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International Journal of Infectious Diseases 25 (2014) 130–135

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Review

Nevirapine versus for patients co-infected with HIV and

tuberculosis: a systematic review and meta-analysis

a,1 b,1 c a a a,

Hai-Yin Jiang , Min-Na Zhang , Hai-Jun Chen , Ying Yang , Min Deng , Bing Ruan *

a

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,

The First Affiliated Hospital, School of Medicine, Zhejiang University

b

Department of Integrated Traditional and Western Medicine, Cancer Hospital of Hangzhou, Hangzhou, Zhejiang, China

c

Department of Infectious Diseases, Jinhua Central Hospital, Jinhua, Zhejiang, China

A R T I C L E I N F O S U M M A R Y

Article history: Objectives: Antiretroviral therapy (ART) reduces the morbidity and mortality of patients infected with

Received 15 January 2014

HIV. Standard ART includes either nevirapine or efavirenz, however the efficacy of these drugs is limited

Received in revised form 8 March 2014

in patients receiving rifampin treatment for tuberculosis (TB). We compared the efficacy and safety of

Accepted 19 April 2014

nevirapine- and efavirenz-based ART regimens in patients co-infected with both HIV and TB through a

Corresponding Editor: Eskild Petersen,

systematic review and meta-analysis.

Aarhus, Denmark

Methods: A comprehensive search of the literature was carried out to identify clinical trials comparing

the efficacy and safety of nevirapine- and efavirenz-based ART regimens in HIV-associated TB. Eligible

Keywords: clinical studies included at least one primary or secondary event; the primary event was virological

HIV

response and secondary events were TB treatment outcomes, mortality, and safety profile.

Tuberculosis

Results: This meta-analysis compared five randomized clinical trials and four retrospective clinical trials.

Rifampin

Both included patients co-infected with HIV and TB; 833 received nevirapine, while 1424 received

Nevirapine

efavirenz. The proportion of patients achieving a virological response by the end of the follow-up was

Efavirenz

higher in the efavirenz group: plasma <400 copies/ml, risk ratio (RR) 1.10, 95% confidence

interval (CI) 1.03–1.17 (p = 0.004); plasma viral load<50 copies/ml, RR 1.07, 95% CI 0.98–1.16 (p = 0.146).

No significant differences were found in either mortality (RR 0.70, 95% CI 0.44–1.13, p = 0.142) or TB

treatment outcomes (RR 1.01, 95% CI 0.96–1.06, p = 0.766). Due to adverse advents, nevirapine-based

regimens significantly increased the risk of discontinuation of assigned ART (RR 0.43, 95% CI 0.23–0.81, p

= 0.009).

Conclusions: Although efavirenz-based ART was associated with more satisfactory virological outcomes,

nevirapine-based ART could be considered an acceptable alternative for patients for whom efavirenz

cannot be administered.

ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-

nc-nd/3.0/).

co-infected patients, the use of certain ART regimens remains

1. Introduction

controversial due to concerns over adverse drug interactions.

Nevirapine and efavirenz, two classes of non-nucleoside reverse

The advent of highly active antiretroviral therapy (ART) has

1 transcriptase inhibitor (NNRTI), are recommended as first-line ART

greatly reduced both the mortality and morbidity caused by HIV. 3

regimens in resource-limited settings. Rifampin, a key component

Among HIV-infected individuals, tuberculosis (TB) has emerged as

of ATT, is a potent inducer of the enzyme system;

one of the most frequent opportunistic infections, and is a leading 4,5

2 activation of this system leads to enhanced clearance of NNRTIs.

cause of death in resource-limited areas. Although both ART and

Efavirenz is recommended by the World Health Organization

anti-TB therapy (ATT) have been shown to improve survival in

(WHO) for patients infected with HIV and TB due to a lower risk of

sub-therapeutic concentration than nevirapine or protease inhi-

6

bitors (PIs). The preferred antiretroviral regimen for co-adminis-

* Corresponding author. Fax: +86 57187236585.

tration with rifampin is two nucleoside

E-mail address: [email protected] (B. Ruan).

