The WHO guidelines for antiretroviral therapy (ART) in resource-limited countries recommend that first-line ART regimens should consist of one nonnucleoside reverse transcriptase inhibitor (NNRTI) and two NRTIs . The rationale for using NNRTIs in first-line ART while sparing protease inhibitors for second line is due to consideration of cost, ease of use, and resistance [2,3].
Two NNRTIs are available for first-line therapy: efavirenz (EFV) and nevirapine (NVP). EFV has two advantages over NVP. First, although EFV and NVP have similar risks of mucocutaneous and liver toxicities, these side-effects are much less frequent and of lower severity with EFV than with NVP . The most frequent side-effects from EFV are transient central nervous system symptoms, which rarely lead to drug discontinuation [5,6]. Second, EFV can be safely routinely prescribed with rifampicine, the first-line treatment for tuberculosis, whereas the interaction between NVP and rifampicine is still unclear . Subsequently, as HIV-associated tuberculosis is extremely common in sub-Saharan Africa, NVP often needs to be discontinued .
However, reports of teratogenicity gave EFV one major disadvantage over NVP. On the basis of animal studies and human case reports [9–11], the United States Food and Drug Administration classifies EFV as a category D drug, thereby strictly recommending against EFV use during pregnancy . The 2010 revised WHO guidelines for ART allow EFV to be prescribed during the second and third trimesters of pregnancy, but not during the first trimester . As a consequence, EFV should not be prescribed in women of childbearing age who are not using effective contraception. Due to limited access and ineffective use of contraception in sub-Saharan Africa [14–16], many physicians prescribe NVP rather than EFV in women of childbearing age .
The consequences of these recommendations are unclear. Neither the additional risk of teratogenicity from EFV compared with NVP nor the potential harmful long-term consequences for women starting ART with NVP rather than with EFV have been accurately assessed. Because EFV is strictly not recommended in women of childbearing age without effective contraception, clinical studies comparing the maternal survival and pregnancy outcomes with both drugs would not be ethical.
We, therefore, used a simulation model to assess the trade-off between potential excess birth defects and potential long-term clinical benefits for women starting ART with EFV, rather than with NVP.
Using a previously validated computer-based simulation model of HIV disease in resource-limited settings [17–19], we projected the clinical benefits for women and the risk of birth defects for their infants in two cohorts of women of childbearing age in Côte d’Ivoire: one started ART with an EFV-based regimen, and the other started ART with a NVP-based regimen. Inputs were derived from cohort studies and clinical trials in sub-Saharan Africa. We used a mean pre-ART CD4 cell count of 154 cells/μl, allowing the prescription of NVP. In the base case analysis, we assumed EFV and NVP had similar efficacy , but that NVP had a higher rate of toxicity-related drug discontinuation as well as a higher rate of fatal toxicity than EFV . In sensitivity analysis, we varied major inputs widely. The main outputs were the number of women alive at 10 years and the cumulative number of birth defects at 10 years for a cohort of women starting EFV compared with one starting NVP. The cumulative number of birth defects was calculated in a separated decisions tree model using the time of exposure to ART, the rate of pregnancy, the rate of live birth, and the rate of birth defect. Using the main outputs, we calculated the ratio of the difference between both cohorts in the absolute number of women alive at 10 years to the difference in the cumulative absolute number of birth defects. Finally, we estimated the excess in birth defect rate with EFV compared with NVP that would equalize the additional number of women alive at 10 years and the additional number of birth defects with EFV compared with NVP.
The Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model is a state-transition, first-order Monte Carlo simulation model of HIV infection incorporating natural history, disease progression, and treatment [18,19,21]. The model divides HIV infection into ‘health states,’ which include an acute state, a chronic state, and death. Simulated patients are randomly selected from an initial distribution of age, CD4 cell count, and HIV-RNA level, and transition monthly to different health states. The probability of transition from one state to another depends on the CD4 stratum and the associated risk of opportunistic infections or death , as well as ART. HIV-RNA levels determine the rate of CD4 cell count decline in the absence of ART . Successful ART decreases HIV-RNA level and increases CD4 cell count. The model also takes into account ART toxicity, ART switching criteria, resistance, and number of ART lines available. Using the model, we simulated outcomes for two cohorts of 100 000 women, one starting ART with EFV and one with NVP.
