Correspondence
AIDS 2012, 26:2117–2120
Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL
Collaboration Cohort
The HIV-CAUSAL Collaboration cohort (HIV-CCC)
has recently reported the unanticipated results of a
comparative analysis showing lower mortality, lower
incidence of AIDS-defining illness, larger increase in
CD4 cell count, and a smaller risk of virologic failure at
12 months for efavirenz compared with nevirapine in
antiretroviral-naive individuals [1]. We would like to
outline some shortcomings of the analysis that, in our
opinion, prevent the acceptance of the results in the way
they have been presented.
First of all, the authors have included individuals starting
nevirapine with any CD4 cell count. Since 2005, there
has been worldwide warning against the initiation of
nevirapine in treatment-naive women with CD4 cell
counts more than 250 cells/ml and men with CD4 cell
counts more than 400 cells/ml due to increased risks of
symptomatic liver toxicity (12-fold and five-fold,
respectively) [2]. This was the result of extensive analyses
done in order to find ways to set bounds to the
administration of the drug to individuals with increased
risk for toxicity, and has been observed since. Out of
7724 individuals treated with nevirapine included in the
HIV-CCC analysis, 1801 had more than 400 CD4 cells.
Moreover, 4746 individuals further had 200–400 CD4
cells, from which women (21.9%) with more than
250 CD4 cells should also have been excluded. These
naive individuals should not start nevirapine. Therefore,
including them in the analysis has no clinical sense and is a
bias that should be avoided. The authors conducted a
sensitivity analysis restricted to those with baseline CD4
cell counts for which nevirapine is recommended and
included chronic hepatitis C infection as a baseline
covariate, and saw no appreciable differences in the
results. Even though these results are not reported,
chronic hepatitis C infection by itself is not a contra-
indication to initiate either nevirapine or efavirenz.
Furthermore, it is hard to understand how the authors
adjusted the results for hepatits C coinfection when no
patient in the cohort had definite hepatitis C infection
and only 0.5% individuals with efavirenz and 0.3% with
nevirapine had definite or probable hepatitis C infection
(Table 1).
The authors consider individuals starting either ‘efavirenz
or nevirapine with a backbone of two or more nucleoside
reverse transcriptase inhibitors (NRTIs)’, or ‘starting
efavirenz or nevirapine and possibly one or more NRTIs
at baseline’. Likewise, individuals were not required to
ISSN 0269-9370 Q 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
start all of the drugs in their regimen on the same day and
were allowed a grace period of 6 months to complete the
regimen. Again, this goes against extensive knowledge
indicating that only triple-drug regimens (i.e. nevirapine
or efavirenz and two NRTIs) are recommended as first-
line regimens, and that all drugs must be started
simultaneously. There are no data suggesting the initiation
of efavirenz or nevirapine with less or more than two
NRTIs in any guideline [3]. Thus, these individuals
should also be excluded from the analysis. The drugs
included in any antiretroviral regimen (both in naive and
pretreated individuals) must be started simultaneously.
The low genetic barrier to resistance of nevirapine,
efavirenz, emtricitabine, and lamivudine would other-
wise ease the development of HIV-1 resistance mutations
and virologic failure [4].
The authors did not undertake an analysis regarding the
choice of the NRTI backbones. They acknowledge not
having enough data for a meaningful analysis. Again, this
is not easy to understand in an analysis that has pooled
14 857 individuals treated with efavirenz and 7724 with
nevirapine. In addition, in Appendix Table 2, it is difficult
to follow the classification of NRTI backbones received
by the patients in categories that are not mutually
exclusive and which sum goes far beyond 100% of the
total (217% for efavirenz and 163% for nevirapine).
Should the results of the study be true, it would be of
paramount interest to ascertain whether the differences
seen between efavirenz and nevirapine are maintained
with the combinations of NRTIs currently used, that is,
coformulated tenofovir/emtricitabine and abacavir/lami-
vudine. Furthermore, the NRTIs have not been matched
between efavirenz and nevirapine categories, despite
existing reported differences in efficacy and toxicity
among different NRTI combinations [5].
Fortunately, efavirenz and nevirapine have been com-
pared in randomized clinical trials. The multicenter
open-label 2NN study – one of the biggest studies ever
done so far in antiretroviral naive individuals –
randomized 1216 individuals to receive efavirenz,
nevirapine once or twice daily, or both [6]. The
difference of treatment failure between the groups
