Virological efficacy and emergence of drug resistance in adults on antiretroviral treatment in rural Tanzania

Access to antiretroviral treatment (ART) of HIV/AIDS has increased substantially over the past few years throughout the developing world. Lower prices of antiretroviral drugs combined with political determination have given rise to one of the greatest public health operations of our time, spearheaded by World Health Organization (WHO), Joint United Nations Programme on HIV/AIDS (UNAIDS) and international non-governmental organizations (NGOs). By December 2007, three million people were receiving ART in low- and middle-income countries, but still this was only 31% of those estimated to be in need of it [1].

ART programs in developing countries are now moving from early pioneer projects to a sustained effort. Inevitably, the long-term challenges of providing ART will become increasingly evident, including late drug toxicities, treatment failure and emergence of drug resistance [2‐4]. Indeed, some have argued that scaling up ART in Africa could create widespread drug resistance [5, 6]. Early reports, however, have documented good adherence to therapy [7] and short-term virological efficacy comparable to industrialized countries [8].

Although several studies on ART efficacy in Africa have been published, the majority have been carried out in larger cities [9‐11], often with NGO support [10, 12], and usually with short follow-up time [9, 10, 12]. However, the majority of Africans reside in rural areas [13], and little is known about the long-term effects of ART in such settings. The key to long-term benefit of ART is sustained suppression of viral replication and avoidance of resistance [14‐16]. Our aim was to assess virological efficacy and emergence of drug resistance in HIV-infected patients up to 4 years after starting first-line ART in a rural Tanzanian hospital.

Virological suppression rates were good up to 4 years after starting ART in a rural Tanzanian hospital. These results are in keeping with early reports from resource-limited settings, where short-term virological efficacy rates were as good as those reported from Europe and North America [8]. We show that suppression of viraemia can be sustained for several years even in rural Africa, where logistical support is challenging and patients often live in poverty. However, like in many other African ART programs the attrition rate was high, and strategies to reduce early mortality and other program losses need to be identified [11, 12, 22, 23].

Experiences elsewhere have shown that poorly managed HIV programs can give rise to widespread drug resistance [24]. A number of factors may have contributed to the sustained virological efficacy of the ART program in the present study. First, all treatment and care for HIV-infected patients was provided free of charge, which has previously been shown to improve treatment efficacy [8]. Second, all patients had three days of adherence counselling with a nurse prior to starting ART. Third, a close collaboration between the clinical staff and a network of community home-based carers ensured follow-up of patients in their villages. Fourth, regular educational peer-support meetings contributed to reduce the stigma and isolation many patients experience after receiving an HIV diagnosis. Fifth, antiretroviral drug supply continuity was uninterrupted from the beginning of the program. And finally, visiting HIV physicians focused on capacity building of local clinical officers, with emphasis on common curable opportunistic infections, such as tuberculosis, candidiasis, cryptococcal meningitis and cerebral toxoplasmosis.

Overall, emergence of drug resistance was relatively uncommon; only 8.5% harboured clinically significant resistance mutations. Although the proportion of patients with drug resistance was low, however, in a high-prevalence country like Tanzania the absolute number of individuals in need of second-line ART can rapidly become substantial. If our results were extrapolated to Tanzania as of December 2007 [1], then 11,500 patients would harbour drug resistance and be in need of second-line ART. Such an extrapolation is not necessarily valid, but it illustrates the magnitude of the problem that drug resistance can inflict on national ART programs. The number of individuals receiving ART has increased 20-fold over the past 4 years in sub-Saharan Africa [1], but access to second-line antiretroviral drugs is still limited in many developing countries due to higher costs and lack of fixed-dose combinations. Our study underscores the growing global need for affordable and convenient second-line antiretroviral regimens.

The prevalence of drug resistance increased with time and reached approximately 15% after 3–4 years on ART. Most previous studies on ART in Africa have focused on early treatment efficacy, showing good virological results with a limited observation time [10, 12, 25]. Only a few studies have assessed long-term (>2 years) emergence of drug resistance in sub-Saharan Africa. An early study from Senegal showed that 12.5% had one or more drug resistance mutations after a median of 30 months on ART [26], whereas a recent study from Côte d'Ivoire found 22% resistance after a median of 37 months on ART [27]. These results should not be used as an argument against HIV treatment in Africa; in fact, the results are comparable to a recent study from Canada, where 20% developed resistance after 30 months on the ART regimen most widely used in resource-limited settings (stavudine/lamivudine/nevirapine) [28]. Thus, emergence of drug resistance appears to occur at a similar rate in Africa as in a Western setting.

