Adverse Effects, Mothers & Children

“[358] Pregnant women identified as HIV-1 infected were referred for enrolment in these two programmes and all eligible women for HAART [[WHO clinical stage 2 or 3 and lymphocytes T CD4+ cell count <350 cells/µl, or WHO 4 or CD4 cell count <200 cells/µl] and their infants were included…The median duration on HAART [combination drug therapy] was 11.7 weeks [MTCT-plus group] whereas the median exposure time to short-course antiretroviral drugs (sc-ART) prophylaxis [Ditrame plus group] was 4.9 weeks…A multivariable analysis demonstrated that HAART initiated before pregnancy and during pregnancy and maternal BMI [body mass index] (<25 kg/m2) were associated with [2-3 times the risk of] LBW [low birth weight] [the HAART group also had 10 babies that spontaneously aborted or were stillborn versus 5 in the sc-ART group]”]

“2024 liveborn infants [in Ethiopia, India and Uganda] randomised in the study had at least one specimen tested before 6 months of age…The modified intention-to-treat population included 986 infants in the single-dose [of Nevirapine] group and 901 in the extended-dose group…393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study…Grade 3 and 4 serious adverse events were common. Overall, 1150 serious adverse events were reported in the first 6 months of life in 739 of the 1887 infants in the modified intention-to-treat population. However, the frequencies of specific serious adverse events were similar between groups. 521 (45%) of the serious adverse events were categorised as laboratory abnormalities. The next most frequent events were gastrointestinal conditions (n=184) and respiratory illnesses (n=158)”

“A 7-month-old girl was admitted to intensive care following resuscitation for a severe metabolic acidosis. Her mother had started highly active antiretroviral therapy (HAART) at 6-weeks gestation before she knew she was pregnant…The mother…was asymptomatic prior to starting HAART with combivir and nevirapine for a CD4 of 200 million/L and viral load of 280,000 copies/mL.”

“A total of 439 [Malawian] children started on ART [anti-retroviral therapy]…By September 2006, 49 children (11%) had died, of whom 35 (71%) died by 3 months and 44 (89%) by 6 months. The cumulative incidence of death at 3, 6, 12 and 24 months after ART was 8, 12, 13 and 15%, respectively…CONCLUSION:: Although children do well on ART, there is high early mortality [!]”

“The prematurity rate (<37 weeks gestation) was higher in women on highly active antiretroviral therapy (HAART) (14.1%, 476/3384) than in women on mono/ dual therapy (10.1%, 107/1061), even after adjusting for ethnicity, maternal age, clinical status and injecting drug use as the source of HIV acquisition [adjusted odds ratio (AOR)=1.51]. Delivery at <35 weeks was even more strongly associated with HAART (AOR=2.34). The effect was the same whether or not HAART included a protease inhibitor. In comparison with exposure to mono/dual therapy, exposure to HAART was associated with lower birthweight standardized for gestational age, and an increased risk of stillbirth (AOR=2.27).”

“[This study] included 1037 HIV-uninfected children born in 1991– 2002…Possible cases with unexplained signs of MD [mitochondrial dysfunction]…were identified through retrospective review. Associations between overall in utero NRTI [nucleoside reverse transcriptase inhibitor or 'nuke'] exposure, and trimester of first in utero NRTI exposure and possible MD were estimated…there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) and to zidovudine (ZDV [AZT]) and 3TC in combination (ZDV/3TC) among cases [of MD] than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC [the risk was more than 10 times higher] and ZDV/3TC [was almost 10 times higher] were significantly higher among cases than non-cases…first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD”

“From August 31, 2003 until October 31, 2005, 151 children initiated HAART at Sinikithemba. Thirteen children died during follow-up (8.6%)…All 13 deaths occurred within the first 5 months of HAART initiation…The most commonly reported causes of death were chronic gastroenteritis and TB…”

“We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana…All women were treated with antenatal zidovudine [AZT]. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment…By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine…Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure. In contrast, virologic failure rates did not differ [statistically] significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo.”

“Despite many unresolved physiopathological questions, there are coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to zidovudine [AZT], alone or in combination with lamivudine [3TC]. This effect may be transitory or persistent. Although, the clinical significance of the various biological and/or histopathological mitochondrial anomalies found at birth in NA-exposed animals or children has not been formally established, the high incidence of mitochondrial neurological diseases observed in the French cohort has not been contradicted to date in other cohorts.”

“Objectives: To estimate the incidence of 29 targeted opportunistic and other infections occurring in the era of HAART between January 1, 2001 and December 31, 2004…There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years…However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era [1988 through 1998]”

“We compared infant feeding patterns, HIV MTCT rates and infant mortality among babies born to HAART and non-HAART women from 5/1/2003 through 9/30/2005.…Results…11 infants died in the HAART group, 3 in the non-HAART group, giving mortality rates of 20.8/100 person-years (PY) and 12.9/100 PY respectively respectively. Infant deaths were associated with a shorter duration of exclusive [no other fluids or solids] or total breastfeeding. Conclusions: Although no HIV MTCT occurred among breastfeeding mothers on HAART, both exclusive and total breastfeeding duration determined infant survival [Note: The conclusions omit the obvious possibility that giving AIDS drugs to mothers makes the babies sicker]”

“A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana, resulting in 694 live first-born infants…All women received a background of zidovudine [AZT] from 34 weeks' gestation through delivery, and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor…20 (2.8%) women had a serious or life-threatening event…5 (0.7%) of 694 live-born infants had a serious or life-threatening event possibly related to single-dose nevirapine. Four were rashes regarded as serious, and one was bilirubin elevation with jaundice treated as neonatal jaundice.”

“A total of 123 women initiated nevirapine as part of combination antiretroviral therapy in the study period. Eight women developed significant hepatotoxicity, including two women who died from fulminant hepatitis. Women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts”

“Lipid values were measured during pregnancy in HIV-infected, treatment-experienced women. A previous history of lipodystrophy [fat redistribution] was associated with significantly higher triglyceride values at all pregnancy trimesters. In multivariate analyses lipodystrophy independently increased the risk of hypertriglyceridemia [high levels of triglycerides in the blood] by threefold at the first trimester, and by eightfold at the second and third trimesters. Protease inhibitor treatment was also independently associated with hypertriglyceridemia…Compared with women without a history of lipodystrophy, women [who had such a history]…had a significantly longer history of antiretroviral treatment (340.3 versus 218.3 weeks).”

“Mandatory HIV testing, and when necessary, mandatory treatment of all pregnant women in Botswana is both a necessary and a vital part of a broader comprehensive strategy for preventing the spread of AIDS in sub-Saharan Africa.”