1

Both authors contributed equally to this work. inhibitors plus efavirenz, however, nevirapine is more widely used

http://dx.doi.org/10.1016/j.ijid.2014.04.020

1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

H.-Y. Jiang et al. / International Journal of Infectious Diseases 25 (2014) 130–135 131

than efavirenz in resource-limited areas due to lower costs, fewer not included in our virological analysis. For RCTs, the RR for

food restrictions, and more convenient dosing. Moreover, nevirapine primary and secondary outcomes were calculated on an intention-

7

is effective for preventing mother-to-child transmission of HIV. to-treat basis. We assessed heterogeneity using the Chi-square-

2

Although several randomized trials have been conducted to based Q-test, with I as a measure of inconsistency; a random-

compare the efficacies of nevirapine- and efavirenz-based regi- effects model was used for comparisons exhibiting a Q-test p value

2 11,12

mens, the use of these drugs remains controversial. Due to of <0.10 or I > 50%. A subgroup analysis of RCTs and non-

differences in methodology, including retrospective designs, non- randomized controlled trials (nonRCTs) was carried out to identify

randomized designs, small sample sizes, and differences in the differences between the two study types and verify the accuracy of

criteria used for scaling adverse events, definitive conclusions our results. Where sufficient studies were available, publication

13

remain elusive. To address these issues, we performed a systematic bias was assessed visually using funnel plots. All of the above

review and meta-analysis of the existing data to compare the analyses were conducted using Stata 11.0 software (StataCorp LP,

efficacy and safety of nevirapine- to efavirenz-based ART when College Station, TX, USA).

administered with rifampin-based ATT.

3. Results

2. Methods

3.1. Search results

2.1. Literature search

Following a search of three databases and the bibliographies of

We searched the medical literature published between January relevant publications, a total of 802 potentially eligible articles

1990 and February 2014 using PubMed, Embase, and the Cochrane were identified. Fifty-six duplicate articles were excluded from the

Database. We conducted the search using the terms ‘efavirenz’, analysis, along with 718 articles deemed irrelevant after reading

‘nevirapine’, and ‘rifampin or tuberculosis or TB’. In addition, we the title and abstract. The remaining 28 potentially relevant papers

examined the bibliographies of reviews, original studies, and relevant were examined thoroughly. Articles were excluded based on the

conference articles, and directly contacted some investigators. inclusion criteria listed in the Methods section, resulting in a total

14–24

of 11 publications referring to nine trials. A flow diagram of

2.2. Inclusion and exclusion criteria the literature search and selection process is given in Figure 1.

3.2. Characteristics of the studies included

Criteria for inclusion were: (1) study design was a randomized

controlled trial (RCT) or cohort study; (2) study subjects were HIV

The characteristics of the nine studies considered in this

patients presenting with concomitant TB; (3) two study arms

16,21,22,24

analysis are presented in Table 1. Four studies were

included standard doses of nevirapine- versus efavirenz-based

17–19,23 20

conducted in Asia, four in Africa, and one in Spain. The

ART; and (4) the ATT was rifampin-based.

total number of patients was 2257. The mean age of participants

The primary outcome was the virological response at the end of

ranged from 32 to 38 years, and the proportion of male participants

follow-up. Plasma viral load (pVL) is a globally accepted endpoint

ranged from 24% to 85%. The duration of ART was 24 to 96 weeks.

used to measure the efficacy of ART. Available data on the

The sample size varied from 33 to 849 patients.

virological response in the studies included were recorded as a

All trials involved patients co-infected with both HIV and TB.

plasma HIV RNA level <50 and <400 copies/ml. It should be noted

Mean baseline viral loads ranged from 5.3 to 5.7 copies/ml, and

that suppression of pVL to 50 copies/ml is a better generalized

8,9 mean baseline CD4 cell counts ranged from 36 to 139 cells/ml. Most

predictor of durable virological success. The secondary out-

trials included patients with pulmonary TB, all of whom received

comes were mortality, TB treatment, and safety profile (risk of

21

rifampin-containing anti-TB regimens. The patients in one study

adverse events and discontinuation of the study because of adverse

initiated nevirapine at the full dose (400 mg/day) without the 2-

events). TB treatment outcomes were defined as per the WHO

10 week lead in dose (200 mg) in order to limit the risk of sub-

guidelines. Studies including at least one primary or secondary

therapeutic nevirapine concentrations during the initiation of

event were eligible for the analysis. Studies published in a language

20

treatment. Thirty patients in one study, treated with 800 mg

other than English were not included, nor were articles published

efavirenz daily, were excluded from our analysis.

as comments, reviews, or editorials. Data from the same trial were

skimmed for relevant information.

2.3. Quality assessment and data extraction

Two authors independently assessed the methodological

quality of the selected studies. To assess the methodological

quality of the included RCTs we used the Cochrane risk of bias

assessment tool. For observational studies we used the Newcastle–

Ottawa quality assessment scale. All relevant information was

collected, including patient demographics, year of publication,

study location, study design, characteristics of the study popula-

tion (age, gender, baseline viral load, and CD4 cell count), ART and

ATT regimens, and follow-up time. To ensure accuracy, two

authors working independently extracted the target data.

