Do NGOs need research?

SolidarMed is a Swiss NGO that supports antiretroviral treatment (ART) programs in four countries of southern Africa. SMART, the SolidarMed ART program, is funded by different donors (Liechtensteinischer Entwicklungsdienst, Swiss Agency for Development and Cooperation and Medicor Foundation). SolidarMed does not establish parallel structures but strengthens the national health structures and policies. Lately, it partnered up with the University of Berne in an attempt to match quality and quantity in its rapidly expanding programs. Also, SolidarMed has invested big efforts in the set-up of a database collecting clinical and laboratory data of patients on ART. Do such co-operations make sense? Is it worth passing time analyzing the present instead of heading towards a future in ever greater need?

ART programs in resource-limited settings: a success story

It is no more than a few years ago that ART was considered illusionary in rural Africa. The huge burden of disease contrasted with lacking medical staff to consult a population with opposing concepts of disease, lacking laboratory capacity to diagnose and stage HIV and AIDS, unaffordable drugs and insufficient transport capacities to make treatment accessible for millions in need.
Universal access to HIV prevention and care by 2010 is a major public health goal. Recent reports as well as the analysis of our database have shown enormous progress towards this goal. HIV testing and counselling, prevention of transmission from mother to child (PMTCT), and ART have been scaled up rapidly and the number of AIDS deaths has decreased due to better access to ART.

Thanks to an unprecedented commitment of private, governmental and non-governmental organizations, ART could be initiated in more than 4 million people worldwide, serving some 42% of the ones in need. Within SMART, 7’000 individuals have initiated antiretroviral treatment since 2005. This is a quantitatively remarkable achievement for a relatively small organization.

Basic assumptions for ART

ART programs in Africa, especially in rural areas like where SolidarMed is working, are still not able to cover the need because human and financial resources are very limited. Due to these restricted resources, ART programs are based on assumptions, which are challenging good clinical practice in the western world. To name just a few:
1. Nurse-based (as compared to physician-based) treatment provides sufficient quality (“Task shifting”)
2. Decentralized (as compared to hospital-based) treatment provides sufficient quality
3. ART with side effects is better than no ART
4. Political, economic and infrastructural commitment is sufficient to guarantee uninterrupted drug supply and sustainability of the service
5. Simplified PMTCT regimens (as compared to combined ART for the mother) work
6. Treatment failure can be identified without viral load monitoring
7. Adherence of failing patients to safer sex practices is sufficient to prevent the spread of resistant viruses

How good is good enough?

Because the ART programs in rural Africa are based on assumptions, the quality of these programs need continuous analysis both as a scientific concept on an international level and in terms of local performance for the targeted population. Many important questions remain open:

How much simplification in algorithms and guidelines is possible while still maintaining quality of care? Single dose Viramune, for example, has failed as a PMTCT strategy leaving behind many mothers with resistant virus. Current strategies, such as the addition of an NRTI (Reverse transcriptase inhibitors) tail to reduce the risk of resistance generation, are still inferior to full ART. The limitations of diagnosing treatment failure solely based on CD4 counts was illustrated in a recent study from Nigeria: 45% of true treatment failures were missed, while 55% of the postulated failures could not be confirmed. And as we know from random controls within our cohort, even clinical treatment failures manifesting as new opportunistic diseases are sometimes disregarded. Clinical research, ideally within multicenter collaborations such as the International epidemiological Databases to Evaluate AIDS (IeDEA), can help to answer such systematic questions.

To what extent can we sacrifice individual care, disregard the exceptions from a rule, in order to facilitate faster scale-up? Maladherence and undiscovered adverse effects, for example, may jeopardize a whole program. In SMART, 2-year retention rates of 50-72% have been documented. Similar results have recently been reported in a systematic review of patient retention in ART programs in sub-Saharan Africa. Is this good enough? Could these numbers be improved with better adherence counseling? With reimbursement of travel costs? With more tolerable drugs? Were lost to follow-ups tracked with sufficient commitment? Stavudine-related lipoatrophy (photo 1) and polyneuropathy are regularly seen in our expert patients – the very first treated and thus the longest exposed to ART. And still, toxic stavudine has not been switched to the available and far less toxic Tenofovir. Obviously, care-givers lack awareness and knowledge to discover drug toxicity and induce appropriate measures. Clinical research can help to identify and address such practical issues.

