Decentralization of viral load testing to improve HIV care and treatment cascade in rural Tanzania: observational study from the Kilombero and Ulanga Antiretroviral Cohort

The number of people living with HIV (PLHIV) on antiretroviral therapy (ART) globally and in Tanzania has been increasing over time with 82% accessing ART in 2020 [1]. HIV viral load (HVL) testing in PLHIV – the preferred monitoring approach by the World Health Organization (WHO) [2] – allows early detection of treatment failure and guides treatment decisions, for example adherence counselling or regimen change. In sub–Saharan Africa, HVL monitoring has been scaled up in recent years with investments strengthening HVL processing hubs and sample transportation systems, to overcome challenges of transport and result transmission especially in remote settings [3]. In Tanzania, the government scaled up routine HVL testing in 2017 through establishment of HVL processing centres (hubs) and policies enabling all PLHIV to receive HVL testing [4, 5]. For remote health facilities, the long distances to referral HVL processing hubs, poor road infrastructures (especially during the rainy season), unreliable transport systems, and the danger of blood sample degradation due to failure of cold chains remain a challenge [6, 7].

For successful HVL monitoring, a reliable testing process with a rapid turnaround time (TAT) is key and affects all stages of the testing cascade including blood withdrawal, sample transport and processing, generation of results, feedback to clinicians and PLHIV, and timely subsequent action. Samples for HVL testing are recommended to be processed and results made available to the clinicians within 14 days for management of treatment [8]. According to the Tanzania National AIDS Control Program guidelines, the first HVL test is done at 6 months after initiation of ART and a second at 12 months. If both viral load results are < 1000 copies/mL, HVL is then monitored yearly. PLHIV with unsuppressed HVL receive enhanced adherence counselling for three months followed by a follow-up HVL test in the fourth month—if reported adherence is > 95%. If the follow-up HVL result is below 1000copies/ml, the patient will continue with the same drug regimen, otherwise the recommendation is to switch to a second-line ART regimen [8].

Gaps in the HVL cascade, such as long TAT, delay in timely initiation of adherence counselling and/or switch to second-line ART in PLHIV with virologic failure (VF) lead to an increased risk of accumulation of drug resistance mutations, development of clinical failure and mortality as well as onwards HIV transmission [9‐11].

We hypothesised that decentralization of HVL testing from a referral laboratory to an on-site molecular laboratory capable of conducting HVL testing, hence avoiding sample transport to a central referral laboratory, will reduce TAT of HVL results. Therefore, we aimed at analysing the HVL monitoring cascade, comparing turnaround times of viral load results when viral load testing was done at an on-site laboratory versus a referral laboratory. We furthermore assessed management and outcome among those with high- and low-level viremia following the national rollout of routine HVL monitoring in a cohort of PLHIV in rural Tanzania.

In this study on the HVL testing cascade from a rural site we could show, that during the first three years after implementation of HVL monitoring, testing coverage among PLHIV on ART was high with 95% and viral suppression was 88%. The median analytical TAT of samples processed at the on-site laboratory was one third of the time compared to samples sent to the referral laboratory. The time until clinical management, however, remained long with 90 days irrespective of the testing site. Among PLHIV with an unsuppressed HVL only 24% had a follow up HVL within the 4 months recommended by the National HIV treatment guidelines. Of those with a LLV, 6% became unsuppressed within a year.

Compared to studies from other rural sub-Saharan African sites showing HVL monitoring coverage rates ranging from 64–90% [3,15], our testing coverage of PLHIV in care reached 95% following HVL monitoring roll-out by the National AIDS Control Program and the implementing partner USAID Boresha Afya—after starting with 22% in 2017 [16]. The viral suppression rate of 88% in our study is close to the 91% found in a previous study from our site [17] and to the national level of 87% (84% of males and 89% of females) assessed during the Tanzania HIV Impact Survey (THIS) 2016–17 [18, 19]. While these numbers are close to the third 90% of the 2020 UNAIDS goals [20], a gap remains to reach the 2030 UNAIDS goals of 95% viral suppression of those on ART [21]. Reaching UNAIDS 2030 goals might be facilitated by the roll-out of integrase inhibitors as first line treatment, which only started 2019 in Tanzania. In our study, first available HVL measurements were used for analysis where only 6% were on dolutegravir based regimen and majority in the  Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) based regimen. [8, 21].