“antiretroviral treatment (ART) cannot eradicate HIV-1 and infected individuals are faced with lifelong therapies…Many currently infected children have been treated according to the 1996 guidelines that recommended early treatment. However…current guidelines (2004) are more cautious regarding the initiation of ART… [when four such Spanish children had treatment stopped they] always presented with good CD4% and remained asymptomatic through all the interruption period. Also, the quality of their lives was improved by being without HAART for many weeks. Our results demonstrate the safety of stopping ART in HIV-infected children (prematurely treated according to current guidelines). Those results are consistent with previous reports in HIV-infected adults.”

“From November 1985 until July 2003, 472 HIV-infected pregnant women [in Barcelona, Spain] were included in this study, of whom 86 (18%) had received HAART prior to pregnancy. The proportion of HIV-infected pregnant women with HAART (defined by any combination including at least three antiretroviral drugs) prior to or during pregnancy was 5% in 1997, 50% in 1998, 87% in 1999, 87% in 2000, 87% in 2001, 97% in 2002 and 91% in 2003. There were six (13/1000) cases of pre-eclampsia without fetal death, five (11/1000) cases of fetal death without pre-eclampsia, and three (6/1000) cases of preeclampsia and fetal death. Pre-eclampsia and fetal death remained very low until 2001 and sharply increased thereafter…In multivariate models, the use of HAART prior to pregnancy [8.9 times higher risk] and tobacco smoking were independent factors associated with the development of pre-eclampsia in HIV-infected women. The variables associated with fetal death in the HIV-infected population in the univariate analysis were age, known duration HIV infection, and HAART prior to pregnancy [7.8 times higher risk]”

“This study will use the NIH-sponsored Women and Infants Transmission Study (WITS) and the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2) HIV-infected pediatric cohorts to determine how left ventricular (LV) function (particularly fractional shortening and contractility) and structure (particularly wall thickness and mass), are affected by cumulative intensity of HAART exposure.”

“Necrotizing enterocolitis (NEC) remains a major cause of mortality and morbidity in premature infants. Risk factors for NEC include prematurity, intestinal hypoxia/ischaemia, formula feeding and colonization of the intestine by pathogenic organisms…The study was performed on premature infants born…from January 1995 to July 2003…Only ‘proven’ (stage IIB) and ‘advanced’ (stages IIIA and IIIB) NEC was included in the study…For each case of NEC, two matched controls were retrospectively chosen…[children of HIV-positive mothers either got banked human milk or formula, those of HIV-negative mothers were often breastfed]…Of the 4009 premature infants, 79 (2%) developed NEC and 62 of these were from the group of 1917 infants born with a PMA of < 32 weeks…Of the seven HIV-positive mothers whose infants developed NEC, six had received antiretroviral drugs during pregnancy. In two, this treatment consisted of zidovudine alone. In four, it consisted of combination therapy with two NRTI (zidovudine and didanosine or lamivudine) and one protease inhibitor.”

“To gain access to hundreds of HIV-infected foster children, federally funded researchers promised in writing to provide an independent advocate to safeguard the kids' well-being as they tested potent AIDS drugs. But most of the time, that special protection never materialized…Several studies that enlisted foster children reported that patients suffered side effects such as rashes, vomiting and sharp drops in infection-fighting blood cells, and one reported a ''disturbing'' higher death rate among children who took higher doses of a drug, records show…Illinois officials believe none of their nearly 200 foster children in AIDS studies got independent monitors [that the National Institutes of Health required]. New York City could find records showing 142 - less than a third - of the 465 foster children in AIDS drug trials got such monitors even though city policy required them…Likewise, research facilities including Chicago's Children's Memorial Hospital and Johns Hopkins University in Baltimore said they concluded they didn't provide advocates for foster kids…Some foster children died during studies, but state or city agencies said they could find no records that any deaths were directly caused by experimental treatments…Researchers typically secured permission to enroll foster children through city or state agencies. And they frequently exempted themselves from appointing advocates by concluding the research carried minimal risk and the child would benefit directly because the drugs already had been tried in adults…Arthur Caplan, head of medical ethics at the University of Pennsylvania, said advocates should have been appointed for all foster children because researchers felt the pressure of a medical crisis and knew there was great uncertainty as to how children would react to AIDS medications that were often toxic for adults…Some states declined to participate in medical experiments. Tennessee said its foster care rules generally prohibit enlisting children in such trials. California requires a judge's order. And Wisconsin ''has absolutely never allowed, nor would we even consider, any clinical experiments with the children in our foster care system,'' spokeswoman Stephanie Marquis said…Officials estimated that 5 percent to 10 percent of the 13,878 children enrolled in pediatric AIDS studies funded by NIH since the late 1980s were in foster care. More than two dozen Illinois foster children remain in studies today. NIH, the government health research agency that funded the studies, did not track researchers to determine whether they appointed advocates. Instead, the decision was left to medical review boards made up of volunteers at each study site. A recent Institute of Medicine study concluded those Institutional Review Boards (IRBs) were often overwhelmed, dominated by scientists and not focused enough on patient protections. The U.S. Office for Human Research Protections, created to protect research participants after the notorious Tuskegee syphilis studies on black men in the 1930s, is investigating the use of foster children in AIDS research. The office declined to discuss the probe. AP's review found that if children were old enough - usually between 5 and 10 - they also were educated about the risks and asked to consent [note that there are several recent cases of teenagers being forced to accept treatment, implying that the age of refusal of treatment is high, but the age of consent is low]. Sometimes, foster parents or biological parents were consulted; other times not.…Illinois officials confirmed two or three foster children were approved to participate in a mid-1990s study of dapsone. Researchers hoped the drug would prevent a pneumonia that afflicts AIDS patients. Researchers reported some children had to be taken off the drug because of ''serious toxicity,'' others developed rashes, and the rates of death and blood toxicity were significantly higher in children who took the medicine daily, rather than weekly. At least 10 children died from a variety of causes, including four from blood poisoning, and researchers said they were unable to determine a safe, useful dosage. They said the deaths didn't appear to be ''directly attributable'' to dapsone but nonetheless were ''disturbing.'' ''An unexpected finding in our study was that overall mortality while receiving the study drug was significantly higher in the daily dapsone group. This finding remains unexplained,'' the researchers concluded. Another study involving foster children in the 1990s treated children with different combinations of adult antiretroviral drugs. Among 52 children, there were 26 moderate to severe reactions - nearly all in infants. The side effects included rash, fever and a major drop in infection-fighting white blood cells.”

“when an experimental drug [Nevirapine in this case] is found to be superior to a control that is not harmful [AZT in this case] (thus replacing a placebo), the effectiveness of the experimental drug is thereby established.”

