (Table 1).
Table 1

The German ClinSurv HIV cohort in the study period 2006–2013

Year/quarter

Patients under observation

Patients under ART time

Observation time

Time under ART or interruption

ART status unknown

Art naive

ART regimens with approved drugs exclusively

ART regimens containing non-approved drugs

Treatment interruptions

ART experienced

TCMs in the CSH

Proportion of interruptions

 

N

Days

   

2006/I

8717

6986

753553

613673

8211

131728

516827

29909

66937

81.4%

84.5%

10.9%

2006/II

8856

7104

773115

630625

7907

134629

533732

32431

64462

81.6%

85.3%

10.2%

2006/III

9002

7214

792169

646716

7742

137766

547485

36102

63129

81.6%

86.2%

9.8%

2006/IV

9075

7281

803312

655415

7530

140415

558719

36453

60243

81.6%

87.0%

9.2%

2007/I

9267

7434

798257

652832

7219

138281

560733

33462

58637

81.8%

87.7%

9.0%

2007/II

9407

7552

820040

671081

7345

141682

579930

33382

57769

81.8%

88.4%

8.6%

2007/III

9564

7689

844690

690514

7304

146945

595635

38313

56566

81.7%

89.1%

8.2%

2007/IV

9683

7828

855138

704369

6948

143877

609239

39403

55727

82.4%

89.5%

7.9%

2008/I

9758

7937

853480

705518

6344

141676

619880

31297

54341

82.7%

89.8%

7.7%

2008/II

9903

8069

863850

716324

5985

141595

632750

31325

52249

82.9%

90.4%

7.3%

2008/III

10031

8206

884551

737289

5895

141423

656479

28383

52427

83.4%

90.7%

7.1%

2008/IV

10124

8340

896771

752357

5982

138495

678973

22195

51189

83.9%

91.0%

6.8%

2009/I

10222

8484

886182

747140

5303

133792

677700

21820

47620

84.3%

91.3%

6.4%

2009/II

10384

8624

910943

769502

4859

136659

700526

21972

47004

84.5%

91.6%

6.1%

2009/III

10569

8814

934456

791390

4779

138362

722970

22322

46098

84.7%

91.8%

5.8%

2009/IV

10697

8989

946177

808947

4660

132635

742278

22853

43816

85.5%

92.0%

5.4%

2010/I

10799

9140

936276

805104

4473

126765

741693

22313

41098

86.0%

92.3%

5.1%

2010/II

10956

9290

958828

827947

4376

126573

768583

21791

37573

86.3%

92.4%

4.5%

2010/III

11123

9468

980925

849665

4289

127041

792663

21195

35807

86.6%

92.4%

4.2%

2010/IV

11171

9617

989771

865271

3898

120674

808229

22985

34057

87.4%

92.3%

3.9%

2011/I

11258

9761

974608

859468

3418

111790

803378

24123

31967

88.2%

92.3%

3.7%

2011/II

11333

9870

994656

880602

3347

110776

824465

25470

30667

88.5%

92.3%

3.5%

2011/III

11467

10030

1013429

901100

3305

109118

845603

26049

29448

88.9%

92.4%

3.3%

2011/IV

11480

10089

1021398

910156

3063

108245

857736

24301

28119

89.1%

92.5%

3.1%

2012/I

11588

10196

1014121

906295

3068

104831

858296

21730

26269

89.4%

92.6%

2.9%

2012/II

11612

10261

1019125

914177

2916

102114

867192

20862

26123

89.7%

92.6%

2.9%

2012/III

11651

10338

1032814

929619

2661

100626

883234

21460

24925

90.0%

92.4%

2.7%

2012/IV

11574

10334

1023954

925347

2423

96245

882817

20421

22109

90.4%

92.5%

2.4%

2013/I

11428

10229

980141

890397

2109

87707

852262

18571

19564

90.8%

92.7%

2.2%

2013/II

11092

9978

960764

876969

1508

82345

843148

16594

17227

91.3%

92.8%

2.0%

2103/III

10760

9725

879002

804520

1199

73313

775500

14296

14724

91.5%

92.7%

1.8%

2013/IV

8358

7610

363973

331301

621

31848

317585

7227

6489

91.0%

92.5%

2.0%

Determined patient numbers, observation time and proportions of treated patients as well as TCM use and treatment interruptions in the ClinSurv HIV cohort.

