Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily.

OBJECTIVES: Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. METHODS: HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. RESULTS: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. CONCLUSIONS: Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.

Spanish validation of the HIV dementia scale in women.

HIV infection is increasing in minority groups, particularly in African American and Hispanic women. Although the incidence of HIV dementia has decreased since the advent of highly active antiretroviral treatment, prevalence of neurocognitive complications has increased as patients are now living longer. This study's purpose was to determine the psychometric properties of the Spanish-language HIV Dementia Scale (HDS) in a group of HIV-infected women. We recruited 96 women: 60 HIV-seropositive and 36 HIV-seronegative. Modification of the HDS into a Spanish-language version consisted of translating the instructions, substituting four words in Spanish (gato, media, azul, piña), increasing 1 second in the psychomotor speed because the Spanish alphabet has more letters than the English alphabet, and not offering clues for memory recall. Cognitive impairment (CI) was defined according to the modified American Academy of Neurology HIV-dementia criteria including an asymptomatic CI group. Statistical analysis consisted of analysis of variance to determine group differences and receiver operator characteristics (ROC) to determine the optimal cutoff point for the screening of CI. HDS-Spanish total score and subscores for psychomotor speed and memory recall showed significant differences between HIV-seronegative and women with HIV-dementia (p < 0.001) and between HIV-seropositive women with normal cognition and those with HIV-dementia (p < 0.001). The optimal cutoff point of 13 or less had performance characteristics of 87% sensitivity and 46% specificity for HIV-associated CI (50.0% positive predictive value, 85.0% negative predictive value). The HDS-Spanish translation offers a useful screening tool with value for the identification of Hispanic women at risk of developing HIV-associated symptomatic neurocognitive disturbances.

Reduction in the perinatal HIV transmission: the experience at the Maternal Infant Studies Center and Gamma Projects at the University of Puerto Rico School of Medicine

The AIDS pandemic had a significant impact in Puerto Rico, especially among the heterosexual populations, in particular women. Women are one of the fastest growing risk groups with HIV/AIDS in the USA and constitute about half of the AIDS cases in the world. During the past 10 years Puerto Rico has ranked among the top 5 jurisdictions in the United States in AIDS cases rates, among men, women and children. In 1987 a universal prenatal HIV screening program was implemented in the University Hospital catchment area consisting of approximately 5,000 deliveries per year. Because of the early identification of pregnant women living with HIV, access to lifesaving clinical research and the implementation of multiple strategies and comprehensive care, the perinatal HIV transmission has been reduced to zero since 1997, with a blip of one case in 2002, and none since then. The availability and access to clinical and behavioral research has been one of the key elements for this success story. The programs involved and responsible for this spectacular outcome, namely the Maternal Infant Studies Center (CEMI-Spanish Acronym) and Gamma Projects at the University of Puerto Rico School of Medicine are described. The cost savings impact of stopping mother-infant perinatal HIV-1 transmission has been calculated to be approximately $34 to $58 million dollars in 10 years. The impact of the effectiveness of these programs in having healthy uninfected infants, prolonging and improving the quality of life of those living with HIV, and providing hope to families affected by this epidemic is incalculable.

Greater adherence to highly active antiretroviral therapy (HAART) between pregnant versus non-pregnant women living with HIV.

One of the most remarkable advances in the control of the HIV/AIDS pandemic has been the introduction of highly active antiretroviral therapy (HAART). The use of HAART has been associated to reductions in AIDS-related mortality in most countries where HAART is available. Unfortunately, the adherence required to keep good control of viral replication is higher than what is required in other medical conditions. Several studies have shown a relationship between adherence and viral suppression ranging between 90-95% required for complete suppression. Multiple factors have been related to adherence among which are: gender, racial/ethnic distribution, age, personality traits, education, alcohol use and others. For women living with HIV there might be additional difficulties to handle in order to be adherent (i.e. multiple family responsibilities). A group of 165 women living with HIV attending a multidisciplinary clinic were interviewed with a 3-day adherence questionnaire. Correlation with clinical information was obtained from the Clinic Data Base. A total of 37 pregnant and 128 non-pregnant women were included in this analysis, 96% of which were on HAART. Complete adherence (100%) was reported by 91% of the pregnant and 70% of the non-pregnant women. (Fisher's exact test 0.009). The majority, 99% knew the names of their medications. There were no differences among groups in scholarity, history or actual cigarette smoking, history or actual drug use, CD4 lymphocyte counts (median or proportion below 350 cells/mm3), mean HIV RNA viral load or the proportion of patients with HIV RNA < 1,000 copies/ml. The transmission rate for the sample of pregnant women was zero. The reported adherence rates to HAART for women living with HIV were highest among the pregnant women. This difference was statistically significant (Chi Sq 0.05). The great majority (93%) reported knowing the names of the medications. In spite of reported barriers to adherence, pregnant women attending a multidisciplinary clinic for HIV care and research, reported good rates of adherence to HAART. This is also reflected in the good perinatal outcomes. Non-pregnant women with lower adherence rates might need additional interventions to improve adherence.

Antiretroviral combination therapy in HIV-1 infected women and men: are their responses different?

