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Short treatment courses
   Last updated: 23.09.05
 
The extent of perinatal transmission in the developing world dwarves that seen in the western world.

The preferred choice for treatment during pregnancy is triple combination antiretroviral therapy (ART), but most public health systems find it difficult to afford to offer ART to all women who need it.

Treating with AZT in the second trimester can also be difficult in low-resource settings where women are commonly seen for antenatal care only very late in pregnancy. In addition, many HIV-positive women do not have their infection diagnosed until shortly before childbirth.

In resource-limited settings, it has thus made sense to study whether shorter treatment regimens could also prevent mother to child transmission, first with AZT and then with other drugs, in particular nevirapine. A wide range of combinations and dosing variations are possible depending upon whether treatment is administered during pregnancy, during labour or to the mother or infant after birth.

Until recently, single dose nevirapine (sdNVP) which consists of one dose to the mother during delivery and one to the infant within 72 hours of birth, has been the standard of care for PMTCT in most resource limited settings. This intervention is simple, effective and economical enough that countries with little healthcare infrastructure have been able to implement large-scale PMTCT programmes.

Results from more recent studies have demonstrated a more effective regimen to be the combination of short course AZT from 28 weeks of pregnancy plus single dose nevirapine at the onset of labour for the mother and a single dose of nevirapine for the infant within 72 hours of birth plus one week of AZT. This regimen appears virtually as effective as triple combination ART, however, it is unlikely to quickly supplant the simpler sdNVP alone regimen in many settings.

Of increasing concern is evidence that exposure to nevirapine during labour may compromise the mother’s subsequent response to nevirapine-containing ART regimens. A percentage of women develop nevirapine resistance because detectable levels of nevirapine persist in the bloodstream for approximately 14-21 days after taking a single dose.

A possible remedy could be giving the mother a dual nucleos(t)ide analogue combination such as AZT/3TC or tenofovir/FTC for four or seven days after childbirth in order to keep the mother from inadvertently being treated by nevirapine monotherapy.

Finally, whilst a number of short treatment courses have been proven effective in reducing the risk of perinatal transmission, the longer-term impact of these interventions must also take into account the ongoing risk of HIV transmission associated with breastfeeding. It remains the case that many women in African and other resource-poor countries are advised to breast-feed their infants due to dangers associated with bottle-feeding; most often a lack of access to clean water. For more information on breastfeeding and HIV, see the entry Breast-feeding in the section Options during pregnancy .

Short course AZT in women who do not breast-feed
Research in Thailand has established that use of AZT during the last four weeks of pregnancy (300mg twice daily) and during labour (300mg every three hours) results in a 50% reduction in the risk of mother-to-child transmission (Shaffer).

In this trial, babies were not given AZT and were not breastfed. Transmission occurred among 18.9% of the 198 women on placebo and among 9.4% of the 194 women on AZT. Baseline CD4 levels and viral loads were similar for the two groups, and the rate of caesarean section was also similar. The treated group had a sustained median viral load drop of half a log. In a substudy, short course AZT was associated with reduced viral load, in both the birth canal and the blood, which in turn reduced HIV transmission (Chuachoowong 2000). These findings suggest that even late identification of HIV infection during pregnancy still offers the opportunity for risk reduction with antiretroviral treatment.

A subsequent Thai study confirmed the efficacy of late antiretroviral initiatives in reducing mother-to-child transmission. This study followed 369 mother-infant pairs for at least two months. It found that short-course AZT for pregnant women (average 24 days) and during labour, and then short course AZT for newborn infants (average 32 days) reduced the rate of HIV transmission to 7.7% in a non-breastfeeding group. The rate was 12.4% in mothers who did not receive the full short-course treatment (Chotpitayasunondh 2002).

A study of women in the New York State area looked at data on 939 infants born to HIV-positive mothers who did not breast-feed. In this population, the transmission rate varied according to when AZT was begun. When AZT was started in the prenatal period, the transmission rate was 6%. There was a 10% transmission rate among babies born to women who began AZT during delivery. Babies first exposed to AZT during the primary 48 hours had a transmission rate of 9%, compared with 18% transmission when AZT was started on day 3 or later, and 27% transmission with no AZT at all (Wade).