“This study will examine how HIV affects the brain and nervous system, learning, and behavior in children on highly active antiretroviral therapy (HAART). Although HAART has resulted in fewer HIV-infected children getting sick and even fewer dying from AIDS, many children on this treatment regimen develop significant brain or nervous system problems, such as learning difficulties, attention problems, hyperactivity, and depression. [note how the study is phrased to ask "how HIV affects the brain and nervous system" although it's quite obvious that the investigators suspect that it is the drugs causing]”

“Among 4372 live births in the European Collaborative Study, the prematurity rate increased to 24.9% in 2000–2004. Antenatal HAART use initiated pre-pregnancy was strongly associated with prematurity, particularly severe prematurity. The implication of increased prematurity is evidenced in high neonatal mortality in these groups (0.66% for infants at 34–36 weeks and 7.37% at < 34 weeks’ gestation)…Our findings of a substantially increased risk of severely curtailed pregnancy duration among women taking HAART antenatally, particularly when initiated prepregnancy, coupled with the very high neonatal mortality rate associated with delivery at these early gestations, are very concerning.”

“We implemented the nevirapine regimen in a real-life situation in Kenya. The perinatal HIV-1 transmission rate at 14 weeks was 18.1%, similar to the 21.7% before the intervention.”

“During a 2-3 month period, 477 HIV-infected children aged >= 3 years in 30 paediatric HIV clinics were assessed at their first visit…Prevalence was 26.0% for any fat redistribution, 8.81% for central lipohypertrophy, 7.55% for peripheral lipoatrophy and 9.64% for…more than one sign of each. Independent predictors of fat redistribution included [CDC] class C disease, female gender, ever used versus never use of protease inhibitors and of stavudine. Increasing time since initiation of antiretroviral therapy was associated with increased severity of fat redistribution.”

“The frequency of premature deliveries and very low birth weight babies being born to HIV-positive mothers has increased significantly since the introduction of HAART in Europe, according to findings from the European Collaborative Study presented on Tuesday at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco…In the period 1995-97, 5.94% of infants were born prior to 34 weeks of pregnancy; by 2001-2003, this proportion had risen to 21.2%. The proportion delivered prior to 37 weeks grew similarly, from 17.1% in 1995-97 to 46.1% in 2001-3. The proportion of very low birth weight babies grew from 0.48% in 1995-97 to 8.05% in 2001-3, and the proportion of low birth weight babies grew from 14.9% to 36.9% in 2001-3. For each measure, the proportion in the period 1998-2000 was midway between the two. Risk factors for premature delivery were found to be age greater than 35 years (OR 2.24 [i.e. 2.24 times more likely in mothers over 35 years]), injecting drug use during pregnancy (OR 2.52), baseline CD4 cell count below 200 (OR 2.36) and protease inhibitor-containing HAART during pregnancy (OR 4.17). Women already taking HAART when they became pregnant, or who commenced HAART in the first three months of their pregnancy, had a significantly higher risk of premature delivery. Infant deaths occurred at a much higher rate than the population average in western Europe, with evidence of a trend towards a higher death rate in the period after 2000 (21.0 per 1000 births in 1999-2000 versus 24.5 per 1000 in 2001-2). The European range is 4.4 - 9.2 deaths per 1000 births in HIV-negative women. Although the number of neonatal deaths was too small for a multivariate analysis to tease out risk factors, 74% of deaths occurred in premature infants, and the median length of gestation of infants that died was 28 weeks.”

“The baby toxicity analysis includes the 629 babies who received the study drug, or whose mother received study drug, with 309 in the zidovudine group and 320 in the nevirapine group. Non-serious adverse events in the babies were reported through age 6–8 weeks and serious adverse experiences were reported through age 18 months. 293/309 (95%) babies in the zidovudine group and 309/320 (97%) in the nevirapine group were followed through age 6–8 weeks; 9/309 and 4/320 babies, respectively, had died before this visit.

At the 18-month visit, 247/309 (80%) and 273/320 (85%) babies in the zidovudine and the nevirapine groups were still being followed up, and 42/309 (14%) and 34/320 (11%), respectively, had died before this visit. Reported serious adverse events among babies with onset during the first 56 days after birth were balanced between the treatment groups: 35/309 (11·3%) in babies receiving zidovudine and 29/320 (9·1%) in those receiving nevirapine. The most frequently reported serious adverse event within 56 days of birth was sepsis followed by pneumonia, asphyxia, dyspnoea, fever, and meningitis. Of the 64 babies with at least one serious adverse experience reported within 56 days, seven (2·3%) in the zidovudine group and two (0·6%) in the nevirapine group were judged to be possibly related to the study drug. Each one of these possibly related serious adverse events were different conditions. In the seven babies in the zidovudine group, serious adverse events were sudden-infant-death syndrome 24 h after delivery, transient tachypnoea at birth requiring oxygen, birth asphyxia with death due to fetal distress after caesarean section, presumed pneumonia 4 days after birth, sepsis and vomiting soon after delivery which resolved with antibiotics within 24 h, haemorrhagic disease of the newborn baby which resolved with vitamin K and antibiotics within 3 days, and an intrauterine death during labour. In the two babies in the nevirapine group, adverse events were transient respiratory distress at birth with meconium staining requiring oxygen, and a non-macerated stillbirth to a mother who received nevirapine 3·5 h before delivery.

Reports of one or more serious adverse events through 18 months of follow-up were also balanced between the groups: 97/309 (31·4%) among babies receiving zidovudine and 109/320 (34·1%) in those receiving nevirapine. Anaemia was reported as a serious adverse event more often in the nevirapine group (9·4% vs 5·5%), however, all reports of serious anaemia occurred after 56 days of life and most are associated with the diagnosis of malaria. The only serious hepatic adverse events reported were one case of jaundice in each group, both occurring at or after age 1 year, and one hyperbilirubinaemia at day 5 in the zidovudine group. There were 76 deaths among 629 (12·1%) babies in follow-up through 18 months (42/309 [13·6%] in the zidovudine group and 34/320 [10·6%] in the nevirapine group). The most frequent cause of death was pneumonia, followed by gastroenteritis/ diarrhoea/dehydration, anaemia, and malaria.