Of concern, among 18 patients with drug resistance mutations, 14 harboured dual-class resistance. All 14 had a combination of M184I/V, conferring resistance to lamivudine, with one or more of K103N, Y181C and G190A, conferring resistance to NNRTIs. Five of these patients also had thymidine analogue mutations (TAMs), associated with cross-resistance to all NRTIs. In 3 patients the standard second-line regimen in Tanzania would not be adequate, i.e. would not introduce at least 2 fully active drugs, which is the recommended strategy in treatment failure [29]. Other studies from low- and middle-income countries, using the same first-line treatment, have found a similar pattern. In a recent study from Angola, 65% of patients with virological failure had dual-class resistance [30]. Furthermore, a study from Thailand found that second-line treatment options, in the absence of newer antiretroviral drugs, were limited for 48% of patients failing their initial regimen [31]. Expanding access to newer antiretroviral drugs, including new HIV drug classes, should be a priority in the global efforts to control HIV/AIDS.

It has been shown that in the presence of a failing ART regimen, resistance mutations accumulate, jeopardizing future treatment options [32]. Early detection of treatment failure rely on viral load measurements, a standard component of ART programs in resource-rich countries [29]. In the present program, like in most resource-limited settings, viral load was not measured routinely, and treatment failure had to be assessed by clinical signs and CD4 cell counts. However, clinical signs and CD4 decline, as recommended by WHO to detect treatment failure in the absence of viral loads, have poor sensitivity and specificity, and result in frequent misclassifications [33, 34]. Hence, there is an urgent need for a simple, affordable viral load assay adapted for use in basic, tropical environments, so that treatment failure can be detected before multiple mutations occur.

In our study only duration of ART was significantly associated with emergence of drug resistance. Baseline anemia and lymphopenia were borderline significant in univariable analysis, and our sample size might have been too small to reveal a true association. Other studies have found that low CD4 cell count and high viral load at baseline increase the risk of drug resistance [35]; however, these measurements were not available in our study.

There were some weaknesses of this study. First, virological efficacy could only be assessed in patients who were alive and in care. A high early mortality accounted for most of the program loss, which probably reflected advanced immunodeficiency at enrolment rather than treatment failure [17]. Many patients were transferred out when the National AIDS Control Program started scaling up ART in other villages, but it is unlikely that this introduced any systematic bias. Among patients who stopped treatment (4.9%) or were lost to follow-up (8.4%), there was probably a proportion who either died or developed drug resistance. Our study must be considered an "on-treatment" analysis, and virological suppression rates and resistance estimates in an "intention-to-treat" analysis would have been poorer. Another limitation of this study was the lack of longitudinal viral load and resistance results. A cross-sectional virological survey may be more influenced by random biological variations and laboratory artefacts, being derived from a single time point. Also, we can not ascertain whether drug resistance mutations existed prior to initiation of ART, which was recently observed in rural South Africa [36], or developed during treatment. However, Haydom Lutheran Hospital was the first ART provider in the area, and single-dose nevirapine was not used for PMTCT, so it is unlikely that there was any significant primary resistance. Furthermore, this study was limited by lack of adherence data, which is considered the most important predictor of resistance [35]; however, adherence estimates would not have altered our conclusions. Finally, this was a hospital based study and probably there was a selection bias towards more advanced immunodeficiency at baseline, which has previously been shown to increase the risk of drug resistance [35]. On the other hand, late presentation has been observed in many African ART programs [10‐12, 25, 37, 38], and we believe our findings can be representative of other similar settings.

We found good virological suppression rates up to 4 years after initiating ART in a rural hospital in Tanzania. These results suggest that ART can be safely scaled up in rural Africa with similar long-term virological efficacy rates as those reported for industrialized countries. However, prevalence of drug resistance increased with time, and dual-class resistance was common, raising concerns about exhaustion of future antiretroviral drug options. Earlier detection of treatment failure and timely switch to second-line ART could reduce accumulation of drug resistance, underscoring the growing need for virological monitoring in resource-limited settings. This study might provide a useful forecast of drug resistance and demand for second-line antiretroviral drugs in rural Africa in the coming years.