Adverse fetal and infant outcomes among HIV-infected women who received either nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based antiretroviral therapy for prevention of mother-to-child transmission.

BACKGROUND: For HIV-infected pregnant and breastfeeding women, antiretroviral therapy (ART) is known to reduce the mother's risk of passing the infection to her child. However, concerns remain about possible associations between various components of different ART regimens and adverse fetal and infant outcomes. As part of a clinical trial in western Kenya for the prevention of mother-to-child transmission (PMTCT) of HIV, pregnant women received one of two different ART regimens. METHODS: The original PMTCT study conducted in Kenya enrolled 522 HIV-infected, ART-naive pregnant women. These women were assigned to receive an ART regimen that included either nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), or nelfinavir, a protease inhibitor. This substudy involves 384 women from the original study who had baseline CD4 cell counts at least 250 cells/µl, and compares the risks of adverse fetal and infant outcomes between the two ART regimens. RESULTS: There were 386 live births (including multiples) and 7 (1.8%) stillbirths. Among live births, there were 67 preterm deliveries, 37 low-birth weight infants, and 14 infant deaths by 6 months. There were no statistically significant differences between the two ART regimens for any of the reported adverse outcomes. CONCLUSION: Although these data do not show significant differences between the NNRTI-based or protease inhibitor-based regimens in serious adverse fetal and infant outcomes, more studies need to be done and careful vigilance is needed to ensure infant safety.

Correlation of Adherence by Pill Count, Self-report, MEMS and Plasma Drug Levels to Treatment Response Among Women Receiving ARV Therapy for PMTCT in Kenya.

Success of antiretroviral therapy depends on adherence to effective treatment. We evaluated four adherence methods and their correlation with immunological and virologic response among women receiving PMTCT. Univariable and multivariable analyses were used to assess how adherence by pill count (n = 463), self-report (n = 463), MEMS (n = 129) and plasma drug level (n = 89) was associated with viral load suppression within a 6 months period. Longitudinal analysis was performed to determine the correlation of CD4 cell count with each measure of adherence. For all measures of adherence, sustained viral suppression was less likely for participants in the lowest category of adherence. Although CD4 cell count increased substantially over time, there was no significant association with adherence by the methods. Multiple strategies can be used successfully to monitor treatment adherence. Persons with ≥95% adherence by any method used in this study were more likely to have a favorable treatment outcome.

Determinants and Experiences of Repeat Pregnancy among HIV-Positive Kenyan Women--A Mixed-Methods Analysis.

OBJECTIVE: To identify factors associated with repeat pregnancy subsequent to an index pregnancy among women living with HIV (WLWH) in western Kenya who were enrolled in a 24-month phase-II clinical trial of triple-ART prophylaxis for prevention of mother-to-child transmission, and to contextualize social and cultural influences on WLWH's reproductive decision making. METHODS: A mixed-methods approach was used to examine repeat pregnancy within a 24 month period after birth. Counselor-administered questionnaires were collected from 500 WLWH. Forty women (22 with a repeat pregnancy; 18 with no repeat pregnancy) were purposively selected for a qualitative interview (QI). Simple and multiple logistic regression analyses were performed for quantitative data. Thematic coding and saliency analysis were undertaken for qualitative data. RESULTS: Eighty-eight (17.6%) women had a repeat pregnancy. Median maternal age was 23 years (range 15-43 years) and median gestational age at enrollment was 34 weeks. In multiple logistic regression analyses, living in the same compound with a husband (adjusted odds ratio (AOR): 2.33; 95% confidence interval (CI): 1.14, 4.75) was associated with increased odds of repeat pregnancy (p ≤ 0.05). Being in the 30-43 age group (AOR: 0.25; 95% CI: 0.07, 0.87), having talked to a partner about family planning (FP) use (AOR: 0.53; 95% CI: 0.29, 0.98), and prior usage of FP (AOR: 0.45; 95% CI: 0.25, 0.82) were associated with a decrease in odds of repeat pregnancy. QI findings centered on concerns about modern contraception methods (side effects and views that they 'ruined the womb') and a desire to have the right number of children. Religious leaders, family, and the broader community were viewed as reinforcing cultural expectations for married women to have children. Repeat pregnancy was commonly attributed to contraception failure or to lack of knowledge about post-delivery fertility. CONCLUSIONS: In addition to cultural context, reproductive health programs for WLWH may need to address issues related to living circumstances and the possibility that reproductive-decision making may extend beyond the woman and her partner.