Base case inputs
Baseline cohort characteristics, morbidity, and mortality data were derived from four studies in Côte d’Ivoire [24–26] (Table 1 [2,8,9,20,24,27–31], all women started ART upon entry into the model). Two lines of ART were available: the first consisted of two NRTIs (tenofovir and emtricitabine) and either EFV or NVP; the second line consisted of two NRTIs (didanosine and abacavir) and lopinavir/ritonavir . Patients had a CD4 cell count assessed every 6 months. HIV-RNA testing was not routinely available. Switching from first to second line was dictated by immunological criteria, as recommended by the WHO in the absence of HIV-RNA monitoring .
In the base case analysis, we used three assumptions, all of which were tested in sensitivity analyses. First, we assumed that EFV and NVP had similar virologic and immunologic efficacy [20,26], and NVP had a higher rate of toxicity leading to drug discontinuation than EFV [8,27,28]. Second, we assumed that the rate of pregnancy was constant over time and disease stage and did not vary from age 25 to 45 years or according to ART regimen [9,29]. Finally, we assumed that the rate of birth defect was 0.2% higher with EFV than NVP, based on data from the US Antiretroviral Pregnancy Registry that had reported a birth defect rate of 2.7% for women on NVP and 2.9% for women on EFV . We used the same birth defect rate as NVP for the other ART regimens.
The main model output was the number of women alive. Secondary outputs included time of exposure to each first-line and second-line ART regimen. We then incorporated the latter time of exposure into a decision tree, which included rates of pregnancy, live births, birth defects, abortions, miscarriages, and stillborns, to calculate the cumulative number of babies born with birth defects at 10 years using the following formula:
10-year number of birth defects = ∑i (Time_expoi × pregnancy rate × live birth rate) × Rate_Bdefi, in which Time_expoi represents total time of exposure to ART regimen i at 10 years; Rate_Bdefi represents the birth defect rate due to ART regimen and i = 1, 2, 3…n, the different lines of ART regimen.
Main outcomes of the study
This study had two outcomes. The primary outcome was the difference in number of women alive per additional birth defect (‘ΔNWA per additional birth defect’), defined as the ratio of the difference in the absolute number of women alive at 10 years to the difference between both populations in the cumulative absolute number of birth defects at 10 years. This outcome was calculated using the following formula:
ΔNWA per additional birth defect = (NWA_EFV − NWA_NVP)/(NBD_EFV − NBD_NVP) in which NWA represents the number of women alive at 10 years; NBD represents the number of birth defects over 10 years.
The secondary outcome was the ‘equivalence birth defect rate difference,’ defined as the difference in birth defect rate per 100 live births that would be necessary to equalize the additional number of women alive at 10 years and the additional number of birth defects with EFV.
Sensitivity analyses were done in three steps.
First, in one-way sensitivity analysis, we varied all major parameters in the model. These included patient and regimen characteristics (age, pre-ART CD4 cell count, virological efficacy of EFV-based and NVP-based regimens, pregnancy rate [32,33], birth defect rate, drug discontinuation, and fatal toxicity rates of EFV-based and NVP-based regimens), as well as program characteristics (interval between clinic visits, interval between CD4 cell counts, third-line ART availability for patients failing second-line ART, rate of lost-to-follow-up, and availability of contraception). The latter included a mixed-scenario in which the women on effective contraception received EFV while the others received NVP. One-way sensitivity analyses were either confidence interval or extreme case range analyses, according to the confidence intervals or extreme values found in the literature.
