Programmes and pitfalls

The National AIDS Control Organisation's programme to prevent mother-to-child transmission of HIV fails to take into account the serious side-effects of the drugs that are under consideration.

THE National AIDS Control Organisation (NACO) has embarked on an ambitious programme aimed at controlling paediatric AIDS (Acquired Immune Deficiency Syndrome). It believes, with reason, that the incidence of human immunodeficiency virus (HIV) infection among antenatal women is more than 1 per cent in the high-prevalence States of Maharashtra, Tamil Nadu, Karnataka, Andhra Pradesh, Manipur and Nagaland. Its immediate concern, therefore, is the increasing risk of mother-to-child transmission (MTCT) in these States. In this context, the Prevention of MTCT, or PMTCT, programme assumes significance. Feasibility studies involving the use of anti-retroviral (ARV) prophylaxis and therapy are under way. The long-term objective is to scale up the programme to make it a nationwide one.

According to NACO Director J.V. Prasada Rao, the PMTCT programme's expansion to the national level is expected to be achieved, using azidothymidine (AZT) or nevirapine, by the end of 2002. For the first three years of the programme, nevirapine will be provided by the United Nations Children's Fund (UNICEF).

The first phase of the feasibility study involved a single-dose application of nevirapine. It began in October 2001 and concluded in December. Encouraged by the results, the second phase has been launched. Nevirapine is the second drug to be tested in India after AZT. In March 2001, NACO conducted feasibility studies using a short-course regimen of AZT, drawing inspiration from AZT trials conducted in the United States and Thailand. In the U.S. trials, conducted in 1993, HIV-infected women were administered AZT orally between 14 and 34 weeks of gestation. They also received AZT intravenously during labour. The drug was administered to the new-born too, for six weeks post-natally. The incidence of transmission of HIV-1 was found to be reduced by 67 per cent. This led to the recommendation of AZT under the public health policy in the U.S. The Thai study reported a 50 per cent reduction in MTCT in cases where AZT was administered to the mother at the dosage of 300 mg twice a day after 36 weeks of gestation and 300 mg every three hours during the time of delivery. This model was used in the pilot study conducted by NACO in January 2000.

The NACO studies, however, have not taken into account the side-effects of and possible resistance to the drugs under consideration. Apart from the established side-effects and the cost factor, the mothers and infants need to be monitored. How this can be worked out in the Indian situation has not been thought out. It is therefore feared that this would be another top-down programme, quite dissociated from the public health realities in India. Organisations such as the AIDS Anti-Discrimination Movement and the Joint Action Council of Kannur have argued that the question of side-effects is being sidestepped despite studies that bear testimony to the ill-effects of the drugs. The Anti-Discrimination Movement has brought out a citizens' report on anti-AIDS drugs and the threat they pose to public health. Titled "Endless and sickening therapies for AIDS", it quotes a paper from a medical journal that states that there are no published reports on the effects of anti-retroviral drugs on HIV-infected persons in India.

NACO embarked on the pilot study in 11 centres, located in the obstetrics and gynaecology departments of 11 institutions in Maharashtra, Tamil Nadu, Manipur, Karnataka and Andhra Pradesh. Its objective, a NACO report titled 'Combating HIV/AIDS in India, 2000-2001' stated, was primarily to assess the feasibility of administering AZT.

All pregnant women who attended the antenatal clinics in these institutions were offered an "HIV group education-cum-counselling" session, supported by an audio-visual session. Written informed consent was obtained from the women to take blood samples for the HIV test. Post-test counselling was provided. The pregnant women were administered AZT on the Thai model, but the infant was not given AZT. Post-delivery, a Polymerase Chain Reaction (PCR) test was done at 48 hours and at two months to determine the HIV status of the infant. The option of breast-feeding was left to the mother, after counselling her on the risks and benefits of the various infant-feeding practices.

The pilot study completed one year in March 2001 and its results are being analysed for operational feasibility, efficacy and related factors such as the acceptability of HIV testing, counselling and breast-feeding. It established that administering short-term AZT intervention was a cost-effective PMTCT strategy. It recommended that NACO expand the strategy to the level of a programme. This, the study stated, would require a massive training exercise, to cover 600 districts in a phased manner. The 11 centres should be designated centres of excellence and their technical expertise could be used for "scaling up PMTCT activities". These institutions would be the nodal training centres, it said.

The feasibility study recommended that the single-dose nevirapine regimen could be a better option to overcome the barrier of doses and durations encountered in the use of AZT. It is significant that of the 751 women who accepted AZT at the 11 institutions, only 658 were monitored.

Prasada Rao said that primary prevention was the larger objective of the PMTCT programme. The idea was to forestall an epidemic and the intervention should not be looked at only as an HIV-prevention programme, he said. An advantage of having Voluntary Counselling and Testing (VCT) centres was that many pregnant women were counselled on matters of reproductive health as well. Prasada Rao said that it was only in a prolonged regimen that drug resistance developed and side-effects emerged.

THE PMTCT programme will be expanded in three stages. In the first stage, all medical colleges in the high-prevalence States will be asked to set up VCT centres, and laboratory technicians will be trained to deal with the demands of the programme. In the second, all district hospitals will be covered, and in the third, medical colleges in the rest of the country will be brought under the programme. "If need be, district-level hospitals in the low-prevalence States will also be covered, but that will come later," Prasada Rao said. An estimated six to seven million mothers can be covered in a year under the programme. Of an estimated 25 million pregnancies a year, six to seven million culminate in delivery in government hospitals and institutions. The majority of them were poor and vulnerable and prone to HIV, Prasada Rao said. From March 2002, pregnant women will be enrolled in these medical colleges.

