Zidovudine- versus Tenofovir-Based Antiretroviral Therapy for the Initial Treatment of HIV Infection in the Ethnic Minority Region of Liangshan Prefecture,Sichuan Province,China

Abstract

Background:

Tenofovir (TDF)-based highly active antiretroviral therapy (HAART), as recommended by the World Health Organization guidelines for HIV-naive patients, has been limited in resource-constrained settings. The aim of this study was to evaluate the effectiveness of zidovudine-(ZDV) versus TDF-based HAART in the Yi minority region of Sichuan Province, China at a single HIV treatment center.

Methods:

The primary end point was the attainment of an HIV viral load <50 copies/mL. Secondary end points included change in CD4 level, adverse reactions, mortality, and sustained virologic suppression.

Results:

Of the 361 total participants, recipients of TDF-based HAART were more likely to achieve viral load <50 copies/mL (60% versus 46%, odds ratio [OR] = 1.7, P = .016) as well as sustained virologic suppression (61% versus 28%, OR = 3.4, P = .001). Tenofovir (adjusted odds ratio [OR_adj] = 1.71, P = .025) and female sex (OR_adj = 1.93, P = .003) were identified as independent predictors of achieving HIV viral load <50 copies/mL in the multivariate logistic regression analysis.

Conclusion:

Among Chinese Yi minority HIV-infected participants, TDF-based HAART was superior to ZDV-based HAART for initial treatment of HIV infection, suggesting TDF-based HAART should be the regimen of choice in China.

Keywords

HIV HAART tenofovir zidovudine HIV viral load

Introduction

Since its inception in 2002, the China National Free Antiretroviral Treatment Program has made tremendous progress in providing highly active antiretroviral therapy (HAART) to over 220 000 patients and has markedly decreased the 5 year mortality rate of Chinese HIV-infected patients.¹ Current Chinese guidelines recommend zidovudine (ZDV) or tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) plus efavirenz (EFV) or nevirapine (NVP) for the initial treatment of HIV.² The 2016 World Health Organization (WHO) guidelines list TDF plus 3TC or emtricitabine as the preferred nucleoside reverse transcriptase inhibitor backbone.³ In response to these guidelines, the China National Free Antiretroviral Treatment Program has expanded the use of TDF. In Sichuan Province, 44% of all HIV-infected patients prescribed HAART in 2013 used a regimen containing TDF and 3TC plus EFV or NVP (Sichuan Center for Disease Control and Prevention, personal communication, May 10, 2014). Although studies comparing TDF- versus ZDV-based regimens for treatment of HIV infection have demonstrated superior safety of TDF- over ZDV-based HAART, data on virologic suppression have yielded mixed results.^4

–10

In 2010, areas of the Liangshan Prefecture located in Sichuan Province had an 11% prevalence of HIV among adults, making this the highest prevalence region in China.¹¹ In a pilot project starting in 2011, our center located in Liangshan Prefecture, replaced ZDV with TDF as part of the preferred HAART regimen for treatment-naive HIV-infected patients. This permitted us to conduct a comparison of TDF- versus ZDV-based HAART in antiretroviral naive HIV-infected individuals in a high-prevalence area of China.

Methods

Setting

The HIV treatment center is part of a general county-level hospital located in a rural area of Liangshan Prefecture, where over 95% of the population is comprised of the Yi ethnic minority group, with the majority employed as farmers. It serves as the referral treatment center for a population of approximately 270 000 people and has over 3500 HIV-infected outpatients currently under treatment.

Study Design and Data Collection

Data were extracted from patient charts stored in the HIV treatment center department of records. All participants enrolled in the clinic and started HAART before December 31, 2012 were considered for entry into the retrospective cohort, including those who were lost to follow-up or died before December 31, 2012. Participants surviving beyond this date who received care in the clinic were additionally observed prospectively for any subsequent end points until December 31, 2013. In order to be included in the study cohort participants must have had (1) documented HIV seropositivity, (2) no prior antiretroviral therapy (ART) exposure, (3) received ZDV/3TC or TDF/3TC in combination with EFV or NVP for at least 3 months, and (4) at least 1 HIV viral load measurement after ART initiation. The primary end point was attaining an HIV viral load <50 copies/mL. Secondary end points included CD4 response defined as change in CD4 count level from baseline to peak CD4 count level achieved, change of ART due to intolerance of ZDV or TDF, and all-cause mortality. Sustained virologic suppression was also analyzed in the subset of participants who had more than 1 viral load measurement and was defined as achievement of all HIV viral loads <50 copies/mL. HIV viral load testing was determined by VERSANT 440 Molecular Systems (Bayer Healthcare, Siemens Healthcare Diagnostics, Germany) in which the lowest level of detection was <50 copies/mL and the BD FACSCount system (Becton, Dickenson and Company, USA) was used to measure CD4 count. This study was approved by the HIV treatment center ethics committee.

