Peripartum Antiretroviral Therapies For Preventing The Risk Of Mother-to-Child Transmission Of HIV

Part I Peripartum Antiretroviral Therapies for Preventing the Risk of Mother-to-Child Transmission of HIV: A Critical Overview of Systematic Reviews or Meta-analysesObjectives:To explore the methodology of critical overview of systematic reviews or meta-analyses;To examine the quality of reporting systematic reviews and meta-analyses of peripartum antiretroviral therapies for the prevention of mother-to-child transmission of HIV;To assess the comparative effectiveness and safety of antiviral therapies for preventing the mother-to-child transmission of HIV during different timing of transmission;To identify the timing of HIV transmission and risk factors for mother-to-child transmission of HIV.Methods:We searched the related databases of PUBMED, EMBASE, CINAHL, AIDSearch, AIDSLINE, AIDSTRIALS, AIDSDRUGS, AIDSinfo, CRD(center of review and dissemination) and three Chinese Databases (CBM, CNKI, VIP), all from date of databases establishment to 20 April, 2007. The Cochrane Library (Issue 4, 2006) was also searched. We also searched the documents of governments and NGOs, as well as abstracts from relevant conferences, including the International AIDS Conferences, the annual Conference on Retroviruses and Opportunistic Infections, etc. Experts in the field of HIV prevention and treatment were contacted to locate any further studies or relevant conference proceedings not included in the databases to ensure that unpublished studies were included. We tracked the reference lists of all pertinent reviews and studies. Other gray literatures were searched by google and other search engines.Systematic reviews and meta-analyses of randomized trials to assess the effects of antiretroviral therapy for preventing MTCT were included. Quality assessment of the included studies was conducted by using two instruments: the quality of reporting of meta-analysis (QUOROM statement) and the Oxman and Guyatt index. The selection, quality assessment and data extraction were performed by two reviewers independently, with confirmation of cross-check. Different opinions were consulted by the third party. Fisher's exact test was used to compare the proportions of categorical variables. We calculated the rate difference (risk difference, RD), number need to treat (NNT) and 95% confidence interval (CI) by using the data extracted from the included systematic reviews or meta-analyses. All statistical tests used two-sided p= 0.05 significance level, unless otherwise stated. The descriptive analyses were used to explain the comparative effectiveness, safety and risk factors of antiviral therapies for preventing the mother-to-child transmission of HIV during different timing of transmission. Analyses were carried out using SPSS version 11.0. Results:Six studies were included, of which two were Cochrane reviews and four individual-patient data meta-analyses. Ten randomized trials were included in the systematic reviews or meta-analyses, including 19 articles and 8 conference abstracts.The quality scores of the studies varied between five and seven by Oxman and Guyatt checklists, and ranged from 12 to 16 by the QUOROM checklist. The methodological quality of the reports met 57.4% (median = 5) and 76.9% (median = 14) of the maximum scores of Oxman & Guyatt index and QUOROM statement. Of these, the quality of 2 Cochrane reviews (Brocklehurst 2002 & 2005) and 2 IPD meta-analyses (Leroy 2005 and BHITSG 2004) was high (Oxman and Guyatt score≥5, QUOROM socore≥14) The quality of other 2 meta-analyses (Leroy 2002 & 2003) was low (Oxman and Guyatt score= 3; QUOROM score =12).Compared with placebo, zidovudine (ZDV)-containing regimen significantly reduced the risk of MTCT of HIV (RD=1-15%, NNT=7-14, p<0.05).There was significant reduction in the risk of MTCT of HIV with long course ZDV in non-breast feeding population (RD=15%, 95%CI=8.2-21.8%; NNT=6.68, 95%CI=4.59-12.26); any ZDV (RD=10.8%; NNT=9.23); short course ZDV in non-breast feeding population (RD=9.4%; NNT=10.63); short course ZDV in breast feeding population (RD=9.3%; NNT=10.70) and short course ZDV in any population (RD=9.3%; NNT=10.72) . But the efficacy of ZDV for preventing MTCT of HIV decreased with prolonged following-up. The short-course ZDV either in breast feeding or non-breast feeding population were still more effective than placebo (NNT=10.7 or 10.6). But the efficacy of ZDV for preventing MTCT of