As breast-feeding and non-Caesarean deliveries are known causes for the transmission of viruses, finding a way out of these is not an easy option for the HIV-positive mothers-to-be. There are realistic problems associated with the health of the infant. The question that arose was whether women who tested HIV-positive would be dissuaded from breast-feeding and also advised a Caesarean delivery.

Anju Singh and Puroshothaman Mulloli of the Joint Action Council are critical of the ARV therapy recommended by NACO. Anju Singh argues that first, given the stigma attached to HIV/AIDS, a woman who does not breast-feed her infant will be noticed at once, and secondly, the infant would be deprived of immunity provided by breast milk. NACO's approach of leaving the option to the women seems unrealistic in the least. One such option, Prasada Rao said, was to give "diluted cow's milk" to the infant.

The Anti-Discrimination Movement has cautioned against the use of AZT. HIV, the group argues, developed resistance to AZT within six months of monotherapy and therefore it should not be used for a single-drug regimen. As for nevirapine, resistance developed rapidly in monotherapy. "What makes drug companies and non-governmental organisations believe that without a basic countrywide infrastructure, ARV drugs can be administered to the estimated 3.7 million patients living with HIV and AIDS?" asks the Anti-Discrimination Movement. The campaign for cheap ARV drugs has sidetracked the crucial issue of drug resistance.

Responding to the emerging evidence of severe drug toxicity, the U.S. federal health authorities issued new guidelines on February 5, 2001. The Joint Action Council spokespersons pointed out that these guidelines backtracked on the long-held policy of "hit hard and early", in recommending that treatment for HIV be delayed as long as possible for people without symptoms. The new ARV therapy guidelines have introduced an element of extraordinary complexity into the treatment regimen. These insist on a number of conditions for the administration of these drugs, which include patient involvement and close medical supervision in monitoring the effects of drugs.

SCIENTISTS in the U.S. take great care to emphasise that not enough is known about HIV/AIDS to set guidelines without qualifying these with several observations so as to introduce as much 'flexibility' as possible. They advise that each patient requires specific responses under the supervision of experts on the use of ARV drugs. The press statement issued by John G. Bartlett, chief of the division of infectious diseases at the Johns Hopkins University Medical Centre and co-chair of the panel that produced the new guidelines, said: "The updated guidelines recognise that we need to make definitive recommendations about the optimal time to start treatment. We highlight the uncertainty, allow for flexibility, encourage an individualised approach to treatment..." Clearly, these treatment regimens, Anju Singh and Mulloli posit, are based entirely on the U.S. experience. At the very least, the use of ARV drugs calls for sophisticated medical supervision as in the U.S. Countries with scarce medical facilities surely call for a different approach to HIV/AIDS care, they state.

Anju Singh and Mulloli pointed out how South Africa stopped the trial of nevirapine, manufactured by Boehringer Ingelheim, in 2000 after five deaths were reported. According to a report in British Medical Journal (April 15, 2000), about 11 per cent of the patients involved in the trial showed signs of liver toxicity. Also, allegations were levelled against the trial organisers that women involved in one trial site had not given their informed consent. The drug was being tested at 16 sites around South Africa for use in the prevention of vertical transmission of HIV. The applicant was the U.S. pharmaceutical company Triangle, which was first told to stop recruiting patients for the trial and then told to stop the trial itself.

In another case, in January 2001, U.S. federal health officials warned that healthcare workers who took nevirapine after possible occupational exposure to the AIDS virus ran the risk of potentially life-threatening side-effects. The Centre for Disease Control and Prevention (CDC) said that it found 22 reported cases of side-effects among people who took the drug fearing exposure to HIV. In one case, a healthcare worker required a liver transplant.

Nevirapine, sold as Viramune, apart from its use to prevent MTCT, is approved for use as an anti-viral drug to treat HIV-infected people. However, the CDC said that "in this setting, the risk of HIV transmission is very low and, in most cases, the risk of taking nevirapine would outweigh the risk of using it for possible prevention of HIV". It also said that the adverse reactions reported among healthcare workers "do not, in any way, apply to the use of nevirapine in other settings."

The Physicians' Desk Reference (PDR 2001) warned that patients should be informed that Viramune therapy has not been shown to reduce the risk of transmission of HIV-1. Insisting on prescribing nevirapine to babies was akin to putting the cart before the horse, it said.

Roberto Giraldo, a scientist on the South African Presidential AIDS Advisory Panel, maintains that nevirapine is a toxic compound. He is giving technical assistance to the South African government in a court trial initiated by a lawsuit brought by Treatment Action Campaign, an NGO, "for not providing nevirapine to every HIV-positive pregnant woman and babies born to HIV-positive mothers". In an October 2001 paper titled "Scientific data against the use of nevirapine in pregnant women, infants, children, and anybody else", Giraldo says that Roxane, the company that produces and commercialises Viramune, has recognised its toxicity.

On nevirapine, the PDR states (as quoted in Giraldo's paper): "At present there are no results from controlled clinical trials evaluating the effect of Viramune in combination with other anti-retroviral agents on the clinical progression of HIV-1 infection, such as the incidence of opportunistic infections or survival." On the other hand, "resistant virus emerges rapidly and uniformly when Viramune is administered as monotherapy...," it says.

What is required is complete transparency on the part of NACO and the Union Health Ministry regarding the methodology, trials and detailed results of the studies. The sections in the NACO report dealing with the study on AZT does not even use the term side-effects. Neither are the details of the nevirapine trials made available for scrutiny by public health persons. The constituency that NACO will be dealing with is not an informed, literate and empowered one: accountability to this section should not be a casualty of the zeal to push anti-retrovirals as life-saving drugs.