The Practicalities of Using Nevirapine for PMTCT in Under-Resourced Settings ppt

Prepared for the Eastern Cape Department of Health by a research consortium comprising the Social Aspects of HIV/AIDS and Health Research Programme of the Human Sciences Research Council

Prepared for the Eastern Cape Department of Health by a research consortium comprising the Social Aspects of HIV/AIDS and Health Research Programme of the Human Sciences Research Council, and the University of Limpopo, Medunsa Campus

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ISBN 0-7969-2125-3

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List of tables and figures iv

3 The aim of this intervention study 7

4 Rationale for designing the Nevirapine Unit Dose Pack 8

5 Nevirapine dosing per National Protocol 9

6 Preparation and distribution of mother and child Nevirapine Pack 10

7 Healthcare worker training 11

8 The role of the pharmacist 12

9 Results: healthcare workers' experiences and perceptions about the Nevirapine pack 13

Figure 6.1: NVP pack label 10

LIST OF TABLES AND FIGURES

South Africa’s response to HIV and AIDS has evolved significantly over the last five years

This has culminated in the implementation of programmes such as the Prevention of

Mother-to-Child Transmission (PMTCT) that mitigate the impact of HIV to women and

their children As a result, this has led to much excitement, innovation, achievements,

opportunities and challenges for the Department of Health

First, I would like to extend words of appreciation to the Human Sciences Research

Council and the University of Limpopo (Medunsa campus) for the commitment and

assistance in implementing the PMTCT programme in the Flagstaff (Qaukeni) area, and

also acknowledge the efforts of the staff working in the rural health facilities in the same

area

Words of gratitude are also due to Dr Olive Shisana, Dr Henry Fomundam, Dr Thabang

Mosala and Prof Karl Peltzer for leading this effort in assisting and supporting the rural

women in Flagstaff to access single-dose Nevirapine for PMTCT

I trust that the lessons learned from this study will be shared nationally and

internationally by all concerned, and will improve services for HIV-infected pregnant

women in rural and under-resourced communities

Ms Nomalanga Makwedini

Director HIV/AIDS & STIs

Eastern Cape Department of Health

FOREWORD

©HSRC 2005

The research consortium would like to thank the Ford Foundation for financial assistance and the healthcare workers (HCW) for making sure that this pilot project was successful Our special gratitude goes to the Department of Health in the Eastern Cape for providing the infrastructure: facilities, provision of Nevirapine, as well as the distribution and stock control of the Nevirapine pack

ACKNOWLEDGEMENTS

AIDS Acquired Immunodeficiency Syndrome

ANC Antenatal clinics

ARV Antiretrovirals

AZT/ZDV Zidovudine

FDA Food and Drug Administration

HCW Healthcare workers

HIVNET 012 HIV Network Prevention Study 012

HSRC Human Sciences Research Council

HST Health Systems Trust

MCC Medicines Control Council

MTCT Mother-to-Child Transmission

NIH National Institutes of Health

NNRTI Non-nucleoside reverse transcriptase inhibitor

PACTG Paediatric AIDS Clinical Trials Group

PMTCT Prevention of Mother-to-Child Transmission

SAINT South African Intra-partum Nevirapine Trial

TAC Treatment Action Campaign

TBA Traditional birth attendant

ABBREVIATIONS AND ACRONYMS

1 Background

In 2001, the South African government developed a Nevirapine (NVP) protocol to be

implemented in 18 selected pilot sites (two per province), for the Prevention of

Mother-To-Child Transmission of HIV (PMTCT) programme The Medicines Control Council

(MCC) had approved NVP for the reduction of vertical transmission of HIV from mother

to child Zidovudine (AZT) protocol at that time had been approved by the Food and

Drug Administration (FDA) and was being used by several developed countries This

proved to be challenging, particularly for developing countries, because of the duration

of treatment and infusion of the injectable form of AZT during labour and delivery In the

Eastern Cape Province, two clinics were selected: the urban Cecilia Makiwane and the

rural Umzimkhulu Clinics, as pilot sites to implement the PMTCT programme following

the NVP protocol

In the landmark case between the South African National Department of Health and the

Treatment Action Campaign (TAC), the court ruled that the government should provide

Nevirapine to HIV-positive pregnant mothers beyond the pilot sites The South African

Cabinet then decided to extend the programme, to prevent transmission of HIV from

mother to child in all health facilities that had an appropriate infrastructure The treatment

was provided to all who needed it beyond the current experimental (pilot) sites It

was therefore crucial for the Human Sciences Research Council (HSRC) to study the

obstacles to effective implementation of this intervention and suggest ways of removing

these barriers The HSRC has been conducting research in the area of PMTCT in three

provinces: Western Cape, Eastern Cape and Gauteng The research began in January 2000,

and some of its findings have been used to amend or modify the PMTCT approach in

several clinical settings

In the Eastern Cape the study was conducted in region E, Qaukeni District The

communities in region E are rated among the most economically disadvantaged, with

relatively poor access to services and less than 50 per cent having access to basic water

supply and sanitation Many derive their household income from the migrant labour

and pension grant systems, and there is a high rate of unemployment (48.5 per cent)

