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Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study
Global Health Sciences Literature Digest
Published November 03, 2008
Journal Article

Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr 2008 Jul 1;48(3):237-40.

Objective

To investigate the possibility of reducing mother-to-child transmission (MTCT) of HIV-1 through breastfeeding by prophylactic antiretroviral (ARV) treatment of infants during the breastfeeding period

Study Design

An open-label, nonrandomized, prospective cohort study

Setting

Study clinic in Dar es Salaam, Tanzania

Participants

The study population consisted of pregnant women who were recruited from three municipal primary health care antenatal clinics and from the antenatal clinic at Muhimbili National Hospital. Eligibility criteria included HIV-1 seropositivity, determined by testing two blood samples, intention to breastfeed, hemoglobin (Hb) level not less than 7g/dL, being aged 18 years or older, willingness to take drugs and to give drugs to the newborn as prescribed, willingness to deliver at the study site, availability for 18 months of follow-up, and being an accessible resident of Dar es Salaam. Enrollment into the study was at 36 weeks of gestation, and women were enrolled from August 2001 until August 2003. Counseled for HIV testing was 10,179 pregnant women, of whom 9,378 were tested and 1,029 (11.0%) were found to be HIV-1 positive. Of these women, 468 (45.5%) were enrolled in the study. Thirteen women were lost to follow-up before delivery, leaving 455 women who delivered 470 infants. After excluding second-born twins, stillborn babies, neonatal deaths, and mothers who decided not to breastfeed, 398 mother-infant pairs were included in the analysis. No statistically significant differences were found between the mothers included in the analysis and the 31 mothers whose babies were lost to follow-up without HIV results.

Intervention

Women who enrolled in the study received normal antenatal, labor, and delivery care. In addition, they received ARV treatment of 300 mg zidovudine plus 150 mg of zidovudine and lamivudine administered twice daily from 36 weeks of gestation, intrapartum, and for 1 week postpartum. This regimen was the same as was given in arm A of the Petra study, which was conducted by the Mitra study authors to determine the efficacy of short-course azidothymidine and lamivudine in PMTCT.(1) Infants were treated with zidovudine (4 mg/kg twice daily) and lamivudine (2 mg/kg twice daily) from birth to 1 week of age, and then with zidovudine alone (2 mg/kg twice daily from weeks 2-4 and 4 mg/kg twice daily after week 4) during breastfeeding (to a maximum of 6 months) and 2 weeks after breastfeeding was stopped. Follow-up appointments were at weeks 1, 3, and 6 and at months 3 through 24 (every 3 months) after delivery. Postnatal care within the study was free of charge for mothers and infants.

A clinical examination was given to the infant at each visit, adverse events since the last visit were documented, and detailed information on feeding practices and changes since the last visit were collected. Blood samples were drawn at each visit (except week 3). Mothers received counseling on infant feeding at every visit, emphasizing exclusive breastfeeding and weaning between 5 and 6 months of age. All infants were given prophylactic treatment with cotrimoxazole from 6 weeks of age to the time when they were shown to be HIV-negative after having stopped breastfeeding. Children diagnosed as HIV positive continued on cotrimoxazole after cessation of breastfeeding. The lamivudine treatment of HIV-infected children was discontinued when the HIV diagnosis was confirmed on a second sample. Antiretroviral therapy for treatment was not available at the time.

Primary Outcomes

The rate of MTCT of HIV-1

Results

In total, 19 children in the study were infected with HIV-1 at 6 months; 15 were infected at 6 weeks and 4 were PCR-negative at 6 weeks, but PCR-positive at month 3 or month 6. Only 1 of the 4 children with late transmission had been given ARV treatment without interruption during the entire breastfeeding period. Cumulative infection rates were 3.8% (95% confidence interval (CI): 2.0%-5.6%) at 6 weeks and 4.9% (95% CI: 2.7%-7.1%) at 6 months after delivery. The only baseline characteristic studied at enrollment that had a significant association with transmission was CD4 percentage (relative hazard [RH]=0.94, 95% CI: 0.9-1.0; P=0.046). Viral load was determined in all transmitting mothers and in three matched controls for each case, and was significantly associated with transmission (risk not given; P=0.012). For the 380 infants who were not infected with HIV at 6 weeks, the cumulated risk of acquiring infection between 6 weeks and 6 months of age was 1.2% (95% CI: 0.0-2.4%). No serious adverse events during the follow-up period were considered to be related to the study medication.

For comparison, the authors used the cohort of children (n=222) in arm A of the Petra study who were in the breastfeeding population and who remained in follow-up at 6 months. Infants in the Petra study also were given zidovudine and lamivudine from birth to 1 week of age, but were not given additional lamivudine thereafter. The Mitra study mothers had significantly lower Hb and CD4 cell counts than did the Petra mothers, as well as fewer cesarean sections. Mitra study infants had significantly lower birth weight. No information on the type of breastfeeding (exclusive vs. mixed) was available in the Petra trial. Kaplan-Meier estimated HIV-1 transmission rates for infants in the Petra study were 5.4% (95% CI: 2.7%-8.1%) at 6 weeks and 11.9% (95% CI: 7.9%-15.8%) at 6 months after delivery.

