Paul M. Bakaki

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

BACKGROUNDnThe AIDS Clinical Trials Group protocol 076 zidovudine prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a significant decrease in vertical HIV-1 transmission in non-breastfeeding women in developed countries. We compared the safety and efficacy of short-course nevirapine or zidovudine during labour and the first week of life.nnnMETHODSnFrom November, 1997, to April, 1999, we enrolled 626 HIV-1-infected pregnant women at Mulago Hospital in Kampala, Uganda. We randomly assigned mothers nevirapine 200 mg orally at onset of labour and 2 mg/kg to babies within 72 h of birth, or zidovudine 600 mg orally to the mother at onset of labour and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily to babies for 7 days after birth. We tested babies for HIV-1 infection at birth, 6-8 weeks, and 14-16 weeks by HIV-1 RNA PCR. We assessed HIV-1 transmission and HIV-1-free survival with Kaplan-Meier analysis.nnnFINDINGSnNearly all babies (98.8%) were breastfed, and 95.6% were still breastfeeding at age 14-16 weeks. The estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were: 10.4% and 8.2% at birth (p=0.354); 21.3% and 11.9% by age 6-8 weeks (p=0.0027); and 25.1% and 13.1% by age 14-16 weeks (p=0.0006). The efficacy of nevirapine compared with zidovudine was 47% (95% CI 20-64) up to age 14-16 weeks. The two regimens were well tolerated and adverse events were similar in the two groups.nnnINTERPRETATIONnNevirapine lowered the risk of HIV-1 transmission during the first 14-16 weeks of life by nearly 50% in a breastfeeding population. This simple and inexpensive regimen could decrease mother-to-child HIV-1 transmission in less-developed countries.

Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial

BACKGROUNDnIn 1999, we reported safety and efficacy data for short-course nevirapine from a Ugandan perinatal HIV-1 prevention trial when 496 babies were followed up to age 14-16 weeks. Safety and efficacy data are now presented for all babies followed up to 18 months of age.nnnMETHODSnFrom November, 1997, to April, 1999, HIV-1 infected pregnant women in Kampala, Uganda, were randomly assigned nevirapine (200 mg at labour onset and 2mg/kg for babies within 72 h of birth; regimen A) or zidovudine (600 mg orally at labour onset and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily for babies for 7 days, regimenB). Infant HIV-1 testing was done at birth, age 6-8 and 14-16 weeks, and age 12 months by HIV-1 RNA PCR, and by HIV-1 antibody at 18 months. HIV-1 transmission and HIV-1-free survival were assessed using Kaplan-Meier analysis. We recorded adverse experiences through 6-8 weeks postpartum for mothers, and 18 months for babies. Efficacy analyses were by intention to treat.nnnFINDINGSnWe enrolled 645 mothers to the study: 313 were assigned regimen A, 313 regimen B, and 19 placebo. Eight mothers were lost to follow-up before delivery. 99% of babies were breastfed (median duration 9 months). Estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were 10.3% and 8.1% at birth (p=0.35); 20.0% and 11.8% by age 6-8 weeks (p=0.0063); 22.1% and 13.5% by age 14-16 weeks (p=0.0064); and 25.8% and 15.7% by age 18 months (p=0.0023). Nevirapine was associated with a 41% (95% CI 16-59) reduction in relative risk of transmission through to age 18 months. Both regimens were well-tolerated with few serious side-effects.nnnINTERPRETATIONnIntrapartum/neonatal nevirapine significantly lowered HIV-1 transmission risk in a breastfeeding population in Uganda compared with a short intrapartum/neonatal zidovudine regimen. The absolute 8.2% reduction in transmission at 6-8 weeks was sustained at age 18 months (10.1% [95% CI 3.5-16.6]). This simple, inexpensive, well-tolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries.

Detection of Kaposi Sarcoma—Associated Herpesvirus DNA in Saliva and Buffy-Coat Samples from Children with Sickle Cell Disease in Uganda

Among 233 children, Kaposi sarcoma-associated herpesvirus (KSHV) DNA was detected in 43% of children seropositive for both K8.1 and orf73, in 29% of children seropositive for K8.1 only, in 14% of children seropositive for orf73 only, and in 7% of children seronegative for both K8.1 and orf73; among 228 mothers, KSHV DNA was detected in 27%, 25%, 4%, and 1%, respectively. KSHV DNA was detected more frequently and at higher levels in saliva than in buffy-coat samples and in children than in mothers. In both children and mothers, detection in saliva was associated with detection in peripheral blood. Detection was associated with K8.1 seropositivity, younger age, and high household density, indicating the importance of in-household person-to-person transmission, likely via saliva.

