1. Background: Knowledge and issues regarding MTCT of HIV

Knowledge and issues are presented throughout the different important phases that constitute the full intervention packages for PMTCT. Three core phases (figure 1) of prevention are identified.

Figure 1 - Five phases of PMTCT

Phase 1: INFORMATION: inform all pregnant women during ANC of their HIV status, in the context of a reproductive health counselling, including appropriate infant feeding recommendations

Phase 2: PROPHYLACTIC TREATMENT: treatment of HIV+ pregnant women with a regimen of anti-retrovirals (ARV)

Phase 3: INFANT FEEDING: support the woman-infant couple in conducting an appropriate method of feeding

In addition, two other phases are critical to the prevention of Mother To Child Transmission and are considered:

Phase alpha: PREVENT: reduce the number of HIV infected children through primary prevention of HIV and family planning education

Phase omega: SUPPORT: support of the HIV-infected mother, her child, and their family

For each of these phases, we first consider the current knowledge, and then identify key issues for implementation. Crosscutting issues for large-scale implementation are presented within the conclusion.

1.1 Transmission timing and mode

What we know:

· Considering 100 children born to mothers who are HIV+ (figure 2), the number of children infected by HIV will be about 30: 5 in pregnancy, 15 during labour and 10 during breast-feeding, in a context of two years of breast-feeding

Figure 2 - Mother-Infant HIV Transmission in Hypothetical Cohort of 100 Children of HIV+ Mothers

The proportion of children (figure 3) infected with HIV antenatally from HIV positive mothers, is nearly five percent. The majority of vertical transmission occurs during time of labour and delivery.

Figure 3 - Proportion of children who are exposed and infected with HIV

Breastfeeding (figure 4) is responsible for about 10% of children born to HIV+ mothers becoming infected. The risk of HIV transmission is linked to the duration of breastfeeding. About half of the breastfeeding transmission occurs after 6 months (Leroy, Miotti).

Figure 4 - Risk of HIV transmission duration of breastfeeding (Miotti et al., 1999)

Phase 1: Informing pregnant women

What we know:

· There is no need to establish laboratories when using HIV rapid tests. Rapid testing can be conducted at the PHC level, with validity equivalent to other methods and a cost of about US$2 per woman tested.

· In low prevalence areas, cost of testing can be reduced by up to 80% when using sera pooling as shown effective in Zaire (Perriens, Behets)

· Evidence from Zambia and Uganda suggests that women and couples that were tested and counseled for HIV (VCCT) actually modified their behaviors by using condoms in a larger extent and reducing their number of partners (Campbell et al, 1997, Downing et al 1998)

· Same day results are well received by users (Zambia and Uganda), reducing the number of necessary contacts with the pregnant women and subsequent administrative hurdles

· Counseling on infant feeding should start during the antenatal period

· When adequately informed, most women accept testing for HIV

Issues:

1. Although no laboratory is necessary, initial training and quality assurance need also to be ensured for rapid tests

2. Testing may put a woman at serious harm due to rendering cultural circumstances. Although this seems to be highly variable between settings; cases of violence have been mostly publicized in South Africa.

3. Technology for sera pooling and rapid testing in low prevalence areas needs to be developed

4. The need for and relevance of extensive counseling to HIV negative women is questionable. An alternative strategy to counseling emerges as “information for all” (group pre-test) and follow-up individual counseling for HIV+ mothers only

5. The benefits of VCCT for pregnant women beyond MTCT are uncertain. Evidence from Uganda and Zambia show some behavioral changes (use of condoms) following the voluntary testing. Yet, the extent of how VCCT contributes to primary prevention is still unknown although the increased knowledge of HIV status in communities is unlikely to be without consequences. Is VCCT an empowering strategy likely to improve the capacity of a community’s response to HIV?

6. Questioned in high prevalence areas is the necessity to test women for HIV when the test costs roughly the same price as the treatment

7. Should countries with high prevalence have a phased approach in which ARV is offered everywhere while VCCT is offered only in selected sites?

Phase 2: Prophylactic Treatment of HIV+ pregnant women

What we know:

· Anti-retrovirals work mainly through two mechanisms: i) reducing the viral load in the mother (a lesser quantity of virus goes to the infant) ii) preventing the virus from “fixating” itself in the child (“post-exposure prophylaxis”)

Figure 5 - Comparison of ACTG 076 and Short-Course Antenatal ARV Study Results

· Consequently, anti-retrovirals reduce transmission when started before and during delivery (Figure 5) but also within 48 hours after delivery (avoiding “fixation” through post-exposure prophylaxis) (Wade)

Figure 6 - Transmission Rate by Timing of Starting ZDV, NY State, 1995-97 (Source: Wade et al., NEJM 1998)

· Affordable short regimens of anti-retrovirals in the antenatal period, during delivery, and in association with replacement feeding, can reduce transmission to about 9-10% overall (Shaeffer)

· Risk reduction through anti-retroviral therapy (figure 6) given in the antenatal period and during delivery persists through the breastfeeding period. The short regimen AZT appears to prevent 10 infections in 100 women treated. The difference persists despite ongoing transmission through breastfeeding (Dabis 1999, Wiktor, Jackson)

· Continuing ARV in breast-fed (figure 7) children is a promising new intervention likely to be effective in avoiding the transmission of HIV through breast-milk and which urgently needs further study

· A regimen linking anti-retrovirals (Nevirapine) and breastfeeding is to be tested in the next few months

· Combining different strategies (reducing viral load, post-exposure prophylaxis) are likely to be additive since they act on different mechanisms

· Anti-retrovirals are generally safe, although some serious side effects (mitochondrial disease) have been observed in a few cases