HIV decreased with prolonged following-up(at 6 weeks, RD=8.7%,NNT=11.4; at 2 year, RD=8.7%, NNT=11.4). The results of 1 IPD meta-analyses (Leroy 2003) showed that the cumulative risks of postnatal transmission (PT) of HIV were similar in the maternal short-course zidovudine and placebo groups in a breastfeeding population(RD=0.7%,95%CI=-4.3-5.6%).The meta-analyses of different courses of zidovudine showed that the risk of MTCT of HIV using long-long course (starting from the 28th week during pregnancy for the mother until 6 weeks after birth for the babies) was lower than short-short course (starting from the 35th week during pregnancy for the mother and until 3 days after birth), the risk difference is 5.9% (95%CI 1.1% to 10.7%, NNT=17). However, the long-short course (starting from the 28th week during pregnancy for the mother and until 3 days after birth for the baby) and the short-long course (starting from 35th week during pregnancy for the mother and until 6 weeks after birth for the baby) did not differ significantly from long-long course (RD=2.3%, 95%CI -1.1% to 5.6%; RD=2.5%, 95%CI -1.5% to 6.5%).Single-dose Nevirapine (NVP) was more effective than ultra-short ZDV in preventing the risk of MTCT of HIV (NNT=9-13, p<0.05). One Cochrane review (Brocklehurst 2005) with limited data from 1 conference abstract showed the addition of NVP to the standard therapy was not effective compared with standard therapy (OR= 1.10, 95% CI =0.42 to 2.86). One IPD meta-analysis (Leroy 2005) showed that when compared with NVP, long course combination therapy of ZDV plus lamivudine, administrated during the antenatal, intrapartum and postpartum period, was more effective in reducing the 6-week MTCT rate (AOR=0.39; P < 0.0005). In contrast, the ultra-short ZDV and placebo increased the MTCT rates (AOR=1.85, P=0.002; AOR=1.66, P=0.0007). The antenatal short ZDV and short course ZDV plus lamivudine were not significantly different with NVP in the 6-week MTCT rates (P=0.72 or 0.17). The combination therapy of zidovudine and lamivudine(ZDV+3TC) indicated a reduction in the risk of transmission compared with placebo, either in long course ZDV+3TC(starting from the 36th week during pregnancy for the mother and until 1 week after birth) or short course ZDV+3TC (starting from intrapartum and until 1 week after birth) (RR=0.52,95%CI=0.35 - 0.76; RR -0.66, 95% CI= 0.46 - 0.94). And long course ZDV+3TC was more effective than ultra-short NVP (adjusted OR=0.39, p<0.0005). While the short course ZDV+3TC was not different with NVP(P= 0.17). The effect of ultra-short ZDV+3TC was similar with NVP(p<0.01).The multivariate analysis showed that the risk of MTCT of HIV was significantly higher with low maternal CD4 cell count and high maternal viral load(the risk increased by 2-8 fold), breastfeeding (AOR=1.54, p=0.002), low birth weight(<2500g)(AOR=1.87, p<0.0001), and the male sex of babies(late postnatal transmission of female sex decreased by 40% compared with male sex, adjusted HR=0.6, 95%CI=0.4-0.9).Conclusion:A little methodological limitation existed in all included systematic reviews and meta-analyses, with higher scores of quality in 4 trials(Brocklehurst 2002, Brocklehurst 2005, Leroy 2005 and BHITSG 2004), and lower scores of quality in 2 trials (Leroy 2002 and Leroy 2003). The selection bias was found in all included studies because some important trials were not included.Antiviral therapy using ZDV alone or in combination with lamivudine or single-dose NVP is effective to prevent MTCT of HIV. In comparison with placebo, ZDV-both long-course and short-course regimens, either in breastfeeding population or not, significantly reduced the risk of MTCT of HIV. Only longer regimen of ZDV+3TC (ZDV+3TC pre/intra/post) was significantly reduced the MTCT rate compared with NVP. Single dose of NVP was more effective than ultra-short ZDV alone or in combination of lamivudine. The antenatal short ZDV and short course ZDV+ lamivudine were not significantly different with NVP.The single-dose NVP and short-course ZDV or ZDV+3TC could be recommended in resource-limited countries. The mutation resistance of antiretroviral drugs should be cautiously monitored. The further studies should be conducted on the long-term safety and effectiveness of ART for preventing the risk of mother to child transmission of HIV. If feasible and affordable, the long course ZDV or ZDV+3TC should be recommended.The low maternal CD4 cell count and high maternal viral