Is Zidovudine Enough?

The World Health Organization (WHO) estimates that only 53% of pregnant women worldwide received any antiretrovirals during pregnancy to prevent mother-to-child HIV transmission in 2009.  In the absence of any intervention, the risk of transmission is high (upto 45%).¹  Therefore it is crucial that infants born to previously untreated mothers receive postexposure prophylaxis.  The current recommendation is to give zidovudine to HIV-infected pregnant women antepartum, during labor, and to their infant(s) for six weeks. This recommendation is based on the pivotal ACTG 076 trial where mother-to-child transmission (MTCT) of HIV was reduced by 66% in the zidovudine group compared with placebo.²

Even with advances in prevention, detection, and treatments for HIV, rates of MTCT are still 12 to 26% and improvement is needed.^3-5  For mothers who live in resource-rich countries, the American Academy of Pediatrics currently recommends that they exclusively formula feed their infant(s) to eliminate HIV exposure.  However, prior to the PACTG 1043 Protocol Team Study, no randomized controlled trials examining postexposure prophylaxis for formula-fed infants in resource-rich countries had been conducted.  A randomized study in South Africa found a similar rate of transmission among formula-fed infants who received zidovudine versus a single-dose nevirapine regimen (11.1% and 7.3% respectively; p = 0.30).⁶  Prophylaxis with combination ART is an increasingly common practice but it is unclear whether adding one or two more antiretroviral drugs to standard zidovudine therapy is safe or more effective.  The PACTG 1043 Protocol Team study addressed this clinically important question.

The PACTG 1043 Protocol Team conducted a randomized, multicenter trial to compare the efficacy and safety of three neonatal ART regimens for the prevention of intrapartum HIV-1 transmission in infants whose mothers did not receive ART during pregnancy.⁷  They enrolled patients from 17 sites (Brazil, South Africa, Argentina, and the United States) between April 2004 and July 2010.  Formula-fed infants born to women with a eripartum diagnosis of HIV-1 infection were randomly assigned to one of three regimens:

• zidovudine-alone group (monotherapy)
• zidovudine + nevirapine (two-drug group)
• zidovudine + nelfinavir + lamivudine (three-drug group)

Table 1 – ART Regimens to Prevent Intrapartum HIV Infection

The primary endpoint of the study was the rate of intrapartum HIV-1 infection at 3 months in infants uninfected at birth.  Infant inclusion criteria included:  age ≤ 48 hours old, gestational age ≥ 32 weeks, weight ≥ 1.5 kg, no life-threatening conditions, and able to tolerate oral medications.  Mothers were excluded from the study who received any ART other than zidovudine during labor. Infants infected in utero, defined as two positive HIV-1 test results at birth, were excluded from the primary efficacy analysis.  Infants who received ART other than zidovudine were also excluded.

Infants were evaluated five times: at birth, between 4-7 days, 10-14 days, 4-6 weeks, and 3-6 months of age.  HIV-1 infection was confirmed when two positive DNA PCR results occurred on different days. Intrapartum infection included infants with a negative HIV-1 test at birth, but who showed a positive result after subsequent testing.

A total of 1684 infants were included in the primary efficacy analysis.  The overall rate of in-utero transmission of HIV-1 was 5.7%, with no significant differences between groups.  Intrapartum transmission was higher in the zidovudine-alone group compared to the two-drug and three-drug groups (4.8% vs. 2.2% vs. 2.4%; p = 0.046).  The two- and three-drug combinations resulted in a clinically significant 50% reduction in intrapartum HIV-1 transmission (NNT < 42).  A subgroup analysis found that higher rates of transmission were independently associated with zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances.  Neutropenia and anemia accounted for the majority of serious adverse events.  Neutropenia was significantly higher in the three-drug group compared with the two-drug and zidovudine-alone groups (27.5% vs. 14.9% vs. 16.4% p < 0.001, respectively).  The study also examined resistance patterns (See Table 2).  Most mutations to nevirapine were conferred in infants infected in utero.  There were no statistically significant differences in resistance patterns in the three groups.

Table 2 – Resistance Patterns

The authors concluded that the prevention of intrapartum HIV-1 transmission with a two- or three-drug ART regimen is superior to the current standard of care —  zidovudine monotherapy — for neonates born to mothers previously untreated with ART.  No significant additional benefit was seen with the three-drug regimen which exhibited a higher incidence of neutropenia and anemia.  The authors suggest that the positive results, ease of administration, and minimal toxicity from the zidovudine plus nevirapine regimen makes this combination an attractive option.

This was a well-designed randomized trial and only 2% of patients were lost to follow-up.  Over 96% of patients attended scheduled visits and were adherent to the treatment regimens.  This study is use of a fixed dosing regimen rather than the traditional weight-based dosing.  The results of this study cannot be applied to the breast-fed population.  Moreover, only 14 subjects were from the United States which potentially limits its application. Although modest, there are also increased costs associated with the two-drug regimen.  Zidovudine monotherapy would cost approximately 73 cents per day (calculated based on the recommended 4 mg/kg/dose twice daily for a 3.6 kg patient).  The two-drug regimen would be double the cost at $1.46 per day (costs were calculated based on the cost to a patient paying in cash at a retail pharmacy in the United States).

The most recent guidelines published by the WHO in 2010 for ART prophylaxis in formula-fed infants recommends a single dose nevirapine plus twice daily zidovudine or nevirapine alone for infants born to mothers with HIV-1 without antenatal care.  In addition, the mother should receive a single dose of nevirapine as
soon as possible during labor and zidovudine plus lamuvidine twice daily for 1 week postpartum.⁸  Based on the PACTG 1043 study, the National Institute of Health recently recommended zidovudine plus nevirapine in situations where antenatal ART has not been given.  But they recommend against the use of additional maternal intrapartum drugs, including single-dose nevirapine.⁹

It is crucial to remember that infant postexposure prophylaxis is not a substitute for early prevention, screening, and treatment of HIV-1 infection in women.  Less than half of the mothers in this study had three or more prenatal visits! Perhaps Benjamin Franklin said it best.  An ounce of prevention is worth a pound of cure.

Based on the available data and given the modest additional cost and favorable side effect profile, we endorse using the two-drug regimen to prevent the intrapartum transmission of HIV in infants whose mothers were previously untreated with ART.  Does this study change your practice?  Do you agree with the National Institute of Health?  Have you adopted dual therapy with zidovudine plus nevirapine for infants born to HIV-1 positive mothers in situations where antenatal ART has not been given?