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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 efavirenz 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 viral load <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 cytochrome P450 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 reverse transcriptase
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 Thailand 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, lamivudine; d4T, stavudine; NVP, nevirapine; EFV, efavirenz; ddI, didanosine; AZT, zidovudine; 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 hepatitis, 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 drug metabolism. 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 rifampicin 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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