Second, we classified the parameters into three groups according to their impact on the outcomes. If the sensitivity analysis on a variable produced a variation in Δ number of women alive greater than ±10 per additional birth defect or a variation in equivalence birth defect rate difference greater than ±3%, that variable was classified as ‘highly sensitive’. If the variation in Δ number of women alive per additional birth defect was between ±5 and ±10 or the variation in equivalence birth defect rate difference was between ±1.5 and ±3%, the variable was classified as ‘moderately sensitive’. Finally, if the variation was less than ±5 for the Δ number of women alive per additional birth defect and less than ±1.5% for the equivalence birth defect rate difference, the variable was classified as ‘minimally sensitive’.
Third, we included all highly sensitive variables in a multiway sensitive analysis.
Base case analysis
During the first 10 years of ART, 92 of the 100 000 women who started ART with EFV experienced severe acute toxicity (of whom none died and all 92 switched to LPV/r), compared with 6000 of the 100 000 women who started ART with NVP (of whom 62 died and 5937 switched to lopinavir/ritonavir). In women who started ART with EFV, the mean time per woman spent on EFV and on LPV/r was 7.03 and 8.61 years, respectively. In women who started with NVP, the mean time spent on NVP and on LPV/r was 6.61 and 8.63 years, respectively. As shown in Table 2, 68 880 of the 100 000 women who started ART with EFV were alive at 10 years, compared with 67 969 women who started ART with NVP. The cumulative number of birth defects that occurred over the 10 years was 1187 in women who started with EFV and 1128 in women who started with NVP. Thus, the difference in absolute number of women alive at 10 years was 911, and the difference in absolute number of birth defects on EFV compared with NVP was 59. The ‘difference in number of women alive per additional birth defect’ was 15, and the ‘equivalence birth defect rate difference’ was 3.4 per 100 live births. As the birth defect rate with EFV was 2.9 per 100, this means that the absolute birth defect rate with EFV had to be greater than 6.3 per 100 live births, and the birth defect rate with EFV had to be more than 2.3 times as higher as the birth defect rate with NVP for the additional number of birth defects to exceed the additional number of women alive at 10 years in women starting ART with EFV (Table 2).
In one-way confidence interval and extreme case sensitivity analysis, both the ΔNWA per additional birth defect and/or the equivalence birth defect rate difference were highly sensitive to the pregnancy rate, the difference in virologic efficacy between EFV and NVP and EFV toxicity-induced drug discontinuation (Table 3).
Decreasing the pregnancy rate increased the ratio of the benefits for women to the risks for children on EFV. When the pregnancy rate decreased from 15  to five per 100 woman-years , the ‘ΔNWA per additional birth defect’ increased from nine to 26 and the ‘equivalence birth defect rate difference’ increased from 1.8 per 100 live births (i.e., absolute birth defect rate with EFV was 4.7 per 100 live births, 1.7 times as high as the birth defect rate with NVP) to 5.3 per 100 live births (i.e., absolute birth defect rate with EFV was 8.2 per 100 live births, three times as high as the birth defect rate with NVP) (Table 3). To make the ‘ΔNWA per additional birth defect’ lower than 1.0, the pregnancy rate had to be over 50 per 100 woman-years.
When assuming that EFV efficacy at 6 months was 2% higher than that of NVP, the ‘ΔNWA per additional birth defect’ increased to 23, and the ‘equivalence birth defect rate difference’ increased to 5.4 per 100 live births (i.e., absolute birth defect rate with EFV was 8.3 per 100 live births, three times as high as the birth defect rate with NVP). To make the ‘ΔNWA per additional birth defect’ lower than 1.0, the efficacy of EFV at 6 months had to be 3% lower than the efficacy of NVP.
