Cover Image
close this bookPost-Durban Update on ARVs for MTCT-prevention (UNAIDS, 2000, 8 p.)
View the document(introduction...)
View the documentShort term efficacy (6 weeks to 3 months)
View the documentLong-term efficacy (12 to 24 months)
View the documentARV and transmission through breast feeding
View the documentDrug resistance with Nevirapine
View the documentConclusion
View the documentReferences

(introduction...)

Tim Farley,a Dirk Buyse and Philippe Gaillard
Department of Reproductive Health and Research
World Health Organization, Geneva, Switzerland
and Jos Perriens
and Department of Policy, Strategy and Research, UNAIDS, Geneva, Switzerland

a Tel: +41 22 791 33 10, fax: +41 22 791 41 71, email: farleyt@who.int

At the 13th AIDS Conference in Durban new data from the following randomized clinical trials on the use of antiretrovirals (ARVs) to prevent mother to child transmission were presented:

· PETRA Trial (South Africa, Tanzania and Uganda)

· Perinatal HIV Prevention Trial (Thailand)

· ANRS/CDC pooled analysis - West Africa (Cd’Ivoire and Burkina Faso)

· SAINT Study (South Africa)

· HIVNET012 trial (Uganda)

· BMS AI455-094 (South Africa).

Observational data from the USA addressed the efficacy and safety of combination ARVs. The attached tables summarize these new results together with the previously available results.

Short term efficacy (6 weeks to 3 months)

A number of different antiretroviral (ARV) regimens have been shown to reduce the transmission of HIV from mother to child (Tables 1 and 2):

· Long course ACTG076/ANRS024 ZDV regimen starting from early pregnancy1

· Short course ARV regimens (ZDV, other ARV, combination of different ARVs), starting generally one month before delivery2-7

· Regimens starting in labour (combination ZDV+3TC or NVP regimens).8,9

Each regimen has advantages and disadvantages with respect to efficacy, potential toxicity, concerns for future treatment options, practicality and feasibility for implementation.


Table 1: Clinical Trials of Antiretroviral Regimens to Reduce Mother-to-Child Transmission Compared with Placebo

Notes

a ZDV: Zidovudine, 3TC: Lamivudine

b Original dosing regimen. Current practice is 300 mg Q12h for mother.

c Maternal antenatal and postpartum doses: ZDV 300 mg, 3TC 150 mg;

Intrapartum dose: Arm A: ZDV 300 mg, 3TC 150 mg; Arms B and C: ZDV first dose 600 mg subsequent doses 300 mg, 3TC 150 mg

Infant dose: ZDV 4 mg/kg, 3TC 2 mg/kg

References (numbers according to final reference list)

1 Connor, NEJM, 1994; 331: 1173
2 Shaffer, Lancet 1999; 353: 773-80
4 Dabis, Lancet 1999; 353: 786-92
3 Wiktor, Lancet 1999; 353: 781-5.
5 Gray, Durban LbOr5


Table 2: Equivalence Trials of Short Course Antiretroviral Regimens to Reduce Mother-to-Child Transmission

Notes

a ZDV: Zidovudine, 3TC: Lamivudine, NVP: Nevirapine, ddI: Didanosine, d4T: Stavudine

b Short-Short arm (35w mother, 3d infant) dropped at first interim analysis since transmission rate significantly worse than Long-Long arm (28w mother, 6w infant).

c Intrapartum dose: ZDV first dose 600 mg subsequent doses 300 mg, 3TC 150 mg.
Maternal postpartum dose: ZDV 300 mg, 3TC 150 mg.
Infant dose: ZDV 4 mg/kg, 3TC 2 mg/kg.

References (numbers according to final reference list)

6 Lallemant Durban LbOr3
7 Gray, Durban TuOrB355
9 Guay, Lancet 1999; 354: 795-802
8 Moodley, SAINT, Durban LbOr2

The early studies compared the efficacy of the ARV regimens against placebo (Table 1) and showed that short course regimens can reduce early transmission rates by 35% to 70% (that is, from about 25% to between 8% and 17%). The efficacy in breastfeeding populations3,4 is lower than in populations where breastfeeding can be avoided.2 The similarity of the results from the two West African studies which both started ZDV from 36 weeks suggests that the addition of the 1 week post-partum dose for the mother in DITRAME did not confer any additional benefit. In the PETRA study10 which compared combination ZDV + 3TC in three different regimens against placebo, Arm A (starting from 36 weeks) was more effective than Arm B (starting in labour), though not significantly so. Arm C (intrapartum only) showed no reduction in transmission rate compared with placebo.

More recent studies did not use a placebo control group, but studied the equivalence of different ARV regimens, most often including a short ZDV regimen (Table 2).