2.4. Statistical analysis

Relative risks (RR) with 95% confidence intervals (CI) were used

to estimate the strength of association between dichotomous

variables. Patients lost to follow-up in retrospective studies were Figure 1. Flow chart of study selection.

132 H.-Y. Jiang et al. / International Journal of Infectious Diseases 25 (2014) 130–135

Table 1

Characteristics of included studies

Study Location Design Sample Male Viral load, CD4 cell Pulmonary Rifampin Intervention Follow-up,

size % copies/ml count, TB % dose months

cells/ml

Arm 1 Arm 2

Manosuthi RCT Arm 1, n = 71 64.8 5.57 74.8 63.4 450–600 3TC+d4T+NVP 3TC+d4T+EFV 48

et al., 2009 Arm 2, n = 71 69.0 5.57 55.8 57.7 mg/day

Swaminathan India RCT Arm 1, n = 57 83 5.55 85 73 450–600 3TC+ddI+NVP 3TC+ddI+EFV 24

et al., 2011 Arm 2, n = 59 77 5.45 83 65 mg/day

Matteelli Burkina Faso RCT Arm 1, n = 33 NR NR NR NR NR 3TC+d4T+NVP 3TC+d4T+EFV 48

et al., 2013 Arm 2, n = 36

Bonnet Mozambique RCT Arm 1, n = 285 60 5.5 86 76 10 mg/kg 3TC+d4T+NVP 3TC+d4T+EFV 48

et al., 2013 Arm 2, n = 285 56 5.7 95 79

Sinha India RCT Arm 1, n = 67 79.1 5.52 137 23.9 NR AZT+3TC+NVP AZT+3TC+EFV 96

et al., 2013 Arm 2, n = 68 59 5.19 139 27.9

Boulle South Africa RC Arm 1, n = 141 37.9 5.3 61 62.8 NR 2NRTI+NVP 2NRTI+EFV 72

et al., 2008 Arm 2, n = 708 26.3 5.3 80 62.7

Manosuthi Thailand RC Arm 1, n = 111 54 5.6 36 44 NR NVP-based regimen EFV-based regimen 48

et al., 2008 Arm 2, n = 77 82 5.7 36 50

Shipton Botswana RC Arm 1, n = 55 NR NR 54 NR NR AZT+3TC+NVP AZT+3TC+EFV 48

et al., 2009 Arm 2, n = 100 61

Villar Spain RC Arm 1, n = 13 84.5 5.3 86 NR NR NVP-based regimen EFV-based regimen 48

et al., 2009 Arm 2, n = 20

RCT, randomized controlled trial; RC, retrospective controlled; 3TC, ; d4T, ; NVP, nevirapine; EFV, efavirenz; ddI, ; AZT, ; NRTI,

nucleoside reverse transcriptase inhibitor; NR, not reported.

3.3. Meta-analysis the efavirenz group compared to the nevirapine group (RR 1.10,

95% CI 1.03–1.17, p = 0.004); this result was consistent with that of

3.3.1. Virological response the nonRCT subgroup analysis (RCTs: RR 1.09, 95% CI 1.01–1.19, p =

Seven studies reported the number of patients achieving a 0.038; nonRCTs: RR 1.11, 95% CI 1.01–1.21, p = 0.032) (Figure 2).

virological response at the end of follow-up, i.e., plasma viral load We also evaluated the virological response in terms of plasma

2

<400 copies/ml. Based on Chi-square and I analyses (Chi-square = viral loads <50 copies/ml at the end of follow-up. Although the

2

5.46, p = 0.486; I = 0%), a fixed-effect approach was used to result was not significantly different at the end of follow-up, there

estimate the RR of efavirenz vs. nevirapine. The pooled data was a trend towards an increase in virological response in patients in

demonstrated a statistically different rate of virological response in the efavirenz group (RR 1.07, 95% CI 0.98–1.16, p = 0.146) (Figure 3).

Figure 2. Comparison of the efavirenz and nevirapine groups by virological response (pVL <400 copies/ml) at the end of follow-up.

H.-Y. Jiang et al. / International Journal of Infectious Diseases 25 (2014) 130–135 133

Figure 3. Comparison of the efavirenz and nevirapine groups by virological response (pVL <50 copies/ml) at the end of follow-up.