To account for differences in background factors, a Cox regression analysis of transmission in the Mitra study and the breastfeeding population in Petra arm A was performed on the pooled data. The transmission of HIV up to 6 months after delivery was more than 50% lower in the Mitra study compared with the Petra study (adjusted RH=2.61; P=0.001). CD4 cell count was the only factor that showed a significant relation to transmission and was differently distributed in both studies. Adjusting for CD4 count gave a slightly increased RH in favor of the Mitra study (from 2.37 to 2.61). Viral load data were not available from Petra trial mothers. In a subgroup analysis of mothers with CD4 counts ≥200 cells/µL, there was also a significantly lower transmission of HIV-1 during breastfeeding in the Mitra study compared with Petra trial arm A (cumulative transmission at 6 months 4.0% [95% CI: 1.6%-6.2%] and 9.9% [95% CI: 5.9%-13.8%], respectively; adjusted RH=2.40; [95% CI: 1.20-4.78]; P=0.013). On pooled data, HIV infection or death at 6 months was significantly lower in the Mitra study than in the breastfeeding population of the Petra trial (adjusted RH=2.75; P<0.001).

Conclusion

The authors conclude that the rates of MTCT of HIV-1 in this study at 6 weeks and 6 months after delivery are among the lowest reported in a breastfeeding population in sub-Saharan Africa. Prophylactic lamivudine treatment of infants to prevent MTCT of HIV during breastfeeding was well tolerated by the infants and could be a useful strategy to prevent breastmilk transmission of HIV when mothers do not need ARV treatment for their own health.

Quality Rating

Based on the Newcastle Ottawa quality rating scale for cohort studies, this study is of good quality; however, there were some limitations. Primarily, the study used a historical control (the Petra study) as a comparison group. The results therefore should be cautiously interpreted due to differences in study design and study populations. The Mitra mothers, for example, were in an immunologically more advanced stage of HIV infection (lower CD4 cell counts) at enrollment compared with the Petra mothers and had more other known risk factors (fewer cesarean sections and lower birth-weight infants). Importantly, these differences would suggest a higher rate of transmission in the Mitra trial, not the lower rates that were found. Additionally, the two studies provided different counseling sessions on breastfeeding to the mothers. No information was collected on type of breastfeeding in the Petra trial, making it difficult to assess the contribution of exclusive breastfeeding in the Mitra trial. Another limitation is that adherence to treatment in the study was not determined.

In Context

A clinical trial in Botswana (the Mashi trial part I) demonstrated low transmission rates at 1 month of age after short-course maternal treatment with zidovudine with or without single-dose nevirapine and infant treatment with zidovudine for 1 month plus single-dose nevirapine (4.3% and 3.7%, respectively).(2) In Côte d'Ivoire, a short-course treatment with zidovudine plus lamivudine plus single-dose nevirapine resulted in a 6-week HIV-1 transmission of 4.7%.(3) The use of extended prophylactic ARV treatment of breastfed infants for preventing postnatal HIV-1 transmission was evaluated in two studies: the Mashi trial in Botswana and the Simba trial in Uganda and Rwanda.(4) Simba trial results are not yet published; however, the Mashi trial (part II) showed a significantly lower 7-month HIV transmission rate in infants of HIV-infected mothers who were formula-fed and given 1 month of prophylactic zidovudine compared with infants who were breastfed and given prophylactic zidovudine for 6 months (5.6% and 9.0%, respectively). The 6-month HIV transmission rate in the Mitra trial was lower than the 7-month transmission rate in the breastfed zidovudine-treated infants in the Mashi trial and similar to the infection rate of the formula-fed infants in the Mashi trial. The cumulative mortality rate at 7 months (4.2%) was similar to the breastfed zidovudine-treated infants in the Mashi trial (4.9%). A randomized trial in Malawi (also presented in this digest) compared single-dose nevirapine plus 1 week of zidovudine (control) to the control regimen plus extended nevirapine with and without zidovudine for 14 weeks.(5) This study also found a comparable reduction in HIV transmission with 10.6% of infants infected in the control group at 9 months compared with 5.2% in the extended nevirapine group and 6.4% in the nevirapine plus zidovudine group.

Programmatic Implications

This study showed that prophylactic lamivudine treatment of breastfed infants of HIV-1-infected mothers was very well tolerated. Additionally, the transmission of HIV-1 up to 6 months after delivery was low and significantly lower than the historical control in which infants received ARV treatment for just their first week of life. Prophylactic ARV treatment therefore should be considered for breastfed infants whose mothers are not taking highly active antiretroviral therapy (HAART) for their own health. Other studies are currently ongoing to determine the efficacy and long-term safety of maternal HAART during the breastfeeding period, given regardless of other indication in the mother. Infants who are given lamivudine monotherapy and acquire HIV infection are at very high risk for the M184V/I mutation and should be assessed for lamivudine resistance or receive an alternate drug. Although studies have shown reversion of this mutation with time, it may be archived and reappear with initiation of HAART.

References

  1. The Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda [Petra study]: a randomised, double-blind, placebo-controlled trial. Lancet 2002;359:1178-86.
  2. Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. AIDS 2006;20:1281-8.
  3. The ARNS1201/1202 DITRAME PLUS Study Group, Dabis F, Bequet L, Ekouevi DK, et al. Field efficacy of zidovudine, lamivudine and singledose nevirapine to prevent peripartum HIV transmission. AIDS 2005;19:309-18.
  4. Thior I, Lockman S, Smeaton L, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: The Mashi Study. JAMA 2006;296:794-805.
  5. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008 Jul 10;359(2):119-29.