Water, Socioeconomic Factors, and Human Herpesvirus 8 Infection in Ugandan Children and Their Mothers

Background:Human herpesvirus 8 (HHV-8) infection is common in sub-Saharan Africa, but its distribution is uneven. Transmission occurs during childhood within families by unclear routes. Methods:We evaluated 600 Ugandan children with sickle cell disease and their mothers for factors associated with HHV-8 seropositivity in a cross-sectional study. HHV-8 serostatus was determined using an HHV-8 K8.1 glycoprotein enzyme immunoassay. Odds ratios for seropositivity were estimated using logistic regression, and factor analysis was used to identify clustering among socioeconomic variables. Results:One hundred seventeen (21%) of 561 children and 166 (34%) of 485 mothers with definite HHV-8 serostatus were seropositive. For children, seropositivity was associated with age, mothers HHV-8 serostatus (especially for children aged 6 years or younger), lower maternal education level, mothers income, and low-status fathers occupation (P < 0.05 for all). Using communal standpipe or using surface water sources were both associated with seropositivity (OR 2.70, 95% CI 0.80-9.06 and 4.02, 95% CI 1.18-13.7, respectively) as compared to using private tap water. These associations remained, albeit attenuated, after adjusting for maternal education and childs age (P = 0.08). In factor analysis, low scores on environmental and family factors, which captured household and parental characteristics, respectively, were positively associated with seropositivity (Ptrend < 0.05 for both). For mothers, HHV-8 seropositivity was significantly associated with water source and maternal income. Conclusions:HHV-8 infection in Ugandan children was associated with lower socioeconomic status and using surface water. Households with limited access to water may have less hygienic practices that increase risk for HHV-8 infection.

High Levels of Epstein-Barr Virus DNA in Saliva and Peripheral Blood from Ugandan Mother-Child Pairs

In Africa, Epstein-Barr virus (EBV) is associated with Burkitt lymphoma. We measured levels of EBV DNA in saliva and buffy coats from 233 asymptomatic Ugandan children with sickle cell disease and their mothers by quantitative real-time polymerase chain reaction. EBV DNA was detected in saliva from 90% of the children (median [interquartile range [IQR]] level, 5.2 [4.2-6.0] log(10) copies/mL of saliva) and 79% of the mothers (median [IQR] level, 4.8 [3.7-5.6] log(10) copies/mL of saliva) (P < .001). EBV DNA was detected in buffy coats from 86% of the children (median [IQR] level, 2.5 [2.2-2.9] log(10) copies/1 x 10(6) peripheral white blood cells [PWBCs]) and 72% of the mothers (median [IQR] level, 2.7 [2.4-3.1] log(10) copies/1 x 10(6) PWBCs) (P = .24). Detection of EBV DNA in saliva was positively correlated with detection in buffy coats. EBV DNA was detected more frequently in saliva and buffy coats than was human herpesvirus 8 DNA. Our results indicate that EBV infection persists, with virus readily detectable in saliva and buffy coats from persons without apparent symptoms in Africa.

Molecular Evidence for Mother-to-Child Transmission of Kaposi Sarcoma–Associated Herpesvirus in Uganda and K1 Gene Evolution within the Host

BACKGROUNDnEpidemiological studies of Kaposi sarcoma (KS)-related herpesvirus (KSHV) indicate that having a KSHV-seropositive mother is a risk factor for KSHV infection in children.nnnMETHODSnWe determined the KSHV K1 sequences in concordantly polymerase chain reaction-positive Ugandan mother-child pairs, to ascertain whether they shared the same viral strain. We also examined sequences amplified from saliva and buffy coat samples from the same subjects, to investigate potential intrasubject sequence differences.nnnRESULTSnWe obtained K1 sequences from 6 of 10 mother-child pairs. In 1 pair, the subtypes differed between mother and child. The mother and child in 2 other pairs shared the same subtype, but the sequences differed. The mother and child in 2 pairs shared KSHV strains with exact (100%) nucleotide homology. The last pair showed evidence of viral strain concordance between mother and child but also showed evidence of evolution of the viral sequence within the child. Of 26 study subjects, 19 showed no evidence of intrasubject K1 sequence variability, but, in 7 subjects, all of whom were children, amino acid variation of 1%-4% was observed.nnnCONCLUSIONSnOur findings are consistent with KSHV transmission from maternal and nonmaternal sources in KS-endemic regions. Our results also provide evidence for ongoing evolution of the K1 gene in KSHV-infected children.