3.3.2. ATT 3.3.3. Mortality

An analysis of 824 patients from three studies revealed no To reduce the heterogeneity of the data, only RCTs were

significant difference in patients who achieved a favorable included in our evaluation of mortality. Heterogeneity was

2

response to anti-TB treatment (RR 1.01, 95% CI 0.96–1.06, p = assessed using an I analysis, with no significant difference

2

0.766), with modest heterogeneity (Chi-square = 2.42, p = 0.299; evident (Chi-square = 4.22, p = 0.239; I = 28.9%). A fixed-effect

2

I = 17.2%) in each group (Figure 4). approach was used to estimate the effects of efavirenz vs.

Figure 4. Comparison of the efavirenz and nevirapine groups by TB treatment outcome, mortality, and discontinuation due to adverse events.

134 H.-Y. Jiang et al. / International Journal of Infectious Diseases 25 (2014) 130–135

nevirapine on mortality. Pooled data from four studies failed to To minimize the heterogeneity of the data, we further

identify a statistically significant difference between the two conducted a meta-analysis based on the type of study (RCT or

groups (RR 0.70, 95% CI 0.44–1.13, p = 0.142) (Figure 4). The most nonRCT), and found that the type of study did not affect the overall

common cause of death was severe infection; no deaths were conclusions. Our conclusions regarding the virological response in

attributed to either of the study drugs. the two treatment groups are consistent with those of Bonnet

19 23

et al. and Boulle et al., whose results had relatively high

3.3.4. Safety profile statistical power with a large sample size. Both studies suggested

No significant heterogeneity in the rate of discontinuation of that nevirapine-based regimens were less effective than efavir-

2

ART was observed between studies (Chi-square = 4.01, p = 0.26; I = enz-based regimens. Furthermore, differences in virological

25.2%). However, a meta-analysis revealed a higher risk of measurements may be a potential source of heterogeneity.

treatment discontinuation due to adverse events in the nevirapine Therefore, we conducted our meta-analyses based on consistent

group (RR 0.43 95% CI 0.23–0.81, p = 0.009) (Figure 4). virological measurements. Using this standardized approach, the

The most common causes for withdrawal of ART were , same trends were found in the efavirenz treatment groups across

skin rash, and psychiatric disorders. Three cases of Stevens– multiple trials.

Johnson syndrome were reported, but these were resolved after Another important issue is the outcome of ATT. The overall rates

discontinuation of nevirapine or switching to efavirenz. Three of favorable response to ATT were comparable between studies,

cases of clinically important psychiatric disorders were reported in with no significant differences between groups. A rifampin-

the efavirenz group. Neurological, gastrointestinal, and cutaneous containing regimen has been recommended by the WHO for the

adverse events were the most common side effects reported in four treatment of TB in patients infected with HIV due to its more

33

studies. favorable outcomes than non-rifampin treatments. ART is also

important for the treatment of TB, as viral suppression is necessary

for the restoration of Mycobacterium tuberculosis-specific CD4+ T

34

4. Discussion cell responses. Accordingly, a combination of ATT and ART has

been shown to reduce both the morbidity and mortality associated

35

To our knowledge, this systematic review is the first to compare with HIV-associated TB. One important caveat, however, is the

the efficacy and safety of standard doses of nevirapine and occurrence of immune reconstitution inflammatory syndrome,

efavirenz in patients co-infected with HIV and TB only. The present which occurs frequently in HIV-infected patients receiving both

review suggests that ART regimens containing efavirenz used in ATT and ART.

association with rifampin were associated with a more successful Regarding the safety profile, our meta-analysis favored

virological response than nevirapine; these findings were consis- efavirenz, as the frequent occurrence of hepatotoxicity and skin

tent across the study design. Our results suggest that ART that reactions contributed to significantly higher rates of discontinua-

includes efavirenz (600 mg per day) should be preferred over that tion due to adverse advents in the nevirapine group. However, the

which contains nevirapine (400 mg per day) for eligible patients overall toxicity profiles of nevirapine and efavirenz were

co-infected with HIV and TB. comparable. It should be noted that efavirenz has been linked

A Cochrane review of seven randomized clinical trials with a higher risk of central nervous system side effects, while

demonstrated that the two drugs provided comparable levels of nevirapine has been found to be a safe therapeutic option for

36

viral suppression in non-TB patients infected with HIV when patients at risk of psychiatric disorders.

combined with two nucleoside reverse transcriptase inhibitors Our results need to be interpreted with caution due to several