load, breastfeeding, low birth weight, and the male sex of babies were the independent risk factors, which increased the risk of MTCT of HIV. The risk factors should be monitored and intervened. Interventions are urgently needed to decrease transmission of HIV through breast-feeding. The biological mechanisms should be addressed to explain the effect of risk factors (eg. the sex of babies.). Part II the Comparative Effectiveness and Safety of Peripartum Antiretroviral Therapies for Preventing the Risk of Mother-to-Child Transmission of HIV: A Systematic Reviews of Randomized Controlled TrialsObjectives:To assess the efficacy, comparative effectiveness and safety of peripartum antiretroviral therapies(ART) for preventing the risk of mother-to-Child transmission(MTCT) of HIVTo compare the results of systematic review with the recommendations of the WHO guideline or national guideline of ART for preventing the risk of MTCT of HIV in China.To provide the evidence and recommendations for the decision making in the guideline of antiretroviral therapies for the prevention of mother-to-child transmission of HIV in China.Methods:A systematic review of randomized controlled trials (RCTs) was conducted by using the methodology of Cochrane reviews. PUBMED, EMBASE, CINAHL, AIDSearch, AIDSLINE, AIDSTRIALS, The Cochrane Library (Issue 1, 2007), AIDSDRUGS, AIDSinfo, CRD(center of review and dissemination) and three Chinese Databases (CBM, CNKI, VIP), were searched from the date of databases establishment to 20 April, 2007. We also searched the documents of governments and NGOs, as well as abstracts from relevant conferences, including the International AIDS Conferences, the annual Conference on Retroviruses and Opportunistic Infections, etc. Experts in the field of HIV prevention and treatment were contacted to locate any further studies or relevant conference proceedings not included in the databases to ensure that unpublished studies were included. We tracked the reference lists of all pertinent reviews and studies. Other gray literatures were searched by google and other search engines.Randomized controlled clinical trials to assess the effects of antiretroviral therapy for preventing MTCT were included. The selection, quality assessment and data extraction were performed by two reviewers independently, with confirmation of cross-check. Different opinions were consulted by the third party. Meta-analysis was conducted by Revman 4.2.9. Data were pooled using fixed effect model if without heterogeneity (p>0.05); Otherwise, sensitivity analysis, subgroup analysis or randomized effect model was adopted. If the data could not be combined, the descriptive analysis was used.Results:Twenty two original studies with 15981 participants met the inclusion criteria, including 43 published articles and 28 conference abstracts. Other 12 RCTs with 26 articles and 20 abstracts were included in this systematic review, which were not contained in the 5 systematic reviews or meta-analyses in part I. The other 9 RCTs were updated. Only 1 RCT(PACTG 185, 2 articles) was excluded which did not meet the purpose.Of these 22 RCTs, 17 (77.3%) was of high quality with Jadad score of 3 or more; while the rest 5(22.7%) was lower quality. Eight RCTs (PACTG076, ANRS049, RETRO-CI, Thai-CDC, Thai-PHPT1, Thai-PHPT2, PACTG316, and Mashi-partl) compared ZDV with placebo, different regimes of ZDV, NVP with placebo, respectively, which were of high quality with the design of multicenter, double-blind, randomized, placebo-controlled trial and large sample size. Nine RCTs(PETRA, SAINT, HIVNET012, Chung2005, Gray2005, NAVZ, Taha2004, Thistle 2007, and Mashi-part2) with moderate quality, compared different regimes of ZDV+3TC with placebo, breast-feeding plus long course ZDV with formula feeding plus short course ZDV, respectively. 