Extended-dose Nevirapine (Viramune) for Infants to Prevent HIV Transmission via Breastfeeding in Ethiopia, India, and Uganda

HIV can be transmitted from mothers to their infants during breastfeeding, and HIV positive women in industrialized countries are therefore advised not to breastfeed.

But in areas where replacement feeding is not acceptable, feasible, affordable, sustainable, and safe, the World Health Organization (WHO) and UNICEF recommend exclusive breastfeeding for at least 6 months. According to WHO, some 200,000 infants are infected with HIV via breastfeeding each year; however, replacement feeding is also potentially hazardous in resource-limited settings, for example due to a lack of appropriate formula or clean water.

Viramune Tablet

Since prophylactic antiretroviral therapy given to mothers during pregnancy and delivery, and to infants immediately after birth, has dramatically reduced the rate of mother-to-child transmission, researchers have explored whether longer treatment might have a similar protective effect in preventing transmission during breastfeeding.

Studies to date have produced mixed results. At the 15th Conference on Retroviruses and Opportunistic Infections (CROI) this past February, 2 research teams reported that extended infant use of nevirapine (Viramune) reduced the risk of HIV transmission during breastfeeding -- at least in the short-term.

In the July 26, 2008 issue of The Lancet, one of these teams reported further details from their study, known as SWEN (Six Week Extended-Dose Nevirapine). The other team also recently published findings from their study, known as PEPI, in the July 10, 2008 New England Journal of Medicine.

An accompanying commentary in The Lancet (reprinted below) looks at the results of these studies and their implications. The issue also includes a letter from 3 of the SWEN investigators discussing their disagreement with some of the study conclusions (also reprinted below).

SWEN Findings

The SWEN investigators conducted 3 trials, in Ethiopia, India and Uganda, to assess whether daily nevirapine given to breastfed infants through 6 weeks of age could decrease HIV transmission via breastfeeding.

Participants were randomly assigned to receive 1 of 2 regimens:

(1) single-dose nevirapine: 200 mg to women in labor and 2 mg/kg to newborns after birth; OR

(2) 6-week extended-dose nevirapine: 200 mg to women in labor and 2 mg/kg to newborn babies after birth plus 5 mg nevirapine daily from days 8-42 for the infants.

The primary endpoint was HIV infection at 6 months of age in infants who were HIV negative by PCR testing at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth.

Results

• 2024 live-born infants randomized in the study had at least 1 specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group).

• The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group.

• At 6 weeks of age, 54 children in the single-dose nevirapine group and 25 in the extended-dose group were HIV positive (0.54; 95% CI 0.34-0.85; P = 0.009).

• At 6 months, 87 children in the single-dose nevirapine group and 62 in the extended-dose group were infected with HIV (relative risk 0.80; 95% CI 0.58-1.10; P = 0.16).

• The primary endpoint of HIV infection at 6 months did not differ significantly in the 2 study arms.

• 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (P = 0.54).

Interpretation of Results

Interpreting these results, the study authors wrote, "Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint -- risk of HIV transmission at 6 months -- suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high."

It should be emphasized that these findings are relevant only for areas where access to safe, affordable replacement feeding is not available; if feasible, HIV positive women are advised not to breastfeed their infants.

The full text of the article is available online (free registration required).

Commentary: Extended Nevirapine Prophylaxis to Prevent HIV Transmission

[Note: The following editorial commentary was published along with the SWEN article in the July 26, 2008 issue of The Lancet.]

Of the 800 000 new pediatric HIV-1 infections each year, breastfeeding underlies at least a third. In developed countries, where water is clean and infant formula affordable, HIV-infected women generally avoid breastfeeding. Yet in many settings where HIV is endemic, infant formula is too costly for most families and its use a stigma of maternal HIV infection. Moreover, replacement feeding can be unsafe; several studies indicate that the HIV-prevention gains made by breastfeeding avoidance or early weaning are largely offset by an increased risk of death from diarrhoea, pneumonia, and malnutrition. Thus the HIV-infected mother of an African or south Asian newborn baby often faces an impossible choice: breastfeed and risk HIV transmission, or do not breastfeed and risk death from another cause.

