Reginald Boulos

Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection

BACKGROUND Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals. METHODS We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival. FINDINGS Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 4.0 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time. INTERPRETATION Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected, PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined.

Response to measles vaccine in Haitian infants 6 to 12 months old. Influence of maternal antibodies, malnutrition, and concurrent illnesses.

To study the factors affecting the serologic response to measles vaccination, we evaluated 595 Haitian infants from 6 through 12 months of age, and their mothers, at the beginning of an immunization program. Thirty-four per cent of the infants had preexisting serologic evidence of measles infections by 11 months of age. Among infants more than nine months of age, those who had had measles had a significantly lower nutritional status than those who had not (P less than 0.01). After vaccination, seroconversion rates increased from 45 per cent at 6 months to 100 per cent at 12 months. The lowest rate of vaccine failure compatible with acceptably low rates of natural infections could be achieved by vaccination after eight months of age. Infants born to mothers with low levels of antibody to measles (hemagglutination-inhibition antibody titers less than 1:40) were significantly more likely to have had natural measles (P less than 0.01) or to have seroconversion after vaccination (P less than 0.001) at 6 to 10 months of age than were infants born to mothers with higher of age than were infants born to mothers with higher titers. Malnutrition and acute infections did not affect seroconversion rates. These data support the World Health Organization recommendation to administer measles vaccine in under-developed countries as soon after nine months of age as possible, regardless of nutritional status or the presence of minor illnesses.

Successful immunization of infants at 6 months of age with high dose edmonston-zagreb measles vaccine

A group of 2097 Haitian infants 6 to 11 months of age were randomized to receive Schwarz or Edmonston-Zagreb strain measles vaccines containing 10− to 500-fold more vaccine viral particles than standard potency vaccines. No unusual adverse reactions were noted. Edmonston-Zagreb vaccines were more effective than equivalent doses of Schwarz vaccines as measured by the proportion of vaccinated children with measles antibody concentrations ≥200 mIU/ml 2 months after vaccination and the persistence of antibody at 18 to 24 months of age. High titer Edmonston-Zagreb vaccine administered at 6 months of age induced antibody concentrations ≥200 mIU/ml in 83% of infants by plaque reduction neutralization and 93% of infants by enzyme-linked immunosor-bent assay with high rates of antibody persistence at 12 to 24 months of age. The World Health Organization recommends high titer Edmonston-Zagreb measles vaccines for routine use at 6 months of age in areas where measles is an important cause of mortality in young infants.

The utility of verbal autopsies for identifying HIV-1-related deaths in Haitian children

Objective:To determine whether deaths among Haitian infants born to HIV-1-sero-negative women could be distinguished from deaths among children born to HIV-1-seropositive women using the verbal autopsy technique. Methods:Mothers of 315 Haitian children who died were interviewed about events leading to the childs death. Three physicians independently reviewed interview data and determined the probable cause of death without knowledge of maternal HIV-1 status or hospital records. The underlying causes of death assigned to the infants were analyzed to determine whether maternal HIV status could be predicted. Results:There was good agreement among the physicians (χ = 0.62) and 90% agreement between hospital records and the verbal autopsy diagnosis. Compared with children born to HIV-1-seronegative women, deaths in children born to HIV-1-seropositive mothers were more likely to be ascribed to a presumptive diagnosis of AIDS (37 versus 21%; P = 0.01). The sensitivity and specificity of verbal autopsies for identifying deaths associated with maternal HIV-1 infection ranged from 37 to 59% and from 69 to 79%, respectively, depending on the classification system used. The predictive positive value of a death believed to be consistent with pediatric HIV-1 infection was 26–30% and the predictive negative value was 85–90%. Conclusion:Verbal autopsies may be useful for distinguishing certain causes of death, but have limited utility for distinguishing deaths associated with maternal HIV-1 infection from deaths among children born to HIV-1-seronegative women.

Introduction of partner referral and treatment for control of sexually transmitted diseases in a poor Haitian community.