25

(NRTIs). In our meta-analysis, patients in the efavirenz treatment limitations. First, the number of eligible studies was small. This

group achieved statistically higher rates of virological response, resulted in a lack of data for some confounding factors, which may

26

likely due to the effects of rifampin on . have influenced the accuracy of the results. Differences in lengths

Rifampin is a potent inducer of the cytochrome P450 enzymes, of follow-up and the analyzed endpoint definitions were potential

which metabolize many drugs, including NNRTI antiretroviral sources of heterogeneity for the included studies. Second, several

5,27

agents. These effects are not uniform across NNRTIs, as the of the available studies had limited power, owing to small sample

current data clearly show a more significant reduction in plasma sizes and high withdrawal rates. Third, due to the limited number

nevirapine concentrations when using standard methods of of published studies, we expanded the search to include nonRCTs

administration and in standard doses, compared to efavirenz. and four retrospective studies in our meta-analysis. The risk of bias

Therefore, standard nevirapine-based regimens pose a greater risk in these types of study is high, further diminishing the statistical

of sub-therapeutic NNRTI concentrations in patients co-infected power of the analyses. While these limitations are important to

with TB. In order to limit the risk of sub-therapeutic nevirapine consider, such problems are inherent to the nature of meta-

28,29

concentrations during the initiation of treatment, nevirapine analyses, as they are based on secondary analyses of primary

at full doses (400 mg/day) without a 2-week lead in dose was given research.

in the trial conducted by Bonnet et al. In a pharmacokinetic study, a In conclusion, the results of this meta-analysis indicate that the

median minimum concentration of plasma nevirapine was efavirenz regimen for patients co-infected with HIV and TB is

observed that was higher than the minimum therapeutic associated with more successful virological outcomes compared to

30

concentration of 3 mg/l. However, the clinical effect was not a standard nevirapine regimen. Therefore, it may be advisable to

confirmed. A more recent meta-analysis concluded that even in choose efavirenz-based ART when co-administered along with a

non-HIV–TB co-infected patients, the efavirenz-based regimen is rifampin-based anti-TB therapy. However, nevirapine-based ART

31

less likely to lead to virological failure compared to nevirapine. could be considered an acceptable alternative in situations where

Therefore, in HIV–TB co-infected patients, even if the lower efavirenz cannot be administered. Accordingly, the best treatment

virological response with nevirapine is likely to be explained by the strategy for this group of patients still involves a considerable

stronger induction of nevirapine by rifampin, we could not exclude degree of clinical judgment.

that part of the reason is also potentially due to the lower intrinsic Funding: This study was funded by the Mega-projects of Science

potency of nevirapine compared to efavirenz. Hence, there is Research for the 12th Five-Year Plan of China, titled ‘‘The prevention

insufficient evidence to recommend a higher dose of nevirapine for and control of AIDS, viral hepatitis and other major infectious

32

patients on rifampin at this time. diseases’’, Grant No. 2013ZX10004904 and the Fundamental

H.-Y. Jiang et al. / International Journal of Infectious Diseases 25 (2014) 130–135 135

treated for TB–HIV co-infection in Botswana. Int J Tuberc Lung Dis 2009;13:

Research Funds for the Central Universities (2014XZZX008). The

360–6.

funders had no role in the study design, data collection and analysis,

18. Matteelli A, Kouanda S, Saleri N, Ouedraogo G. Efficacy and safety of nevirapine-

decision to publish, or preparation of the manuscript. vs efavirenz based ART in TB/HIV patients in Burkina Faso: a clinical and

pharmacokinetic study. Abstract 47462. 20th Conference on Retroviruses

Conflict of interest: The authors declare that they have no

and Opportunistic Infections; 2013.

competing interest.

19. Bonnet M, Bhatt N, Baudin E, Silva C, Michon C, Taburet AM, et al. Nevirapine

versus efavirenz for patients co-infected with HIV and tuberculosis: a random-

ised non-inferiority trial. Lancet Infect Dis 2013;13:303–12.

Appendix A. Supplementary data

20. Villar Garcia J, Vallecillo G, Gonzalez-Mena A, Sorli Redo L, Lopez Colomes JL,

Guelar Grimberg A, et al. Nonnucleoside analogue use with in HIV-

Supplementary data associated with this article can be found, in infected patients with tuberculosis. HIV Med 2009;10:39–40.

the online version, at http://dx.doi.org/10.1016/j.ijid.2014.04.020. 21. Swaminathan S, Padmapriyadarsini C, Venkatesan P, Narendran G, Ramesh

Kumar S, Iliayas S, et al. Efficacy and safety of once-daily nevirapine- or

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