In today's Lancet [July 26, 2008], investigators from the Six Week Extended-Dose Nevirapine Study point towards a solution to this seemingly intractable problem. They report three coordinated randomised trials that were done separately in Uganda, Ethiopia, and India, and combined in a preplanned analysis (of more than 2000 infants). SWEN is thus not a trial acronym, but is a convenient abbreviation for the extended-dose nevirapine regimen. In each country, breastfeeding HIV-exposed infants were randomly allocated to receive 5 mg of daily oral nevirapine from days 8 to 42 of life (the SWEN regimen) or no additional drug. All participants received at least intrapartum and neonatal single-dose nevirapine, and some, in India, received other antenatal antiretrovirals as well (mostly zidovudine).

In the primary analysis, which excluded infants already infected at birth, the SWEN regimen failed to achieve a statistically significant reduction in transmission risk at 6 months of age. It did, however, seem to improve key secondary endpoints, such as transmission at 6 weeks of age (2.5% vs 5.3%, intervention vs control; risk ratio 0.54, 95% CI 0.34-0·85) and HIV-free survival at 6 months of age (8.1% vs 11.6%; 0.73, 0.55-0.97).

Importantly, the SWEN regimen was well tolerated with no substantially increased risks of rash, liver damage, neutropenia, or other adverse outcomes.

Although soundly designed and executed, the trials had some curious features. First, in Uganda, there was a much lower prevalence of HIV infection at birth in babies randomised to the control group (4.3%) than to the SWEN regimen (9.6%). Because neither the control nor the SWEN regimen would be expected to affect in-utero infection, we must assume that this imbalance occurred by chance, and represents a failure of the randomisation procedure to equally allocate this important confounder between the study groups. The imbalance is unfortunate, because inclusion of infections present at birth in the planned secondary analysis all but negates the protective effect of the SWEN regimen at both 6 weeks and 6 months of follow-up.

Second, although the SWEN regimen seems to have protected against infant death (1.1% of babies died by 6 months of age in the experimental group vs 3.6% in the control group, a statistically significant difference), most of this protection was seen in infants who were HIV-uninfected at their last visit. That visit was on average 2 weeks before death. This finding, too, is a head-scratcher, for it suggests that nevirapine confers a survival advantage unrelated to its HIV-prevention effect. Further, it is the inclusion of these deaths in a combined outcome of HIV-free survival that makes the 6-month trial outcomes statistically significant.

The new results with the SWEN regimen may be better understood in comparison with the recently published PEPI study, a similar randomised trial undertaken at six sites in Malawi. PEPI compared a 14-week regimen of daily nevirapine in infants with the current standard of care in Malawi: single-dose intrapartum and neonatal nevirapine plus 1 week of infant prophylaxis with zidovudine. Compared with the results with the SWEN study, the PEPI intervention was longer (14 weeks), used a higher dose of infant nevirapine, and started prophylaxis immediately after birth (rather than waiting a week). At 9 months of age, 10.6% of liveborn infants uninfected at birth in the standard of care group had become infected, compared with 6.4% in the extended-dose nevirapine group, a highly statistically significant finding. (The PEPI trial also evaluated a third regimen, of the nevirapine intervention plus the addition of 14 weeks of infant zidovudine, which proved no more effective than nevirapine alone but was more toxic.)

One interpretation of these two studies is that while the SWEN regimen is partly effective, the PEPI regimen is more so. Perhaps, in the SWEN study, the extended dose of nevirapine was too low, or the duration of prophylaxis too short. Whether the PEPI regimen is truly better than the SWEN regimen cannot be known with certainty without a head-to-head comparison. However, the PEPI intervention produced a more definitive result, and covers a longer period of infant risk. It is thus our view that policy makers should recommend the PEPI regimen in settings where it is feasible, and take the results with the SWEN regimen as key supporting evidence that infant prophylaxis with nevirapine is safe and effective. Whether additional protection could be conferred by extending the period of infant prophylaxis throughout the entire breastfeeding period is unknown (but plausible), and currently the focus of at least two studies. The PROMISE study, planned by the IMPAACT network of the US National Institutes of Health, will investigate extended prophylaxis with nevirapine, among other interventions. The PROMISE-PEP study, funded by the French Government, will study extended prophylaxis with lamivudine.