· The short-short arm of the PHPT study (from 35 weeks to 3 days postnatal) was significantly less effective than the long-long regimen(from 28 weeks to 6 weeks postnatal), and was dropped at the first interim analysis. At that time the transmission rates were 10.6% and 4.1%, respectively. The other three arms (long-short, short-long, long-long) showed comparable transmission rates (between 6% and 8%), except that the intrauterine transmission rate for the regimens starting at week 28 was 1.8%, significantly lower than the 5.0% observed with the short-long regimen starting from week 35. The authors concluded that while 6 weeks ZDV in infants may not add benefit when mothers had received the long antenatal treatment, it may prevent some infections when mothers receive only the shorter treatment.6

· The BMS A455-094 study presented preliminary results based on the first 204 women randomised. The preliminary results do not suggest any clear differences between the four regimens studied. The final study is anticipated to include a total of 360 women.7

· The HIVNET012 study showed that NVP was significantly more effective than an intrapartum-only ZDV regimen. This particular ZDV regimen has not been included in other studies. The study originally included a placebo arm that was dropped after results from the CDC Thailand study2 became available. The transmission rate was 37% in women assigned placebo, compared with 20% among those concurrently assigned to the ZDV arm, based on 19 and 15 women respectively (P = 0.45), suggesting that the ZDV regimen may have had some benefit.9

· The SAINT study, involving two regimens starting in labour, showed that the PETRA Arm B regimen (from onset of labour to 1 week postpartum and postnatal) was equivalent to a NVP regimen slightly different from that used in HIVNET012.8

An observational study from the USA in women receiving combination ARV treatments reported very low transmission rates - 1.1% among those receiving HAART and 3.9% among those receiving combination therapy which did not include a protease inhibitor.11

Long-term efficacy (12 to 24 months)

Three studies provided information on whether the short-term benefits of the different ARV regimens is maintained in infants exposed to HIV through breastfeeding (Table 3). The pooled analysis from the West African studies showed that the difference in transmission rates at 3 months was still present up to 24 months.12 Similarly for the HIVNET012 study up to 12 months follow-up.13 By contrast the PETRA study reported that the differences seen in HIV-free survival between study arms at 6 weeks had decreased by 18 months.5 However, it is unclear whether this diminution of the difference is due to increased HIV transmission or to non-HIV-related mortality. The PETRA Study team announced that further information on the exact timing of transmission through breastfeeding from their trial will be available in September 2000.

Table 3: Long term follow-up in breast feeding populations

Trial

Ref

Intervention

Early transmission

Late transmission




Age

Rate

Difference

Efficacya

Age

Rate (%)

Difference

Efficacya

West African pooled analysis

12

ZDV from 36 w

3m

16%

9%

35%

24m

22%

8%

28%



Placebo

3m

25%



24m

30%



HIVNET012

13

NVP

6-8 w

12%

8%

41%

12m

16%

8%

35%



ZDV Intrapartum

6-8 w

20%



12m

24%



PETRAb












Arm A

5

From 36w + 1w pp

6 w

8%

11%

57%

18m

21%

6%

21%


Arm B


In labour + 1 w pp

6 w

12%

7%

36%

18m

25%

2%

7%


Arm C


In labour only

6 w

19%

0%

2%

18m

28%

-1%

-4%


Placebo



6 w

19%



18m

27%



Note

a Prevented fraction (1 - rate in active group/rate in comparison group)
b Endpoint: HIV transmission and mortality (= 1- HIV-free survival)

References (numbers according to final reference list)

12 Wiktor, Durban TuOrB354
5 Gray, Durban LbOr5
13 Owor, Durban LbOr1

ARV and transmission through breast feeding

With all of the ARV regimens, transmission of HIV through breastfeeding remains a concern. The risk of HIV transmission through breastfeeding is in the range of 10 - 20% between birth and 18 to 24 months.14 Factors associated with increased risk in transmission through breastfeeding include mother’s viral load, low CD4 cell counts, clinically advanced HIV infection, and breast inflammatory or infectious processes. One study has suggested that exclusive breastfeeding is associated with a lower risk of HIV transmission than mixed feeding,15 though this observation has yet to be confirmed by other research.

The investigators of both the PETRA and the CDC/ANRS study highlighted the importance of identifying interventions to prevent HIV transmission through breastfeeding. Work to address the issue of transmission through breast milk is already underway. Trials that assess the use of antiretrovirals to decrease breast milk transmission are being planned in a number of countries (Botswana, Cd’Ivoire, Uganda and others). In addition methods to inactivate HIV in breast milk are being developed.16,17

Drug resistance with Nevirapine

WHO convened an expert panel in March 2000 to review the reported NVP resistance in mother infants pairs receiving NVP as part of an MTCT-prevention package.18 The impact of these new data on the efficacy of the regimen in future pregnancies, future treatment options (of both mother and newborn), the disease progression and possibility of spread of resistant virus in the population was considered. The panel concluded that the new information was not considered sufficient to interfere with plans to make NVP more widely available in pilot MTCT-prevention programmes or in research settings. But there was insufficient information to recommend wide-scale implementation of NVP for MTCT prevention.19

At the Durban conference, the previous report from HIVNET006 of NVP-resistance observed in 20% of 15 women was confirmed in HIVNET012 where 7 of 30 transmitters showed selection of resistant virus at 6 weeks. In addition 3 of 7 infected infants showed resistance mutations.20

The changing time horizon for access to ARV treatment brings a new dimension to the question of drug resistance reported in women and children exposed to Nevirapine for MTCT prevention.

