Antiretroviral therapy

Long-course zidovudine treatment

The success of the Paediatric AIDS Clinical Trials Group (PACTG) trial PACTG076 of the use of zidovudine (ZDV) in pregnancy in asymptomatic women has been a major advance in the prevention of mother-to-child transmission of HIV-1²⁵⁵. Zidovudine given orally after 14 weeks of pregnancy, intravenously during labour and for six weeks to the neonate in a non-breastfed population has been shown to reduce mother-to-child transmission of HIV-1 significantly. This has become the standard of care during pregnancy in many developed countries, with a concomitant decrease in reported transmission rates^111,113.

In this randomized placebo-controlled trial conducted in France and the USA, in a non-breastfeeding population, treatment with ZDV [100 mg 5 times daily] or placebo was started between 14-34 weeks of pregnancy [median 26 weeks]. Women also received intravenous ZDV or placebo during labour and the infants received oral ZDV [2 mg/kg 4 times daily] or placebo for six weeks. All women had CD4+ counts >200 per cubic mm, were symptom free and had not previously received ZDV. The first interim analysis on 356 mother-infant pairs demonstrated a rate of mother-to-child transmission of 25.5% in the placebo group, and 8.3% in the ZDV group. Treatment with ZDV achieved a 67.5% reduction in transmission risk. The drug was well tolerated in the short-term in the pregnant women and the neonates.

The effect of ZDV in reducing transmission appears to be partly through the reduction of maternal viral load, although transmission occurred at a wide range of viral loads in the PACTG076 study^163,256. An additional level of protection through post exposure prophylaxis in the infant is also hypothesized, as ZDV readily crosses the placenta¹¹¹.

Further evidence for a post-exposure effect comes from a retrospective New York State study of the efficacy of abbreviated zidovudine regimens. Women who received ZDV from the prenatal period had a transmission rate of 6.1%. When treatment was commenced intrapartum, transmission was 10%, when started within 48 hours of birth 9.3% and when started on day 3 or later, transmission was 18.4%²⁵⁷,²⁵⁸.

Reassurance that in-utero exposure to zidovudine does not appear to produce any unexpected long-term effects has been supported by a follow-up study among the uninfected children born to women participating in ACTG076²⁵⁹. This study reported follow-up information from 122 uninfected children in the zidovudine group and 112 uninfected children in the placebo group. Median age of the children at time of last follow-up was 4.2 years with a range of 3.2-5.6 years. No differences could be detected in any parameters of growth, cognitive and developmental function assessed by the Bailey Scales of Infant Development, immunologic function, cardiac function or ophthalmologic function. In addition there were no late deaths and no malignancies detected in this group.

The use of long-course ZDV in pregnancy is recommended as the standard of care in Europe, the USA and in some other countries, including Brazil and Thailand^{260,261,262,263,264}. The introduction of this policy has led to a dramatic reduction in the reported transmission rates in France and the USA^18,265,70. In France, a two-thirds reduction in transmission [from 14% to 5%] has been reported²⁶⁵. Transmission rates in Los Angeles have dropped from 30% to 10%, in North Carolina from 21% to 8.5%^131,266. However, the success of the intervention depends upon the access of HIV positive women to therapy. In areas where utilization of antenatal care is low, and thus access to counselling, testing and drug provision is reduced, the efficacy will be lower. This has been shown in the Bronx, New York, where only 40% of HIV-infected women were identified before birth and less than half of these received ZDV²⁶⁷.

The use of ZDV in this regimen is not directly applicable to most women in the developing world where the majority of mother-to-child transmission occurs. This is because of the high cost of the intervention (in the USA the regimen costs over US$ 1000 per mother-child pair); the logistics of monitoring of blood parameters, drug reactions; intravenous infusions during delivery and treatment to the newborn for six weeks. In addition, the intervention needs to be introduced early on in pregnancy, when most women in resource-poor settings only attend antenatal care late in pregnancy. Lack of access to counselling and testing in these settings limits the use of antiretrovirals in pregnancy. Women in developing countries have higher rates of anaemia, which may be exacerbated by antiretroviral treatment, and may differ in disease status from those in developed countries.