Following the success of the Thai short course study noted above, researchers recruited 1,437 Thai women to a double-blind study designed to evaluate four AZT regimens in the prevention of mother to child transmission. These were a long maternal course begun at 28 weeks gestation, plus 6 weeks treatment for the infant (Long-Long, or LL); or a long maternal course plus a short course for the child of just 3 days treatment (Long-Short, or LS); a short maternal course beginning at 35 weeks, plus the long infant course (Short-Long, or SL); or a short maternal course plus a short infant course (Short-Short, or SS). Maternal AZT was dosed 300mg twice daily, and 300mg given orally, every three hours during labour. The infant dose was 2mg/kg every 6 hours. All infants were formula fed, and underwent HIV testing by DNA-PCR at day 1, 45, 60 and 180 days of life. Treatment was described as well-tolerated, and compliance to both treatment and formula as good.

An interim analysis found an increased risk of transmission in the SS group (10.5%) compared with the LL group (4.1%), resulting in the discontinuation of the SS arm. After 180 days of life, transmission rates were 6.5% in LL, 4.7% in LS, and 8.6% in SL. This means that the LS and the SL were established as statistically equivalent with the LL. When data were pooled for a secondary analysis, short maternal treatment was associated with a higher infection rate at birth (transmission rate 5.1% short maternal, 1.6% long). Therefore, while the six week infant course may add no benefit to a three day course where mothers begin treatment at 28 weeks, it may be useful where women receive a shorter treatment course.

The study group noted that transmission rates in the LL group was similar to that observed in ACTG 076, where AZT treatment begun at 14 weeks gestation plus six weeks therapy for the infant was associated with a transmission rate of 8.3%. They suggest, therefore, that maternal treatment begun before 28 weeks may not provide additional benefit (Lallemant).
Short course AZT has not been associated with the development of clinically significant resistance (Ekpini 2002).

Short course AZT in breastfeeding women
Two large trials investigating the use of short treatment courses with AZT in African women have reported results. Both involved women who breastfed their children. In the Ditrame Project (ANRS 049a) conducted in West Africa, women received AZT from weeks 36-38 of pregnancy until delivery, plus AZT during labour, plus AZT for 8 days after delivery (with no treatment to the infant); or an AZT placebo (until the Thai short course study was reported, when the placebo comparison was disbanded).

The initial analysis involved 200 mother-infant pairs from the treated arm and 201 from the untreated arm. Caesarean sections were very uncommon (2.5%) but about 9 in 10 women were breastfeeding at six months after birth; and 4 in 10 at fifteen months. After fifteen months follow-up of the infant, the transmission rate amongst treated mothers was 19% compared with 28% in the untreated group; a reduction in the risk of transmission of 30%. The probability of being infected at 3, 6 and 15 months was significantly lower in the treated group (Dabis).

A study in Cote d'Ivoire, named RETRO-CI, investigated a short course of AZT given after 36 weeks pregnancy and during labour. 140 treated women were compared with 140 who received a placebo. There were no withdrawals due to side-effects, and all babies were breastfed. After three months, 26% of babies in the placebo group were identified as HIV-infected, compared to 17% in the treated group (Wiktor 1999).

A pooled 24-month analysis of these two studies has now been presented. Women in Ditrame received AZT for a median of 28 days, and 26 in RETRO-CI. Among 662 live-born children, 21 had no HIV test. Breastfeeding continued for a median of 13.8 months. The transmission rate at six weeks was 23.6% in the placebo group and 14.0% in the AZT-exposed children. By 24 months, rates were 30.2% and 22.5% respectively. The risk of transmission was therefore 26% lower in AZT-exposed children. Transmission rates during the postnatal period, defined as the period following the first 30 days of life, were similar across arms, however; 9.0% AZT and 8.2% placebo. This highlights the need for effective interventions which prevent transmission through breast-feeding (Leroy 2002).

Adding 3TC to AZT in women who do not breast-feed
Two non-randomized open label studies investigated the effect of the combination of AZT/3TC. In the first and larger study, ANRS 075, 445 pregnant women were all given standard course AZT starting during the second trimester (Mandelbrot). At week 32, 3TC 150 mg bid was added. During labour, women received AZT intravenously, and after childbirth, the infants were treated with AZT 2 mg/kg qid plus 3TC 2 mg/kg twice daily for 6 wks.

The combination was extremely effective with only a 1.6% rate of transmission. This compared favorably to the 076 study in which transmission occurred in 7.6% of infants, and to a historic control of AZT use in pregnancy from 1994-97 where there was a 6.8% rate of transmission.

