Introduction

Advances in antiretroviral therapy (ART) had turned HIV/AIDS into a chronic　disease [1-5]. As a consequence of living longer, chronic kidney disease (CKD) has become an important cause of morbidity and mortality in HIV-infected patients [1,3-5]. Several studies have reported increased prevalence of CKD, ranging from 4.9% to 8.4% in such patients [6-9]. In addition to the established risk factors, such as aging, diabetes mellitus (DM) and hypertension [2,10], other factors related to the virus itself and to the treatment [e.g., exposure to tenofovir (TDF), a commonly used antiretroviral (ARV)], are thought to be related to nephrotoxicity in HIV-infected patients[2,11,12].

To date, the benefit of TDF first line treatment is considered to outweigh the risk of TDF-induced nephrotoxicity. A recent meta-analysis study has reported that the use of TDF is associated with a statistically significant though only modest renal dysfunction, and recommended no restriction of TDF use when regular monitoring of renal function and serum phosphate levels is impractical [13]. Furthermore, the 2010 WHO guidelines for ART in adults and adolescents recommended TDF as part of the first line regimens (URL: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf).

However, several studies have reported that low body weight is an independent risk factor for TDF-associated nephrotoxicity and might lead to potentially higher risk for larger drug exposure and thus, more severe toxicity [14-17]. Under such scenario, regional prevalence of CKD may influence the approach to screening and monitoring of HIV-infected patients initiated on ART. In particular, most nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), such as TDF and 3TC/FTC, are excreted by the kidney and may require dose adjustment in individuals with reduced glomerular filtration rate (GFR), and may require more intensive monitoring in patients with pre-existing CKD.

Following the 2010 WHO guidelines, the use of TDF has been increasing rapidly in Vietnam, where patients are more likely to have smaller body weight compared to Caucasians. At this stage, little is known about CKD among Vietnamese HIV-infected patients. In this context, it is important to determine the prevalence of CKD and its risk factors including TDF exposure and low body weight in this region. The present study was conducted to evaluate the above factors in Vietnamese HIV-infected patients.

Methods

Results

Discussion

We documented in the present study the prevalence of CKD and the associated risk factors in our Vietnamese cohort. CKD was identified in 7.3% of the patients between October 2011 and April 2012. Although severe renal dysfunction was observed in only 2 cases, we consider this finding quite alarming in our study setting, since it is more than double that reported in a previous study (3.1%) on the prevalence of CKD among Vietnamese healthy volunteers aged more than 40 years [19]. Our cohort comprised relatively younger and stable patients on ART with a mean age of 36.4 years.

In addition to the high prevalence of CKD, a striking finding in this study was that TDF use has increased steeply since the 2010 WHO ART guidelines that recommended the use of TDF; TDF use was also an independent risk for CKD in Vietnamese, in addition to low body weight. We reported previously that Japanese patients with small body weight (<59 kg) treated with TDF were at high risk of renal dysfunction [16], whereas those with body weight of >67 kg had negligible risk, similar to the patients reported by Cooper et al [13]. One experimental study of rhesus macaques also reported that TDF-associated nephrotoxicity was dose-dependent [20]. The mean body weight of the patients enrolled in the present study was 55 kg, which is about 30 kg less than that of American males of similar age (88 kg) (URL:http://www.cdc.gov/nchs/data/nhsr/nhsr010.pdf). To prevent TDF-related CKD in patients with a small body weight, the efficacy and safety of low-dose TDF adjusted to low body weight should be evaluated in a clinical trial.

One study argued that the initial decline in eGFR following the commencement of TDF therapy stabilized later after the first 6 months [21]. However, whether or not the initial decline stabilizes later in patients with low body weight remains to be documented in a longitudinal study of our cohort. It is true that the future risk of TDF-related CKD is still uncertain. In this study, almost all patients who experienced renal dysfunction continued the same ART regimen because renal dysfunction was relatively moderate as shown in Table 1. Although one severe case showed improvement of renal function after cessation of TDF, normalization of renal function after withdrawal of TDF was reported to be incomplete in some cases [22]. Previous studies recommended dose reduction of drugs that are cleared by the kidney, such as lamivudine and TDF, when Ccl falls below 50 ml/min [23], to avoid further worsening of renal dysfunction. Early detection of eGFR decline is important for switching from TDF to AZT or abacavir to preserve renal function. Despite those concerns, however, there is no doubt that TDF is still an important drug with enough anti-HIV potency and less mitochondrial toxicity among NRTIs. In this regard, serum creatinine should be monitored even in resource-limited situations.

Furthermore, another study that compared patients with or without TDF use depicted that TDF was more likely to be used in the salvage regimen so far; patients on TDF had the longer duration of ART and more positive viral load (Table 2). Based on this analysis, patients on TDF were more likely to develop CKD, although the mean body weight was not significantly different between the two groups. In addition, in terms of another antiretroviral agent, protease inhibitor (PI), also known as a risk factor for CKD [11], 97 (12.6%) patients used PIs (all PIs were ritonavir boosted lopinavir). Of 97 patients, 83 (85.6%) were co-administered with TDF. Although univariate analysis suggested that the use of PIs was associated significantly with CKD, multivariate analysis did not (Table 3). The reason of this result could be explained by the short duration of co-administration and its effect as a confounding factor for TDF use.

The present study has several limitations. Due to its cross-sectional nature, we can only draw association of events and not demonstrate causative relationship between TDF and renal dysfunction. Further longitudinal studies are required to determine the impact of the aforementioned factors on renal function. Second, co-infection with HCV, a known risk factor for CKD, was not included in this analysis due to lack of available data in our cohort. The prevalence of HCV in Vietnamese is relatively high because injecting drug use is one of the main routes of infection in Vietnam. We are adding data for a longitudinal study on TDF toxicity in our cohort. Lastly, the Modification of Diet in Renal Disease formula (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) is commonly used for evaluation of renal function at present [24-26], however, the racial coefficient for Vietnamese is currently not available. In addition, serum creatinine was measured by the Jaffe method in our study, which is difficult to apply to MDRD or CKD-EPI since those formulations are based on measurement of serum creatinine by the more widely used enzyme method. For this reason, our study utilized Ccl to assess renal function.

Despite these limitations, the results of the present study call for attention to active pharmacovigilance of TDF. The results identified TDF exposure as a significant and independent risk for CKD in Vietnam, although the duration of TDF use is still relatively short. Further longitudinal study is required to evaluate the impact of TDF on renal function in Vietnam and other countries with small-body weight patients.

Supporting Information

Acknowledgments

The authors thank Ms. Keiko Saito and Ms. Nguyen Thi Huyen for the excellent assistance. The authors also thank all the clinical staff at the National Hospital of Tropical Diseases for their help in the completion of this study.