Women are the fastest growing segment of the AIDS cases in the United States. They constitute nearly half of all the AIDS cases worldwide. Recent advances in Highly Active Antiretroviral Therapies (HAART) have reduced AIDS mortality remarkably. But as longer use of these combination regimens makes evident, unexpected side effects are now reported that might reflect gender-based differences in occurrence. Controversy still exists in relation to the level of HIV-1 quantification in men and women and its association with disease progression. Women have been reported to have lower viral loads with equal progression or higher progression with equal viral loads. This finding has not been consistent in all studies. Psychosocial variables, such as poverty, lack of care and young age, adversely affect more women than men. If the viral dynamics are thought to be different, then the response to treatment might be as well. So far, the effectiveness of HAART has been seen equally among men and women. Barriers to adherence, such as caregiving burdens, multiplicity of roles and fear of disclosure, might disproportionately affect women. By far the best news is that the survival of both men and women has improved with the newer therapeutic advances.

Mother-to-child HIV-1 transmission: state of the art and implications for public policy.

During the past five years there have been significant advances in the knowledge of the factors that affect mother-to-infant HIV-1 transmission. Diverse interventions have been designed and proven effective in reducing the risk of such transmission. In reviewing the pivotal literature in such respect implications for public policy are also analyzed. Because of the constant evolution of the interventions, the public policies also need constant revisions. The impact of viral load assessment during pregnancy and its relationship to transmission risks is discussed, as well as the effectiveness of elective Caesarean delivery. The latter has both positive and negative aspects which merit consideration. Newer approaches, such as highly active anti retroviral therapies (HAART), which have shown to decrease the AIDS mortality, have also shown zero transmission in small cohorts. Shorter and cheaper interventions are also somewhat effective and are good alternatives to resource poor countries.

[Women and HIV/AIDS: barriers and new challenges]. / La mujer ante el VIH/SIDA: barreras y nuevos desafíos.

Women have been placed at a vulnerable situation regarding the HIV epidemic. Recent advances in antiretroviral therapies have placed in evidence the gender disparities and the new challenges to overcome them. The mortality of AIDS has decreased dramatically in the United States and Puerto Rico as a consequence of new combination therapies. Still, women constitute the fastest growing group of AIDS cases. There are gender differences in access to treatment and care, economic income and social and personal power. Among women's barriers to care are the lack of knowledge about AIDS in women by health providers, the family responsibilities and the burden and fear of disclosure. The authors suggest the need for empowerment as strategy for attaining better health and improving the quality of life in women living with HIV.

Redefining empowerment and sexual negotiation for women living with HIV.

The HIV/AIDS epidemic has presented many challenges to both: researchers and care providers. In addition, the concepts and models of human behavior needed a re-examination in response to this pandemic. We are redefining both empowerment and sexual negotiation for women living with HIV. Empowerment is defined as a process of awareness throughout which women recognize their capacity to achieve individual and social changes. This process involves a mental and spiritual awareness that will enable them to focus on their physical, psychological and social aspects. For women living with HIV, this is also a strategy for survival. For women living with HIV, sexual negotiation is a straightforward issue: it is either safer sex or nothing. Safer sexual practices then are a consequence or by-product of the process of empowerment. To facilitate this process our approach is directed to the individual, in an attempt to reach the inner power source that all human beings share.

Obstetric factors and mother-to-infant transmission of HIV-1.

Mother-to-infant HIV transmission has been reported to occur during pregnancy (in utero), at delivery, or postpartum (breast feeding). There are a multiplicity of variables or cofactors that may influence such transmission. Among the obstetric factors reported to be more strikingly associated with mother-to-infant transmission are preterm delivery, low birth weight and birth order in twin pregnancies. Perhaps the most controversial issue in obstetric management is the association of mode of delivery and transmission. Some large studies and metaanalyses have found a protective effect of cesarean section varying from odds ratios of 0.8 to 0.56. Unfortunately, those large studies have not included the duration of rupture membranes in their analyses. When such a variable (duration of ruptured membranes) is taken into account, the protective effect of the cesarean section may disappear. The impact of such obstetric variables on transmission can be explained by the hypothesis that a significant proportion of the perinatal transmission occurs intrapartum and is related to the dose exposure (time and concentration) of the presenting part to the genital tract virus load and to the maternal blood virus load. Currently, routine cesarean section is not recommended as a strategy for the prevention of vertical transmission. Although prospective studies are underway to elucidate the effect of cesarean section on transmission, the results are academic if recent potent antiviral agents are demonstrated to reduce or minimize the viral load in blood and in cervicovaginal secretions. Meanwhile, the current management of the delivery process should have as a goal the reduction of the presenting part to the cervicovaginal secretions by preserving the intactness of the membranes and by the proper use of invasive procedures when clinically indicated.

[Guidelines for the management of women with HIV infection]. / Recomendaciones para el manejo de mujeres con infección VIH.

During the second decade of AIDS the spread of this disease has encompassed most areas of the world. In Puerto Rico the epidemic has been different than in the mainland USA. Our initial cases were mostly associated to intravenous drug use and subsequently heterosexual transmission. Sexual transmission of HIV is the principal cause of AIDS for women in Puerto Rico. AIDS is also the principal cause of death in young women in Puerto Rico (ages 25-40). Therefore the counselling to women has to include the universality of the risk. Data from seroprevalence studies show a high prenatal seroprevalence (1%) in the San Juan Metropolitan Health Region. In view of the high prenatal seroprevalence, universal offering of HIV counselling and testing is recommended. Gynecologic evaluation is essential in the follow-up of women with HIV infection and should include frequent evaluations to determine the frequent occurrence of premalignant lesions in the cervix that may be associated to immunosuppression.