The PACTG076 trial was conducted in a non-breastfeeding population, and the efficacy of the regimen in a breastfeeding population needs to be determined, as any reduction in transmission prior to or during labour may be negated by an increased transmission from breast milk^264,268. The acceptability of these interventions in developing countries will require further study ^{111,252,269,270}.

Some resistant strains of virus have been reported after ZDV treatment to prevent transmission^178,179,271. Although resistance appears to be uncommon, there has been concern about the use of ZDV monotherapy in the management in any subsequent pregnancy^179,271.

The results from the PACTG076 trial and the ZDV in Pregnancy Register show as yet no evidence of teratogenicity or short-term adverse effects in the fetus or newborn. In addition follow-up to age four of uninfected children who were exposed to in-utero zidovudine has also revealed no medium term adverse effects²⁵⁹. However, longer term follow-up is still required and larger groups of children need to be followed to determine whether rare but serious adverse effects may occur^131,272,273. However, recent reports of ZDV toxicity in mice^274,275 have renewed concern about the long-term effects of the drug. A consensus panel convened by the National Institutes for Health in early 1997 advised that the evidence was not sufficient to alter the recommendations for the use of ZDV in pregnancy. Children exposed to ZDV in pregnancy should be monitored for long-term toxicity effects.

It has been suggested that ZDV use in pregnancy would be a cost effective intervention in both developed and developing countries if implementation problems can be overcome^{276,277,278,279}. The use of shorter regimens or other antiretroviral drugs provides a feasible alternative.

Short-regimen of zidovudine therapy

Shorter drug regimens in pregnancy would be more feasible in resource-poor settings. Results from some developed country studies suggest that antenatal oral ZDV alone may be as effective as antenatal, intrapartum and postpartum regimens^280,281. To date three randomized trials of short-regimen have been published from resource-poor settings.

A trial of short-regimen zidovudine treatment in Thailand has shown a significant effect in preventing transmission²⁵¹.

The Bangkok Perinatal AZT Study, was a randomized placebo-controlled trial to evaluate the safety and efficacy of a short-regimen of oral zidovudine [ZDV] administered during late pregnancy and labour to reduce the risk for perinatal HIV transmission. The regimen was 300 mg ZDV orally twice daily from 36 weeks gestation until the onset of labour and 300 mg every three hours from the onset of labour until delivery. All women were advised not to breastfeed and were provided with infant formula, and it is important to bear in mind that these results are directly applicable only to formula-fed infants²⁵¹.

Transmission in the treatment group was 9.4% [95% confidence interval, 5.2%-13.5%] and 18.9% [95% confidence interval, 13.2%-24.2%] in the placebo group, representing a 50% reduction in transmission risk [95% confidence interval, 15.4%-70.6%].

A further trial of short-regimen in over 350 women conducted in Burkina Faso and Cd'Ivoire compared placebo with oral zidovudine, started between 36 and 38 weeks gestation at 300mg twice daily, followed by a single loading dose of 600mg at the onset of labour followed by oral zidovudine 300mg twice a day to the mother continued until seven days after delivery²⁸². In this trial over 85% of infants were breastfed for longer than three months. By six months of age, HIV transmission was diagnosed in 33 children born to 180 women in the zidovudine group and 52 born to 175 women in the placebo group. The efficacy of zidovudine was thus estimated at 38% (95% confidence intervals 5% - 60%). There was no evidence of 'catch up' by the treated group during the period of breastfeeding up to 180 days. Data for children older (and breastfed for more) than six months are not yet available.

A further trial conducted in 260 women in Cd'Ivoire randomized women to receive either oral zidovudine 300mg twice a day from 36 weeks until the onset of labour or matching placebo²⁸³. At the onset of labour zidovudine 300mg was given every three hours until delivery versus placebo. In this trial population, over 95% of the infants were breastfed by their mothers and by three months of age 19 out of 115 babies in the zidovudine group were HIV infected compared with 30 out of 115 in the placebo group. This represents a relative risk of transmission of 0.63 (95% confidence intervals 0.38 - 1.06). The transmission risk at three months was similar to the transmission risk seen at four weeks also suggesting that breastfeeding had not produced a substantial narrowing of the difference between the two groups.

