A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers

BACKGROUND: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy. METHODS: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan-Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis. RESULTS: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5-15.0] and 16.3% (95% CI,13.4-19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1-3.2; P = 0.032), maternal CD4 cell count < 500 x 10(6) cells/l (OR, 2.5; 95% CI,1.3-5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0-6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3-3.8; P = 0.006). CONCLUSION: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.     

The effect of rapid HIV-1 testing on uptake of perinatal HIV-1 interventions: a randomized clinical trial

OBJECTIVE: We examined whether HIV-1 testing using a rapid assay increases the proportion of pregnant women obtaining HIV-1 results and the uptake of perinatal HIV-1 interventions. METHODS: Pregnant women attending public health clinics in Nairobi were offered voluntary counselling and testing for HIV-1. Consenting women were randomly assigned to receive either rapid or conventional HIV-1 testing. Women randomly assigned to rapid testing were allowed to receive same-day results or to return later. The results for women randomly assigned to conventional enzyme-linked immunosorbent assay (ELISA) testing were available after 7 days. HIV-1-infected women were referred for antiretroviral prophylaxis to prevent mother-to-child transmission of HIV-1. RESULTS: Among 1282 women offered voluntary HIV-1 testing and counselling, 1249 accepted testing, of whom 627 were randomly assigned to rapid testing and 622 to conventional testing. The median duration between testing and obtaining results was 0 days for women who received rapid testing compared with 11 days for women who received conventional testing. The percentage receiving HIV-1 results was significantly higher among women who received rapid testing compared with conventional testing. Of 161 HIV-1-seropositive women, only 24 received antiretroviral prophylaxis. The uptake of perinatal HIV-1 interventions did not differ between HIV-1-seropositive women randomly assigned to rapid testing or conventional ELISA testing. CONCLUSION: Rapid HIV-1 testing significantly increased the proportion of women receiving HIV-1 results, which is important for sexual and perinatal HIV-1 prevention. The challenge remains to improve the uptake of perinatal HIV-1 interventions among HIV-1-seropositive women.     

Compliance with antiretroviral regimens to prevent perinatal HIV-1 transmission in Kenya

OBJECTIVE: To compare compliance and infant HIV-1 infection risk at 6 weeks with the Thai-CDC and HIVNET-012 antiretroviral regimens in a field setting. DESIGN: Randomized clinical trial. SETTING: Tertiary hospital antenatal clinic in Nairobi, Kenya. PARTICIPANTS: HIV-1 infected women referred from primary care clinics. INTERVENTIONS: Thai-CDC zidovudine regimen or HIVNET-012 nevirapine regimen. MAIN OUTCOME MEASURES: Women were considered compliant if they used >or= 80% of the doses. Infants were tested for HIV-1 at 6 weeks.RESULTS Seventy women were randomized to Thai-CDC and 69 to HIVNET-012 regimens. More women were compliant with the antenatal (86%) than the intrapartum (44%) Thai-CDC regimen doses ( P= 0.001). Ninety-seven per cent took the maternal and 91% gave the infant dose of the HIVNET-012 regimen (P = 0.2). Overall, 41% were compliant with the Thai-CDC regimen and 87% with the HIVNET-012 regimen ( P< 0.001). Compliance with the Thai-CDC regimen was associated with partner support of antiretroviral use [odds ratio (OR), 3.0;, 95% confidence interval (CI), 1.0-9.1] and knowledge at recruitment that antiretroviral drugs could prevent infant HIV-1 (OR, 2.9; 95% CI, 1.0-8.1). Compliance with the HIVNET-012 regimen was associated with partner notification (OR, 8.0; 95% CI, 1.5-50) and partner willingness to have HIV-1 testing (OR, 7.5; 95% CI, 1.4-40). There was a trend for a higher risk of transmission with the HIVNET-012 regimen than with the Thai-CDC regimen (22% versus 9%; P= 0.07). CONCLUSION: Compliance with the Thai-CDC and HIVNET-012 regimens was comparable to that in efficacy trials. Partner involvement, support and education on perinatal HIV-1 prevention may improve compliance and increase the number of infants protected from HIV-1 infection.     