Big doctor is watching you!

Task shifting from doctors to nurses as well as decentralization from hospital to health centers have fundamentally changed the role of physicians. Instead of being care-givers on a 1:1 basis, their clinical impact now has to be indirect through a team of nurses. Instead of caring for individual patients the doctors have to teach, supervise and coach. Clinicians have to turn into health managers. The electronic database has proven very efficient to support doctors in this chore: It can provide an overview of the performance within the program, with a possibility even to focus on individual sites: How many new treatments have been started? What is the proportion of children on ART (which has been shown to be an independent quality measure)? Is the laboratory follow-up performed regularly? Also, the database can be used as a management tool. Having nurses collect information on adverse events or opportunistic diseases on the treatment form/in the database raises the awareness for these issues. And it obliges the physicians to provide the clinical tools needed.

How long will it last?

We have learnt that no ART regimen completely suppresses HIV replication. Even short treatment interruptions increase the risk for resistance generation, because replicating viruses are exposed to subinhibitory concentrations of antiretroviral drugs. Subinhibitory concentrations are too low to kill viruses, but high enough to select for resistance mutations. This is particularly important for Nevirapine and Efavirenz, the two standard drugs in Africa. Their long half-life allows once-daily dosing, but results in extensive subinhibitory drug exposure once treatment is discontinued. In Africa, there are dozens of reasons for a cut in drug supply, which puts patients at a higher risk for treatment failure – despite the high commitment of patients and their treatment partners to therapy. Once treatment failure is discovered, access to second-line regimens with protease inhibitors is needed. Protease inhibitors, however, are much more expensive, have more adverse effects and a multitude of drug interactions that, for example, almost prohibit a concomitant tuberculostatic therapy.

It is better to know

Fortunately, viruses have to pay a prize for resistance: Mutated viruses replicate more slowly and therefore are less virulent than the original, the wild type viruses. If failing treatment is maintained, resistant viruses circulate in the blood and thus can be transmitted by unprotected sexual intercourse. After treatment discontinuation, however, the wild type viruses archived in the lymphatic tissues reemerge, overgrow the fitness-reduced mutated viruses that subsequently disappear from the blood, but equally are archived in the lymphatic tissues. Hence, months after the discontinuation of a failing treatment, the patient will be far less likely to transmit resistant, but rather wild type virus. From an epidemiologic point of view, two consequences emerge: While successful treatment prevents infection from unprotected sexual intercourse, patients on a failing regimen represent a double risk, as they are not aware of being contagious and as they may transmit resistance. As a consequence, failing patients have to practice safer sex or discontinue treatment-related selection pressure to at least only transmit wild-type viruses. But how identify failing patients in the absence of viral load measurement?

Quality buys time

Let’s face it: An HIV-positive individual in Africa has not much more than one good chance for treatment success – if he is “lucky enough” to be infected with a wild-type virus. If treatment fails on a population level and resistant viruses start circulating, the race is over. These years of successful first-line therapy are our window of opportunity. Within this timeframe, people must become educated enough to practice preventive methods such as safer sex. Within this timeframe, health systems must provide sufficient coverage to systematically test and treat HIV-positive mothers. An enormous chore. We are convinced that clinical research – by improving the quality of our ART programs through direct and immediate feedback of results and implementation of recommendations – can enlarge this window of opportunity. NGOs do need research.

*Dr. Christoph Fux ist Leiter a.i. Universitätspoliklinik für Infektiologie, Inselspital Bern, Kontakt: ChristophAndreas.Fux@insel.ch

Dr. Karolin Pfeiffer works as Program Manager with SolidarMed in Luzern. Kontakt: k.pfeiffer@solidarmed.ch. http://www.solidarmed.ch/