The exact composition of ART regimens of the CSH is shown in Figure 3. The proportion of non-TCM regimen among NRTI/NNRTI and NRTI/PI dramatically decreased over the study period. Non-TCM regimens were most frequently observed among minor regimen which was the only group with a slight increase of only 1% over the study period. The differentiated analyses of the group minor regimens without TCM showed that over the study period, the proportion of any non-TCM-NRTI containing regimen (TCM-NRTI [+X]) as well as the proportion of regimens consisting of two PIs or PI monotherapy decreased, whereas the dual combinations PI/AI, PI/II and other NRTI-free regimens increased continuously from 2007 to 2013 (Figure 4).
Figure 3
Figure 3

Composition of ART regimens of patients in the ClinSurv HIV cohort.

Figure 4
Figure 4

Composition of minor non-TCM containing ART regimens of patients in the ClinSurv HIV cohort.

Antiretroviral prescription data (APD)

The number of TCM-containing prescriptions increased from 1,778,070 prescribed DDDs in 2006/I to 3,838,620 prescribed DDDs in 2013/IV.

Taking into account the number of days per quarter led to the number of patients receiving SHI covered TCM containing ART. We observed a systematic seasonal variation, with a disproportionately high number of prescriptions in the last quarter of each year. The number of patients receiving SHI covered TCM-containing ART increased from 19,756 persons in 2006/I to 41,724 persons in 2013/IV. The proportion of persons covered by SHI was different in the respective federal states and ranged from approximately 80% to 90%. The weighted proportion of persons covered by SHI used for the calculation was on average 83.7% over the study period (Table 2).
Table 2

German population, SHI coverage and calculated weighted SHI-coverage factor

Year/quarter

German population

Number of people in SHI

SHI-coverage nationwide

Weighted SHI-coverage factor

2006/I

82314906

70013157

85.1%

83.2%

2007/I

82217837

70022112

85.2%

83.5%

2008/I

82002356

69952132

85.3%

83.4%

2009/I

81802257

69719142

85.2%

84.1%

2010/I

81751602

69473638

85.0%

84.3%

2011/I

81843743

69311329

84.7%

83.3%

2012/I

81843743*

69398840

84.8%

83.9%

2013/I

81843743*

69521912

84.9%

84.0%

*updated data for 2012 and 2013 not available yet.

Determining the number of people living with HIV receiving ART

After accounting for patients without SHI by adding 16.3% to the patient numbers derived from APD, the numbers of people living with HIV receiving TCM-containing ART in Germany were 23,751 in 2006/I and increased to 49,719 in 2013/IV. By compensating for regimens not containing TCMs, the number of all people living with HIV receiving ART was estimated at 28,101 in 2006/I and increased continuously to 53,776 in 2013/V. Taking into account those who had interrupted therapy led to the total number of HIV-infected people with ART experience in Germany. Due to the observed seasonal variation, we smoothed the trend by using a negative binomial regression with quadratic time trend. The total number of all HIV-infected people with ART experience in Germany increased from 31,500 (95% CI 31,000-32,000) in the first quarter of 2006 to 54,000 (95% CI 53,000-55,500) individuals by the end of 2013 (Table 3 and Figure 5). The average difference between the number of patients in Germany who had initiated ART and those who had left observation because of emigration or death was estimated to be an average of 2,900 persons per year.
Table 3

Step by step calculated data underlying the estimation of the number of people living with HIV receiving ART in Germany, 2006 to 2013

Year/quarter

Days per quarter

DDDs of TCM from APD

Persons receiving SHI-covered TCM

Weighted SHI-coverage factor

People living with HIV treated with TCM

TCMs in the CSH

People living with HIV receiving ART in Germany

Proportion of interruptions in the CSH

HIV-infected people with ART experience in Germany (PT_E)

PT_E statistically smoothed

95% CI

95% CI

PT_E smoothed and rounded N (95% CI)

2006/I

90

1778070

19756

83.2%

23751

84.5%

28101

10.9%

31547

31505

30796

32229

31500 (31000-32000)

2006/II

91

1910070

20990

83.2%

25222

85.3%

29586

10.2%

32953

32198

31559

32848

32000 (31500-33000)

2006/III

92

1975770

21476

83.1%

25824

86.2%

29960

9.8%

33203

32896

32321

33480

33000 (32500-33500)

2006/IV

92

2114310

22982

83.1%

27641

87.0%

31757

9.2%

34971

33600

33082

34125

33500 (33000-34000)

2007/I

90

1982490

22028

83.5%

26385

87.7%

30092

9.0%

33064

34310

33838

34787

34500 (34000-35000)