Figure 7 - % of breast-fed children infected by HIV (Dabis et al., 1999)

· Resistance can appear after a few weeks (Nevirapine) or months (AZT) of treatment. Short regimens do not lead to resistance

· ARV can be low cost. While AZT costs US $50 per regimen, Nevirapine US $1 to 3 per regimen. PMTCT is at the level of cost-effectiveness and affordability of EPI even in low HIV prevalence areas such as Thailand and Malaysia. (Prescott, Thaineua, Marseille)

· The cost of Nevirapine is roughly about the same cost of a HIV rapid test

Figure 8 - Efficacy of Nevirapine on HIV transmission among breast-fed infants (Guay, 1999)

Issues:

1. Introduction of anti-retrovirals on a large scale is possible and should not be conditional to availability, affordability or acceptability of replacement feeding

2. Benefits of VCCT/ARV should be balanced with potential harm due to discrimination

3. Benefits linked to implementing the anti-retroviral component before establishing the VCCT capacity are to be weighed against the benefits of VCCT: Should we give Nevirapine to all women in high prevalence areas?

4. Rapid production of health outcomes versus women’s rights to know about their status - Is VCCT an empowering strategy to better respond to HIV?

5. The possibility that future ARV regimens for women and breastfed infants will be as effective as existing ARV regimens in combination with replacement feeding

Phase 3: Infant Feeding

What we know:

· There exists a large probability for a reduction (nearly 50%) in HIV transmission if breastfeeding were stopped at 6 months, but there is still much that remains unknown. (Leroy, Miotti)

Figure 9 - Feeding modes and HIV Transmission (Coutsoudis, 1999)

· Mixed-fed children are more likely to acquire HIV than exclusively breastfed children. These findings are consistent with the existing knowledge on the impact of exclusive breastfeeding on protection of the intestinal mucosa and non-transmission of HIV through intact physiological barriers. (Coutsoudis et al, 1999) (Victora et al, 1987)

· With appropriate communication strategies, it is possible to convince mothers to exclusively breastfeed. (BFHI)

· Early replacement feeding has constraints linked to cultural breastfeeding habits and stigma associated with not breastfeeding

· In Kenya, children of HIV+ mothers, who are replacement fed, are less likely to acquire HIV than breast-fed children, but die in large numbers in the first 6 months of life. Mortality at age 2 was found to be similarly high in both groups (220 per thousand in urban areas compared to the overall U5 mortality rate in Kenya of 70 per thousand) although the families had access to water, mothers had at least 8 years of education, and children received adequate medical care (an exceptionally favorable situation). (Nduati)

Figure 10 - Randomized Trial of Formula vs. Breast Feeding, Kenya

	Formula Breast
	(n=162)	(n=171)
Compliance	70%	96%
HIV Transmission (2 yrs)	19.1%	35.7%
Mortality (2 yrs)	20%	24.4%

U5MR Kenya: 70 per thousand

Urban setting, access to water, clinical trial, 8 years of primary education

Source: R. Nduati, unpublished data

Issues:

1. Replacement feeding is likely to contribute to increased mortality in families affected by AIDS in areas with poor access to water and low level education of mothers, wiping out the benefit of decreased HIV transmission. Should it therefore be offered as a “choice” in those areas? Are the poor, HIV+ mothers likely to introduce replacement feeding and conduct mixed feeding in the perceived best interest of the child?

2. In development are strategies that discourage mixed feeding with appropriate cultural and socio-economic context for a given area. These options may include in the future, replacement feeding, or exclusive breast-feeding, and ARV until 4-6 months with early cessation of breastfeeding.

3. Exclusive breastfeeding and ARV given to pregnant women and breastfed infants in association with early weaning may have a higher impact and be more cost-effective in reducing U5 mortality rates in developing countries than ARV and replacement feeding.

Phase alpha: Reduction of the number of HIV+ women

What we know:

· Promotion of condoms is effective when targeted to high risk situations and when effectively implemented on a large scale (commercial sex in Thailand)

· Life skills are capacity building strategies for future generations to better respond to the HIV crisis

· Mobilization of communities and sectors is possible

· Treatment of STIs contributes to reducing HIV incidence (Grosskurth)

· Family planning can be successfully integrated into existing PHC services

Issues:

1. How to mainstream “life skills” training and reach coverage

2. How to reinforce PHC services and systems to integrate quality family planning and STI treatments

3. How to approach condom promotion and family planning activities in UNICEF supported programs

Phase omega: Support to HIV+ women, their children and their families

What we know:

· Children born in families affected by HIV have a higher U5 mortality than the average as a result of increased mortality from HIV and other causes

· The above Kenya study suggests that the cost-effectiveness of PMTCT might be lower than anticipated according to efficacy studies illustrating children saved from HIV may die from other causes

· HIV affected families suffer economically and need financial support

· The presence and adequate care from mothers are the keys to child survival

· Treatment and OI prophylaxis improve the well being of mothers

· Cost of care for HIV+ children places a burden on families in low-income countries

· In developing countries, 70% of HIV-infected children survive to age 2 (Cote D’Ivoire) compared with 50% that are still alive at age 9 in developed countries (Europe)

Issues:

1. PCP prophylaxis given to all children of infected mothers in their first months and to HIV+ children after birth will prove to be cost-effective

2. The care-support-protection package will be further developed ensuring appropriate care to HIV-infected children and preventing premature death from other causes to children of HIV+ mothers

3. What other interventions should be included in the “minimum package” to be offered to HIV+ mothers: weaning food supplements, vitamin A, PCP prophylaxis, TB diagnosis and care? What are the indicators to be taken into account to define this package (HIV and TB prevalence, vitamin A deficiency)?