| As antiretroviral therapy (ART) is provided on a rapidly increasing scale in Rwanda, it is becoming increasingly important to try and systematically characterize and assess the incidence of (treatment-limiting) adverse effects of treatment, which in developed countries have been demonstrated to be the most frequent reason for having to modify treatment. Currently very limited systematically collected information is available within the African setting, although physicians involved in antiretrovirals (ARV) treatment programmes report that anemia, rash, and peripheral neuropathy are frequently seen as relatively short-term side-effects, and lipoatrophy and possibly lactic acidemia/acidosis as patients are being treated for longer. Side-effects may not only result in significant morbidity, but may also promote non-adherence and thereby contribute to treatment failure. Anemia is a known adverse effect of zidovudine (AZT) but may also be associated with underlying HIV infection itself, as well as with iron and vitamin deficiencies (folic acid, vitamin B12) and other infections including malaria. In contrast, use of d4T is associated with an increased risk of peripheral neuropathy, lactic acidemia/acidosis and lipoatrophy. The latter is of particular concern given its poor reversibility and potentially stigmatising nature. For these reasons, treatment guidelines in the North no longer list treatment combinations including stavudine (d4T) as options for first-line therapy. In contrast, WHO recommends both d4T- or ZDV-based triple antiretroviral regimens for use in Africa. The choice between these is largely based on cost and availability within donor programmes. In general, d4T-based regimens being less expensive, these are currently most frequently prescribed in most African settings. Apart from issues dealing with cost, a high prevalence of anaemia especially in patients presenting with advanced HIV disease and which has been shown to be independently associated with an increased risk of death both in developed and resource-limited settings, may also favour d4T over ZDV-based regimens, particularly in the first months of treatment. In Africa, where currently few and frequently no second line ART options are available at all, it is of all the more importance to initiate regimens that simultaneously offer both optimal efficacy and tolerability, both over the short- and longer term. NRTI-associated mitochondrial toxicity is thought to play an important role in the pathogenesis of several of these toxicities. Host genetics, both at the level of the nuclear and mitochondrial DNA is expected to influence the degree to which these toxicities may occur in geographically diverse patient populations. We propose to conduct a prospective observational study to systematically characterize and assess the incidence, severity and possible risk factors for anemia, peripheral neuropathy, lactic acidemia/acidosis, and changes in body fat distribution (lipodystrophy) in 200 consecutive adult men and women (100 men, 100 women) without clinical evidence of concomitant tuberculosis, starting HAART according to national Rwandan ART treatment guidelines with either d4T- or AZT-based HAART regimens in the context of established ARV treatment centers. The project will strengthen the study site in its capacity to carry out cohort studies and to analyse data of such studies. Better knowledge about the incidence of the above-mentioned adverse effects in this site will also be important for appropriately designing clinical trials of antiretroviral treatment strategies aimed at preventing these toxicities. This is crucial given that currently there are no effective specific treatments for reversing lipoatrophy, lactic acidosis and peripheral neuropathy. Although severe anemia of course may be symptomatically treated by blood transfusion, this carries a high cost and therefore is preferably prevented. Treatment is largely provided according to national treatment guidelines. By virtue of these guidelines, the TRAC/CHUK clinics in Rwanda in principle provide d4T-3TC-NVP as first-line and AZT-3TC-NVP as second-line treatment. An improved knowledge of the incidence of and risk factors (including genetic) for the above-mentioned main treatment-limiting toxicities within regular ARV treatment settings in Africa will therefore be relevant not only to inform clinicians, but hopefully also to guide policy makers with respect to future decisions concerning the implementation of alternative affordable effective and safer first-line treatment regimens/strategies in this resource-limited region of the world. Examples of such strategies could for example include the initiation of d4T-containing regimens during the first months of treatment to avoid exacerbation of anemia with the use of ZDV, followed by proactive switching to ZDV-based regimens to avoid or delay lipoatrophy over the longer term. |