A downside in this study was that 39% of the women developed the M184V 3TC resistance mutation — though this was only observed in those who took 3TC for more than four weeks. Resistance could be reduced by using a shorter course of 3TC

A smaller study in Thailand looked at a short course of AZT/3TC in 106 pregnant women with HIV (Chaisilwattana). Starting at week 34, women were given AZT 300 mg plus 3TC 150 mg both twice-daily and AZT 300 mg plus 3TC 150 mg both every three hoursr during labour. Newborn infants were treated with AZT 2 mg/kg qid for four weeks.

Again, the regimen was highly effective. At 18 mos, only 2.8% of the infants were HIV-infected, compared to 11.7% historical control with AZT alone.

Short course AZT/3TC in breastfeeding women
The PETRA study was designed to investigate the use of a short course of AZT and 3TC. Women from South Africa, Uganda and Tanzania were randomised into four arms:
  • AZT/3TC at 36 weeks, during delivery and in the infant for one week (A)

  • AZT/3TC during delivery and in the infant for one week (B)

  • AZT/3TC during delivery (C)

  • no treatment (this placebo arm was stopped following the results of the Thai study) (P).


1,457 women were randomised to treatment before the placebo arm was abandoned, and in total 1797 were enrolled. Average CD4 count was 450 cells/mm3. One third of deliveries were by caesarean section, and of these, one third were planned. Two thirds of women breastfed, for a median duration of 24 weeks.

However, follow-up to 24 months provides stark evidence of the potential impact of breast-feeding, and its associated HIV transmission risk. At six weeks following delivery, the proportion of infants who were either HIV-positive was 5.7% in Arm A, 8.9% in Arm B, 14.2% in Arm C and 15.3% in the placebo arm. At 18 months, rates of HIV infection were 15%, 18%, 20% and 22% respectively. Despite the early benefit of antiretroviral therapy, this benefit is dimimished over time in a breastfeeding cohort (Petra Study Team 2002). Analysing the effects of mode of delivery on transmission, caesarean section was found to reduce the risk of transmission in Arms A and B, but not in Arms C or P.

In a smaller preliminary study, 20 women were treated with AZT/3TC or 3TC alone from week 38 of pregnancy until one week after delivery. Babies were treated for one week, commencing 12 hours after birth. At the onset of labour, the mean viral load drop was 1.5 log in both treatment arms. Testing at weeks one and two did not confirm any cases of vertical transmission (Moodley).

Nevirapine during labour in breastfeeding women
Findings from two large trials involving African women have demonstrated that single-dose nevirapine (one dose taken at the onset of labour, and one dose for the child within 72 hours of birth) can reduce the rate of HIV transmission significantly. This cheap and effective way of reducing vertical transmission has made possible the widespread implementation of PMTCT programmes in resource poor countries.

In a study called HIVNET 012, women were given two doses of nevirapine, one (200mg) administered to the mother at the onset of labour and the other (2mg/kg) given to the baby at day 3. 626 woman/baby pairs were randomly assigned to either this nevirapine regimen, or an AZT regimen involving treatment of the mother during labour (600mg at onset, then 300mg every three hours), and for the infant during the first week of life (4mg/kg twice daily).

The estimated risks of transmission in the AZT and nevirapine groups were 10.4% and 8.2% at birth; 21.3% and 11.9% by age 6-8 weeks; and 25.1% and 13.1% by age 14-16 weeks, respectively. This represents a 47% reduction in the risk of transmission amongst those receiving nevirapine, compared with AZT, up to 14-16 weeks. Both regimens were generally well tolerated and adverse events were similar in each group (4.4% and 4.7% respectively for serious events) (Guay).

Further follow-up from HIVNET 012 suggests that the reduction in the risk of transmission associated with nevirapine prophylaxis persists for at least the first year of life, despite the ongoing risk posed by breastfeeding. Nevirapine was more effective in reducing transmission than AZT in women with CD4 counts below 200. At 18 months the risk of transmission rate in mothers with advanced disease was 31.6% in the nevirapine group versus 54.9% in the AZT group. Women with CD4 counts between 200-350 also showed a reduced risk of transmission in the nevirapine arm (Jackson 2003)

On the downside, the use of short course nevirapine during labour may lead to drug resistance (Eshleman 2001). In HIVNET 012, resistance was more likely in women with high viral load and low CD4 counts. Genotypic sequencing was performed prior to administration of nevirapine and at six weeks after delivery in a sub-group of women in HIVNET 012. No mutations were detected pre-therapy, but six weeks after labour, 21 of 111 women showed drug resistance. Furthermore, about half of infants infected by week 8 were infected with a nevirapine resistant strain of HIV. Women with subtype D appear to be more at risk of nevirapine resistance that women with subtype A.

