This study reports the findings of the first prospective, randomised, controlled study comparing of nurse versus doctor managed ART. Mortality, viral suppression, CD4 cell count response and a composite end-point reflecting multiple aspects of ART delivery, demonstrated that nurse monitored therapy was not inferior to doctor monitored therapy. These findings support observational data from other treatment programmes reporting successful use of task shifting in HIV care in both resource-limited (South Africa, Mozambique, Rwanda and Lesotho) and resource-rich countries (Netherlands, United Kingdom) [28
] as well as for other disease management [34
Expansion of ART services is urgently required in resource-poor countries in order to achieve universal access targets by 2010 [35
] and further expansion will be needed with initiation of universal testing and treating strategies [36
]. There was no difference in mortality, viral failure or immune recovery between the study arms although there was a non-significant trend toward increased failure in the nurse arm for patients with advanced HIV disease. This study therefore supports the strategy of “task shifting” and indicates that HIV management by nurses can be safe and effective, probably even for those patients commencing therapy with advanced HIV infection, although further studies over longer duration may be required in this sub-group.
Although both study strategies successfully managed drug related toxicities, the study does highlight a high frequency of lipomorphologic changes and lactate elevation associated with use of regimens including stavudine. Recent WHO and South African guidelines have moved away from reliance on stavudine [37
] however, it remains widely used in resource-poor HIV therapy programs [12
]. In our study the overall drug toxicity frequency appeared to be lower than earlier reports of stavudine based toxicities which resulted in drug substitutions in excess of 20% after three years [39
]. The dose reduction of stavudine to 30 mgs after the first year of the study which was in line with WHO recommendations [27
] may have reduced drug limiting toxicities somewhat. However, two of the study deaths were due to hyperlactatemia, a recognised complication of stavudine use.
Randomised controlled studies are frequently considered the “gold standard” on which treatment policies should be based. However, there may be some caveats in applying trial findings to non-study settings and other populations. The study did not necessarily replicate the typical conditions under which therapy is presently delivered in resource-poor settings. For instance, in addition to structured training in the use of ART, all the clinical staff in the study received protocol-specific training in the conduct of ethical research including Good Clinical Practice, didactic clinical management and had access to ongoing telephonic clinical support if required. However, widespread “task shifting” will require increased training, a redefinition of scope of practice for nurses and a clinical support structure. The study results also cannot be generalized to settings where multiple first-line antiretroviral therapy options may be used to individualize patient treatment, which in-turn may reduce dose-limiting treatment toxicities.
A strength of our study was that it was performed at busy primary care clinics located in South African communities with a high-burden of HIV where large scale task shifting will be required. The cadré of nurse used in our study, the primary care nurse, are the staff whose role as clinician is being increasingly utilised in HIV and other fields such as tuberculosis in the South African health care system. In order to limit the “contamination” between the arms of the study, once the participants were randomised scheduled visits were booked for different days of the week. A weakness of the study is the limited time over which participants were on-study. At only two years of follow-up the chance of divergence of the arms may still have been limited.
The study demonstrated a high overall composite endpoint rate in both nurse and doctor treated arms (48% vs. 44%). A stringent definition of treatment strategy failure included the traditional virologic failure (10-11%), dose-limiting toxicity (16-17% using d4T regimens), death (3%) and all clinic losses (15-17%) that translate to failure of the treatment strategy to maintain patients on antiretroviral therapy. These rates are not dissimilar to other studies despite our use of a more stringent definition of study loss, and use of a Stavudine-based antiretroviral therapy regimen with stringent criteria for hyperlactataemia and clinical toxicity [40
]. There was also a high rate of loss to follow-up on this study, but again not dissimilar to other studies in resource constrained settings [40
]. The future of large-scale antiretroviral programmes make it important to understand how this loss evolves over time. There were some small differences in diagnosing some grade three or four laboratory adverse events as well as some clinical diagnoses, which could have an impact on wider roll-out of nurse based ART care. These could be addressed by more focused training on monitoring of laboratory data as well as implementation of simple algorithms of when further neurologic workup by a doctor is necessary.
It should be noted that the study design did not address “nurse initiated” antiretroviral therapy because the prescription of licensed medication in South Africa is restricted to doctors. Implementation of nurse initiated therapy would therefore require additional changes to the existing legislation. However, the new national HIV strategic plan does envisage initiation of therapy by doctors together with wide scale task shifting to nurses for ongoing patient management [20
In conclusion, primary health care nurses were shown to be non-inferior to doctors in monitoring first-line antiretroviral therapy in a public health ART program in South Africa. The results of this study strongly support the expanded access to treatment using models of task shifting in primary health care.