Analysis and Statistics

Categorical and continuous data were analyzed by the Cochran–Mantel–Haenszel test and the Wilcoxon rank sum test, respectively. Differences in mortality rates were analyzed by Kaplan-Meier survival analysis. Factors found to be associated with the primary outcome in univariate analyses were entered into a multivariate logistic regression model. A backward hierarchical strategy was employed, sequentially removing covariates without a significant effect on the model. Variables demonstrating associations with the primary end point (P < .10) after adjustment for the other covariates were retained in the final model. All reported P values were 2-sided with a P < .05 considered statistically significant. All statistical analyses were performed using SPSS (version 22).

Results

Demographic and Clinical Characteristics

Of the 361 participants meeting the inclusion criteria, 240 (66%) were started on a TDF-based regimen and 121 (34%) on a ZDV-based regimen (Table 1). The 2 groups did not differ with respect to gender, history of intravenous drug use, coinfection with hepatitis C, or in the mean number of HIV viral loads measured per year. In participants who had a baseline CD4 count, the TDF group had higher mean baseline CD4 count than the ZDV group (399 ± 230 versus 302 ± 139, mean ± standard deviation [SD] cells/mm³, P < .001). Compared to those on ZDV-based therapy, those starting TDF-based therapy were slightly older (35.9 ± 6.9 versus 32.5±9.1 years, P < .001), had fewer mean number of CD4 measurements per year (2.1 ± 1 versus 2.3 ± 1.1, P = .015), were earlier in mean time to first viral load measurement after starting HAART (331 ± 138 versus 389 ± 195 days, P = .004), had shorter mean length of follow-up (565 ± 163 versus 834 ± 240 days, P < .001), and were paired less with NVP (5% versus 21%, P < .001).

Table 1.

Baseline and Follow-up Characteristics.

Variable	All Participants, N = 361 (Mean ± SD)	ZDV-Based Regimen, n = 121 (Mean ± SD)	TDF-Based Regimen, n = 240 (Mean ± SD)	P Value
Mean age, years	34.8 ± 7.9	32.5 ± 9.1	35.9 ± 6.9	<.001
Female	49%	47%	51%	.41
History of intravenous drug use	61%	58%	63%	.44
Positive hepatitis C serostatus	45%	44%	46%	.66
Mean baseline CD4 count, cells/mm³	n = 206, 354 ± 199	n = 96, 302 ± 139	n = 110, 399 ± 230	<.001
Mean CD4 measurements per year	2.2 ± 1.1	2.3 ± 1.1	2.1 ± 1	.015
Mean HIV viral load measurements per year	0.89 ± 0.5	0.89 ± 0.53	0.89 ± 0.47	.94
Mean time to first viral load after starting HAART, days	350 ± 161	389 ± 195	331 ± 138	.004
Mean length of follow-up, days	655 ± 230	834 ± 240	565 ± 163	<.001
Received NVP as NNRTI	10%	21%	5%	<.001

Abbreviations: HAART, highly active antiretroviral therapy; NVP, nevirapine; SD, standard deviation; TDF, tenofovir; ZDV, zidovudine; NNRTI, non-nucleoside reverse transcriptase inhibitor.

Primary End Point

A total of 144 (60%) of the 240 participants in the TDF group and 56 (46%) of the 121 participants in the ZDV group achieved an HIV viral load <50 copies/mL (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.1-2.66, P = .016). To examine if dissimilar rates of NVP use between the 2 treatment groups had a substantive effect on the primary end point, EFV-only containing regimens were analyzed in both treatment groups. The OR of achieving the primary end point still trended toward favoring the TDF group (OR = 1.6, 95% CI = −0.98 to 2.6, P = .057).