All adverse events (serious and non-serious) that occurred in the first 6–8 weeks were significantly more frequent in babies randomly assigned to zidovudine, with 288/309 (93·2%) babies in the zidovudine group having at least one adverse event compared with 260/320 (81·3%) in the nevirapine group (p<0·0001; table 4). Certain conditions were substantially more frequent among the babies in the zidovudine group, including jaundice (18·4% vs 5·6%), skin infections (17·5% vs 9·7%), and pustular rash (4·5% vs 0·6%). The only condition with a difference in rates between groups larger than 3% and more frequent in the nevirapine group was dermal exfoliation (4·9% vs 8·4%), all of which were graded mild or moderate. In most cases this was described as “normal peeling skin of the newborn”; however, in four cases (three in the nevirapine group, one in the zidovudine group) the diagnosis was exfoliative dermatitis. No cases of Stevens-Johnson syndrome were reported. Within the first 56 days of life there were 21 cases of maculopapular rash, none of which was serious (12 cases in the zidovudine group and nine in the nevirapine group). Rashes in general were more commonly reported for the zidovudine group (26·2% in the zidovudine group and 18·4% in the nevirapine group). There were no significant differences between treatment groups in serious grade 3 or 4 laboratory toxicity for babies that we studied, and no reports of grade 3 or 4 abnormalities in liver enzymes (alanine aminotransferase) were reported in either group.”

“A rash occurred in 20% of patients (15/74), and was severe (grade 3–4) requiring the cessation of treatment in four children (5%). In the other 11 children, the rash was managed with antihistamines. The rash developed after a median of 9 days (1–44) of treatment, and lasted a median of 10 days (1–60)…One child had elevated hepatic transaminases and discontinued nevirapine, but she also had hepatitis C infection. 5 children experienced grade 3 neutropenia that may have been attributable to concomitant medication. No other grade 3 or 4 adverse events were documented. Grade 1 and 2 adverse events related or possibly related to nevirapine, but possibly attributable to concomitant medication, included: vomiting (n=8); diarrhoea (n=7); unexplained fever (n=8); headache (n=3); dizziness (n=2); paraesthesia [hallucination] (n=3); alopecia [hair loss] (n=3); nail dystrophia (n=2); hepatomegaly [swollen liver] (n=1); muscle pain (n=1); gall bladder sludge (n=1); elevated cholesterol and triglyceride levels associated with pancreatitis (n=1); neutropenia (n=15); anaemia (n=3); leucopenia (n=6); abnormal liver functions: raised alanine aminotransferase (n=7), raised bilirubin (n=2) and raised gamma-glutamyl transferase (n=3).”

“Amid the plethora of new and newly validated interventions, there are signs that the child survival effort has lost its focus. For example, levels of attention and effort directed at preventing the small proportion of child deaths due to AIDS with a new, complex, and expensive intervention seem (although no investment data are available) to be outstripping the efforts to save millions of children every year with a few cents’ worth of ITMs [insecticide treated materials], oral rehydration therapy, or efforts to promote breastfeeding. This must change.”

“30 PI[Protease Inhibitor]-treated and 20 PI-naive [untreated] children were evaluated (76% prepubertal). PI-treated children had significantly higher total cholesterol, LDL-cholesterol and triglycerides…Clinical and immunological HIV categories, viral load, CD4 cell count…were not significantly associated with serum lipids, insulin resistance or abdominal adipose tissue distribution [indicating that it is the therapy, not HIV, that is the cause of this metabolic abnormality]”

“During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change.”

“Although all children in group 1 [with persistent metabolic acidosis] received ART [antiretroviral therapy] (versus 146/167 in group 2) a univariate comparison for this variable was not [statistically] significant [due to the small number of children in the study not taking ART, however the risk was 4.75 times higher among those taking ART]”

“There were no serious adverse effects in the mothers [but double the rate of anemia at delivery (the end of the course of therapy), and also more mothers with elevated levels of aspartate aminotransferase, blood urea nitrogen and creatinine]. Adverse events noted in neonates were anemia (in 6 neonates), elevated transaminase levels (in 1), and thrombocytopenia (in 3) [but the authors forgot to mention, in the abstract, that 15 were later hospitalized for a variety of conditions, some quite likely therapy related]…Short-course therapy with zidovudine plus lamivudine appeared to be safe and effective for prevention of perinatal transmission of HIV-1 [but this trial did not have a placebo, so this statement is purely hypothetical]”

“Drugs typically administered to prevent the transmission of human immunodeficiency virus (HIV) accounted for 25% of all the reported adverse events through maternal exposure [in the United States]. HIV drugs with >10 case reports each were zidovudine [AZT] (177), lamivudine [3TC] (57), nelfinavir (56), and nevirapine (44). Without data about how frequently these drugs were prescribed to prevent HIV transmission, it is not possible to tell whether zidovudine was more toxic in this therapeutic setting than similar drugs…A wide spectrum of adverse events were associated with the HIV-related drugs, including 110 cases (35%) with an outcome of congenital defect or permanent disability, 103 (34%) cases involving initial or prolonged hospitalization or a life-threatening event, and 23 (7%) with death as the reported outcome. [Note that it is estimated that only 1% to 10% of adverse drug reactions are reported]”

“In nonfasting and fasting conditions, [HIV-positive] children of the PI [Protease Inhibitor taking] group had higher total cholesterol, triglycerides, and LDL [Low Density Lipoprotein] cholesterol levels compared with the non-PI group…After fasting, 8 (47%) of 17 patients in the PI group presented with hypercholesterolemia [high blood cholesterol] as a result of an increase of LDL cholesterol and 11 (65%) had hypertriglyceridemia…The long-term complications of dyslipidemia [disruption of fat metabolism] are of major concern in the growing HIV-infected child.”

“The association of HIV-1-related immune deficiency with a low rate of pre-eclampsia [eclampsia is a serious pregnancy disorder characterized by convulsions, coma, high blood pressure, protein in the urine, accumulation of fluids and about a 25% rate of fetal mortality] the restoration of this rate in women treated with triple antiretroviral therapy to the expected rate indicates a pivotal role of the immune system in the pathogenesis of pre-eclampsia…Seven of the nine patients had unusually severe preeclampsia. 4 [of the 9 HIV+ women on HAART with pre-eclampsia] had HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets) and 3 had intrauterine deaths (table 1)”

“Our study shows that cardiac dysfunction [heart problems] occurs frequently in children with HIV infection…The relative risk of death during the 5-year follow-up period in children who had cardiac impairment or CHF [congestive heart failure] was 8.5 to 14.6 times higher than in the children without these complications…The majority of patients in this study were treated with a wide variety of antiretroviral agents available between 1990 and 1996 or intravenous immunoglobulin…some HIV-infected children continue to have evidence of cardiac dysfunction even with an undetectable HIV viral load [indicating that the cardiac dysfunction is probably not due to HIV]…Several isolated reports have described the HIV virus in myocardial or pericardial tissue, whereas others have proposed that HIV cardiomyopathy may be related to antiretroviral medications.”

