CHAPTER 8

Let us now return to the matter of MTCT and nevirapine.

Roxane is a pharmaceutical company that produces nevirapine, selling it under the brand name Viramune. This company published the following warning (in capital letters) in the Physicians' Desk Reference (PDR 2001), considered the best available source of information on the safety of medications for humans:

"WARNING: SEVERE LIFE-THREATENING SKIN REACTIONS, INCLUDING FATAL CASES HAVE OCCURRED IN PATIENTS TREATED WITH VIRAMUNE. THESE HAVE INCLUDED CASES OF STEVEN-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, AND HYPERSENSITIVE REACTIONS CHARACTERISED BY RASH, CONSTITUTIONAL FINDINGS, AND ORGAN DYSFUNCTION. PATIENTS DEVELOPING SIGNS OR SYMPTOMS OF SEVERE SKIN REACTIONS OR HYPERSENSITIVITY REACTIONS MUST DISCONTINUE VIRAMUNE AS SOON AS POSSIBLE. SEVERE AND LIFE-THREATENING HEPATOTOXICITY, INCLUDING FATAL HEPATIC NECROSIS, HAS OCCURRED IN PATIENTS TREATED WITH VIRAMUNE. RESISTANT VIRUS EMERGES RAPIDLY AND UNIFORMLY WHEN VIRAMUNE IS ADMINISTERED AS MONOTHERAPY, THEREFORE, VIRAMUNE SHOULD ALWAYS BE ADMINISTERED IN COMBINATION WITH ANTIRETROVIRAL AGENTS."

PDR 2001 also says:

" Patients should be informed that Viramune therapy has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.Viramune is not a cure for HIV-infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections."

It also says that:

" Evaluation of the pharmacokinetics of nevirapine in neonates is ongoing" and " the safety profile of Viramune in neonates has not been established." (Our emphasis).

PDR 2001 further says:

" Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis (transaminases elevations, with or without hyperbilirubinemia, prolonged partial thromboplatin time, or eosinophilia), has occurred in patients treated with Viramune."

The most recent guidelines of the US government on HIV treatment were issued on February 5, 2001. With regard to HIV-infected pregnant women, the Guidelines say:

" Guidelines for optimal antiretroviral therapy and for initiation of therapy in pregnant HIV-infected women should be the same as those delineated for non-pregnant adults. Thus, the woman's clinical, virologic and immunologic status should be of primary importance in guiding treatment decisions. However, it must be realised that the potential impact of such therapy on the fetus and infant is unknown.Long-term follow-up is recommended for all infants born to women who have received antiretroviral drugs during pregnancy.(Our emphasis).

" There are currently minimal data available on the pharmacokinetics and safety of antiretroviral agents during pregnancy for drugs other than ZDV (AZT).There are insufficient data available at present to justify the substitution of any antiretroviral agent other than ZDV for the purpose of reducing perinatal HIV transmission; further research will address this question.
" It is important to recognise that the predictive value of in vitro and animal screening tests for adverse in humans is unknown."

In the Summary to the Guidelines, the point is made that:

" Patient education and involvement in therapeutic decisions is important for all medical conditions, but is considered especially critical for HIV infection and its treatment." (Our emphasis.)

(NB: these observations are reiterated in the updated Guidelines published in February 2002.)

We emphasise the observation underlined in the last but one paragraph above to draw attention to the fact that the US scientists who drew up the Guidelines sought to highlight the point that the treatment of HIV should not be approached in a routine manner, however experienced, in general, the medical personnel that is then called upon to deal with this condition.

As we have also pointed out, the Guidelines also say that HIV-positive pregnant women should also be handled and prepared in the same way as any other adult with regard to treatment. We will therefore quote at some length what the Guidelines say on this matter.

" Care should be supervised by an expert.Before initiating therapy in any patient, however, the following evaluation should be performed:

· Complete history and physical (AII)
· Complete blood count, chemistry profile (including serum transaminases and lipid profile (AII)
· CD4+ T lymphocyte count (AI)
· Plasma HIV RNA Measurement (AI)

" Additional evaluation should include routine tests pertinent to the prevention of OIs, if not already performed (RPR or VDRL, tuberculin skin test, toxoplasma IgG serology, and gynecologic exam with Pap smear), and other tests as clinically indicated (e.g., chest X-ray, hepatitis C virus (HCV) serology, ophthalmic exam) (AII). Hepatitis B virus (HBV) serology is indicated in a patient who is a candidate for hepatitis B vaccine or has abnormal liver function tests (AII), and CMV serology may be useful in certain individuals, as discussed in the "USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with the Human Immunodeficiency Virus" (2) (BIII).

" It is necessary for the patient to be entered into a continuum of medical care and services, including social, psychosocial, and nutritional services, with the availability of expert referral and consultation. In order to achieve the maximal flexibility in tailoring therapy to each patient over the duration of his or her infection, it is imperative that drug formularies allow for all FDA-approved NRTI, NNRTI, and PI as treatment options."