HIV-1 seropositive women in the Philippines: pregnancy outcome and perinatal transmission of HIV-1.

Annual surveillance studies were initiated in 1985 to determine the incidence and prevalence of HIV-1 infection in female prostitutes registered through the Social Hygiene Clinic System of the Philippine Department of Health. All of the confirmed HIV-1 seropositive women detected in the above surveys who could be contacted were followed up about every three months to monitor their clinical and immunological status. Since we regularly interviewed and examined these HIV-1 seropositive women, we were able to note the occurrence of pregnancies following HIV diagnosis. By September 1990, 54 HIV-1 seropositive women (aged 18-35) detected from the above surveys had been interviewed and examined. Twenty-six of these HIV-1 positive women had a total of 37 pregnancies. Eight were pregnant at the time of HIV diagnosis: three term deliveries, one premature delivery (PD) at eight months, three abortions, and one lost to follow-up while still pregnant. Five of these eight had repeat pregnancies: two term deliveries, two abortions, and one lost to follow-up while pregnant. Eighteen other women became pregnant one or more times after HIV diagnosis: seven term deliveries, 13 abortions, two PDs, one ectopic pregnancy terminated, one currently pregnant, and one lost to follow-up during pregnancy. There was no clear indication from clinical examinations and CD4+ cell counts that pregnancy exacerbated the course of HIV-1 related disease in these women. One of the 12 term infants has died and eight have developed non-specific findings that are suggestive but not diagnostic of HIV infection.2+ strongly seropositive by both ELISA and Western blot assay at 16 months.     

Genital tract human immunodeficiency virus type 1 (HIV-1) shedding and inflammation and HIV-1 env diversity in perinatal HIV-1 transmission

This study sought to identify genital tract characteristics associated with vertical transmission of human immunodeficiency virus type 1 (HIV-1). HIV-1 DNA and RNA, HIV-1 env diversity, and inflammatory cells were quantified in cervicovaginal lavages (CVLs) of 24 women enrolled in the Women and Infants Transmission Study; 7 women transmitted HIV-1 perinatally. Vaginal candidiasis, HIV-1 culture positivity, levels of HIV-1 DNA and cell-free RNA, and HIV-1 env diversity were significantly higher in the CVLs of transmitters. CVL HIV-1 DNA levels correlated with higher levels of inflammatory cells and cell-free HIV-1 RNA. Of subjects with paired blood and CVL specimens, there was more HIV-1 env heterogeneity between blood and CVLs in transmitters than in nontransmitters. In summary, increased HIV-1 shedding is correlated with a more complex population of HIV-1 quasispecies in the genital tracts of parturient women, which may increase the probability that a fetotropic strain is transmitted.     

PASSHIV-1 treatment of patients with HIV-1 infection. A preliminary report of a phase I trial of hyperimmune porcine immunoglobulin to HIV-1.

OBJECTIVE: To study the safety of intravenously administered porcine-derived hyperimmune immunoglobulin to HIV-1, PASSHIV-1, in humans. METHODS: Fourteen HIV-1-infected individuals were treated for 5-7 days with intravenous infusions of highly purified PASSHIV-1 (> 95% pure). Two of the 14 patients were retreated 3 months later with PASSHIV-1 for an additional 5 days to evaluate side-effects from retreatment with porcine immunoglobulins. RESULTS: Ten of the patients had no side-effects from PASSHIV-1 therapy. Three patients experienced transient urticarial eruptions, which responded to antihistamine administration and did not require discontinuation of therapy. One patient, who received concomitant administration of human gammaglobulin, experienced serum sickness (type 3 hypersensitivity reaction). All patients demonstrated a significant improvement in fatigue (100% response), weight (all those with previous weight loss gained weight), fever (100% response), polyneuropathy (100% response), bronchitis (100% response), candidiasis (100% response), diarrhea (100% response), and dermatitis (100% response). One out of the five patients with Kaposi's sarcoma demonstrated > 50% improvement. Mean CD4+ cell counts in the group rose from 143 +/- 263 to 234 +/- 323 x 10(6)/l 4-6 months following completion of therapy (P = 0.013, paired Student's t-test); CD4+ counts rose > twofold in six individuals. p24 antigen, present in four patients, was negative following therapy in all patients. Other laboratory parameters that responded to therapy included: platelet counts (71% response), leukopenia (57% response), elevated lactic dehydrogenase (100% response), and elevated alkaline phosphatase (100% response). PASSHIV-1 was well tolerated by HIV-1-infected individuals. CONCLUSION: This therapy appears to be efficacious in ameliorating some of the clinical aspects and symptoms of HIV-1 infection.     

