Lynne M. Mofenson

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

BACKGROUND The 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. METHODS From 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. FINDINGS Nearly 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. INTERPRETATION Nevirapine 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.

Guidelines for preventing opportunistic infections among HIV-infected persons - 2002

Introduction In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV) (1-3). These guidelines, which are intended for clinicians and health-care providers and their HIV-infected patients, were revised in 1997 (4) and again in 1999 (5), and have been published in MMWR (1, 4, 5), Clinical Infectious Diseases (2, 6, 7), Annals of Internal Medicine (3, 8), American Family Physician (9, 10), and Pediatrics (11); accompanying editorials have appeared in JAMA (12, 13). Response to these guidelines (e.g., a substantial number of requests for reprints, website contacts, and observations from health-care providers) demonstrates that they have served as a valuable reference for HIV health-care providers. Because the 1995, 1997, and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since acquired immunodeficiency syndrome (AIDS) was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of improved recognition of opportunistic disease processes, improved therapy for acute and chronic complications, and introduction of chemoprophylaxis against key opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating OIs. HAART has reduced the incidence of OIs and extended life substantially (14-16). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy (14-16). However, certain patients are not ready or able to take HAART, and others have tried HAART regimens but therapy failed. Such patients will benefit from prophylaxis against OIs (15). In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART (15). Clearly, since HAART was introduced in the United States in 1995, chemoprophylaxis for OIs need not be lifelong. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by CD4+ T lymphocyte counts for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART is logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care, and potentially facilitate adherence to antiretroviral regimens. In 1999, the USPHS/IDSA guidelines reported that stopping primary or secondary prophylaxis for certain pathogens was safe if HAART has led to an increase in CD4+ T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens. For recommendations regarding discontinuing chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4+ T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, certain inconsistencies in the format of these criteria are unavoidable. Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4+ T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OIs. For primary prophylaxis, whether to use the same threshold at which prophylaxis can be stopped (derived from data in studies addressing prophylaxis discontinuation) or to use the threshold below which initial prophylaxis is recommended, is unknown. Therefore, in this revision of the guidelines, in certain cases, ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the indicated threshold for restarting both primary and secondary prophylaxis is 200 cells/L. For all these recommendations, the Roman numeral ratings reflect the lack of data available to assist in making these decisions (Box). Table. System Used to Rate the Strength of Recommendations and Quality of Supporting Evidence During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. Periodic teleconferences were held to develop the revisions. Major Changes in These Recommendations Major changes in the guidelines since 1999 include the following: Higher level ratings have been provided for discontinuing primary prophylaxis for PCP and Mycobacterium avium complex (MAC) when CD4+ T lymphocytes have increased to >200 cells/L and >100 cells/L, respectively, for 3 months in response to HAART (AI), and a new recommendation to discontinue primary toxoplasmosis prophylaxis has been provided when the CD4+ T lymphocyte count has increased to >200 cells/L for 3 months (AI). Secondary PCP prophylaxis should be discontinued among patients whose CD4+ T lymphocyte counts have increased to >200 cells/L for 3 months as a consequence of HAART (BII). Secondary prophylaxis for disseminated MAC can be discontinued among patients with a sustained (e.g., 6-month) increase in CD4+ count to >100 cells/L in response to HAART, if they have completed 12 months of MAC therapy and have no symptoms or signs attributable to MAC (CIII). Secondary prophylaxis for toxoplasmosis and cryptococcosis can be discontinued among patients with a sustained increase in CD4+ counts (e.g. 6 months) to >200 cells/L and >100200 cells/L, respectively, in response to HAART, if they have completed their initial therapy and have no symptoms or signs attributable to these pathogens (CIII). The importance of screening all HIV-infected persons for hepatitis C virus (HCV) is emphasized (BIII). Additional information concerning transmission of human herpesvirus 8 infection (HHV-8) is provided. New information regarding drug interactions is provided, chiefly related to rifamycins and antiretroviral drugs. Revised recommendations for vaccinating HIV-infected adults and HIV-exposed or infected children are provided. Using the Information in This Report For each of the 19 diseases covered in this report, specific recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing first episodes of disease, and 3) preventing disease recurrences. Recommendations are rated by a revised version of the IDSA rating system (17). In this system, the letters AE signify the strength of the recommendation for or against a preventive measure, and Roman numerals IIII indicate the quality of evidence supporting the recommendation (Box). Because of their length and complexity, tables in this report are grouped together and follow the references. Tables appear in the following order: Table 1 Dosages for prophylaxis to prevent first episode of opportunistic disease among infected adults and adolescents; Table 1. Prophylaxis to Prevent First Episode of Opportunistic Disease among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 2 Dosages for prophylaxis to prevent recurrence of opportunistic disease among HIV-infected adults and adolescents; Table 2. Prophylaxis to Prevent Recurrence of Opportunistic Disease, after Chemotherapy for Acute Disease, among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 3 Effects of food on drugs used to treat OIs; Table 3. Effects of Food on Drugs Used to Prevent Opportunistic Infections Table 4 Effects of medications on drugs used to treat OIs; Table 4. Effects of Medications on Drugs Used to Prevent Opportunistic Infections Table 5 Effects of OI medications on drugs commonly administered to HIV-infected persons; Table 5. Effects of Opportunistic Infection Medications on Antiretroviral Drugs Commonly Administered to Persons Infected with Human Immunodeficiency Virus (HIV) Table 6 Adverse effects of drugs used to prevent OIs; Table 6. Adverse Effects of Drugs Used in Preventing Opportunistic Infections Table 7 Dosages of drugs for preventing OIs for persons with renal insufficiency; Table 7. Dosing of Drugs for Primary Prevention of or Maintenance Therapy for Opportunistic Infections Related to Renal Insufficiency Table 8 Costs of agents recommended for preventing OIs among adults with HIV infection; Table 8. Wholesale Acquisition Costs of Agents Recommended for Preventing Opportunistic Infections among Adults Infected with Human Immunodeficiency Virus Table 9 Immunologic categories for HIV-infected children; Table 9. Immunologic Categories for Human Immunodeficiency Virus-Infected Children, Based on Age-Specific CD4+ T Lymphocyte Counts and Percentage of Total Lymphocytes Table 10 Immunization schedule for HIV-infected children; Table 10. Recommended Immunization Schedule for Human Immunodeficiency Virus (HIV)-Infected Children Table 11 Dosages for prophylaxis to prevent first episode of opportunistic disease among HIV-infected infants and children; Table 11. Prophylaxis to Prevent First Episode of Opportunistic Disease among Infants and Children Infected with Human Immunodeficiency Virus Tabl