“We report the case histories of two HIV-1 positive women in the third trimester of pregnancy who presented with acute lactic acidosis and acute pancreatitis, respectively. One case was fatal for mother and baby. Both women had been stable on regimens containing stavudine and didanosine for at least 2 years before their acute presentations. We speculate on the differential diagnosis, discuss possible reasons for an increased risk of these presentations in pregnant women taking antiretrovirals, and advocate increased vigilance of these women, particularly in the last trimester.”

“There were statistically significant differences among the five groups of children [1. control group children of HIV-negative mothers given no drugs, 2. children given Nevirapine [NVP] and AZT born of HIV+ mothers given NVP, 3. children given NVP of HIV+ mothers given NVP, 4. children given NVP and AZT of HIV+ mothers given no drugs and 5. children given NVP of HIV+ mothers given no drugs] at 6 weeks of age (P , 0.0001): mean ALT [Serum alanine aminotransferase, a measure of liver enzymes] values were higher among children who received treatment compared with control children. In addition, compared with mean ALT values at birth, the mean ALT values declined among the control group but increased in three of the four treated groups. However, among the four groups of children who received antiviral treatment there were no statistically significant differences in mean value of ALT at 6 weeks of age. Based on conventional tables currently used to assess severity of this parameter (see Methods), the increases in ALT values were mild (grade 1 only)...At 6 weeks of age, both hemoglobin and hematocrit values were significantly lower among antiviral drug-treated groups of infants. The hemoglobin mean value was 11.7 g/dl in the control group versus 10.4–10.9 g/dl among treated groups; hematocrit mean value was 34.2% in the control group versus 30.7–31.8% for the treated groups...At 6 weeks of age, platelet [clotting cell] counts were significantly lower among the treated groups of children compared with control children...In the control group, 82% of 133 infants had a normal hemoglobin level (> 9.5 g/dl) compared with 70–78% among the treated groups...More treated infants showed grades 1 and 2 severity compared with control infants: 12.8–15.1% among treated groups of infants compared with 9.8% among control infants had grade 1 severity; 5.3–9.7% among treated groups of infants compared with 3.8% among control infants had grade 2 severity...the hematological changes were more noticeable among HIV-infected children, with the exception of granulocyte percentage which was lowest among infants whose mothers had received intrapartum NVP. These data suggest that infection with HIV also contributes to these changes. Distinguishing between the adverse effects of short term antiretroviral drugs and HIV infection of the infant could be difficult. This is a potential limitation of this study. No reference values are available for HIV-exposed but untreated infants and we were not able to recruit a comparison group for ethical reasons. Our data did not show significant differences among the four treated groups of children either at birth or at 6 weeks of age. Therefore, it is not possible to distinguish between effects due to NVP alone or to its combination with ZDV. This is further compounded by the fact that both NVP and ZDV have been reported to be associated with hematologic abnormalities....We have monitored some important safety parameters among Malawian infants. Although hepatic and hematological changes were observed with these ultra-short post-exposure prophylaxis antiretroviral regimens, these alterations were minimal and within expected limits based on previous studies. Assuming that most HIV infections of the neonate occur intrapartum or close to the time of delivery, it appears that both acquisition of HIV infection and antiretroviral drugs contribute to hepatic and hematological changes in the neonate. We will continue to monitor the clinical conditions and hematological parameters of these infants up to the age of 2 years. These results could guide the implementation of antiretroviral treatment programs in similar pediatric populations.”

“The cohort comprised 2123 women who received antiretroviral therapy during pregnancy…and 1143 women who did not…After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not; the rate of low birth weight (<2500g) was [also similar]; and the rate of very low birth weight (<1500g) was 2% for the group that received antiretroviral therapy and 1% for the group that did not [that’s double]. The rates of low Apgar scores (<7) and stillbirth were also similar…[What the abstract omits is the evidence that combination antiretroviral therapy with protease inhibitors shows some worrying results (although not always statistically significant, because of the small size of this group (137 women)). Table 4 shows, after adjustment for other risk factors, a 50% greater risk of premature delivery (compared with no therapy), 36% of very premature delivery (<32 weeks), 70% of low birth weight and 142% increased risk of very low birth weight (<1500g). Obviously this means that the risks of these events were lower with monotherapy and combination therapy without a Protease Inhibitor. However, the abstract also does not mention that some baseline variables in the no-therapy group were distinctly different, and may represent important confounding factors. Women with no therapy all delivered in 1990-1994 versus 1994-1998 for women taking therapy during pregnancy. The rate of tobacco use was significantly higher in women taking no therapy (55% versus 34%), the rate of alcohol use (41% versus 23%) and, most importantly, the rate of illicit drug use during pregnancy (42% versus 23%)]…[This study] did not have information on early pregnancy loss, congenital abnormalities, or long-term outcomes for the infants. We were unable to assess the effect of the duration of antiretroviral therapy on the outcomes of pregnancy…some women [may have] started antiretroviral therapy too late to be at risk for premature delivery [i.e. after 32 weeks or after 37 weeks]”

“Potential fetal toxicity of antiretroviral prophylaxis include adverse pregnancy outcome, such as low birth weight, preterm delivery, or fetal/neonatal death, and congenital abnormalities. Possible short-term adverse effects on the woman and infant include hematologic abnormalities, liver or other organ dysfunction, rash, or serious toxicity causing death…Theoretical long-term risks of prophylaxis for the child include organ toxicity secondary to mitochondrial dysfunction, development of malignancy, or other unknown effects. For the child who becomes infected despite prophylaxis, concerns include development of antiretroviral drug resistance or an adverse effect on HIV disease course [i.e. exposure to AIDS drugs in the womb can make AIDS more likely to happen in the child]”

“Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART) . . . Currently, HAART combinations that include zidovudine (ZDV [AZT]) and lamivudine (3TC) are highly effective in preventing HIV-1 vertical transmission; most children are born with no evident adverse clinical effects. However, ZDV is a moderately strong transplacental carcinogen in mice, and potential long-term consequences of fetal exposure to most HAART combinations remain unknown . . . experiments were performed in Erythrocebus patas monkeys given human-equivalent drug exposure protocols. Pregnant monkeys were dosed with either no drug (n = 2), 40.0 mg ZDV/day . . . for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/day . . . for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC…values for ZDV-DNA incorporation were similar in fetuses exposed to ZDV alone and those exposed to ZDV plus 3TC. Values for 3TC-DNA in fetal organs were greater than or equal to values for ZDV-DNA, indicating that the total DNA damage sustained by fetuses exposed to both drugs was at least double that observed in fetuses exposed to ZDV alone. Telomere shortening, determined by Southern blot with a telomeric probe, was observed in most organs of the three animals exposed in utero to ZDV plus 3TC [but not with just ZDV/AZT]. Overall, these studies demonstrate that monkey fetuses exposed in utero to the combination ZDV plus 3TC sustain a higher level of drug-DNA incorporation and show evidence of more telomere damage than monkey fetuses exposed to ZDV alone.”