2007/II

91

2106480

23148

83.3%

27776

88.4%

31434

8.6%

34396

35024

34588

35465

35000 (34500-35500)

2007/III

92

2174850

23640

83.3%

28383

89.1%

31844

8.2%

34687

35743

35330

36159

35500 (35500-36000)

2007/IV

92

2326950

25293

83.3%

30377

89.5%

33926

7.9%

36841

36467

36066

36872

36500 (36000-37000)

2008/I

91

2204460

24225

83.4%

29023

89.8%

32312

7.7%

35009

37195

36794

37600

37000 (37000-37500)

2008/II

91

2418270

26574

83.5%

31814

90.4%

35196

7.3%

37964

37926

37516

38339

38000 (37500-38500)

2008/III

92

2498580

27158

84.3%

32211

90.7%

35508

7.1%

38226

38661

38237

39089

38500 (38000-39000)

2008/IV

92

2680710

29138

84.2%

34578

91.0%

38009

6.8%

40781

39399

38957

39845

39500 (39000-40000)

2009/I

90

2562540

28473

84.1%

33844

91.3%

37072

6.4%

39595

40139

39678

40604

40000 (39500-40500)

2009/II

91

2719650

29886

84.1%

35529

91.6%

38809

6.1%

41336

40882

40403

41366

41000 (40500-41500)

2009/III

92

2792580

30354

84.3%

36015

91.8%

39239

5.8%

41667

41627

41132

42127

41500 (41000-42000)

2009/IV

92

2980560

32397

84.0%

38544

92.0%

41876

5.4%

44274

42374

41866

42887

42500 (42000-43000)

2010/I

90

2829630

31440

84.3%

37290

92.3%

40385

5.1%

42556

43121

42605

43643

43000 (42500-43500)

2010/II

91

2952420

32444

84.0%

38619

92.4%

41794

4.5%

43783

43869

43348

44396

44000 (43500-44500)

2010/III

92

3060450

33266

84.1%

39564

92.4%

42800

4.2%

44681

44618

44096

45146

44500 (44000-45000)

2010/IV

92

3208470

34875

84.0%

41494

92.3%

44947

3.9%

46790

45367

44847

45892

45500 (45000-46000)

2011/I

90

3021690

33574

83.3%

40316

92.3%

43696

3.7%

45388

46115

45599

46636

46000 (45500-46500)

2011/II

91

3162900

34757

83.2%

41771

92.3%

45256

3.5%

46888

46862

46349

47379

47000 (46500-47500)

2011/III

92

3301830

35889

83.2%

43160

92.4%

46721

3.3%

48301

47607

47095

48124

47500 (47000-48000)

2011/IV

92

3414960

37119

83.2%

44619

92.5%

48217

3.1%

49756

48351

47832

48874

48500 (48000-49000)

2012/I

91

3268320

35916

83.9%

42827

92.6%

46271

2.9%

47652

49092

48555

49634

49000 (48500-49500)

2012/II

91

3356700

36887

83.8%

44007

92.6%

47543

2.9%

48944

49831

49260

50407

50000 (49500-50500)

2012/III

92

3447960

37478

83.6%

44816

92.4%

48483

2.7%

49819

50566

49942

51197

50500 (50000-51000)

2012/IV

92

3632040

39479

83.6%

47240

92.5%

51089

2.4%

52344

51298

50599

52006

51500 (50500-52000)

2013/I

90

3467760

38531

84.0%

45861

92.7%

49478

2.2%

50591

52026

51230

52834

52000 (51000-53000)

2013/II

91

3657690

40194

84.0%

47861

92.8%

51555

2.0%

52585

52748

51834

53677

52500 (52000-53500)

2103/III

92

3768660

40964

84.0%

48791

92.7%

52657

1.8%

53639

53466

52413

54539

53500 (52500-54500)

2013/IV

92

3838620

41724

83.9%

49719

92.5%

53776

2.0%

54849

54178

52967

55416

54000 (53000-55500)

Figure 5
Figure 5

SHI-covered TCM prescriptions and estimated numbers of HIV infected people with ART experience in Germany, 2006 to 2013. Step by step estimation of the number of HIV-infected people with ART experience shown as smoothed and rounded numbers, exact numbers are shown in Table 3.

Discussion

We estimated the number of people living with HIV who received ART based on SHI prescription data and on ART history data from the CSH. An underlying assumption was that the ART regimens and treatment interruptions recorded in the CSH would similarly apply to HIV-infected people outside of the cohort and that the prescription numbers in the APD would be comparable with all people living with HIV in Germany.