RISK FACTORS FOR PERINATAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 IN WOMEN TREATED WITH ZIDOVUDINE

BACKGROUND Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

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

BACKGROUND In 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. METHODS From 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. FINDINGS We 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. INTERPRETATION Intrapartum/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.

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent Hiv-1 vertical transmission (hivnet 012)

ObjectiveTo examine the emergence and fading of NVP resistance (NVPR) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DesignWe examined NVPR in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. MethodsPlasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. ResultsNVPR mutations were detected in 21 out of 111 (19%) women tested 6–8 weeks after delivery. The rate of NVPR was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVPR mutations faded from detection within 12–24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVPR. NVPR mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6–8 weeks of age. The most common NVPR mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVPR. ConclusionsNVPR was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVPR mutations were detected in women versus infants. NVPR was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission.

BACKGROUND Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings. METHODS Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth. RESULTS Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P<0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug. CONCLUSIONS Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. (ClinicalTrials.gov number, NCT00115648.)

Perinatal Transmission of Human Immunodeficiency Virus Type 1 by Pregnant Women with RNA Virus Loads <1000 Copies/mL

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

The Relationship between Serum Human Immunodeficiency Virus Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in HIV-1—Infected Children

Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was >100,000 copies/mL (95% confidence interval [CI], 1.4-3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2-4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3-2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6-4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log 10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1-3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% Cl, 1.2-1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.

Perinatal Transmission of Hepatitis C Virus from Human Immunodeficiency Virus Type 1-Infected Mothers

Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-1-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of < 10(5) copies/mL. Women dually infected with HIV-1 and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low.

Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis.

Objective:To estimate antiretroviral therapy (ART) adherence rates during pregnancy and postpartum in high-income, middle-income, and low-income countries. Design:Systematic review and meta-analysis. Methods:MEDLINE, EMBASE, SCI Web of Science, NLM Gateway, and Google scholar databases were searched. We included all studies reporting adherence rates as a primary or secondary outcome among HIV-infected pregnant women. Two independent reviewers extracted data on adherence and study characteristics. A random-effects model was used to pool adherence rates; sensitivity, heterogeneity, and publication bias were assessed. Results:Of 72 eligible articles, 51 studies involving 20 153 HIV-infected pregnant women were included. Most studies were from United States (n = 14, 27%) followed by Kenya (n = 6, 12%), South Africa (n = 5, 10%), and Zambia (n = 5, 10%). The threshold defining good adherence to ART varied across studies (>80, >90, >95, 100%). A pooled analysis of all studies indicated a pooled estimate of 73.5% [95% confidence interval (CI) 69.3–77.5%] of pregnant women who had adequate (>80%) ART adherence. The pooled proportion of women with adequate adherence levels was higher during the antepartum (75.7%, 95% CI 71.5–79.7%) than during postpartum (53.0%, 95% CI 32.8–72.7%; P = 0.005). Selected reported barriers for nonadherence included physical, economic and emotional stresses, depression (especially postdelivery), alcohol or drug use, and ART dosing frequency or pill burden. Conclusion:Our findings indicate that only 73.5% of pregnant women achieved optimal ART adherence. Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the postpartum period. Further research to investigate specific barriers and interventions to address them is urgently needed globally.