Where there is a reasonable expectation that non-nucleoside reverse transcriptase inhibitors (NNRTIs) will be used as part of treatment for HIV infection in either the mother or the child, considerations about resistance suggest that the use of an MTCT-prevention regimen which does not include NVP may be preferable. However, in settings where NNRTIs are not expected to be available in the near future, the costs and operational advantages of the NVP regimen make it a very attractive option. Such issues will be discussed at a consultation to be convened by WHO in October 2000 at which all information on the efficacy and safety of different ARV regimens, and the risks of transmission through breast milk will be reviewed.

Conclusion

A range of ARV regimens are effective in reducing the MTCT of HIV. Each regimen has advantages and disadvantages with respect to efficacy, potential toxicity, concerns for future treatment options, and practicality and feasibility for implementation. Whatever ARV regimen is used, transmission of HIV through breastfeeding remains a concern.

These issues will be discussed in October 2000 at a consultation convened by WHO on behalf of the UNAIDS/UNFPA/UNICEF/WHO InterAgency Task Team on Mother to Child Transmission of HIV.

References

1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331: 1173-80.

2. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999; 353: 773-80.

3. Wiktor SZ, Ekpini E, Karon JM, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cd'Ivoire: a randomised trial. Lancet 1999; 353: 781-5.

4. Dabis F, Msellati P, Meda N, et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cd'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. Lancet 1999; 353: 786-92.

5. Gray G, for the PETRA Trial Management Committee. The Petra study: early and late efficacy of three short ZDV/3TC combination regimens to prevent mother-to-child transmission of HIV-1, Abstract LbOr5, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

6. Lallemant M, Le Coeur S, Kim S, et al. Perinatal HIV Prevention Trial (PHPT), Thailand: Simplified and shortened zidovudine prophylaxis regimens as efficacious as PACTG076, Abstract LbOr3, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

7. Gray G, McIntyre J, Jivkov B, et al. Preliminary efficacy, safety, tolerability, and pharmacokinetics of short course regimens of nucleoside analogues for the prevention of mother-to-child transmission (MTCT) of HIV, Abstract TuOrB355, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

8. Moodley D, on behalf of the SAINT Investigators Team. The SAINT trial: Nevirapine (NVP) versus zidovudine (ZVD) + lamivudine (3TC) in prevention of peripartum HIV transmission, Abstract LbOr2, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

9. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354: 795-802.

10. Gray G. Early and late efficacy of three short ZDV/3TC combination regimens to prevent mother-to-child transmisison of HIV-1, Abstract LbOr5, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

11. Blattner WA, Cooper E, Charurat M, et al. Effectivenss of potent anti-retroviral therapies on reducing perinatal transmission of HIV-1, Abstract LbOr4, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

12. Wiktor SZ, Leroy V, Ekpini ER, et al. 24-month efficacy of short-course maternal zidovudine for the prevention of mother-to-child HIV-1 transmission in a breast feeding population: A pooled analysis of two randomized clinical trials in West Africa, Abstract TuOrB354, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

13. Owor M, Deseyve M, Duefield C, et al. The one year safety and efficacy data of the HIVNET 012 trial, Abstract LbOr1, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

14. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries - Translating research into policy and practice. JAMA 2000; 283: 1175-82.

15. Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM, for the South African Vitamin A Study Group. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a prospective cohort study. Lancet 1999; 354: 471-6.

16. Jeffery B, Webber L, Mokhondo R. Determination of the effectiveness of inactivation of HIV in human breast milk by Pretoria Pasteurisation, Abstract MoPeB2201, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

17. Joergensen A. Pasteurisation of HIV contaminated breast milk, Abstract LbPp122, 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.

18. Becker-Pergola G, Guay L, Mmiro F, et al. Selection of the K103N Nevirapine resistance mutation in Ugandan women receiving NVP prophylaxis to prevent HIV-1 vertical transmission (HIVNET-006), 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Jan 30 - Feb 2, 2000.

19. World Health Organization. Use of Nevirapine to reduce mother-to-child transmission of HIV (MTCT) - WHO review of reported drug resistance. Available at: http://www.who.int/reproductive-health/publications/nevirapine/report.htm (24 March 2000).

20. Jackson JB, Mracna M, Guay L, et al. Selection of Nevirapine (NVP) resistance mutations in Ugandan women and infants receiving NVP prophylaxis to prevent HIV-1 vertical transmission (HIVNET-012), 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.