It is likely that the six week follow-up could have under-estimated the number of women who developed nevirapine resistance. Over a year later, these resistance mutations had disappeared in the absence of treatment in all eleven women tested. Whilst it is possible that resistant mutants remain archived as minority sub-species too small to be picked up by resistance testing, this wild-type majority would be expected to remain sensitive to the effects of nevirapine, allowing the drug to be re-used. Researchers propose therefore that the emergence of resistance mutations is not sufficient reason to delay the implementation of this effective intervention in resource-poor settings.

This proposal is supported by the findings of another nevirapine prophylaxis study. According to the South African SAINT study, nevirapine at labour, and after childbirth for both mother and infant is as effective in reducing the rate of perinatal mother to child transmission of HIV as a seven-day course of dual therapy. SAINT enrolled over 1,300 HIV-positive pregnant women. Participants were randomised to a nevirapine arm, where treatment consisted of a single dose of the NNRTI given at the onset of labour, another dose 24 to 48 hours after delivery, plus a single dose to the newborn; or to receive a short course of dual nucleoside analogue therapy. The regimen in the dual therapy arm involved a standard dose of AZT and 3TC given at the onset of labour, and then three hourly doses until delivery. Treatment then continued for the next seven days for both mother and baby.

Results are available for just over 650 deliveries in each arm of the SAINT study. Treatment was administered less than two hours before birth in a quarter of cases in both groups. Following birth, mothers were counselled on the risks and benefits of breast-feeding and given the choice over whether to bottle or breast-feed their child. In each arm, 40% of women elected to breast-feed. Eight weeks after birth, there was no difference observed between the rate of HIV infection or death across the two treatment arms, with a rate of 12.5% in the dual therapy arm and 14.3% in the nevirapine arm (Moodley).

McIntyre presented safety data from the SAINT study. Both regimens were generally well-tolerated by both mothers and children, and there was no difference in infant mortality between arms. There was no evidence that the use of nevirapine was associated with liver toxicity, a concern levelled at manufacturers Boehringer Ingelheim by the South African government following an earlier trial (McIntyre 2000).

Short course AZT plus single-dose nevirapine
The most recent large randomised, double-blind, placebo controlled PMTCT study demonstrated that providing mothers and newborns with a single dose of nevirapine, in addition to short-course AZT treatment greatly reduces the rates of mother-to-baby transmission of HIV (Lallemant).

The study recruited 1844 HIV-positive pregnant Thai women between 2001 and 2003. In addition to standard AZT therapy, women were randomised into one of three treatment arms. In the nevirapine-nevirapine arm the mother was provided with a single dose of nevirapine during delivery and the infant with a single dose of the drug between 48 and 72 hours after birth. In the nevirapine-placebo arm the women were provided with a single dose of nevirapine during labour, but the infant received a placebo 48 to 72 hours after birth. In the placebo-placebo arm both the mother and infant were given a placebo.

Interim analysis was performed in May 2002, at which point investigators stopped recruitment to the placebo-placebo arm. Transmission rates were 1.1% in the nevirapine-nevirapine arm, 2.1% in the nevirapine-placebo arm, but 6% in the placebo-placebo arm (p < 0.001).
In the final analysis, transmission rates were 1.9% in the nevirapine-nevirapine arm and 2.8% in the nevirapine-placebo arm.

Several other studies have demonstrated the benefits of nevirapine when combined with short-course AZT. An observational study of short course AZT and nevirapine (women received AZT from 36 weeks gestation and nevirapine during labour, and the infants received a week with AZT and a since dose of nevirapine at day 3) is being conducted in Abidjan, CÙte d’Ivoire. Forty-two percent of these women opted for breast milk substitutes, 47% exclusively breastfed, and only 11% opted for mixed feeding. Data on 371 women has found a transmission rate of about 7% at 6 weeks follow-up (Dabis 2003).

