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 . 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.
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.