Secondary End Points

There was no difference in change of CD4 counts from baseline to peak between the 2 treatment groups (TDF group, N = 109, +184 CD4 cells/mm³; ZDV group, N = 95, +153 CD4 cells/mm³, P = .31). There were no differences with respect to age, history of intravenous drug use, hepatitis C virus status, or treatment group in those who had and did not have a baseline CD4 count measurement. There were 26 adverse events that led to study drug substitution, 22 (18% of all ZDV group participants) in the ZDV group and 4 (2% of all TDF group participants) in the TDF group (OR = 13, 95% CI = 4-38, P < .001). Although the raw mortality rate in the ZDV group was higher than the TDF group (2.2 deaths/100 person years [PY] versus 0.4 deaths/100 PY, respectively), the study was not powered for this end point, and it did not achieve statistical significance in the Kaplan-Meier survival analysis. In participants who had more than 1 viral load measurement, 31 (57%) of the 54 in the TDF group and 20 (28%) of the 71 participants in the ZDV group achieved sustained undetectable viral load (OR = 3.4, 95% CI = 1.6-7.3, P = .001). There were more mean number of viral loads measured for the ZDV group than the TDF group (2.3 versus 2.1, 95% CI for difference in means 0.03-0.34, P = .028).

Univariate and Multivariate Analysis of Factors Associated with Achieving HIV Viral Load <50 Copies/mL

Factors associated with achieving HIV viral load <50 copies/mL in the univariate analyses were regimen (OR = 1.71 favoring TDF group, 95% CI = 1.1-2.66, P = .016), gender (OR = 1.96 favoring females, 95% CI = 1.29-2.99, P = .002), and not having a history of intravenous drug use (OR = 1.7, 95% CI = 1.1-2.61, P = .017). In the multivariate logistic regression model, only regimen (adjusted odds ratio [OR_adj] = 1.71 favoring TDF group, 95% CI = 1.07-2.72, P = .025) and gender (OR_adj = 1.93 favoring females, 95% CI = 1.24-2.99, P = .003) were associated with achieving HIV viral load <50 copies/mL (Table 2).

Table 2.

Factors Associated with Achieving HIV Viral Load <50 copies/mL on Univariate and Multivariate Analysis.

Factor	Univariate Analysis, OR (95% CI)	P Value	Multivariate Analysis, Adjusted OR (95% CI)	P Value
Regimen
TDF	1.71 (1.1-2.66)	.016	1.71 (1.07-2.72)	.025
ZDV	1	.016	1	.025
Gender
Female	1.96 (1.29-2.99)	.002	1.93 (1.24-2.99)	.003
Age	not applicable		1.01 (0.98-1.04)	.4
IVDU
Negative	1.7 (1.1-2.61)	.017	1.28 (0.45-1.38)	.4
Positive	1	.017	1	.4
HCV
Negative	1.17 (0.76-1.81)	.46	1.19 (0.88-2.09)	.4
Positive	1	.46	1	.4

Abbreviations: CI, confidence interval; IVDU, intravenous drug user; HCV, hepatitis C virus; OR, odds ratio; TDF, tenofovir; ZDV, zidovudine.

Discussion

This observational study from a county-level HIV treatment center is the first to our knowledge to analyze the use of TDF in Chinese HIV-infected ART-naive patients as initial HAART. The TDF treatment group was significantly superior to the ZDV treatment group in achieving an HIV viral load <50 copies/mL and sustained virologic response. The association of TDF with improved virologic outcomes was also observed in the logistic regression model when the analysis was adjusted for several other clinically relevant factors.

These data are consistent with the findings from the Study 934 Group, a randomized clinical trial from the United States and Europe comparing EFV–FTC (emtricitabine)–TDF (after 96 weeks the regimen was changed to EFV plus co-formulated FTC-TDF) with EFV plus coformulated 3TC/ZDV which found TDF-based therapy superior to ZDV-based therapy in achieving and maintaining HIV viral load <400 copies/mL (71% versus 58%, respectively, P = .004) after 144 weeks of treatment.⁴ In a cohort study from India, fixed-dose TDF-based HAART also showed significantly lower virologic failure as compared to fixed-dose ZDV or stavudine-based HAART.⁵ Likewise, another prospective cohort study from South Africa showed in subgroup analysis that single tablet EFV-LMV-TDF was superior to EFV plus fixed-dose LMV-ZDV in achieving an undetectable viral load.⁶ In contrast, 1 large randomized clinical trial from low-, intermediate-, and high-income countries compared EFV plus coformulated FTC/TDF to EFV plus coformulated 3TC/ZDV,⁵ and 2 observational cohort studies from South Africa and 1 from China examining EFV or NVP, 3TC, and TDF versus EFV or NVP, 3TC, and ZDV found no difference in virologic suppression between treatment groups.^8
–10 One possible explanation for the discrepancy in the results could be that the use of coformulated EFV/FTC/TDF in the Study 934 Group conferred an advantage over ZDV-based HAART that the other studies could not detect using nonsingle pill coformulated TDF-based HAART. It is possible that even though our study did not use coformulated regimens, medication adherence to once daily TDF-based HAART was higher than twice daily ZDV-based HAART in our patient population with high rates of poverty and drug use, resulting in superior virologic outcomes in the TDF group.