The risk of drug resistance for mother
However, the development of resistance remains a concern in women exposed to short course nevirapine remains a concern. A substudy of the Thai trial found that exposure to sdNVP compromised some mother's subsequent response to antiretroviral therapy with nevirapine or the related drug efavirenz (these non-nucleoside reverse transcriptase inhibitors (NNRTIs) are largely cross resistant) especially if HAART begins within six months of birth (Jourdain).

Of the 1844 women from the original trial, a total of 269 women with a CD4 cell count below 250 cells/mm3 began a HAART regimen including nevirapine after birth. Blood samples were obtained ten days after delivery to look for resistance mutations. Viral load was measured at baseline, and then after three and six months of HAART.

A total of 221 of the women had received a single dose of nevirapine during delivery. The remaining 48 women had not.

After six months of nevirapine-based HAART, 49% of women who had received the the single dose of nevirapine during delivery had a viral load below 50 copies/ml compared to 68% of women who did not (p = 0.03). Mutations conferring resistance to NNRTIs were detected in the blood samples obtained ten days after delivery of 32 women. The most frequent mutations were K103N, G109A and Y181C. A viral load below 50 copies/ml was achieved by 38% of women with these mutations at month six, compare to 52% of women treated with nevirapine at delivery who did not develop these mutations.

A viral load above 35,000 copies/ml at baseline (p < 0.001), and exposure to nevirapine during delivery (p = 0.01) were all associated with virological failure at six months.

Another study has found that breast milk seems to be a reservoir for nevirapine-resistant virus and thus breast fed infants may be at risk of contracting a resistant strain of HIV (Lee 2003).

For women in resource-poor nations, sdNVP containing regimens have a number of advantages, including its simple administration and its relatively low cost. Whilst discrete drug costs naturally do not reflect the additional costs involved in healthcare provision, the price of a two dose nevirapine regimen has been well-publicised; 25 South African Rand (which equates to two pounds fifty in Sterling, or around four US dollars). To put this in context, 290 million Africans survive on less than one US dollar per day.

US and Zambian researchers have raised concerns about high levels of NNRTI resistance identified in women exposed to single dose nevirapine treatment. The study considered resistance mutations, the rate and persistence of resistance selection and fitness of these mutations. Plasma was collected at 0, 2, 8, 20 and 32 weeks post-partum. They found from patient sequences that 76% of women harboured NNRTI-associated mutations at any given time-point in the study. At 2 weeks 75% of available samples showed a presence of Y181C (57%), K103N (25%), V106A/M (19%) and Y188C (14%). By week 8, reversion to wild type was observed in 44% of samples, although the emergence of new mutations was reported in 7% of these samples. At week 8, the most common mutations were found to be K103N (28%) and V106A and Y181C (6% each). The authors conclude that whilst Y181C predominates in early evolution, K103N is retained as the significant mutation by week 8 (Kantor 2003).

Recent evidence has added to the concern surrounding the risk of resistance in mothers given nevirapine during labour. Highly sensitive tests that can detect very small populations of drug-resistant virus have shown that nevirapine resistance may be more common that previously thought and may persist for up to two years. In one study, 50 South African women in whom no resistance mutations were seen using standard tests were tested using the high sensitivity technique. This revealed 16 cases of the K103N mutation and five of Y181C, leading the investigators to estimate a true rate of resistance of around 65% (Johnson 2005).

A similar study examined resistance using highly sensitive tests in nine mothers and five infants from the HIVNET 012 study, showing persistence of the K103N mutation in three of the mothers' and one of the infants' samples between twelve and 24 momths after delivery (Flys 2005). Despite these findings, further research is needed to determine the impact of these low frequency mutations on the mothers' treatment outcomes.

Dual nucleos(t)ide cover for nevirapine after birth
A South African study suggests that giving zidovudine and lamivudine for four to seven days after birth to mothers who have received single dose nevirapine during labour significantly reduces the risk that they will develop resistance to nevirapine, and may preserve their future treatment options (McIntyre).

Investigators conducted a prospective trial called the Treatments Options Preservation Study (TOPS) involving 300 mother-infant pairs. The study had three treatment arms 1) sdNVP, or 2) sdNVP plus four days of Combivir (zidovudine/lamivudine combination tablet), or 3) sdNVP plus seven days of Combivir. Twice-daily Combivir was started in the mothers during labour and in their babies as soon as possible after birth.