Epidemiologic and clinical features of HIV-infected and HIV-uninfected ugandan children younger than 18 months

Methods: Groups of HIV‐infected and HIV‐uninfected infants younger than 18 months (mainly younger than 6 months) were compared to identify clinical features that could differentiate the two groups. The HIV‐infected group also was compared with HIV‐infected children older than 18 months. Recruitment was as follows for the group younger than 18 months: 708 children admitted with sepsis and clinical features suggestive of HIV infection were screened for HIV1 and HIV2 by HIV enzyme‐linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR) was undertaken on all ELISA‐seropositive blood samples (270). HIV infection was confirmed in 136 (19.2%), 438 (61.9%) were HIV‐seronegative, 27 (3.8%) were HIV seroreverters, 36 (5.1%) were HIV‐seropositive but PCR negative (uninfected), and 71 (10.0%) were indeterminate. One hundred thirty‐six HIV‐infected children were compared with 501 uninfected children. Confirmed HIV‐infected children older than 18 months attending the pediatric HIV clinic were compared with the 136 HIV‐infected children younger than 18 months. Results: Under 18 months, the median age of HIV‐infected children (n = 136) was 4.0 months (range, 3 d‐18 mo) and the median age of the uninfected children (n = 501) was 1.0 month (range, 3 d‐18 mo). HIV‐infected children were more likely to have had injections, chloroquine, and nystatin, and to have attended a health center or hospital (p < .001). In the HIV‐infected group, the Z score for weight‐for‐age was ‐1.75, length‐for‐age ‐0.78, and weight‐for‐length 1.86, significantly lower scores than those of the uninfected group, which were ‐0.60, ‐0.23, and 3.05, respectively (p < .05). The mean head circumference was below the third percentile in 40% of HIV‐infected compared with 22% of uninfected children (p < .001). Overall, 56 (8%) children had marasmus, 6 (0.8%) kwashiorkor, and 3 (0.4%) marasmic kwashiorkor. Sixteen percent of the HIV‐infected and 7% of uninfected children had marasmus (p < .05). The 1989 revised World Health Organization clinical criteria for diagnosis of AIDS had sensitivity, specificity, and positive predictive values of 28%, 98%, and 93%, respectively. Older than 18 months (n = 109), the median age was 24 months (range, 18‐60 mo). The following were significantly more common in HIV‐infected children older than 18 months than in those younger than 18 months: bacille Calmette‐Guérin vaccination scar, parotid enlargement, nonspecific generalized dermatitis, and chronic diarrhea (p < .001). Oral candidiasis was more common in the group younger than 18 months (p < .001). In infants examined in the hospital for infective conditions, oropharyngeal candidiasis, ear discharge, dermatologic disorders, generalized lymphadenopathy, lobar consolidation, hepatosplenomegaly, and failure to thrive, especially marasmus, were important indicators of HIV infection.

Effectiveness of repeat single-dose nevirapine for prevention of mother-to-child transmission of HIV-1 in repeat pregnancies in Uganda

Background: Single-dose nevirapine (SDNVP) is widely used to prevent mother-to-child HIV transmission in resource-limited settings. Given detection of resistant mutants among women who receive SDNVP, concerns have arisen over the efficacy of SDNVP in repeat pregnancies. Methods: Retrospective data were collected from SDNVP-exposed and -unexposed women from the HIV Network for Prevention 012 trial who subsequently received SDNVP in another pregnancy. Prospective data were collected from pregnant women who were SDNVP exposed or unexposed before delivery. Kaplan-Meier and Cox regression analyses were used to estimate rates of HIV infection and HIV-free survival among infants born to women with or without prior SDNVP exposure. Results: In the retrospective cohort, the infection rates were 11.3% and 16.7% for 104 infants of NVP-exposed and -unexposed mothers, respectively (P = 0.41). In the prospective cohort, among 103 infants of NVP-exposed and -unexposed mothers, the 12-month infant HIV infection rates were 20.5% and 18.7% (P = 0.81) and HIV-free survival rates were 74.4% and 78.1% (P = 0.66), respectively. Conclusions: There was no increased risk of infant HIV infection among SDNVP-exposed women compared with -unexposed women. These findings support current international guidelines to offer SDNVP to HIV-infected pregnant women, regardless of previous SDNVP exposure, when more complex prophylaxis regimens are not available.

IgA antibodies to human immunodeficiency virus in serum, saliva and urine for early diagnosis of human immunodeficiency virus infection in Ugandan infants

The value of HIV-1 IgA antibodies for early diagnosis of HIV infection in infants in serum, saliva and urine was investigated at Mulago Hospital, Kampala. Sensitivity and specificity in serum of HIV-infected infants at different ages were: 0 to 1 months, 88 and 95%; 1 to 3 months, 88 and 97%; 4 to 6 months, 80 and 96%. They decreased between 67 and 77% and 80 to 91%, respectively, in older age groups. Sensitivity for saliva was lower (53 to 79%) and urine only 37 to 62%, although specificity was reasonably high (>85%). The high proportion of infants with raised HIV IgA in the first months of life (88%) may represent prenatal infection. Sensitivity of serum and especially salivary and urinary HIV IgA is too low to be of practical value for early diagnosis of HIV infection in infants.