In the 2006–2013 observation period, substantial increases were observed for the number of people living with HIV receiving ART and for the number of HIV-infected people with ART experience in Germany. Concomitantly, the use of regimens that included TCMs increased continuously, whereas treatment interruptions in the CSH decreased remarkably.

In an earlier estimation approach by Kollan et al., the calculation was based on the daily drug dosages of all substances. In our opinion, the new approach of calculating the number of individuals based mainly on unambiguous drugs (TCMs in this study) offers a simple and appropriate method that could be further adapted for other investigations.

At the beginning of the observation period, the percentage of CSH regimens that did not include TCMs was 15%, and it decreased by half over time.

In Germany and other industrialised countries with a large number of available antiretroviral drugs, the share of TCMs would need to be taken into account when using this approach to estimate the number of people living with HIV under antiretroviral treatment. However, in countries with fewer antiretroviral drug options, the number of people living with HIV receiving ART could potentially be calculated exclusively using the number of delivered TCMs, which would be a reliable and simple estimation method. Assuming that the proportion of TCM use in Germany will continue to increase, this approach could become even more effective for calculating German estimates.

The total number of all HIV-infected people with ART experience in Germany was estimated to be 31,500 in the first quarter of 2006 and increased continuously to 54,000 individuals by the end of 2013. According to our estimation, the observed study population of the CSH represents more than 20% of all treated patients in Germany. In the CSH all patients who are seen in the centres are automatically included into the cohort without the need for written informed consent. The CSH is therefore the least biased source available and is the largest nationwide cohort of HIV-positive patients. Nonetheless, the CSH in this study is only used to determine the corresponding proportion of non-TCM and treatment interruptions. In our opinion, the demographics do not affect the TCM proportion of those with access to ART. In order to verify this approach with regard to more uncommon ART regimens and first-line subsequent regimens we analysed the composition of regimens of the CSH patients. As shown, the vast majority of ART regimens in the CSH are main regimens which include two or three NRTIs and another drug class such as NNRTIs, PIs, INIs (Figure 3). This applies for first-line therapies as well as for following regimens considering we pooled all data of CSH patients together for the analysis of ART regimens, and therefore regimens after first-line therapy naturally had a greater impact. Non-TCM regimens were most frequently observed within the group minor regimen which was also the only group with a slight increase of only 1% over the study period. Until 2010, within the minor regimen group double or mono PIs and non-TCM-NRTI containing regimens were most frequently observed, and from 2010 to the end of the observation period NRTI-sparing regimens, e.g. PI/AI and PI/INI continuously increased. If the prescribing patterns regarding regimens without TCMs would change in the future then this would have to be considered for our approach. However, this is not the case for the described study period.

It is interesting to note the considerable decline in CSH treatment interruptions. This reflects recent findings showing that there are more risks than benefits from so-called drug holidays [35-37]. In current HIV treatment guidelines, structured treatment interruptions are no longer recommended and are only considered individually under special circumstances [38]. However, currently between 2% of interruption time is apparently an inevitable fact.

In the APD data, we observed a systematic seasonal effect, with the fewest prescriptions at the beginning of each year and the most by the end of the year. We speculate that this effect may be caused by differing patient demand driven by practical considerations with regard to the beginning of the new year (i.e., Christmas holidays, closing of medical offices) and/or prescription co-payments whose reimbursements depend on the annual amounts of all individual co-payments within a calendar year.

Our approach may lead to an overestimation of the number of people receiving continuous ART by patients receiving only short-term ART. This might be relevant in case of discontinuation of therapy early in a quarter or when patients received a PEP.

When a person discontinued therapy before the medication was consumed, we counted that person as someone who was treated, but this person would not get prescriptions in the next quarter, and the overestimation would have been offset in the next billing period.

Representative data regarding the number of PEP prescriptions are rare. Studies regarding PEP are often performed in certain populations with limited significance for the general public. To account for the overestimation resulting from PEP prescriptions, we attempted to determine the number of PEP prescriptions using available studies and sources. We assumed that most PEP prescriptions would come from physicians who were authorised for the special care of patients with HIV/AIDS according to the HIV/AIDS Quality Assurance Agreement (§ 135 para 2 SGB V). According to our findings, the number of PEP prescriptions was estimated to be approximately 2400–2800 per year in Germany [39,40]. Considering that 12 PEP prescriptions are necessary to result in one patient treated per year, an overestimation of approximately 200 to 233 patients in total could have occurred. In terms of the total number of approximately 54,000 people living with HIV receiving ART in Germany, the resulting overestimation would be comparatively small.