The use of nevirapine as a component of any non-suppressive prophylactic regimen is controversial, because the agent rapidly induces resistance to the non-nucleoside reverse-transcriptase inhibitor (NNRTI) class of antiretroviral drugs. A meta-analysis estimated that 52% of infants who become infected with HIV despite a single dose of nevirapine will develop NNRTI resistance. It is probable that nearly all infants who become infected while receiving an extended prophylactic course of nevirapine monotherapy will develop such resistance. Should this mitigate enthusiasm for breastfeeding prophylaxis with extended-dose nevirapine? Probably not. In the study reported today, 54 babies randomised to the control group were found to be HIV-infected at 6 weeks of life, compared with 25 babies who received the SWEN regimen. Assuming that 52% of infants in the control group and 100% of infants in the SWEN group develop resistance, we find that the numbers of babies developing resistance are essentially the same (28 vs 25). Thus the SWEN regimen prevented 29 additional infections at the cost of, at most, three additional NNRTI-resistant infections. Clearly, the induction of any resistance should be avoided, but it seems that extended-dose nevirapine regimens will save many babies without conferring any additional risk of NNRTI resistance to the population beyond that of single-dose nevirapine.

Although the science of perinatal HIV prevention develops briskly, its implementation founders. Globally, we continue to do poorly at providing access to even the simplest pediatric HIV-prevention services. A recent report from WHO, UNICEF, and UNAIDS stated that less than a third of at-risk infants worldwide are currently receiving any prophylaxis at all, and that in some regions, such as west and central Africa, this proportion may be as low as 11%.

Thus, there is just as much room for benefit in expanding coverage of simple services as there is in implementing more efficacious (and complex) interventions in populations that already have access.

Extended infant prophylaxis with nevirapine is simple enough to be implemented almost anywhere. It represents a long-awaited, if partial, solution to a mother's impossible choice. We should not delay.

(We declare that we have no conflict of interest.)

Letter from Study Authors

[Note: There was some disagreement among the study authors about the findings of the SWEN study. The full text of the three dissenting authors' letter, published in the July 26, 2008 issue of The Lancet, follows.]

Correspondence: Nevirapine to Prevent HIV Transmission via Breastfeeding

MA Phadke, PM Bulakh and NA Kshirsagar

We, the co-principal investigator from India on the study of 6-week extended-dose nevirapine (July 26, p 300) and co-workers, are at variance with the way the paper has been presented and interpreted. The study team has concealed crucial parts of the findings under complex statistical analysis and disguising adjustments.

First, the simple conclusion is that nevirapine given to infants for 6 weeks did not significantly reduce HIV transmission, compared with single-dose nevirapine, at the primary endpoint of 6 months. This endpoint was determined before the study began and was based on the fact that nevirapine given for the baby's first 6 weeks (when HIV transmission via breastfeeding is very high) would last for another 10-14 days owing to its long half life, and that it takes between 10 days and 4 months for the baby to become PCR positive after entry of the virus. Therefore the fact that PCR positivity was lower at 6 weeks of age in the extended-treatment group than in the single-dose group does not reflect the effect of 6 weeks of treatment at all.

Second, about 40% of infants in both groups had grade III or IV side-effects (rashes, neutropenia, or elevated aminotransferases). The study team has not shown the duration of neutropenia, which could have varied with single-dose and 6-week regimens. One can imagine the clinical consequences of prolonged neutropenia.

Third, the study team has analysed all "intention to treat cases (modified)". However, if one wants to study the efficacy of a drug, one should analyse the per-protocol population. The intention-to-treat population is more relevant for safety studies. Use of the per-protocol population for efficacy analysis has been questioned since some patients might discontinue a drug if they do not feel better and would thus get eliminated, skewing the results. But this subjective factor is not relevant to the present study, where the primary endpoint is objective -- i.e., becoming HIV positive. If both intention-to-treat and per-protocol populations had been studied together and both gave identical results, confidence in the trial would have increased.