When assuming that EFV had the same rate of severe toxicity, leading to drug discontinuation as NVP, the ‘ΔNWA per additional birth defect’ was 4.0 and the ‘equivalence birth defect rate difference’ was 0.9 per 100 live births (i.e., absolute birth defect rate with EFV was 3.8 per 100 live births, or 1.4 times as high as the birth defect rate with NVP) (Table 3). To make the ‘ΔNWA per additional birth defect’ lower than 1.0, the absolute rate of EFV severe toxicity leading to drug discontinuation had to be 7.0%, that is, 0.7% higher than NVP's base case rate of severe toxicity.
If a third-line ART regimen was available in the country, the ‘ΔNWA per additional birth defect’ ranged from five to 12, and the ‘equivalence birth defect rate difference’ ranged from 1.2 to 2.5 per 100 live births, depending on third-line efficacy (Table 4). When assuming a scenario under which EFV is given only to women who take contraception while other women receive NVP, both the ‘ΔNWA per additional birth defect’ and the ‘equivalence birth defect rate difference’ were at least as high as in the base case analysis and tended to be even higher with decreasing rates of pregnancy in women receiving contraception. If loss-to-follow-up rates were considered, the women in both strategies did worse in terms of survival, and there were fewer birth defects (Table 4). As a result, there was no substantial change in the main results.
Finally, we varied EFV efficacy compared with NVP and EFV toxicity-induced drug discontinuation in different scenarios of pregnancy rates to estimate the impact of three-way variations on the ‘equivalence birth defect rate difference’ (Fig. 1). In settings with medium rates of pregnancy (Fig. 1a), an equivalence birth defect rate difference lower than 1% was found in two situations: first, when the rate of EFV toxicity-inducing drug discontinuation was higher than 1% and the EFV 6-month virological suppression was 2% lower than the NVP 6-month virological suppression; and, second, when the rate of EFV toxicity-inducing drug discontinuation was higher than 2% and the EFV 6-month virological suppression was 1% lower than the NVP 6-month virological suppression.
Although EFV is better tolerated than NVP, many women start ART with NVP in sub-Saharan Africa. This is mainly due to the fear of EFV teratogenicity, which may be higher than that of NVP. This is a particular concern in countries where pregnancy rates are high and where contraception is not widely available.
Many physicians, however, are concerned with guidelines that recommend the more toxic NVP for women on the basis of a suspected, but not clearly known, higher rate of teratogenicity with EFV. Starting ART with a more toxic drug may lead to a switch in ART regimen earlier, thus shortening the time on effective ART for women in countries where the number of available ART lines is limited. This, in turn, may decrease long-term survival. Because EFV is strictly contraindicated in women without effective contraception, randomized trials could not be conducted to measure the rate of teratogenicity in women starting ART with EFV, and compare it with women starting ART with NVP. Furthermore, even if such trials were feasible, they would be unable to estimate outcomes over a 10-year period.
Models can explore long-term clinical outcomes in situations in which trials are not feasible or ethical. In this study, we used a simulation model of HIV infection to compare survival in women and pregnancy outcomes at 10 years in cohorts of women starting ART with EFV or with NVP in Côte d’Ivoire. Using a conservative approach, we first assumed that the two drugs had similar virological efficacy, and that the only differences between drugs were a higher rate of acute toxicity in women with NVP and a higher rate of birth defects in infants with EFV. We used published data for the difference in toxicity for which there is extensive evidence [6,8,34]. For birth defect rates, we first assumed that the difference between drugs was reasonably small [29–31]. We then did extensive sensitivity analyses on all of these parameters.
We found that starting ART with the drug that leads to the lowest rate of switching due to acute toxicity provides a benefit in survival at 10 years, even when assuming that both drugs have the same efficacy. In a cohort of 100 000 women, there were 911 more women alive at 10 years with EFV compared with NVP, approximately a 0.9% benefit. Albeit small, the additional number of women alive was higher than the additional number of birth defects occurring with EFV compared with NVP over 10 years (59 birth defects). Consequently, the ratio of additional number of women alive per additional number of birth defect was very high (15 NWA per addition birth defects). To make the additional number of women alive equivalent to the additional number of birth defects, the rate of birth defects with EFV needed to be at least 2.3 times the rate with NVP, a very unlikely figure. These outcomes were found under conservative assumptions regarding differences in toxicity and efficacy between EFV and NVP. When assuming that EFV may have a slightly higher rate of virologic efficacy than NVP [34–39], or that NVP may have a higher rate of fatal toxicity than that we used in the base case [28,34], we found results even more favorable to EFV.
