Dissident AIDS Database

NIAID paper : HIV causes AIDSAfricaPerinatal transmissionNevirapine study
The trouble with nevirapine
 Brink Anthony
  (Guay L 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 on 4 September 1999) In January 2001 nevirapine was approved by the SAMCC for use as a single drug to prevent mother to child transmission of HIV, on the strength of a study by Laura Guay which “was originally designed to be a randomised, placebo-controlled, double-blind phase three trial of 1500 mother-baby pairs to investigate the safety and efficacy of oral zidovudine and oral nevirapine for the prevention of vertical mother to child transmission of HIV-1 from pregnant women to neonates in Uganda.” The transmission rate (assessed at 14-16 weeks) among mothers on AZT was 25.1%. and 13.1% for nevirapine (nevirapine was declared 48% more effective than AZT). Problems 1) Guay soon dropped the placebo control group for ethical reasons (the transmission rate among women given placebos and AZT was then about 25%) even though untreated mother to child transmission rates vary hugely from place to place according to all reports (from approximately 50% to 10%) and that placebo administration has been reported to have magical effects even concerning mother to child transmission 2) “After randomisation, on-site study staff and investigators became aware of the treatment and infection status of the mother-baby pairs. Mothers also knew to what study group they had been assigned after randomisation and were the infection status of their babies during the study.” So it was inevitable that at least some of the pregnant women would do anything to reduce the chances including pill sharing of AZT, nevirapine and other drugs between group (“many doses [of AZT] were given unobserved. Mothers were identified before labour and given the drug to take at home.”) 3) There is an uncertainty whether Guay included in her study women positive according to a single ELISA or positive according to an ELISA ‘confirmed’ by western blot (both cases seem likely true) : since further testing always leads to the exclusion of a large % of single ELISA positives, many of the single ELISA positive women may not have been infected. 4) “Maternal plasma HIV-1 RNA levels were…not significantly different at delivery from baseline.”, which is hard to reconcile with her claim that the drug worked by lowering the transmission risk by lowering the concentration of viruses in the mother 5) Havlir et al reported in 1995 (JID 171: 537-45) that in vivo, the minimum concentration of nevirapine for a virological response (prevention of HIV replication) is 3.4 to 8mg/ml but the nevirapine plasma concentrations that Guay achieved (more than 100 ng/ml) never came anywhere even close to that. 6)  “HIV-1 infection [among babies] was defined as a positive qualitative HIV-1 RNA assay confirmed by a quantitative HIV-1 RNA assay or HIV-1 culture on a second blood sample. If babies died after only one positive RNA assay on the sample, we classified the baby as being infected.” [no matter what caused the baby’s death] but Roche states that the qualitative RNA test used in her study is “For research use only. Not for use in diagnostic procedures.” The same goes about the quantitative RNA test used as a confirmation (commonly referred to as a ‘viral load’ test) : “The Roche Amplicor HIV-1 Monitor Test v1.5 is not intended to be used…as a diagnostic test to confirm the presence of HIV-1 infection.” 7) If the mother’s virus has had nine months to reach the baby through the placenta, the umbilical cord, and all those shared fluids, and thereafter ingratiate itself into the baby’s DNA, how can a single pill of nevirapine administered just before birth can prevent this, especially if the manufacturer admits that it’s ineffective on its own no matter how much of it and for how long you take it? Particularly since administration of nevirapine alone has no effect on CD4 cell counts, and no significant effect on ‘HIV RNA’. Since its putative activity is reverse transcriptase inhibition, the drug is notionally only able to prevent the infection of new cells – not eradicate HIV from already infected cells, or prevent such cells from expressing new HIV particles, Guay cites a couple of speculative studies proposing that mothers infect their babies during labour and birth. 8) When giving nevirapine to women entering labour, it takes an average of 4.6 hours for an oral dose of 200 mg to reach its maximum concentration in the blood. Since women generally deliver at between 0.9 and 10.5 hours after dosing, and nevirapine takes between 1-8 hours to reach maximum plasma concentration, an unascertained number must give birth before the target concentration can be reached. 9) The rates of serious adverse events occurrence and clinical or laboratory abnormalities in mothers were similar in the two groups (respectively 4,5% and 81%). The most frequent adverse clinical event was bacterial or viral infection, followed by parasitic infection, anaemia and maculopapular rash.” The “laboratory abnormalities” – at a sky-high rate – detected after the drugs were given were not specified in the report. ” 10)  “The rate of serious adverse events in the two groups [of babies] was similar up to the 18-month visit (around 20%)… The most frequent cause of serious adverse events within 56 days of birth were sepsis, pneumonia, fever, congenital anomaly, asphyxia, and dyspnoea, maculopapular rash, and anaemia. “The frequency and severity of laboratory-detected toxic effects, including neutropenia [depleted immune cells], thrombocytopenia [depleted clotting platelets], and abnormalities in creatinine [energy metabolism] or bilrubin [breakdown product of haemoglobulin], were similar in the two groups.” But again, Guay didn’t think to share the numbers with us. “38 babies (6.8%) died (22 (7.9%) in the zidovudine group, 16 (5.7%) in the nevirapine group). The most frequent causes of death were pneumonia, followed by gastroenteritis, diarrhoea, dehydration and sepsis.”  11) Guay : “ The data from our trial do not change recommendations in the USA, Europe for…use of the three-part zidovudine regimen for prevention of transmission.”