The predominant housing type is a traditional mud-and-stick hut, with people living in

dispersed homesteads It has a population density of 39 persons per square kilometre,

far below that of Gauteng (385 per square kilometre) and KwaZulu-Natal (100 per square

kilometre) The poverty rate (percentage of population in poverty) is 63.3 per cent, the

second highest in the country The Human Development Index for the Eastern Cape

was 0.51 in 1999 This is far lower than the rest of South Africa, with the exception of

the Limpopo Province (Mahlalela, Rohde, Meidany, Hutchinson & Bennett 2001:3–5; RSA

National Treasury 2001:2–3) In the study area, two hospitals, Holy Cross and St Elizabeth,

render maternal health services They have five fixed clinics and a few mobile points

1.1 HIV prevalence in the Eastern Cape Province

Data from the annual antenatal survey conducted by the Health Department, show high

levels of infection among pregnant women attending antenatal clinics (ANC) in the

Eastern Cape, and especially in region E where this study was being conducted

The overall HIV prevalence among antenatal care attendees for the Eastern Cape, had

risen from 21.5 per cent in 1998 to 22.0 per cent in 1999 and 24.0 per cent in 2000 to

The Practicalities of Using Nevirapine for PMTCT in Under-resourced Settings

2

©HSRC 2005

27.1 per cent in 2003 (Department of Health 2004) These figures are important for this study since they provide an indication of the number of women who need PMTCT services Region E has the highest levels of infection in the Eastern Cape, and the prevalence of HIV infection is increasing by more than one per cent annually

In an HSRC baseline study in the Qaukeni district, data was collected on 1 534 pregnant women recruited at initial ANC visits in five PMTCT clinics (n=936), and 598 women from the community around the five clinics prior to ANC in the Flagstaff region (Peltzer et al., 2004) The study found the following:

1) Access to healthcare for pregnant women in most healthcare facilities was restricted

by distance Only one in ten women was able to access hospital services within 30 minutes from where they lived Clinics were slightly more accessible than hospitals More than one in five women were able to access clinics services within 30 minutes from their homes However, two-thirds of the pregnant women took more than one hour to get to the nearest hospital, and almost one-third spent more than an hour getting to the nearest clinic (see Table 1.1)

2) Further evidence of lack of access to health services was that 42 per cent of those women who had delivered before (n=995) delivered at home (see Table 1.2), and that one in four women delivered at home without the services of a healthcare provider or a traditional birth attendant (TBA)

Table 1.1: Access to healthcare facility for pregnant women in the Flagstaff district, Eastern Cape

Time spent to get to nearest hospital Number of pregnant women Percentage

Time spent to get to nearest clinic

Table 1.2: Place where pregnant mothers delivered their last baby in the Flagstaff district, Eastern

It was thus very obvious that women who delivered at home could not benefit from the

full administration of NVP to the pregnant woman in labour and the newborn infant

The HSRC study identified gaps, which included the major obstacle of dispensing and

administering NVP, particularly to newborns in rural settings The HSRC research team

designed an intervention measure (the Nevirapine pack) to improve NVP dispensing

and administration within the required timeframe, thereby complying with the stipulated

national protocol

Background

of anti-retrovirals (ARVs) are increasingly being used The finding that NVP reduced mother-to-child transmission (MTCT) of HIV by about 50 per cent in resource-constrained settings, at the cost of one pill to the mother and one dose of NVP syrup to the infant, was potentially one of the most hopeful discoveries in children and HIV research in the last decade (Nielson, 2004). HIV can be transmitted from the infected mother to her child during pregnancy, labour and delivery, or through breastfeeding In the absence of breastfeeding, most infections occur during labour and delivery It has been reported that transmission rates ranged from 13 to 32 per cent in industrialised countries and from 25

to 48 per cent in developing countries (World Health Organisation, 2001) Recent reports from the Centre for Disease Control however, show rates to be as low as three per cent

in industrialised countries

The use of antiretroviral drugs during pregnancy and delivery has been shown to be effective in reducing the transmission of HIV from mothers to infants These regimens reduce the risk of MTCT by decreasing viral replication in the mother and through prophylaxis of the infant during and after exposure to the virus Remarkable reductions

in paediatric HIV infection rates have been observed in industrialised countries since