“149 (78%) of 192 children experienced moderate or worse toxicity while receiving initial therapy [in this trial of various combinations of 3 or 4 AIDS drugs], and 44 (23%) of 192 experienced severe or worse toxicity…The most commonly observed adverse events were skin rash (53(28%)); nausea/vomiting (44(23%)); and temperature >= 38.5C (40(21%))…Administration of initial randomized study treatments was permanently discontinued for children with (1) an HIV RNA copy number > 10,000 copies/ml (32(17%)); (2) toxicity of medication intolerance (13(7%)); or (3) other reasons, including poor adherence to the study regimen and parental request for withdrawal of the patient from the study (29(15%))”

“Although 17 (53%) of 32 patients [Dutch children who had not previously used protease inhibitors] experienced adverse events, combination therapy was well tolerated by almost all children…The most common indinavir-related side effects were as follows: diarrhea (in 6 children), vomiting (in 6), loss of appetite (in 5), headache (in 3), abdominal pain (in 4), and hematuria (in 5) [note that diarrhea and weight loss (associated with vomiting and loss of appetite) are two of 4 symptoms needed for an AIDS diagnosis in third world countries]”

“130 children were randomised [to placebo or 3 combinations of zidovudine, lamivudine and abacavir]...24 serious adverse events occurred in 18 children. Of these, four were clinical events: 1 death, one hypersensitivity reaction to abacavir, one stroke, and one vomiting [none on placebo]. Of the 20 laboratory grade 3 or 4 events, most frequent were neutropenia (12) and thrombocytopenia (3). 3 children in each of the NRTI groups had one or more episodes of neutropenia...6 children permanently stopped drugs after minor adverse events: vomiting, cutaneous reaction, fever assumed to be early hypersensitivity and anemia. 2 other children stopped abacavir permanently because of hypersensitivity reactions thought to be associated with abacavir [but later ‘judged’ not to be]”

“The frequency of seizures was studied in a prospective cohort of French children born to HIV-1-infected mothers. The analysis was restricted to the 4426 uninfected children, whether or not exposed to antiretrovirals....exposure to antiretrovirals was significantly associated with the risk of febrile [fever-associated] seizure: 24 of the 30 children who experienced such seizures had been exposed to antiretroviral drugs. The cumulative risk at 18 months was 11 [treated children] versus 4.1 not treated per 1000 [the paper notes that the risk in the general population the risk by 18 months was about 50% higher than in the untreated children, implying that due to limitations in the study the rate in the treated children might be similarly higher as many occurrences may have gone untreated]”

“From 1984 to 2000, 357 HIV positive pregnant women were assisted in the Hospital Universitario La Fe, Valencia (Spain). A total of 163 were under antiretroviral treatment: 71 zidovudine monotherapy, 44 polytherapy including a PI [Protease Inhibitor], and 48 polytherapy without a PI...there were seven stillborn children: one (0.5%) in women without treatment, two (2.8%) in the monotherapy group, none in the group with polytherapy without a PI, and four (9.1%) with polytherapy including a PI...Further studies should be carried out to assess the safety of these therapies [drug regimes including protease inhibitors]”

“The authors report a case of a full-term male neonate [baby] born to a 34-year-old woman with heterosexually acquired asymptomatic HIV infection...receiving zidovudine, stavudine and efavirenz therapy before pregnancy...[once she was determined to be pregnant] antiretroviral therapy was switched to...lamivudine, stavudine and nelfinavir at 24 weeks of pregnancy...The baby was born at the 38th week...presenting with a lumbo-sacral mass compatible with a myelomeningocele [sac containing part of the spinal cord and cerebrospinal fluid caused by failure of the neural tube to close. In the accompanying photo this is approximately the size of the baby’s head]...In animal studies, efavirenz crosses the placenta...Teratogenic effects have been observed in 3 out of 20 fetuses from efavirenz-treated cynomolgus monkeys [but teratogenic effects have also been observed with AZT]”

“CD4 cell percentage decrease in group 1 [HIV-positive children with normal CD4 cell counts], despite HAART. In CDC groups 2 [moderately low CD4 cell counts] and 3 [low CD4 cell counts], the percentage increased with slopes of 0.057 [hardly at all] and 0.3 [moderately]…The effect of HAART on HIV-1 load in our group of children did not differ significantly on the basis of immunologic status at the time of initiation of HAART. Total virus suppression by current methods of detection was achieved in 34.8%, 25% and 32% [in children in groups 1, 2 and 3]”

“The optimum time to initiate HAART [Highly Active Anti-Retroviral Therapy] in asymptomatic HIV disease remains controversial because of difficulties with long-term adherence, the occurrence of drug resistance, and the development of side effects that are not benign [i.e. potentially fatal], such as lipodystrophy [fat redistribution], hyperlipidemia [serious metabolic abnormality] with associated diabetes mellitus and cardiovascular complications, lactic acidosis [build up of lactic acid in the blood], and mitochondrial toxicity [mitochondria are energy regulating organelles found in every cell in the body]. Long-term effects on growth and health are not known because controlled studies were limited to 2 years of follow-up...In our study, HAART had the greatest effect on immune reconstitution when started in patients with the greatest immunosuppression [lowest CD4 cell counts]. The effect on virus load was similar among the groups, as described elsewhere for adults [i.e. HAART does not suppress ‘viral load’ believed by some to be a measure of the amount of HIV]. These observations raise doubt of the need to start potent antiretroviral therapy in asymptomatic HIV infection when significant viremia is used as the only decision criterion...Our results support the delay of HAART for asymptomatic HIV infection until more advanced stages (immunological or clinical) of the disease occur. Additional long-term clinical studies are needed to adequately assess the safety of delaying early HIV-1 treatment with HAART in children. Such studies should assess, in particular, the risk of central nervous system HIV infection and the clinical use of markers of disease progression in addition to or in lieu of HIV titer in children.”

“The effect of highly active antiretroviral therapy (HAART) in 85 children infected with human immunodeficiency virus type 1 (HIV-1) was compared retrospectively among Centers for Disease Control and Prevention (CDC) immunologic groups 1-3...The results support the option of delaying HAART in early asymptomatic HIV-1 disease in children and the use of other markers of disease progression, in addition to virus load.”