assigned nevirapine twice daily or efavirenz was not
significant [5.9% (95% confidence interval 0.9–12.8),
P ¼ 0.091], but equivalence within the predefined 10%
limits could not be demonstrated. Efavirenz and
nevirapine had similar median increases in CD4 T cells
2117
2118 AIDS 2012, Vol 26 No 16
over 48 weeks (overall P ¼ 0.8), and there were no
differences in mortality or AIDS-defining illnesses (25
deaths during the study). In a sensitivity analysis, both
efavirenz and nevirapine displayed similar rates of HIV-1
plasma viral load decline during the first 2 weeks
of treatment, even in individuals with more than
100 000 copies/ml at baseline [7].
Furthermore, both efavirenz and nevirapine have
demonstrated noninferior efficacy against boosted ataza-
navir in their pivotal randomized trials in treatment-naive
individuals [8,9].
It is, therefore, surprising to see that the authors do not
cite these trials and do not analyze in the discussion the
possible reasons underlying the discordance seen between
the randomized clinical trial and their multicohort study.
This is particularly worrying concerning mortality, with
significant differences found in the HIV-CCC in later
years (beyond 20 months). It must be reminded that the
2NN study had a 3-year extended follow-up, with low
rates of disease progression or death, without differences
between arms (nevirapine once or twice daily 4.2% and
5.8%, and efavirenz 6.3%; P ¼ 0.85) [10]. Obviously, the
number of participants was lower in the randomized
study, and small differences could have been lost due to
this limitation. Nevertheless, reporting that those on
nevirapine were 65% more likely to die than those on
efavirenz can deeply disturb those individuals treated with
nevirapine if the result is not tempered with caution in
view of the data reported in huge randomized clinical
trials.
Even though prospective cohort studies can be more
reliable than retrospective ones, they are equally open
to confounding by indication and their results must
be interpreted with prudence. Constructing inverse
probability weights for marginal structural models, a
sophisticated statistical technique, remains influenced by
confounding by indication and can be still misleading. A
high awareness of this issue must remain, particularly
when the results do not match what has been reported
from randomized clinical trials.
Acknowledgements
Conflicts of interest
Josep M. Llibre has received funding for research or
payment for conferences or participation on advisory
boards from Abbott, Boehringer-Ingelheim, Bristol-
Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck
Sharp & Dohme, Tibotec and ViiV Healthcare. Daniel
Podzamczer has received funding for research or payment
for conferences or participation on advisory boards from
Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb,
Gilead Sciences, Glaxo-Smith-Kline, Janssen-Cilag,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Merck Sharp & Dohme, Pfizer, Tibotec and ViiV
Healthcare.
Josep M. Llibrea,b and Daniel Podzamczerc, aHIV Unit,
University Hospital Germans Trias i Pujol, bLluita
contra la SIDA Foundation, and cUnidad VIH, Servicio
de Enfermedades Infecciosas, Hospital Universitari de
Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain.
Correspondence to Josep M. Llibre, HIV Unit, Hospital
Universitari Germans Trias i Pujol, Ctra de Canyet, s/n,
08916 Badalona, Spain.
Tel: +34 93 497 8887; fax: +34 93 465 7602;
e-mail: jmllibre@flsida.org
Received: 2 July 2012; accepted: 10 July 2012.
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nevirapine-containing regimens on immunologic, virologic and
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Guidelines for the use of antiretroviral agents in HIV-1-infected
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50:872–881.
5. Gallant JE, Dejesus E, Arribas JR, Pozniak AL, Gazzard B,
Campo RE, et al. Tenofovir DF, emtricitabine, and efavirenz
vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med
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Gazzard B, et al. Comparison of first-line antiretroviral therapy
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Montaner JS, et al. Plasma HIV-1 RNA decline within the first
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virologic efficacy: a 2NN substudy. J Acquir Immune Defic
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et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug
regimen for initial treatment of HIV-1. Ann Intern Med 2011;
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Villanueva J, et al. Nevirapine versus atazanavir/ritonavir, each
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Miller S, et al. A randomized comparative trial of first-line
antiretroviral therapy with regimens containing either nevira-
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Abstract WEPEB032.
DOI:10.1097/QAD.0b013e328357f60f
 Correspondence 2119