On average, the increase in the number of people living with HIV receiving ART was approximately 2,900 persons per year in Germany. This increase should not be confused with the number of persons who initiated therapy, but rather represents the difference between people who initiated ART and those who discontinued treatment because of emigration or death. Thus, the true number of persons who began treatment is probably higher than the observed difference.

The proportion of people covered by PHI differed among the federal states. Those federal states with higher PHI coverage, e.g. City-States, tend to be those with a higher number of prescriptions. We therefore used a weighted SHI-coverage factor based on the data for each federal state and applied it to the antiretroviral prescription data in order to improve the estimates. Using the nationwide SHI-coverage factor would underestimate the total number by 1.6% (N = 650 persons).

With this study, we provide a nationwide estimate and a useful tool for calculating the number of people living with HIV who received ART, those with ART experience and the increase in ART usage between 2006 and 2013 in Germany using the available number of prescriptions and surveillance data from the CSH.

This approach can be useful to estimate the number of people living with HIV and those receiving ART in other countries. Additionally, the described methodology could potentially be used and adapted for other investigations or medications in the future.

Limitations

The described approach has some limitations. One limitation is an overestimation resulting from the cases that were discussed above. Of those cases, the number of PEP prescriptions is the most uncertain, which could be the main limitation.

Overall, our aim was to estimate the number of treated patients among all persons with access to ART. We do not aim to, and therefore do not, estimate the number of non-treated patients among all people infected with HIV in Germany.

Lamivudine is approved for the treatment of hepatitis B with a dose of 100 mg once daily for persons not infected with HIV. The use of lamivudine with approval for HIV therapy (150 mg and 300 mg) in the treatment of hepatitis B of HIV-negative individuals attributable to economic considerations cannot be excluded. However, the off-label use of HIV-labelled lamivudine would require an alternative dosing regimen by administration on alternating days and/or by dividing the pills, which we consider impractical in reality.

A limitation with regard to applying this approach in the future is that if TCM prescribing patterns, such as the currently discussed dual NRTI-sparing therapies, or other treatment practices significantly change, the impact of a second source (in our case, the CSH) on the estimate would be greater.

Conclusions

This report describes the first comprehensive approach to estimating the number of people living with HIV who receive ART. The study provides a possible approach for determining the number of people receiving specialised HIV medical care in Germany. This method allows for contrasting the numbers of people living with HIV receiving ART derived from different sources or estimation approaches. This approach can be useful to estimate the number of people living with HIV and those receiving ART in other countries. The described methodology could be used and adapted for different investigations or medications in the future. Non-TCM regimens and CSH treatment interruptions declined notably. Assuming that this trend will continue in the future, the number of people living with HIV receiving ART could be estimated exclusively using TCM-containing prescriptions. In other settings with fewer available antiretroviral drugs, the estimation would be even more robust.

It is also of interest to note trends in antiretroviral therapy with regard to NRTI-free regimens. In this context, the relevance of data from cohort studies remains very high for observing and assessing such developments.

Notes

Declarations

Acknowledgements

The authors are grateful to the patients who joined the ClinSurv HIV cohort and to all collaborative treatment centres. The authors would like to thank Viviane Bremer for her helpful and constructive comments on the manuscript. We are grateful to Katie Ann Jacques for her critical feedback and advice on this article.

Authors’ Affiliations

(1)
Robert Koch Institute, Department of Infectious Disease Epidemiology, HIV/AIDS, STI and Blood-borne Infections, Berlin, Germany
(2)
Clinic for Immunology and Rheumatology, Infectious Diseases Unit, Medical University Hannover, Hannover, Germany
(3)
ICH Study Centre Hamburg, Hamburg, Germany
(4)
Ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
(5)
Clinic of Internal Medicine, University Köln, Köln, Germany
(6)
Department of Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany
(7)
Department of Infectious Disease, Med IV, University Hospital of Munich, Munich, Germany
(8)
Section Infectiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
(9)
Department of Internal Medicine, University of Bonn, Bonn, Germany
(10)
Clinic for Dermatology, Infectious Diseases, University Hospital Essen, Essen, Germany
(11)
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
(12)
Medical Clinic, University Schleswig Holstein, Campus Kiel, Germany
(13)
University Hospital Rostock, Rostock, Germany

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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