“children who had received combination therapy were estimated to have a non-[statistically-]significantly increased rate of clinical progression”

“The study cohort included 92 HIV-1-infected and 439 uninfected children...FTT [failure to thrive among children of HIV-positive women] was associated with a history of pneumonia, maternal use of cocaine, crack or heroin during pregnancy, infant CD4+ T-cell count and any antiretroviral therapy by 3 months of age...Antiretroviral therapy (nonprotease inhibitor) was independently associated with FTT in our cohort...ZDV [AZT], in particular, alters mitochondrial metabolism and may have direct nutritional effects”

“[Of 195 mother-infant pairs] 9 children (4.6%) with congenital abnormalities were reported. Compared with the 148 infants not exposed to ART or folate antagonists [including PCP therapy with cotrimoxazole or pyrimethamine] during the first trimester, first trimester exposure to both therapies (n=13 [23%]) was associated with a 7-fold increased risk of congenital abnormalities. No congenital abnormalities were observed in the 34 infants exposed to either ART alone or folate antagonists alone during the first trimester…severe immunosuppression [very low CD4 cell counts] has so far not been associted with fetal abnormalities and is unlikely to be a confounder”

“Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and 5 naive to any antiretroviral treatment (untreated). 6 HAART-treated children showed clinical evidence of lipodystrophy [abnormal fat redistribution]...HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children.”

“Risk of progressing to severe immunodeficiency [abnormal CD4 cell counts] was 64% higher [in this group of HIV-positive European children, mostly with mothers involved with intravenous drugs] when receiving ART [Anti-Retroviral Therapy] [Note that the risk of death was higher in untreated children in the first year and 6th to 10th year, but lower in the 2nd to 5th year. No information was given on the association between living conditions, fetal exposure to drugs and illness.]”

“A total of 397 adverse events, 180 biological (ie, involving hematologic or blood chemistry alterations) and 217 clinical in nature, were reported among 238 of the 452 children in the lamivudine[3TC]- zidovudine[AZT] cohort. Altogether, 151 hematologic adverse events, defined as moderate to severe according to the age-adjusted ACTG classification,17 occurred during exposure to study drugs. These mostly consisted of neutropenia (81 cases) or anemia (68 cases), leading to blood transfusion because of clinical symptoms in 9 infants (5 had mild symptoms (pallor or tachycardia [abnormally rapid heartbeat]) and 4 had severe symptoms (cardiac insufficiency or dyspnea)) and to premature treatment discontinuation for 19 children. Of the children with hematologic...Liver abnormalities without proven cause were recorded in 6 children ...Of the 217 clinical adverse events reported among children, most were [judged to be] due to a known cause unrelated to study drugs [but without a true control, this is impossible to say with assurance]... 16 children (4%) had major birth defects, including 4 cardiac malformation cases, 4 cases of polydactyly, 3 talipes cases, and 1 case each of congenital diaphragmatic hernia, hydronephrosis, imperforate anus, genu recurvatum with a suburethral cyst, and hypospadia. 1 child each had Down syndrome, Ito nevus, and sickle cell anemia...Neurologic signs/symptoms were reported in 12 children who did not have HIV infection and had no other known infectious or genetic disease.”

“Adverse Events in the Lamivudine-Zidovudine Group: 124 adverse events were reported in 99 [pregnant] women. Most of these events were [judged to be] related to documented pregnancy-related or postpartum complications [but without a placebo-control group, this cannot be verified]. 2 women discontinued study drugs because of elevation of transaminase levels...Hemoglobin levels of less than 8 g/dL occurred in 29 women, half of whom had a known cause of anemia not related to study drugs. There were no cases of lactic acidosis. 38 adverse events were reported related to fetal well-being in 37 pregnancies”

“[A news article on this oral abstract] reported three cases of unexplained neonatal lactic acidosis and hypoglycemia, either alone or in combination, in non-HIV-infected infants exposed perinatally to Retrovir (zidovudine, AZT), Epivir (lamivudine, 3TC) and Viramune (nevirapine). At birth, two of the three infants had severe acidosis, with a pH less than 7.1, and the third infant, as well as one of the 2 infants with lactic acidosis, had severe and persistent hypoglycemia.”

“A total of 195 children were randomised to zidovudine (immediate [IMM]) or matching placebo (deferred[DEF]) in a multicentre double blind trial in vertically HIV infected children with early disease (the PENTA 1 trial). Median follow up in the blinded phase was 1.9 years. Thereafter, individual children were unblinded...Four children (three IMM, one DEF) died during the blinded phase. In two (both IMM) children, death was HIV related...There was an early delay in progression to AIDS in favour of the IMM group during the first year of follow up, followed by a non-significant reversal of that trend in years 3 to 5...Grade 3 or 4 neutropenia [abnormally low neutrophil white blood cell counts] was the most frequent serious adverse event (seven events in four IMM; two events in two DEF). Two children in each group had grade 4 elevations of transaminases [liver enzymes]. Significantly more children in the IMM (n = 13) compared with the DEF (n = 3) group stopped therapy because of an adverse event (all grades, p = 0.02), most commonly because of neutropenia (three IMM, zero DEF), or nausea or vomiting (nine IMM, two DEF)...Our data show that after 3 months of age, many vertically infected children have slow progression of disease, in the absence of therapy. With uncertainties about long term efficacy and toxicity, a case can be made for delaying ART in the well asymptomatic child.”

“Doctors throughout Europe are being warned of a potentially fatal side effect if pregnant women infected with HIV take Bristol-Myers Squibb's AIDS drugs Zerit (stavudine) and Videx (didanosine)...the European Medicines Evaluation Agency (EMEA) said seven cases of lactic acidosis--three of them fatal--had been reported worldwide in pregnant women taking the two drugs in combination...Lactic acidosis occurs when the body's cells are unable to convert food into usable energy. The condition causes excess acid to accumulate in the body, potentially damaging vital organs such as the liver and pancreas...the EMEA pointed out that lactic acidosis is a known side effect of the class of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). The use of this class of drugs is not recommended during pregnancy unless the potential benefit clearly outweighs the potential risks [note that AZT is a drug in this class that is heavily promoted for use during pregnancy].”

“Examination of the genotoxic and mutagenic effects of two NRTIs [Nucleoside Reverse Transcriptase Inhibitors], zidovudine (AZT) and didanosine (ddI) in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure...Dose-related increases in DNA incorporation of AZT and mutagenicity at the HPRT and TK loci...were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans...children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life”

“We found that lower height z score and non-white race were associated with a change in functional status scores in all scales. Other significant univariate predictors of change in at least 1 category included current clinical symptoms, and antiviral medications (mean: -10.8-point vs -1.9-point change in Total Score).”

“Given that the long-term medical consequences of HAART are unclear, the refusal to implement this therapy despite its possible medical benefit is within the range of appropriate parental decision making.”