Blunted fetal growth by tenofovir in late pregnancy

Tenofovir disoproxil fumarate (TDF) is recommended for 35 weeks of gestation
pregnant women coinfected with HIV and hepatitis B 110
virus to prevent mother-to-infant transmission of both 100 +2.0SD

viruses [1]. However, the safety of TDF in pregnancy is 90

+1.5SD

still controversial, especially with regard to its effects on mean

Biparietal diameter (cm)

80
–1.5SD
fetal growth and bone mineralization. 70 –2.0SD

60
Here, we describe a 32-year-old HIV-1-infected Asian
50
pregnant woman, who showed blunted fetal growth during
40
TDF treatment. She had been treated during the first
30
33 weeks of pregnancy with abacavir, lopinavir/ritonavir
20
and raltegravir based on multiple viral mutations. As plasma
10
concentrations of raltegravir were persistently low,
00
treatment was switched to TDF at 35 weeks of gestation, Gestational week 14 18 22 26 30 34 36 38
until delivery at 38 weeks. The fetal growth curves of 90

biparietal diameters and femur length were within the 80

+2.0SD

normal ranges before starting TDF; however, the growth +1.5SD

of both parameters was significantly blunted after starting 70 mean

–1.5SD
TDF (Fig. 1). Furthermore, tubular reabsorption rates for

Femur length (cm)

60 –2.0SD
phosphate, urinary b2-microglobulin and alkaline phos-
50
phatase were 88%, 2776 mg/L and 435 U/L, respectively,
during the TDF-treatment period, compared with 97%, 40

140 mg/L and 182 U/L, respectively, during the non- 30

TDF-treatment period. Plasma TDF concentration in the
20
mother was 3536 ng/mL at 4 h after dosing and 776 ng/mL TDF-
in cord blood. The infant was delivered by cesarean section 10 non-TDF-treatment period
treatment
period
without HIV-1 infection, and weighed 2218 g (
2 SDs for 00
Japanese infants), with a height of 45.0 cm (
1.5 SD), and a Gestational week 20 24 28 32 34 36 38

head circumference of 29.5 cm (
2 SD). Furthermore, U-BMG (mg/L) 140 2776

moderate tubular dysfunction was observed at birth (serum %TRP (%) 97 88

calcium: 7.4 mg/dL, serum phosphate: 4.6 mg/dL,
alkaline phosphatase: 560 U/L, urine b2-microglobulin:
1780 mg/L), together with a high plasma TDF concen-
tration [102 ng/mL at 24 h after delivery (28 h after
mother’s dosing)]. Although the body length was
persistently short throughout the first 3 months (less than