1994, when the Paediatric AIDS Clinical Trials Group (PACTG) Protocol 076 showed that administration of Zidovudine to women from the 14th week of pregnancy and during labour, and to the newborn, decreased the risk of MTCT by nearly 70 per cent, in the absence of breastfeeding Other clinical trials have shown that short-course antiretroviral regimens using either the combination Zidovudine and Lamivudine, or Nevirapine alone, also substantially decreased the risk of HIV transmission

After the results of the HIV Network Prevention Study 012 (HIVNET 012), carried out in Uganda, had shown a 47 per cent decrease in MTCT, using only one dose of 200mg NVP

to the mother during labour and a 2mg per kg dose to the baby within 72 hours of birth, NVP was acclaimed as the most cost-effective PMTCT intervention in developing countries

or in resource-limited areas

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds directly

to HIV-1 reverse transcriptase, slowing the rate of viral DNA synthesis and thereby inhibiting viral replication Nevirapine is rapidly absorbed when given orally to adults, and has a long elimination half-life (t1/2) of approximately 40 hours Nevirapine crosses the placenta efficiently after a single oral 200 mg dose to the mother at the onset of labour In infants, median (t1/2) ranges from 45 to 72 hours for elimination of the maternal Nevirapine, and from 37 to 46 hours for the elimination of a single 2mg per kg neonatal dose

There has however been a lot of scientific debate on the role of NVP prophylaxis, its efficacy, its safety and most importantly, on the issue of resistance Concerns have been expressed that there may be a risk of selecting HIV-1 strains that are resistant to NVP in infected mothers or infants who have received one or two doses of the drug

Research questions regarding the interface of prevention of peri-natal HIV transmission,

antiretroviral drug resistance, and antiretroviral treatment differ between resource-rich

and resource-limited settings In resource-rich settings, a critical question is whether

antiretroviral resistance among treatment-experienced pregnant women and increasing

rates of resistance among antiretroviral-naive pregnant women, will result in higher rates

of peri-natal transmission, reversing the currently successful peri-natal HIV prevention

efforts In resource-limited settings, where antiretroviral therapy may become more

available in the near future, critical questions revolve around whether widespread use of

antiretrovirals such as NVP, ZDV, and Lamivudine (3TC) for PMTCT will lead to increased

risk of treatment failure among women and infants who become infected despite

prophylaxis, both of whom may later require antiretroviral drugs for their own healthcare

The lack of data to address these questions has contributed to increased tension between

treatment and peri-natal prevention advocates (Fowler et al., 2003)

2.1 NVP registration and use for PMTCT in South Africa

The MCC is a statutory body that was established in terms of the Medicines and Related

Substances Control Act 101 of 1965, to oversee the regulation of medicines in South

Africa The MCC was appointed by the Minister of Health and its main purpose is to

safeguard and protect the public through ensuring that all medicines that are sold and

used in South Africa are safe, therapeutically effective and consistently meet acceptable

standards of quality

In April 2001, the MCC gave conditional approval status to the use of NVP as

monotherapy for the reduction of MTCT of HIV The conditional status made it incumbent

upon Boeringer-Ingelheim, the manufacturer of the product (the applicant), to monitor

and report on safety, resistance and efficacy Nevirapine monotherapy was subsequently

launched in 18 pilot sites in the country, two per province (one rural and one urban)

In a case that was brought by the TAC against the government in April 2002 however,

the Pretoria High Court ordered that the use of NVP monotherapy was to be expanded

beyond the 18 pilot sites and be made available countrywide A clinical trial to determine

the efficacy of oral AZT and oral NVP for prevention of vertical transmission of HIV-1

infection in pregnant Ugandan women and their neonates (HIVNET 012), was sponsored

by NIH and conducted by investigators from Johns Hopkins University in the USA and

Makerere University in Uganda The results provided the basis for MCC’s approval of

NVP for that indication Prior to this study, the FDA and the MCC had already approved

the use of NVP in combination with other ARVs for the treatment of HIV infection in

adults and children The study was started in 1997 and completed in 1999, with the

results, published in Lancet, concluding that NVP significantly reduced the risk of HIV

transmission from mother to child Following the use of NVP in South Africa, there were

concerns, discussions and debates by the MCC and scientists on the degree of its efficacy

and the clinical significance of resistance This debate was aggravated by the withdrawal

(by the applicant) of a NVP application to the FDA in March 2002, due to non-conformity

with FDA regulatory requirements in the collection of primary data during the conduct

of the study The MCC engaged the applicant and national and international scientists on

the issue of efficacy and resistance in particular, for over a year In July 2004 the MCC

concluded that ’the risk-benefit profile of NVP monotherapy has changed and therefore

no longer recommends its use for prevention of MTCT of HIV’ It was further stated that

’council decision applies to all monotherapy interventions when used to reduce the risk

of transmission of HIV from mother to child during labour Council is of the view that

combination therapy should be considered for this indication’