Focus group discussions were held with women attending slum-based antenatal clinics and with male partners of pregnant women separately to evaluate knowledge and attitudes regarding sexually transmitted diseases (STDs) and acceptability of a proposed antenatal STD screening and treatment programme, including partner management. Subsequently, antenatal women found to have a STD were asked to refer their partner(s) for STD treatment. The institutions routine procedure of internal referral to the curative center was evaluated for loss to follow-up. Focus group participants described common STD syndromes, knew that a pregnant woman could transmit a STD to her child, and knew that all sex partners needed to be treated for STDs. Discussion participants disagreed on the possibility of asymptomatic STDs and mentioned other ways of contracting STDs beside sexual transmission. The response to the proposed programme was positive. Of 331 male partners named by antenatal women who were found to have at least one STD, 101 (30%) presented at the clinic through index referral, and an additional 38 (11.5%) presented because of health worker referral. Of the 59 men sent to the curative center for care, only 26 (44%) received treatment. The study demonstrated that in Haiti, partners of antenatal STD patients can be treated without apparent adverse effects. However, internal referrals to separate treatment centres should be avoided. Following this study, education efforts have emphasized the curable nature of STDs, the threat of vertical transmission, and frequent asymptomatic presentation of STDs to promote prevention and treat more partners of STD patients.

Maternal IgG1 and IgA antibody to V3 loop consensus sequence and maternal-infant HIV-1 transmission

MatemaI lgG1 aod IgA antibody to V3 loop coosensus seqwnce and matemaI-infant HIV-1 trtmsmissioa Markham R.B.; Coberly J.; Ruff A.J.; Hoover D.; Gomez J.; Holt E.; Desormeaux J.; Boulos R.; Quinn T.C.; Halsey N.A. USA LANCET 1994 343/8894 (390-391) Maternal-infant transmission of HIV-I occurs in l3-40% of pregnancies. Studies of transmission of maternal immunity to HIV antigens have used antigens from viruses not represented of clinical isolates and have been conflicting. Using a consensus peptide sequence based on HIV isolates found in Haiti, we found that Haitian mothers who transmitted infection to their offspring had significantly higher mean concentrations of IgGl antibodies to the V3 loop of the primary neutralising domain of the viral envelope (gp 160) than non-transmitters (P = 0.02). Concentrations of IgA antibody to this domain were similar in transmitters and non-transmitters.

Early diagnosis of perinatal HIV infection by detection of viral specific IgA antibodies

Early tllqpds of perinatal HIV infection by detection of viralspecifk IgA antibodi~ Quinn TC,‘Kline RL, Halsey N; Hutton N; RutT A; Butz A; Boulos R; Modlin JF Blalock 1111, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21205, USA J AM MED ASSOC 1991 266124 (3439-3442) Objectives To evaluate the clinical utility of a human immunodeficiency virus (HIV)&4 serological assay for diagnosis of perinatahy acquired HIV infection. Design Coded serum samples prospectively collected from children born to HIVinfected mothers and uninfected mothers were analyzed by HIV-IgA immunoblot. Setting A university hospital in Baltimore, MD and an outpatient clinic in Port-au-Prince, Haiti. Population Five hundmd thirty-nine serum samples were obtained sequentially from 278 children born to HIVinfected women (116 from The Johns Hopkins Hospital and 62 from Port-au-Prince) and from 42 control children born to HIV-seronegative children in Port-au-Prince. Outcome Measures Results from the HIV-IgA serological assays were compared with the known infection status of the child at 15 months of age as determined by the standard IgG Western blot and the clinical classification of the Centers for Disease Control. Sensitivity, specificity and predictive values were calculated at different ages and collectively for children 3 months of age or older. Results The HIV-IgA assay was positive in one of six specimens from HIV-infected children under 1 month of age, six of nine specimens from infected children at 3 months of age and 160 of 161 specimens from 47 HIV-infected children 6 months of age or older. Of 334 specimens from 243 uninfected children, 333 were negative by the HIV-IgA assay. The overall sensitivity and the specificity of the IgA assay for children older than 3 months of age were 97.6% and 99.7% and the positive and negative predictive values were 99.4% and 98.7%, respectively. Conclusion Although the HIV-@4 assay had a low sensitivity within the first months of life, the high sensitivity, specificity and predictive values of this assay demonstrate its utility for the diagnosis of perinatally acquired HIV infection after the third month of age. Early diagnosis with this relatively simple and inexpensive serological assay should aid in the implementation of antiviral therapy and provide useful information for the care of children born to HIV-infected mothers in both developing and developed countries.