5 RCTs(HIVNET023, Moodleyl998, PACTG1022, BMS AI-094 and Kovacs2005) with lowest quality of phase I/II trials, compared with different regimes of NVP, ZDV+3TC with 3TC, ZDV+3TC+NFVwith ZDV+3TC+NVP, d4T, ddI with ZDV.Zidovudine monotherapy:Based on four trials with 2385 participants any zidovudine regimen (both long course and short course, either in breast feeding population or not) versus placebo significantly reduces the risk of mother-to-child transmission of HIV by 43%-50%. The incidence of stillbirth, infant mortality, maternal mortality, premature delivery, low birth weight, birth defects, any adverse drug reaction (ADR) either in mothers or in children, any antenatal, intrapartum or postpartum complication were no difference between ZDV and placebo(p >0.05).One trial with 1437 participants compared with the different courses of ZDV. The 'long-long' course (from 28 weeks in pregnancy for the mother and for the baby until 6 weeks old) decrease the risk of transmission by 61%, when compared with 'short-short' course of zidovudine (from 35 weeks in pregnancy for the mother and for the baby until 3 days old). However, the effectiveness of the 'long-short' course (from 28 weeks in pregnancy for the mother and for the baby until 3 days old) and the 'short-long' course (from 35 weeks in pregnancy for the mother and for the baby until 6 weeks old) did not differ from that of the 'long-long' course. There was no difference between the different courses of ZDV in the incidence of stillbirth, neonatal mortality, infant mortality within 1 year, maternal mortality, premature delivery, low birth weight, birth defects, any adverse drug reaction (ADR) either in mother or in children(p >0.05). One trial with 1200 participants compared formula-fed plus short course zidovudine with breastfed plus long course zidovudine. The formula-fed plus ZDV reduced the risk of transmission by 35%-39% from 7 months to 18 months after birth, and associated with a higher mortality rate at 7 months than the breastfed plus zidovudine group (9.3% vs 4.9%; P=.003). The incidence of stillbirth, low birth weight, birth defect or any ADR both in mothers and children was no difference between the two goups.Stavudine (d4T), didanosine (ddI), d4T+ddIBase on 1 trial with 373 participants, there was no difference between d4T, ddI, d4T+ddI and ZDV in the prevention of MTCT of HIV by using both per-protocol analysis or intention-to-treat analysis. The infant mortality in d4T group was lower than that of d4T+ddI group. But there was no difference between the other groups. The incidences of ADR in all 4 groups were similar.One trial with 41 participants showed that the rates of toxicities were similar between the ddI+ZDV group and the ddI+placebo group. However, infants in the ddI+placebo arm were more likely to have experienced grade 3 or greater chemical toxicity than infants in the ddI+ZDV arm,(8/20 vs. 2/21; RR=0.24,95%CI=0.06-0.99,p=0.019), and these toxicities occurred significantly earlier (RR-5.265; 95% CI =1.113-24.914, p=0.013).NevirapineThree trials with 4059' participants compared the nevirapine + standard antiretroviral therapy (ART) with ART. One trial(Thai-PHPT, 1844participants) demonstrated that when nevirapine was given to mothers already receiving standard antiretroviral therapy with ZDV, both the NVP-NVP and NVP-Placebo decreased the risk of transmission by 91% or 82% than placebo-placebo group). However, due to the use of highly active ART(HAART), there appeared to be no additional advantage(p>0.05). Two trials(Thai-PHPT2 and Mashi-partl, 2553 participants) showed that in the setting of short course zidovudine, the effectiveness in infant or maternal single dose nevirapine(sdNVP) group were similar with in the group where both mother and infant received sdNVP. The safety of ART+NVP was similar with ART alone (p>0.05).One small trial(75 participants) demonstrated that the rates of infants infection, mortality and any ADR of NVP either once weekly, twice weekly , or once daily were similar(p>0.05).Meta-analysis of 3 RCT(1753 participants) showed that that sdNVP given to mothers and babies was more effective than an intrapartum and post-partum regimen of zidovudine (decreased the risk by 44%-65%). The incidences of stillbirth, infant and maternal mortality, low birth weigh, ADR of mothers and children were similar between the two groups (p>0.05).Three RCTs(3153 participants) compared the effect of NVP+ZDV with NVP. When the mother and infant did not receive any ART or NVP, ZDV appeared additional advantage either in HIV infection rate or cumulative rate (RR=0.63,95%CI=0.42-0.96, p=0.03; RR=0.73, 95%CI=0.56-0.96, p=0.02). However, when the mother and infant received intrapartum NVP+ZDV or sdNVP, there appeared no additional advantage(p>0.05). The incidences of stillbirth, grade 3 or greater ADR and average birth weigh were similar between the two groups (p>0.05).Combination Therapy of Zidovudine and Iamivudine(ZDV+3TC)One large trial(PETRA, 1797 paricipants) demonstrated combination therapy using zidovudine and lamivudine (3TC) decreased the risk of transmission by 35%-65% within 15 months