Finally, the study team conclude that nevirapine ought to be given for longer than 6 weeks. This recommendation is inappropriate, since the risk of transmission via breastmilk is highest in the early weeks of life and falls as age advances. It is wrong that a drug which has not shown significant benefit and which has serious toxic effects in 38.4% of babies should be tried for longer and at a time when the risk of transmission has decreased. No drugs might be required at all, or some other strategy such as weaning foods might help.

It might be more prudent to follow WHO/UNICEF guidelines for developed countries and to make formula feeding safe, sustainable, acceptable, and affordable for mothers in developing countries. The cost, training, and manpower involved in giving 6 weeks of nevirapine to such women could be better used to educate them and supply milk substitutes in a hygienic form, thus bringing them in line with the developed world.

(MAP was the principal investigator in India. PMB is a laboratory director and had a vital role nearly throughout the trial. NAK was part of the study team and did pharmacokinetic studies on nevirapine. We declare that we have no conflict of interest.)

Commentary: SWEN--When Authors Disagree

[Note: The editors of The Lancet wrote a commentary on the disagreements between the study authors, the editors' attempts to find a resolution, and their final decision to publish the article, 2 commentaries, and the letter from the dissenting authors. The full text follows.]

In today's [July 26, 2008] Lancet, the SWEN (Six Week Extended-Dose Nevirapine) Study Team reports a combined analysis of three randomised trials done in Ethiopia, India, and Uganda to assess the effect on HIV transmission, from the mother, of daily nevirapine given to breastfed infants until 6 weeks of age. In an unusual step, we also publish today a Correspondence letter from Mrudula Phadke, the co-principal investigator of the Indian trial site, and colleagues, who dispute the interpretation of the findings of the combined analysis.

Phadke had made clear to the SWEN authors her objections to submission, and exhaustive attempts were made by the authors, the Indian Council of Medical Research in New Delhi, and the sponsor -- the US National Institutes of Health (NIH) -- to resolve matters. The independent Community Advisory Board for the study in Pune also supported submission. Finally, the recommendation of the NIH was that submission should be decided by majority vote of the manuscript's authorship team.

Except for Phadke, every member of the original SWEN writing team approved submission, and the authors informed The Lancet about the dispute and efforts to resolve it. The journal sent the manuscript for external peer review, and, inviting a revised manuscript, added that we could not proceed to publication unless the dispute was resolved -- our usual course in such situations. In response, the corresponding author, Robert Bollinger, re-stated that all efforts had been made to resolve the disagreement, and that they had reached stalemate.

Phadke then contacted the journal, asserting that the way the data from India were presented in the manuscript was a misrepresentation (the revision and reviewers' comments had been shared with Phadke by the SWEN writing team).

The editors wrote to the NIH to ask for their official response to the dispute; the NIH confirmed that they had been kept fully informed about the problems during preparation of the submitted manuscript, that they were confident that there had been no breach of research integrity on the part of the authors, and that every effort had been made to achieve consensus on the submitted manuscript.

The Lancet also sought advice from the Committee on Publication Ethics (COPE), who agreed with the journal's suggestion to invite Phadke to write a Correspondence letter for publication outlining her concerns and for the journal to write an accompanying Comment to document the course of events.

Disputes among authors are one of the most difficult situations for editors to deal with. In this case, the editors felt -- and COPE agreed -- that all possible attempts to come to an agreement had been made. In our opinion, publication of these important data, with complete disclosure, is the best course of action.

8/01/08

References

Six Week Extended-Dose Nevirapine (SWEN) Study Team. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. The Lancet 372(9635): 300-313. July 26, 2008. (Full text)

JSA Stringer and BH Chi. Commentary: Extended Nevirapine Prophylaxis to Prevent HIV Transmission. The Lancet 372: 269-270. July 26, 2008.

MA Phadke, PM Bulakh, and NA Kshirsagar. Correspondence: Nevirapine to Prevent HIV Transmission via breastfeeding The Lancet 372 (9635): 287. July 26, 2008.

P Pini and S Kleinert. Commentary: SWEN -- When Authors Disagree. The Lancet 372 (9635): 457. July 26, 2008.