“Newborn outcomes [27 pregnancies mostly among women who tested positive for illegal drugs]…[include] 5 infants born with birth weights less than 2500g [5-1/2 lb] were born to women who received a protease inhibitor…There was 1 full-term, unexplained stillbirth with no gross birth defects. The mother had started taking zidovudine [AZT] and lamivudine at 15 weeks’ gestation. The infant with microcephaly [abnormally small head] was born [to a mother who was a heroin user] taking zidovudine during the first trimester, and lamivudine was added at 16 weeks’ gestation.”

“Two popular HIV drugs may cause birth defects and should be avoided by pregnant women until more is known about their effects, German researchers said on [September 28, 1999]. They found the two drugs, both members of a class known as protease inhibitors, caused abnormal eye development in baby rats. Kai Riecke and colleagues at Freie Universitat Berlin gave the two drugs, Merck's indinavir, known as Crixivan, and Abbott Laboratories' Norvir, or ritonavir, to pregnant rats. They had to stop the ritonavir after a week because it made the rats sick. The rats stayed on the indinavir for the full terms of their pregnancies. Seven of the 236 baby rats exposed to indinavir in the womb were born missing one eye, and two of the 113 baby rats exposed to ritonavir had a missing eye, Riecke's team reported. Fur and teeth also developed later than normal in some of them, they said.”

“Adverse events and toxic effects: The rates of maternal serious adverse events were similar in the two groups (4·4% in the zidovudine group, 4·7% in the nevirapine group [and there was no placebo]). One mother in the zidovudine group died 2 weeks after delivery and had bronchopneumonia. One serious event, anaemia, was possibly associated with zidovudine, but excessive blood loss at delivery may have accounted for the anaemia. The occurrence of clinical or laboratory abnormalities in mothers was similar in the two groups (82·2% in the zidovudine group and 80·7% in the nevirapine group had at least one such event). The most frequent adverse clinical event was bacterial or viral infection, occurring in 18·2% of women receiving zidovudine and 20·4% of those receiving nevirapine, followed by parasitic infection in 12·4% and 15·0%, respectively, followed by anaemia in 10·5% and 13·1%, respectively. Nine mothers (four in the zidovudine group, five in the nevirapine group) had maculopapular rash, but no case was serious.

In babies, adverse events were uniformly recorded up to age 6 weeks, whereas only serious adverse events continued to be recorded at each visit up to age 18 months. The rate of serious adverse events in the two groups was similar up to the 18-month visit (19·8% in the zidovudine group, 20·5% in the nevirapine group), with the median age at last visit being 183 days (IQR 102–276). 38 (6·8%) babies died (22 [7·9%] in the zidovudine group, 16 (5·7%) in the nevirapine group). The most frequent cause of death was pneumonia, followed by gastroenteritis, diarrhoea, dehydration, and sepsis. The most frequent causes of serious adverse events within 56 days of birth were sepsis, pneumonia, fever, congenital anomaly, asphyxia, and dyspnoea. Of the 59 serious adverse events reported in the first 56 days of life, those that occurred in four (1·4%) babies in the zidovudine group and in two (0·7%) babies in the nevirapine group were judged to be possibly, but unlikely to be, related to study drug. In the four babies in the zidovudine group, adverse events were sudden-infant death syndrome 24 h after delivery, transient tachypnoea at birth requiring oxygen, birth asphyxia with death due to fetal distress after caesarean section, and presumed pneumonia 4 days after birth. In the two babies in the nevirapine group, adverse events were transient respiratory distress at birth with meconium staining requiring oxygen, and a non-macerated stillbirth to a mother who received nevirapine 3·5 h before delivery.

18 babies had maculopapular rash, no case of which was serious (nine in the zidovudine group, nine in the nevirapine group). Within the first 56 days of life, 22 babies had grade 3 anaemia (nine in the zidovudine group, 13 in the nevirapine group), with haemoglobin values ranging from 85–118 g/L. No case was judged to be serious or clinically important. The frequency and severity of laboratory-detected toxic effects, including neutropenia, thrombocytopenia, and abnormalities in creatinine or bilirubin, were similar in the two groups.”

“There were 5 serious adverse events [out of 8 participants!] including two deaths in the infants in cohort 1 [Nevirapine to mother only]. Only one of the five serious adverse events was thought by the investigators to be possibly, but not likely study drug related [but, without a control group, it is possible that all adverse events were related]...In cohort 2 [Nevirapine to mother and child] there were 7 serious adverse events [out of 13 participants!], including 2 infant deaths, although none were related to the study drug”

“On January 22, 1997 Tia Dubay died of complications directly related to her HIV condition despite being on a medically prescribed drug therapy treatment. She died a few days short of her fourth birthday and suffered terribly during the last many months of her life. Understandably, this circumstance shook what faith Ms. Emerson had with such powerful drug therapy. However, on her family doctor's advice she reluctantly started Nikolas on similar drug therapy in the fall of 1997.”

“11 [of 90] children had been withdrawn from study for disease progression [in other words, it didn't work for them] and 10 because of possible lamivudine-related toxicity, and 6 had died...In summary, this study confirms that lamivudine can be safely given to children with HIV infection and that it has a favorable pharmacokinetic profile and evidence of antiretroviral activity”

“Stavudine [d4T] was well-tolerated [by a group of 37 HIV+ children] and there were no dose-related clinical or laboratory adverse events...Thirty-five of 37 subjects experienced serious clinical adverse events, including infection (33 subjects), lymphadenopathy (19 subjects), hepatosplenomegaly (15 subjects), chills and fever (12 subjects), and development of an AIDS-defining condition (four subjects)...Clinical adverse events of lesser severity that were reported by more than 20% of subjects included rhinitis (76%), cough (70%), diarrhea (68%), rash (62%), nausea and vomiting (51%), abdominal pain (43%), anorexia (41%), respiratory disorder (38%), headache (35%), pharyngitis (32%), pruritis (30%), pain (22%), peripheral neurologic symptoms (22%), and nervousness (22%)”

“Transfusion was required in 14 [of 21 AZT-treated] patients because of low levels of hemoglobin. Dose-limiting neutropenia occurred in most patients who received doses of 1.4 mg per kilogram per hour or more...The major limitation of the therapy was hematologic toxicity--a decrease in both the hemoglobin concentration and the white-cell count...Regardless of the starting dose, nearly all patients had a transient drop in their neutrophil counts within 10 days of the initiation of AZT therapy...In three of the five children who died, evidence of a response to AZT, particularly neurodevelopmental improvement, was present at the time of death [i.e. the children were getting better, only they died first]”