These results demonstrate that short-regimen of oral zidovudine appears to be safe and effective at reducing the risk of mother-to-infant HIV transmission. Of importance for many developing countries is that whether women do or do not breastfeed does not appear to make a substantial difference to the effectiveness of treatment. Other trials of reduced courses of ZDV alone are underway in Africa, and Haiti (see Table 3).

A reduction in the cost of zidovudine for developing countries has been announced by the manufacturers after negotiation with UNAIDS and in response to the results of the Thailand study²⁸⁴. This will assist in the implementation of these strategies. The World Health Organization has prepared guidelines for the use of antiretroviral drugs in developing countries²⁸⁵.

Combination therapy and other antiretroviral drugs

The UNAIDS co-ordinated PETRA trial uses a combination of ZDV and 3TC (lamivudine), and has been undertaken in predominantly breastfeeding populations in five sites in South Africa, the United Republic of Tanzania and Uganda. Long-term follow-up of the children is in progress but interim early efficacy results at six weeks of age of the infant have been reported. This trial compared the effectiveness of three different drug regimens with placebo. Arm A received zidovudine and 3TC from 36 weeks gestation, during labour and for one week postpartum to mother and child. Arm B received zidovudine and 3TC from the onset of labour and for one week postpartum to mother and child. Arm C received zidovudine and 3TC during labour only. Over 1790 women were recruited in all. The risk of transmission by six weeks of age in Arm A was 8.6%, in Arm B 10.8%, Arm C 17.7% and in the placebo group 17.2%. The study population continues to be followed up and the majority of women are breastfeeding²⁵⁴.

A recent French study, presented in abstract only, reported the use of 3TC (lamivudine) commencing at 32 weeks gestation in addition to the standard ACTG 076 zidovudine regimen²⁸⁶. Babies were treated with both drugs until six weeks of age. Two hundred women receiving this combination were compared with a cohort of 899 women receiving zidovudine alone. The rate of transmission in the combination group was 2.6% compared with 6.5% in the zidovudine group. This study was not a randomized trial and other factors may explain the decrease in transmission risk. One finding, however, was that two uninfected babies having received ZDV+ 3TC died of a neurological disorder due to a mitochondrial myopathy. This condition is rare and two neonatal deaths in 200 women suggest that 3TC or the drug combination may be responsible.

The use of non-nucleoside reverse transcriptase inhibitors (NNRTI) for the prevention of perinatal transmission is another possible approach. Nevirapine is a NNRTI with potent antiretroviral activity and a favourable safety profile but in which there is rapid development of drug resistance limiting the duration of its effect. Of particular interest is that the drug achieves high circulating levels which are long-lasting, raising the possibility of a one dose treatment in labour. Efficacy studies have commenced in South Africa and Uganda.

The use of combination antiretroviral therapy is becoming more common, with greater reductions in viral load. Recent recommendations for drug therapy for HIV advise the use of at least two agents, with the possible addition of a protease inhibitor^287,288,289 although rapid advances in the therapy of HIV infection means that such recommendations change frequently. Patients receiving this level of treatment may have undetectable viral loads. There has been little experience to date with the use of most of these drugs in pregnancy and many of the newer antiretroviral (ARV) drugs have not been fully evaluated for long-term effects on the infants. Table 4 shows the status of the USA's Food and Drug Administration (FDA) classification of the available antiretroviral drugs, while long-term animal toxicity studies and more experience in pregnant women are awaited. Phase I trials are completed or in progress for nevirapine, stavudine, didanosine, lamivudine, MKC-442 and the protease inhibitors¹¹¹. DMP-266 (Efavirenz, Sustiva) was shown to cause moderate to serious birth defects in monkeys, and may not be suitable for use in early pregnancy.

Table 4:FDA classifications of antiretroviral drugs for use in pregnancy^290,291

Classification:

A: Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later trimesters)

B: Animal reproduction studies fail to demonstrate a risk to the fetus but well controlled studies of pregnant women have not been conducted

C: Safety in human pregnancy has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus

D: Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks

X: Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit

Assuming favourable safety profiles, the use of combination therapy may be more effective in reducing mother-to-child transmission, by the greater reduction of viral load, and may be the most appropriate course in those countries where this is possible. However, cost and supply considerations will limit the availability of these drugs, and the issue of resistance development and the desirability of continuing therapy after pregnancy will have to be considered¹⁷⁹.