Maternal resistance to the drugs was assessed two and six weeks after labour using genotypic resistance testing. HIV transmission from mother-to-baby was determined by using HIV DNA or RNA testing two and six weeks after birth.

Interim data are available for the first 61 mothers with six weeks of follow-up and HIV sequencing. On entry to the study the median CD4 cell count was 318 cells/mm3 and median viral load was 32,600 copies/ml. All the women were infected with HIV subtype C. HIV sequencing at weeks two and six showed that nine of the 18 women (50%) randomised to receive single dose nevirapine alone had NNRTI resistance compared to only one of the 20 (5%) women randomised to receive single dose nevirapine plus four days Combivir, and three of the 23 women (13%) treated with single dose nevirapine and seven days of Combivir.

In light of the study's preliminary findings, the sdNVP arm has been discontinued. The study will continue in order to determine which of the remaining two arms is superior. A number of other ongoing studies are also evaluating the efficacy of this approach with AZT/3TC and other antiretroviral drugs.

Other short course interventions with multiple drugs
The Ditrame Plus study team in Abidjan, Cote d’Ivoire, added nevirapine given according to the HIVNET 012 protocol to AZT+3TC treatment given to pregnant mothers from week 32 (until three days after the baby's birth) and followed by giving AZT to the baby for the first 7 days of its life. The outcome was that they achieved an HIV transmission rate below 5% after follow-up of infants to 4-6 weeks of age (Dabis 2003).

The NVAZ trial in Malawi gave 1119 infants one dose of nevirapine (2mg/kg weight) or one dose of nevirapine (2mg/kg) plus one week of treatment with zidovudine (AZT) twice daily (4mg/kg). None of the infants had received nevirapine in the 72 hours after birth, and none of the mothers had received any antiretroviral treatment. Six to eight weeks after birth infants not lost to follow-up were tested for HIV with a viral load test. This result was compared with a sample of blood taken at birth to see whether the infant had been infected during the period of treatment. 7.7% of the AZT+nevirapine group and 12.1% of the nevirapine group had become infected with HIV, showing that AZT+ nevirapine had a greater protective effect (Taha 2003).

However, these interventions do not provide protection during the breastfeeding period. This issue is covered in more detail in Breast-feeding in Anti-HIV therapy: Options during pregnancy.

Short course d4T, ddI in breastfeeding women
Results from a pilot study evaluating the safety and effectiveness of short course nucleoside analogue therapy in the prevention of mother to baby HIV transmission had suggested that regimens involving ddI and d4T merit further investigation.

HIV-positive pregnant South African women were randomised to one of four treatment arms at 34-36 weeks of pregnancy. Mothers received a short treatment course of either d4T alone, ddI alone, AZT alone, or d4T with ddI. Mothers and infants were followed for six weeks after delivery, and given formula feed to eliminate the transmission risk associated with breast-feeding. Infants received the same treatment as their mother, at standard paediatric doses for the first six weeks of life.

Data were available for 204 women, 54 of whom received ddI, 50 women being randomised to each of the other three arms. 210 infants were born to these women, and these were equally distributed across the four study arms. At entry, average maternal viral load was 4.5 log copies and average CD4 count was 399 cells. Most women delivered vaginally. 12% of deliveries were by elective caesarean section, and 20% by emergency caesarean section, rates which were described as typical for this clinic.

At six weeks after delivery the rate of HIV infections was 3.6%, and was comparable across the treatment arms. When the infants who discontinued treatment because of death, or because they were HIV infected, were included in the analysis, this rate rose to 9.0%. The study was not powered to detect differences between the four regimens, only equivalence (Gray 2000a).

In January 2001 the US FDA issued a warning regarding the use of d4T with ddI in pregnancy which has been linked to an increased risk of a condition called lactic acidosis. For further information see Combination therapy in pregnancy .

Other short course interventions with multiple drugs
The Ditrame Plus study team in Abidjan, Cote d’Ivoire, added nevirapine given according to the HIVNET 012 protocol to AZT+3TC treatment given to pregnant mothers from week 32 (until three days after the baby's birth) and followed by giving AZT to the baby for the first 7 days of its life. The outcome was that they achieved an HIV transmission rate below 5% after follow-up of infants to 4-6 weeks of age (Dabis 2003).
The NVAZ trial in Malawi gave 1119 infants one dose of nevirapine (2mg/kg weight) or one dose of nevirapine (2mg/kg) plus one week of treatment with zidovudine (AZT) twice daily (4mg/kg). None of the infants had received nevirapine in the 72 hours after birth, and none of the mothers had received any antiretroviral treatment. Six to eight weeks after birth infants not lost to follow-up were tested for HIV with a viral load test. This result was compared with a sample of blood taken at birth to see whether the infant had been infected during the period of treatment. 7.7% of the AZT+nevirapine group and 12.1% of the nevirapine group had become infected with HIV, showing that AZT+ nevirapine had a greater protective effect (Taha 2003).

