- Email: [email protected]
HIVNET 012 and Petra
CORRESPONDENCE
and the importance of antiretroviral therapy to treat maternal HIV-1 infection. We agree that our goal should be appropriate antiretroviral therapy for all pregnant women and family members who require it. The hope is that existing programmes will expand to include the provision of care and treatment. However, as we work towards that goal, we must be pragmatic. Do we let 2000 infants become infected every day because we do not have access to optimum treatment but do have a proven effective intervention for mother-tochild transmission? And, does an HIV-1-infected pregnant woman in a developing country not have the right to make a decision to try to prevent infection of her child? Until we can provide these women with the antiretroviral drugs they deserve, the least we can do is to provide them with the means and the choice to protect their children. Catherine M Wilfert Elizabeth Glaser Pediatric AIDS Foundation, 1917 Wildcat Creek Road, Chapel Hill, NC 27516, USA (e-mail: [email protected]) 1
2
3
4
5
Jackson JB, Musoka P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362: 859–68. Beckerman KP. Long-term findings of HIVNET 012: the next steps. Lancet 2003; 362: 842–43. Havlir D, Eastman S, Gamst A, Richman DD. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol 1996; 70: 7894–99. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET012). AIDS 2001; 15: 2951–57. Cunningham CK, Chaix M-L, Rekacewicz C, et al. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent human immunodeficiency virus type 1 transmission: a substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002; 186: 181–88.
Sir—Karen Palmore Beckerman states in her Commentary1 that the HIVNET 012 protocol did not affect child survival. We strongly disagree with this assertion. First, the study was powered to assess significant differences in HIV-1 transmission, not survival. Second, as shown in figure 3, children in the nevirapine group fully achieved the expected level of survival benefit that would be mediated through the documented level of reduction in HIV-1 incidence. Third, the 18-month
mortality was higher in the zidovudine group than the nevirapine group (13·6% vs 10·6%),2 and these differences would be expected to widen owing to the higher number of HIV-1infected children in the zidvoudine group, and the increasing likelihood of HIV-1 disease progression as the children get older; HIVNET 012 will be able to assess this prospect, because infants are being followed-up until they reach 5 years of age. We agree with Beckerman that the effect of single-dose nevirapine on future treatment options is a concern that urgently needs research. We disagree that it is a foregone conclusion that there will be an adverse effect. Data from the Pediatric AIDS Clinical Trial Group3 protocol 316 indicate that nevirapine resistance was not reduced by coadministration of additional antiretrovirals if there was persistent viral replication when nevirapine was given; therefore coadministration of 2–3 days of postnatal zidovudine or lamivudine is unlikely to decrease resistance. We also agree with Beckerman that combination antiretroviral therapy during pregnancy and post partum will be better than single-dose nevirapine at reducing transmission and beneficial to maternal health, and is a goal to be worked towards. However, in Uganda today, despite the best intentions, fewer than 2% of HIV-1-infected individuals are receiving any form of antiretroviral treatment. Even with the expected implementation of the Global AIDS Fund and Bush AIDS Relief Program over the next few years, most HIV-1-infected individuals who need treatment will probably not receive it. In the meantime, 2000 babies are becoming HIV-1-infected each day. In our opinion, saving thousands of lives today with a simple, safe, affordable intervention should take precedence over the alternative of not using it because of concerns that future and uncertain treatment options might be limited with nevirapine’s use. *Brooks Jackson, Francis Mmiro, for the HIVNET 012 study team Department of Pathology, Johns Hopkins University, Carnegie 415, 600 North Wolfe Street, Baltimore, MD 21287, USA (e-mail: [email protected]) 1
2
3
Beckerman KP. Long-term findings of HIVNET 012: the next steps. Lancet 2003; 362: 842–43. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18 month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362: 859–68. Cunningham CK, Chaix M-L, Rekacewicz C, et al. Development of
resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002; 186: 181–88.
Author’s reply Sir—Ed Cooper is correct to point out that “induction” of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance is a misuse of the word (albeit a common one), which should be replaced by “selection” or “induction of detectable resistance”. Charles Darwin, we assume, would be among those most eager to examine the hypothesis that NNRTI resistance, which does not seem to render virus unfit,1 will “fade” to clinical insignificance. Catherine Wilfert argues that none of the single-dose nevirapine studies has shown 100% resistance, and indeed none has. However, Kantor and colleagues—the only group to examine 2-week, maternal HIV-1 clade C post-nevirapine samples— reported that 76% of exposed women had detectable resistance.2 Given that the assay used cannot detect minority or archived populations, the actual prevalence of clinically significant NNRTI resistance remains higher than 76% and, in fact, could approach 100%. The suggestion by Brooks Jackson and Francis Mmiro that the statistically insignificant difference in 18-month child survival between nevirapine and zidovudine prophylaxis groups “would be expected to widen” is a hope that many of us share. However, neither their own calculations of significance (p=0·253), nor the original study design and power calculations (as they point out) support such a conclusion. Jackson and Mmiro join Wilfert in pointing out that treatment with other antiretroviral agents did not prevent the appearance of NNRTI resistance in the Pediatric AIDS Clinical Trial Group Protocol (PACTG) 316.3 However 66% of the PACTG participants studied received suboptimal single or dual combination antiretroviral therapy and all patients had evidence of ongoing viral replication, with the lowest viral load reported being 152 copies per mL. Similarly, the Thai-US Centers for Disease Control collaboration4 found evidence of NNRTI resistance in 15% of women who received single-dose nevirapine during labour after zidovudine prophylaxis from 34 to 36 weeks of pregnancy. The median
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
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245
and the importance of antiretroviral therapy to treat maternal HIV-1 infection. We agree that our goal should be appropriate antiretroviral therapy for all pregnant women and family members who require it. The hope is that existing programmes will expand to include the provision of care and treatment. However, as we work towards that goal, we must be pragmatic. Do we let 2000 infants become infected every day because we do not have access to optimum treatment but do have a proven effective intervention for mother-tochild transmission? And, does an HIV-1-infected pregnant woman in a developing country not have the right to make a decision to try to prevent infection of her child? Until we can provide these women with the antiretroviral drugs they deserve, the least we can do is to provide them with the means and the choice to protect their children. Catherine M Wilfert Elizabeth Glaser Pediatric AIDS Foundation, 1917 Wildcat Creek Road, Chapel Hill, NC 27516, USA (e-mail: [email protected]) 1
2
3
4
5
Jackson JB, Musoka P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362: 859–68. Beckerman KP. Long-term findings of HIVNET 012: the next steps. Lancet 2003; 362: 842–43. Havlir D, Eastman S, Gamst A, Richman DD. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol 1996; 70: 7894–99. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET012). AIDS 2001; 15: 2951–57. Cunningham CK, Chaix M-L, Rekacewicz C, et al. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent human immunodeficiency virus type 1 transmission: a substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002; 186: 181–88.