Preferential in-utero transmission of HIV-1 subtype C as compared to HIV-1 subtype A or D

OBJECTIVE: To determine whether different HIV-1 genotypes present in a single cohort, in Dar es Salaam, Tanzania, showed differences in timing for transmission from mothers to their infants. METHODS: We determined the maternal viral load, transmission time, and the HIV-1 envelope (env) subtype of 253 HIV-1-infected infants enrolled in a randomized double-blind placebo-controlled trial to examine the efficacy of vitamins in decreasing mother-to-child transmission in Tanzania. Classification of HIV-1 positivity in utero was based on PCR results at birth. Infants were classified as intrapartum infected if they scored negative for the sample collected at birth and positive for the sample collected at 6 weeks of age. RESULTS: We found significant differences in the distribution of transmission time according to subtype. A higher proportion of HIV-1 with subtype C env (C-env) was transmitted in utero than HIV-1 with subtype A env (A-env), subtype D env (D-env), or both combined. CONCLUSIONS: The identification of patterns of mother-to-child transmission times among HIV-1 genotypes may be useful in the selection of drug regimens for chemoprophylaxis. Based on our results, the efficacy of regimens administered only at labor may not protect as large a fraction of infants born in geographical regions with subtype C-env epidemics as compared to epidemics in regions where subtypes A-env and D-env predominate in the population.     

Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection

BACKGROUND: A vaccine is needed to prevent human immunodeficiency virus type 1 (HIV-1) infection. METHODS: A double-blind, randomized trial of a recombinant HIV-1 envelope glycoprotein subunit (rgp120) vaccine was conducted among men who have sex with men and among women at high risk for heterosexual transmission of HIV-1. Volunteers received 7 injections of either vaccine or placebo (ratio, 2 : 1) over 30 months. The primary end point was HIV-1 seroconversion over 36 months. RESULTS: A total of 5403 volunteers (5095 men and 308 women) were evaluated. The vaccine did not prevent HIV-1 acquisition: infection rates were 6.7% in 3598 vaccinees and 7.0% in 1805 placebo recipients; vaccine efficacy (VE) was estimated as 6% (95% confidence interval, -17% to 24%). There were no significant differences in viral loads, rates of antiretroviral-therapy initiation, or the genetic characteristics of the infecting HIV-1 strains between treatment arms. Exploratory subgroup analyses showed nonsignificant trends toward efficacy in preventing infection in the highest risk (VE, 43%; n=247) and nonwhite (VE, 47%; n=914) volunteers (P=.10, adjusted for multiple subgroup comparisons). CONCLUSIONS: There was no overall protective effect. The efficacy trends in subgroups may provide clues for the development of effective immunization approaches.     

An effective and safe protocol involving zidovudine and caesarean section to reduce vertical transmission of HIV-1 infection

OBJECTIVE: To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. INTERVENTIONS: Elective caesarean section before labour, usually at 36-38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen). RESULTS: Of 179 mother-infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0-4.7] and 12.6% (6.4-19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6-8 weeks. CONCLUSION: A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.     