However, these interventions do not provide protection during the breastfeeding period. This issue is covered in more detail in Breast-feeding in Anti-HIV therapy: Options during pregnancy.

Toxicity to infants
Short course therapy with drugs such as AZT and 3TC may have cause genetic changes called mitochondrial toxicity in infants exposed to these drugs before birth. The long-term health effects of drug exposure is unknown. See Combination therapy in pregnancy under the subheading 'NRTI toxicity - impact on infants' for details.

Current thinking is that the proven benefits in avoiding HIV infection outweigh possible rare side-effects of drug exposure.

Two short course studies have explored potential mitochondrial toxicity amongst patients. For example, a comparative study of short-course AZT among nearly 400 pregnant women in Thailand found no significant adverse events were associated with AZT exposure in utero although five children exposed to AZT developed febrile convulsions (a brief seizure relatively common in infants) compared to only one of the placebo group (Chotpitayasunondh). Neurological symptoms are a sign of mitochondrial toxicity.

Researchers from Cote d'Ivoire reported that 45% of 140 infants exposed to antiretrovirals in the Ditrame Plus study had at least one lactate measurement above 2.5mmol/l, and 14.8% had two measurements above 2.5mmol/l. Elevated lactate in the blood is a sign of mitochondrial toxicity. Objective clinical symptoms of high lactate such as weight loss were not observed, and elevated lactate resolved spontaneously in all but three cases (Ekouevi 2003).

Cost effectiveness in the developing world
Researchers from the US and Uganda assessed the cost effectiveness of the nevirapine short course regimen used in the HIVNET 012 study (see above) in a hypothetical cohort of 20,000 pregnant women in sub-Saharan Africa. The regimen cost between $5 and $55 per disability-adjusted life year (DALY). Higher cost related to a presumed seroprevalence of 3% (where the regimen was given to all pregnant women), and 4.5% (where a targeted programme provided treatment only to women who tested HIV-positive). Given that seroprevalence is assumed to be 15-30% in much of sub-Saharan Africa, the authors found the regimen to be cost effective (Marseille).

References
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Chaisilwattana P et al. Short-course therapy with zidovudine plus lamivudine for prevention of mother-to-child transmission of human immunodeficiency virus type 1 in Thailand. Clinical Infectious Diseases 35(11):1405-13. 2002.

Chotpitayasunondh T et al. Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal HIV Transmission Study Group. Pediatrics 107(1):E5, 2001.

Chotpitayasunondh T et al. Impact of short-course zidovudine regimen on transmission risk and risk factors for perinatal HIV transmission, Bangkok, Thailand. Fourteenth International AIDS Conference, Barcelona, abstract WePeB5928, 2002.

Chuachoowong R et al. Short-course antenatal zidovudine reduces both cervicovaginal human immunodeficiency virus type 1 RNA levels and risk of perinatal transmission. Journal of Infectious Diseases 181(1):99-106, 2000.

Dabis F et al. 15-month efficacy of maternal oral zidovudine to decrease vertical transmission of HIV-1 in breastfed African children. Lancet 354(9195), 1999.

Dabis F et al. A short course of zidovudine + peripartum nevirapine is highly efficacious in preventing mother-to-child transmission of HIV-1: the ANRS 1201 DITRAME-plus study, Abidjan, CÙte d’Ivoire. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 854, 2003.

Dabis F et al. Effectiveness of a short course of zidovudine + lamivudine and peripartum nevirapine to prevent HIV-1 mother to child transmission. The ANRS 1201 Ditrame Plus trial, Abidjan, Cote D'Ivoire. Antiviral Therapy 8 (1): S236, 2003.

Ekouevi DK et al. Hyperlactatemia in neonates exposed peripartum to a short course of antiretrovirals to prevent mother-to-child transmission of HIV (PMTCT): the ANRS 1209 study, Abidjan, CÙte d’Ivoire. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 218, 2003.

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