compared with placebo, when the combination was given during the antenatal and intrapartum period(long course) or during the intrapartum and postpartum(short course). However, there was no evidence that ultra-short course ZDV+3TC was sufficient to decrease the risk of transmission compared with placebo. The long course or short course ZDV+3TC was more effective than postpartum(ultra-short course) ZDV+3TC from 6 weeks to 3 months after birth, which reduced the risk of transmission by 41%-65%. The safety of different course of ZDV+3TC and placebo were similar(p>0.05).One large trial(SAINT, 1317 paricipants) showed that the effectiveness and safety of intrapartum and postpartum ZDV+3TC were similar with sdNVP given to the mother and infant(p>0.05).One small trial(Moodley1998, 20 participants) demonstrated that no infant infection was found both in ZDV+3TC and 3TC alone (all from week 38 of pregnancy to 1 week after delivery) within 2 weeks after birth; while only 1 infant infected at 12 months. Both regimens were well-tolerated in women and newborns.One small trial (PACTG1022, 39 participants) showed that more severe toxicities related with the hepatic toxicities(Stevens-Johnson syndrome, fulminant hepatic failure, hepatitis, increased ALT, nausea and vomiting,etc.) in ZDV+3TC+NVP group have been observed than ZDV+3TC+NFV group(5/17 vs. 1/21,p=0.07). The trial were ceased early.Conclusions:The evidence based on the meta-analyses of large RCTs with high quality showed that: 1. Any ZDV (both long course or short course), single dose NVP and the combination therapies of ZDV plus 3TC are effective to prevent MTCT of HIV.2. Short course ZDV and sdNVP are more economic and feasible, which are recommended as simplified regimes by WHO. But the disadvantage is the risk of resistance (especially in NVP), which should be monitored and balanced carefully.3. Single dose of NVP is more effective than short course and ultra-short course ZDV with less expensive and easier to use. It is recommended as minimum regime for preventing MTCT of HIV by WHO.4. Postpartum ZDV(even short course) plus sdNVP, is more effective than sdNVP alone. Which is recommended as alternative intervention for infants born to women living with HIV who have not received antepartum or intrapartum therapy or prophylaxis by WHO.5. In setting of long course ZDV to prevent MTCT of HIV, sdNVP (either to mother or to infant) appears additional advantage, and similar effects with sdNVP(both to mother and to infant). The peripartum ZDV(from 28 week in pregnancy to 1 week after delivery) plus sdNVP(for both mother and infant) is recommended by WHO as the alternative long-course regime. The recommended sdNVP for both mother and infant should be changed into sdNVP for mother or for infant to reduce the resistant of NVP.6. When highly active ART (HAART) is adopted to prevent the peripartum transmission of HIV, sdNVP(both to mother and to infant) appears no additional advantage. If the resource is available, HAART should be recommended as useful interventions for preventing the MTCT of HIV.7. The effect of intrapartum and postpartum ZDV+3TC is similar with sdNVP. The short course ZDV+3TC(from 38 week of gestation to 1 week after delivery) is similar with 3TC. Intrapartum and postpartum ZDV+3TC is recommended as alternative intervention for preventing MTCT among pregnant women living with HIV who have not received antepartum therapy or prophylaxis.8. If feasible and affordable, long course ZDV+3TC(from 28 gestation to 1 week after delivery) is more effective than short course ZDV+3TC or sdNVP.9. Peripartum ART in combination with formula-fed will dramatically reduce the risk of mother-to-child transmission of HIV, and also decrease the risk of resistant and adverse events of ART.The evidence from the meta-analyses of small RCTs with low quality demonstrated that:10. There is no difference among Stavudine(d4T), didanosine (ddI), their combination and ZDV. But there are some limitations of safety. It is possible that the ddI+ZDV is more safer than ddI alone. Because of limited evidence with low quality, further studies on their effective and safety are required.11. ZDV+3TC+NFV or ZDV+3TC+NVP are the first-line drugs for the prevention of MTCT of HIV by WHO and China. But only one small trial showed that some severe toxicities related to the hepatic disorder were observed in both group, especially in ZDV+3TC+NVP group. The further studies on their safety and effectiveness are needed.