(NB: In the immediate preceding paragraphs, 'A' stands for "Strong, should always be offered"; 'B', for "Moderate, should usually be offered. 'I' stands for "At least one randomised trial with clinical endpoints; 'II', for "Clinical trials with laboratory endpoints; and 'III', for "Expert opinion".)

With regard to the immediate foregoing, at least three questions arise in the South African context.

Are these Guidelines being followed by our medical practitioners?

Does the public health system have the capacity to implement these guidelines?

If this capacity does not exist, would it be ethical for our doctors nevertheless to prescribe anti-retroviral therapy?

If our medical practitioners do not follow the Guidelines as indicated above, would they not be guilty of justiciable malpractice?

Recently, in October 2001, Eleni Papadopulos-Eleopulos et al, published a monograph entitled: "Mother to Child Transmission of HIV and its Prevention with AZT and Nevirapine." We will quote a few paragraphs from this monograph, which we will identify as EPE.

EPE says:

" As far back as 1988, there was evidence that the antibody tests in children are non-specific. It is accepted by all AIDS experts that a child can have positive antibody test without being infected. This is because maternal antibodies cross the placenta as early as the 12th week of gestation. As a result of normal catabolism, the level of these antibodies decreases post partum and by 9 months of age they are no longer present in the child. In other words, if the HIV antibody test is specific, any child who has a positive HIV antibody test beyond 9 months should remain positive for the remainder of his or her life. In the only study providing a detailed analysis of post partum loss of infant HIV seropositivity, the European Collaborative Study, approximately 23% of the children became seronegative between birth and 9 months. However, 59% became seronegative between 9 and 22 months. Since the latter cannot be due to loss of maternal antibodies, the only explanation is that: (!
i) the antibody test is non-specific or; (ii) the children managed to clear HIV infection without treatment. If 23% of children test positive because of maternal antibodies and in 59% the test is non-specific, how certain can one be that in the remaining 18% of children the test will also not seroconvert after 22 months? Or if the test remains positive it is true positive?" (Our emphasis).

All the studies of transmission of HIV from mother to child use the Roche Amplicon PCR to detect neonatal HIV infection, as HIV antibody detection by HIV ELISA cannot be used in the first 18 months due to the persistence of maternal antibodies in the infant's circulation.

Yet the US CDC states that PCR must not be used to diagnose HIV infection in adolescents and neonates. It then says that nevertheless it can be used in infants!

We should also note that the abundant 'copies per ml' that PCR detects in the bloodstream are not whole virus particles, despite the misleading appellation of 'viral load'. They are genetic material whose sequence is the same as that of constituents of the HIV genome.

Therefore, 'high viral load' on PCR does not automatically assume profound infection with HIV. This is presumably why the manufacturers caution against use of the test to diagnose HIV infection - lest they be sued by a patient who subsequently proves not to have HIV infection.

Despite all this, all the evidence for reduction of vertical transmission using antiretroviral drugs is premised on the detection of neonatal HIV infection using PCR. Not surprisingly, the evidence is consequently self-contradictory, with a proportion of so-called infected babies spontaneously becoming disease free in the first 9 months and later, while another subset initially negative, developing positive PCR despite the mother abstaining from breast feeding.

Most puzzling of all is the finding from the (still unpublished!) PETRA B study in which the well-known Dr Glenda Gray was a principal investigator.

This study demonstrated that at 18 months following birth, there was no difference in HIV free survival between the infants whose HIV positive mothers had been given AZT plus 3TC just before birth, and those whose HIV positive mothers had received placebo.

Perhaps not surprisingly, Dr Gray's PhD thesis, which is presumably largely based on this study, is, several years later, still in the 'pipeline' and unpublished. Is this because the study shows that antiretroviral therapy for HIV positive pregnant women does not, in fact, "save babies' lives"?

The EPE also cites a study conducted in 1999 by researchers from France and Rwanda. Among other things, this study said:

" Of 436 eligible children, 54 were diagnosed as infected.A total of 347 children were considered uninfected.In HIV-1 infected children, the most frequently observed clinical signs were chronic cough, failure to thrive, and generalised lymphadenopathy, which also were reported among the most frequent HIV-related conditions in other developing countries. Chronic cough and failure to thrive were present in almost half of the initial patterns of symptomatic disease in our series. However, these three conditions were also common in uninfected children. In our cohort, the most specific findings of HIV-infection were oral candidiasis and chronic parotitis, a pattern similar to the one observed in the New York City cohort.Twenty-eight (52%) infected children and 13 (4%) uninfected children died during follow-up.The risk of death was not significantly higher in children who had developed AIDS in comparison to the other children. No specific combination of clinical manifestations was!
associated with differences in survival. Biologically, neither the maternal CD4 cell count at day 15 nor the child's CD4/CD8 ratio at 6 months of age was predictive of death."