There are several limitations to this study. First, we used birth defect rates from the Antiretroviral Pregnancy Report (APR), which pools data from different sources . Other studies reported different birth defect rates [9,29,31]. Furthermore, other model inputs were also from different African countries. However, we varied birth defect rates and other inputs widely in sensitivity analysis and found that the outcomes were robust. Second, our primary outcome is an atypical one, as it posed survival in women against birth defects in children. One may argue that birth defects and women's deaths are altogether different. Birth defects not only lead to a higher risk of death in children [40,41] but also to consequences in terms of quality of life [42,43] that we did not take into account in this study. Finally, both birth defects and women's death may also affect other family members both in terms of mortality and of quality of life [44,45] that we also did not take into account. For a direct comparison of outcomes in women and in infants related to the use of NVP or EFV, or for a cost-effectiveness analysis, QALYs quality-adjusted life years and disability adjusted life years would be more appropriate outcomes than the ones we used. However, our aim was not to compare adult deaths to birth defect, but to evaluate in parallel the severe clinical outcomes related to the use of NVP or EFV in both the infants and their mothers. For the infants, the most severe outcome associated with EFV is birth defect. For the mothers, the most severe outcome associated with starting ART either with EFV or with NVP is death. The first outcome can be measured early. The second one requires a long-term analysis, because its most important determinant is not virological efficacy but the rate of toxicity-induced drug discontinuation. Showing these two outcomes in parallel could allow people to take the long-term survival of mothers into consideration when debating the merits of EFV versus NVP. Currently birth defects are considered the most important part of this debate, and survival in mothers is rarely taken into consideration.
Our aim was not to suggest that birth defects are preferable to women's deaths. Our aim was to estimate the extent to which recommending NVP over EFV might affect women's long-term survival. Our analysis suggests that women's survival could be substantially improved if EFV was recommended first in all women of childbearing age, and that the additional number of birth defects would be likely to be lower than the additional number of women alive over a 10-year period. This trade-off should be carefully considered when recommending first-line ART regimens in resource-limited countries.
E.N.O. provided the concept and design, performed the doing runs and calculations, drafting and writing of the manuscript, and tables and figures.
X.A. and K.A.F. provided the conception and design, clinical expertise, modeling expertise, and critical revision of the manuscript.
A.Y.W. provided the modeling expertise, doing runs and calculations, and critical revision of the manuscript.
J.C. and H.E.H. provided the modeling expertise and revision of the manuscript.
C.D., S.E., and R.M. provided the clinical expertise and revision of the manuscript.
D.G. provided the input data and revision of the manuscript.
R.P.W. provided the clinical expertise, modeling expertise, and revision of the manuscript.
The authors extend their gratitude to the entire Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International team and investigators including X.A., Ingrid Bassett, Linda-Gail Bekker, Andrea Ciaranello, C.D., Timothy Flanigan, K.A.F., Sue J. Goldie, Nagalingeswaran Kumarasamy, Marc Lipsitch, Elena Losina, Neil A. Martinson, Kenneth Mayer, Eugene Messou, E.N.O., A. David Paltiel, Stephen Resch, George R. Seage III, Soumya Swaminathan, R.P.W., Milton C. Weinstein, Robin Wood, and Yazdan Yazdanpana.
This research was supported by the Agence Nationale de recherche sur le Sida et les hépatites virales (ANRS 12212), France and the National Institute of Allergy and Infectious Diseases (R01 085276), USA.
Conflicts of interest
All authors declare no conflicts of interest.
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