Quantifying HIV-1 transmission due to contaminated injections

Assessments of the importance of different routes of HIV-1 (HIV) transmission are vital for prioritization of control efforts. Lack of consistent direct data and large uncertainty in the risk of HIV transmission from HIV-contaminated injections has made quantifying the proportion of transmission caused by contaminated injections in sub-Saharan Africa difficult and unavoidably subjective. Depending on the risk assumed, estimates have ranged from 2.5% to 30% or more. We present a method based on an age-structured transmission model that allows the relative contribution of HIV-contaminated injections, and other routes of HIV transmission, to be robustly estimated, both fully quantifying and substantially reducing the associated uncertainty. To do this, we adopt a Bayesian perspective, and show how prior beliefs regarding the safety of injections and the proportion of HIV incidence due to contaminated injections should, in many cases, be substantially modified in light of age-stratified incidence and injection data, resulting in improved (posterior) estimates. Applying the method to data from rural southwest Uganda, we show that the highest estimates of the proportion of incidence due to injections are reduced from 15.5% (95% credible interval) (0.7%, 44.9%) to 5.2% (0.5%, 17.0%) if random mixing is assumed, and from 14.6% (0.7%, 42.5%) to 11.8% (1.2%, 32.5%) under assortative mixing. Lower, and more widely accepted, estimates remain largely unchanged, between 1% and 3% (0.1-6.3%). Although important uncertainty remains, our analysis shows that in rural Uganda, contaminated injections are unlikely to account for a large proportion of HIV incidence. This result is likely to be generalizable to many other populations in sub-Saharan Africa.     

Phase I/II trial of HIV-1 hyperimmune globulin for the prevention of HIV-1 vertical transmission in Uganda

OBJECTIVES: To assess the safety, tolerance, pharmacokinetics, and virologic and immunologic changes associated with the use of Ugandan HIV hyperimmune globulin (HIVIGLOB) in HIV infected pregnant Ugandan women and their infants. DESIGN: A prospective, phase I/II, three-arm dose escalation trial of HIVIGLOB. METHODS: HIVIGLOB was prepared from discarded HIV infected units of blood collected from the National Blood Bank in Kampala. From June 1996 to April 1997, 31 HIV positive pregnant women were enrolled with HIVIGLOB infusions given at 37 weeks gestation and within 16 h of birth for infants. The first 10 mother-infant pairs were infused at a dose of 50 mg/kg, followed by 11 pairs at 200 mg/kg, and 10 pairs at 400 mg/kg. Study participants were followed for 30 months. RESULTS: Thirty-one women and 29 infants were infused with HIVIGLOB. The infusions were safe and well tolerated by the women and their infants at all doses. There were no significant changes in virologic or immunologic parameters after HIVIGLOB infusion. Pharmacokinetic properties of this product were similar to other immune globulin products with a median half-life of 28 days in women and 30 days in infants. CONCLUSION: An HIV immune globulin product derived from HIV infected Ugandan donors is safe, well tolerated, and has pharmacokinetic properties consistent with other immunoglobulin products. Data suggest that a 400 mg/kg dose of HIVIGLOB would be the most appropriate dose for a subsequent efficacy trial of HIVIGLOB for the prevention of mother to child HIV transmission.     

Vaginal lavage with chlorhexidine during labour to reduce mother-to-child HIV transmission: clinical trial in Mombasa, Kenya

OBJECTIVES: To evaluate the effect of vaginal lavage with diluted chlorhexidine on mother-to child transmission of HIV (MTCT) in a breastfeeding population. METHODS: This prospective clinical trial was conducted in a governmental hospital in Mombasa, Kenya. On alternating weeks, women were allocated to non-intervention or to intervention consisting of vaginal lavage with 120 ml 0.2% chlorhexidine, later increased to 0.4%, repeated every 3 h from admission to delivery. Infants were tested for HIV by DNA polymerase chain reaction within 48 h and at 6 and 14 weeks of life. RESULTS: Enrolment and follow-up data were available for 297 and 309 HIV-positive women, respectively, in the non-lavage and the lavage groups. There was no evidence of a difference in intrapartum MTCT (17.2 versus 15.9%, OR 0.9, 95% CI 0.6-1.4) between the groups. Lavage solely before rupture of the membranes tended towards lower MTCT with chlorhexidine 0.2% (OR 0.6, 95% CI 0.3-1.1), and even more with chlorhexidine 0.4% (OR 0.1, 95% CI 0.0-0.9). CONCLUSION: The need remains for interventions reducing MTCT without HIV testing, often unavailable in countries with a high prevalence of HIV. Vaginal lavage with diluted chlorhexidine during delivery did not show a global effect on MTCT in our study. However, the data suggest that lavage before the membranes are ruptured might be associated with a reduction of MTCT, especially with higher concentrations of chlorhexidine.