Interestingly, subgroup analysis of the Labhardt study from South Africa showed no difference in virologic outcomes between TDF and ZDV based regimens which used NVP as the NNRTI.⁶ Additionally, a small randomized clinical trial from France¹² and a large retrospective cohort study from Nigeria¹³ showed NVP-LMV-TDF was actually inferior to NVP-LMV-ZDV. In the small subset of patients receiving NVP as the NNRTI in our study, there was no significant difference in obtaining undetectable viral load between TDF- and ZDV-based regimens, though our study was not powered to detect a difference. Similar to our data, the aforementioned studies also found better tolerability and less drug substitutions with TDF-based regimens than with ZDV-based regimens.^4

–9 Our study demonstrated no difference in increase of CD4 count from baseline, which is consistent with the above-mentioned studies. As in our study, there was no difference found in mortality between TDF- and ZDV-based regimens in observational studies from South Africa⁸ and Zambia.¹⁴

Multiple studies from China using non–TDF-based regimens in the majority of Han Chinese ethnicity participants have found higher proportions of participants achieving virologic suppression (72%-92%) than that observed in our cohort.¹⁰ ^, ^15

–19 However, a cross-sectional survey set in the same locality and with participants closely matching our cohort demographic had similar virologic responses to our study using non–TDF-based regimens. Yi ethnic minority, intravenous drug use, and illiteracy were all correlated with poor outcomes.²⁰ The percentage of intravenous drug users in our study was much higher (61%) than that reported in a countrywide HIV-infected patient registry (22%), which found intravenous drug use a strong predictor of delayed HAART initiation and death.²¹ It is likely that the high levels of substance use and poverty in our population contributed to the inferior outcomes in both treatment groups.

A larger proportion of female participants achieved HIV viral load <50 copies/mL than male participants regardless of treatment group. Data from other cohort studies have also shown that female HIV-infected patients had better virologic and immunologic response to HAART than males.^22
–24 A possible explanation for the gender discrepancy in our cohort is that males were much more likely to have a history of intravenous drug use (91% of males versus 31% of females) and therefore likely had poorer general health and a more disordered lifestyle leading to lower treatment adherence.

Our study had several limitations worthy of mention. As with any unrandomized observational cohort study, there is the possibility of unmeasured confounders and bias that could have affected outcomes. There were many participants with missing baseline CD4 count data which may have affected the power to detect a difference in the change in CD4 level from baseline. Mortality statistics were dependent on family reporting and were not linked to any public database, thus our study may have underestimated true mortality rate. Because the majority of participants in the ZDV treatment group initiated HAART at an earlier calendar date than participants in the TDF treatment group, there is the potential for temporal bias. It is possible that improvements in adherence counseling and management of adverse reactions at a later time could have favored TDF. Our analysis was from a single center, with all participants belonging to the Yi ethnic minority, thus potentially limiting the generalizability of our results.

Our study also has several strengths. It describes one of the largest published Chinese HIV HAART-naive single-center cohorts, and to our knowledge is the first to report on use of TDF treatment in China. The study was conducted in a “real-world” setting, where participants were part of a large clinical HIV treatment program and were managed according to standard care. Selection bias was minimized in our study because prior to October 2011, ZDV-based HAART was the preferred regimen, whereas after that date TDF-based HAART became a preferred therapy. Additionally, due to the practice environment, we had a complete accounting of patients on HAART.

In conclusion, we have demonstrated that in a HAART-naive Chinese patient cohort, TDF-based HAART is clinically superior to ZDV-based HAART both in terms of efficacy and tolerability. We believe our study supports the use of TDF as a component of initial HAART in China and adds to the data to support the use of TDF in resource-constrained countries as outlined in the WHO guidelines.

Footnotes

Acknowledgments

The authors are grateful for the support of Lewu Xuewen (HIV Treatment Center Director) and Ma Fanghua (HIV Treatment Center Outpatient Department Medical Director). The authors also thank the doctors, counselors, staff, and patients and their families at the HIV Treatment Center who made this research possible.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Jonathan Shuter was supported, in part, by the Clinical Core of the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health (NIH AI-51519).

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