Sir—Karen Palmore Beckerman states in her Commentary1 that the HIVNET 012 protocol did not affect child survival. We strongly disagree with this assertion. First, the study was powered to assess significant differences in HIV-1 transmission, not survival. Second, as shown in figure 3, children in the nevirapine group fully achieved the expected level of survival benefit that would be mediated through the documented level of reduction in HIV-1 incidence. Third, the 18-month
mortality was higher in the zidovudine group than the nevirapine group (13·6% vs 10·6%),2 and these differences would be expected to widen owing to the higher number of HIV-1infected children in the zidvoudine group, and the increasing likelihood of HIV-1 disease progression as the children get older; HIVNET 012 will be able to assess this prospect, because infants are being followed-up until they reach 5 years of age. We agree with Beckerman that the effect of single-dose nevirapine on future treatment options is a concern that urgently needs research. We disagree that it is a foregone conclusion that there will be an adverse effect. Data from the Pediatric AIDS Clinical Trial Group3 protocol 316 indicate that nevirapine resistance was not reduced by coadministration of additional antiretrovirals if there was persistent viral replication when nevirapine was given; therefore coadministration of 2–3 days of postnatal zidovudine or lamivudine is unlikely to decrease resistance. We also agree with Beckerman that combination antiretroviral therapy during pregnancy and post partum will be better than single-dose nevirapine at reducing transmission and beneficial to maternal health, and is a goal to be worked towards. However, in Uganda today, despite the best intentions, fewer than 2% of HIV-1-infected individuals are receiving any form of antiretroviral treatment. Even with the expected implementation of the Global AIDS Fund and Bush AIDS Relief Program over the next few years, most HIV-1-infected individuals who need treatment will probably not receive it. In the meantime, 2000 babies are becoming HIV-1-infected each day. In our opinion, saving thousands of lives today with a simple, safe, affordable intervention should take precedence over the alternative of not using it because of concerns that future and uncertain treatment options might be limited with nevirapine’s use. *Brooks Jackson, Francis Mmiro, for the HIVNET 012 study team Department of Pathology, Johns Hopkins University, Carnegie 415, 600 North Wolfe Street, Baltimore, MD 21287, USA (e-mail: [email protected]) 1
2
3
Beckerman KP. Long-term findings of HIVNET 012: the next steps. Lancet 2003; 362: 842–43. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18 month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362: 859–68. Cunningham CK, Chaix M-L, Rekacewicz C, et al. Development of
resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002; 186: 181–88.
Author’s reply Sir—Ed Cooper is correct to point out that “induction” of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance is a misuse of the word (albeit a common one), which should be replaced by “selection” or “induction of detectable resistance”. Charles Darwin, we assume, would be among those most eager to examine the hypothesis that NNRTI resistance, which does not seem to render virus unfit,1 will “fade” to clinical insignificance. Catherine Wilfert argues that none of the single-dose nevirapine studies has shown 100% resistance, and indeed none has. However, Kantor and colleagues—the only group to examine 2-week, maternal HIV-1 clade C post-nevirapine samples— reported that 76% of exposed women had detectable resistance.2 Given that the assay used cannot detect minority or archived populations, the actual prevalence of clinically significant NNRTI resistance remains higher than 76% and, in fact, could approach 100%. The suggestion by Brooks Jackson and Francis Mmiro that the statistically insignificant difference in 18-month child survival between nevirapine and zidovudine prophylaxis groups “would be expected to widen” is a hope that many of us share. However, neither their own calculations of significance (p=0·253), nor the original study design and power calculations (as they point out) support such a conclusion. Jackson and Mmiro join Wilfert in pointing out that treatment with other antiretroviral agents did not prevent the appearance of NNRTI resistance in the Pediatric AIDS Clinical Trial Group Protocol (PACTG) 316.3 However 66% of the PACTG participants studied received suboptimal single or dual combination antiretroviral therapy and all patients had evidence of ongoing viral replication, with the lowest viral load reported being 152 copies per mL. Similarly, the Thai-US Centers for Disease Control collaboration4 found evidence of NNRTI resistance in 15% of women who received single-dose nevirapine during labour after zidovudine prophylaxis from 34 to 36 weeks of pregnancy. The median
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
245