2 SD), the hand X-ray at 1 and 3 months showed no signs
of osteopenia or rickets.
The present case raises two concerns with regard to the
safety of TDF in pregnancy. TDF can reduce bone mineral
density [2]. Van Rompay et al. [3] reported that treatment
of infant macaque with high-dose TDF caused proximal
tubular dysfunction, growth retardation and osteomalacia.
Our findings suggest that administration of TDF during
pregnancy caused fetal disordered bone growth through
modest proximal tubular dysfunction. However, it is not
clear whether maternal TDF-associated tubular dysfunc-
tion will cause future bone growth retardation in infants. A
large cohort study reported that significantly shorter height
was observed at age 1 year in TDF-exposed infants [4],
which is generally considered as one of the symptoms of
mild rickets. However, in our case, despite the persistently
shorter height of the infant (less than
2 SD) throughout
the first 3 months of life, hand X-ray at 3 months showed
no findings of osteopenia or rickets. Second, plasma TDF
concentrations in our case were 10-fold higher than the
ALP (U/L) 182 435
Fig. 1. Serial changes in fetal biparietal diameters, femur
length and proximal tubular function during pregnancy.
Between 20 and 33 weeks of gestation [non-tenofovir dis-
oproxil fumarate (TDF)-treatment period], the growth curves
of biparietal distance, femur length and proximal tubular
function were within the normal ranges. However, the
increases in biparietal distance and femur length were
blunted after 35 weeks of gestation (TDF-treatment period),
with a worsening of all markers of proximal tubular function.
U-BMG, urine b2-microglobulin; %TRP, tubular reabsorption
rate for phosphates; ALP, serum alkaline phosphatase.
previously reported values [5], probably reflecting the
mother’s small body size (weight: 47 kg), and consequently
higher placental transfer of TDF to the fetus. Asian
pregnant women, who have smaller body size, may impose
a more severe effect on fetal growth retardation than that
reported previously. The effect of TDF in pregnancy and its
impact on fetal growth needs to be evaluated in more detail.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2120 AIDS 2012, Vol 26 No 16
Ei Kinaia, Shinichi Hosokawab, Hideto Gomibuchic,
Hiroyuki Gatanagaa, Yoshimi Kikuchia and Shinichi
Okaa, aAIDS Clinical Center, bDepartment of Pedia-
trics, and cDepartment of Obstetrics and Gynecology,
National Center for Global Health and Medicine,
Tokyo, Japan.
Correspondence to Ei Kinai, MD, AIDS Clinical Center,
National Center for Global Health and Medicine,
Toyama 1-21-1, Shinjuku-ku, Tokyo, Japan.
Tel: +81 3 3202 7181; fax: +81 3 3202 7198;
e-mail: ekinai@acc.ncgm.go.jp
Received: 30 July 2012; accepted: 1 August 2012.
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1. Panel on Treatment of HIV-Infected Pregnant Women and Pre-
vention of Perinatal Transmission. Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for
Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States. 2011. http://aidsinfo.nih.
gov/ContentFiles/PerinatalGL.pdf.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas
P, et al. Bone mineral density and fracrtures in antiretroviral-
naive persons randomized to receive abacavir-lamivudine
or tenofovir disoproxil fumarate-emtricitabine along with
efavirenz or atazanavir-ritonavir: AIDS clinical trials group
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1791–1801.
3. Van Rompay KKA, Brignolo LL, Meyer DJ, Jerome C, Tarara R,
Spinner A, et al. Biological effects of short-term or prolonged
administration of 9-[2-(phosphonomethoxy) propyl] adenine
(tenofovir) to newborn and infant rhesus macaques. Antimicrob
Agents Chemother 2004; 48:1469–1487.
4. Siberry GK, Williams PL, Mendez H, Seage GR III, Jacobson DL,
Hazra R, et al., for the Pediatric HIV/AIDS Cohort Study (PHACS).
Safety of tenofovir use during pregnancy; early growth out-
comes in HIV-exposed uninfected infants. AIDS 2012;
26:1151–1159.
5. Flynn PA, Mirochnick M, Shapiro DE, Bardequez A, Rodman J,
Robbins B, et al., PACTG 394 Study Team. Pharmacokinetics
and safety of single-dose tenofovir disoproxil fumarate and
emtricitabine in HIV-1-infected pregnant women and
their infants. Antimicrob Agents Chemother 2011; 55:5914–
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DOI:10.1097/QAD.0b013e328358ccaa