EPE also quotes the WHO, as follows:

" In the 1989 'Report on the Meeting of the Technical Working Group on HIV/AIDS in Childhood', World Health Organisation, global programme on AIDS, it is stated:

" Many infections that are common in children, particularly in developing countries (such as pneumonia and diarrhoea), mimic the HIV infection in their clinical signs.Because of the incompletely defined spectrum of disease in infancy and childhood and the limitation of correct laboratory diagnostic tests (antibody, PCR, virus culture, HIV antigens, in vitro antibody production) there is no clear standard against which to measure existing or proposed paediatric AIDS definition." (Our emphasis).

One of the conclusions that EPE draws from its extensive study of existing scientific material on MTCT is that:

" There is no valid method to prove infection of the child with HIV. There is no proof that any of the tests used to prove infection are HIV specific. Neither are the tests reproducible or standardised. This is well illustrated by the fact that there are few studies in which the same methodology and tests are used (in some studies an "in-house" definition of MCT is used) and the extreme variability in the findings of different groups, the findings are not consistent even within one and the same group or even with the site in the same study. This is best illustrated in the ECS and the Ariel project studies. There is nothing specific either in regard to the immune deficiency (T4 decrease) or the clinical signs, symptoms and diseases, that is, AIDS reported in infants and children of HIV positive mothers and used to prove MCT of HIV. Such abnormalities existed in infants and children long before the AIDS era, and in fact, in high frequency in the two groups in which the claims for MCT of HIV have been obtained, that is, in women living in poverty and using drugs.At present, there is no proof that HIV, even if it is assumed to be present in pregnant mothers, is perinatally transmitted to their offspring." (Our emphases.)

EPE also says:

" The pharmacological mode of action of nevirapine can only prevent infection of cells not already infected. Thus, when given to the mother, it could prevent transmission only if the child is not already infected.

" Since nevirapine like AZT is capable only of preventing infection of new cells and is unable to inhibit the expression of HIV within already infected cells or eradicate the virus, when the drug is given to neonates, especially three days post partum, it will have no effect on MCT in utero or during labour and delivery. Under these circumstances nevirapine may prevent transmission via breast feeding and then only for a very short period of time (days). However, since,

(a) a single dose of 200mg administered to the mother leads to a drug concentration in milk much lower than the concentration necessary to have an anti-retroviral effect;

(b) the concentration reached in the infant after a single dose of 200mg to the mother and 2mg/Kg to the infant is much lower than that necessary to induce an anti-HIV effect;

such a regime of the drug cannot inhibit MCT via breast milk even for a very short period of time.

" Given the pharmacological action of the drug and its pharmacokinetics, one wonders how anyone can propose a protocol like that used in the Uganda study and expect an effect on MCT?

" In recommending nevirapine as mono or combination therapy it is important to consider that not only is its anti-viral effect even when administered for lengthy periods limited and of extremely short duration, but that it confers resistance to the treatment with other anti-retrovirals. It is also significant that the European Agency for the Evaluation of Medicinal Products recommends the use of nevirapine only for combination therapy and only for 'infected patients with advanced or progressive immunodeficiency.'

" At present, no proof exists that children become infected by their mothers either in utero or post partum with a unique human retrovirus, HIV or (that) this can be prevented by AZT or nevirapine."

EPE also quotes a 1998 study carried out by Ian Timaeus of the London School of Hygiene and Tropical Medicine. Relying on this study EPE says:

" It is worth emphasising that infant and child mortality fell in Uganda in the early 1990s despite the severity of the HIV epidemic in this country. Presumably developments acting to improve child health have outweighed the impact on mortality of the spread of HIV. Thus, these estimates suggest that the HIV epidemic exerts an important but not decisive influence on trends in infant and child mortality. Without additional data (said Timaeus), one cannot separate the impact of AIDS on infant and child mortality from that of other factors.

" In other words, in Africa no proof exists of an increased mortality in children above that reflected by the 'enduring impact of under-development', resulting from HIV infection, not even in Uganda, where no less an authority on HIV and AIDS than Robert Gallo reported that as far back as 1973, 50/75 (67%) of a sample of 75 children were infected with HIV. This means that a similar proportion of mothers and presumably fathers in Uganda would also have been infected in 1973. If the HIV antibody tests do prove HIV infection and if HIV is the cause of AIDS one should have witnessed an inexorable decline in the Ugandan population over the past twenty years. Instead:

" Timaeus says: 'The population in Uganda has increased from the 4.9 million enumerated in the 1948 census to 6.5 million in 1959; 9.5 million by 1969; 12.6 million by 1980; and 16.7 million were enumerated at the 1991 census. Uganda's population is growing at a rate of 2.5 per cent which leads to an estimated population of 21 million people by 1998. It is estimated that 47 per cent of the population is under 15, while only 3 per cent are above 65 years. Thus the population is young and has in-built potential to grow (momentum) as the large proportion of children become parents.'.

" The one necessary and sufficient measure to decrease childhood mortality in the developing world, including death from 'AIDS', as well as the phenomena claimed to prove HIV infection and thus the putative mother-to-child-transmission of 'HIV', is to eliminate poverty."

(NB: the population of Uganda is now 23 million!)