The overall analytical TAT in this real-life rural sub-Saharan African setting was 27 days and analytical TAT at on-site lab was 21 days which are still notably longer than the 14 days recommended by Tanzanian’s National AIDS Control Programme guidelines [8]. The reason was mostly the high number of samples to be processed, as the on-site lab was also a referral laboratory of neighbouring health centres, and a back-up laboratory of the regional laboratory in case of stockouts of reagents or breakdown of machines. Thus, the on-site lab had at times faced significant backlog of samples with limited staff. Additionally, the manual paper work necessitated by the semi-automated National system contributed to workload. On top, results had again to be manually entered in the electronic patient record system. Furthermore, the on-site lab in 2020 faced a half-year stock out of reagents due to the COVID-19 pandemics. The improvement of the analytical TAT by performing the HVL in an on-site laboratory compared to a referral laboratory has previously been reported by others. Studies from sub-Saharan Africa using similar definitions showed median TATs ranging from 15–67 days [22, 23]. A study from Malawi could show a substantial impact of distance from the laboratory to the clinic on the TAT, suggesting inefficiency of specimen transfer as a factor driving longer turnaround times [24]. This was confirmed by a reduction of the median analytical TAT for HVL results of about 3 times after implementation of testing at the on-site laboratory in our study (from 59 to 21 days. Major reasons are inconsistent transport availabilities, weather conditions affecting road conditions, reagent stockouts, equipment and electricity shutdowns and administrative delays [22‐24]. Thus, there is a clear benefit of a molecular laboratory capable of conducting HVL testing located in remote areas with high patient numbers. Additionally, point of care platforms such as GeneXpert can reduce the TAT of the results [25] and thus benefit clinically unstable PLHIV with a same day result for HVL targeted monitoring and clinical decision making. In this study, however the number of GeneXpert tests done was very low and therefore not analysed separately.

Disappointingly, the analytical TAT did not affect the time until the patient received the results (overall TAT). The most important challenge was to track patients and convince them to come to an earlier than planned appointment. Reasons for not coming early indicated by PLHIV were socioeconomic constraints – mostly small-scale farmers and fishermen – with inability to come up for transport costs. A considerable number of PLHIV in our study (835 (19%)) live ≥ 50 kms away from the clinic with poor road infrastructure and are usually prescribed drugs for three months. In addition, the procedures in place to track PLHIV with an unsuppressed HVL as per National HIV treatment guidelines were only partially successful as, even if PLHIV have phones, they frequently are not reachable due to network and electricity shortages. Innovative methods of HVL results feedback to PLHIV such as use of mobile short message services might help in overcoming this challenge [26, 27]. The majority of PLHIV with an unsuppressed HVL had re-suppressed at the follow-up testing (63%), which is an indicator for non-adherence rather than resistance and supports the strategy of enhanced adherence counselling. Etoori et al. showed a re-suppression rate in Swaziland of 62% [9] while Glass et al. reported a lower re-suppression rate of 45% in Lesotho [28]. In our study, interestingly, 65% of PLHIV were already on second line at the time first HVL measurement, indicating previous persistent treatment adherence problems. We reported a similar finding from a study of PLHIV switched to second line treatment in whom 13.1% had VF and no resistance could be documented at the time of switch nor after 6–12 months on second line treatment [29].

Until recently, the WHO guidelines defined an unsuppressed HVL using a threshold of ≥ 1000copies/mL [2]. Discussion on the implications of HVL results between 100 and 999copies/mL was ongoing after increasing evidence of poor outcome in patients with LLV [30‐32]. Our study reports 9% frequency of LLV. Data from other sites are quite diverse with some reporting high rates of LLV of 23%—38% frequency [33, 34], while others show similar figures around 2–9% [29, 35, 36].

Only in mid of this year, the WHO has updated its guidelines and newly defines virologic suppression as a HVL < 50copies/ml. VF remains defined as two HVL ≥ 1000copies/ml. The recommendation is to do adherence counselling and retest HVL in all patients with HVL values > 50copies/ml [2].

In our study, 6% of those with LLV progressed to unsuppressed HVL in a median time of 9 months hence these PLHIV may benefit from closer monitoring. High-level resistance to at least two drugs has also been documented among PLHIV with LLV of 84–94%. PLHIV having high-level resistance to at least two drugs of NNRTI-based first-line ART regimen in studies from Lesotho [30, 31].

The strength of our study is the prospective real-life setting large cohort of PLHIV. The limitations of our study were: first, no resistance testing was done to identify the reasons for high HVL in particular, among those with unsuppressed HVL who switched to second line ART before having follow up HVL and thus we could not determine if the decision to switch to second-line ART was justified or not. Second, we could not assess the impact of adherence counselling among those with unsuppressed HVL. Similarly, we could not verify if all who had treatment switch to second line had treatment adherence counselling as per the national’s HIV treatment guidelines. Third, analytical TAT at both on-site and referral laboratories may have been affected by stock out of reagents, breakdown of machines, which may result to huge backlog of samples affecting TAT results.

Robust HVL monitoring is achievable in rural remote resource limited settings and with reduced turnaround time of viral load results. The majority of PLHIV with VF were already on second-line ART indicating persistent adherence problems, meaning that it is crucial enhanced treatment adherence counselling is done timely and early enough to prevent HIV drug resistance development.