A Comparison of Methods for Analyzing Viral Load Data in Studies of HIV Patients.

HIV RNA viral load (VL) is a pivotal outcome variable in studies of HIV infected persons. We propose and investigate two frameworks for analyzing VL: (1) a single-measure VL (SMVL) per participant and (2) repeated measures of VL (RMVL) per participant. We compared these frameworks using a cohort of 720 HIV patients in care (4,679 post-enrollment VL measurements). The SMVL framework analyzes a single VL per participant, generally captured within a "window" of time. We analyzed three SMVL methods where the VL binary outcome is defined as suppressed or not suppressed. The omit-participant method uses a 8-month "window" (-6/+2 months) around month 24 to select the participant's VL closest to month 24 and removes participants from the analysis without a VL in the "window". The set-to-failure method expands on the omit-participant method by including participants without a VL within the "window" and analyzes them as not suppressed. The closest-VL method analyzes each participant's VL measurement closest to month 24. We investigated two RMVL methods: (1) repeat-binary classifies each VL measurement as suppressed or not suppressed and estimates the proportion of participants suppressed at month 24, and (2) repeat-continuous analyzes VL as a continuous variable to estimate the change in VL across time, and geometric mean (GM) VL and proportion of participants virally suppressed at month 24. Results indicated the RMVL methods have more precision than the SMVL methods, as evidenced by narrower confidence intervals for estimates of proportion suppressed and risk ratios (RR) comparing demographic strata. The repeat-continuous method had the most precision and provides more information than other considered methods. We generally recommend using the RMVL framework when there are repeated VL measurements per participant because it utilizes all available VL data, provides additional information, has more statistical power, and avoids the subjectivity of defining a "window."

Isoniazid-associated hepatitis in adults infected with HIV receiving 36 months of isoniazid prophylaxis in Botswana.

BACKGROUND: The World Health Organization recommends 36 months of isoniazid preventive therapy (36IPT) for adults infected with HIV living in TB-endemic countries. We determined the rates and risk factors for isoniazid-associated hepatitis with the use of 36IPT. METHODS: One thousand six adults infected with HIV received 36IPT during a pragmatic randomized trial set in Botswana public health clinics providing HIV care. Enrollment exclusion criteria included jaundice or elevations of serum transaminases (ESTs) > 2.5-fold the upper limit of normal (ULN). Participants with any CD4+ lymphocyte count were eligible and received antiretroviral therapy (ART) when CD4+ < 200 cells/µL. 36IPT was stopped for severe hepatitis (more than fivefold ULN EST) but not for moderate hepatitis (2.5-fold to fivefold ULN EST). RESULTS: Pharmacy refill records showed 2,237 person-years of isoniazid receipt; 48% of participants initiated ART by 36 months. A total of 1.9% (19 of 1,006) of participants were diagnosed with severe hepatitis; three had jaundice and two of these developed hepatic encephalopathy. Another 3.1% (31 of 1,006) of participants experienced moderate hepatitis. Thirty-eight percent (19 of 50) of participants with moderate to severe hepatitis concomitantly received ART. Forty percent (20 of 50) of moderate to severe cases occurred within the first 2 months of IPT and during this period were not associated with receipt of ART at baseline (hazard ratio, 1.49; 95% CI, 0.20-11.1; P = .70). CONCLUSIONS: Adults infected with HIV receiving 36IPT did not have an increased incidence of moderate to severe hepatitis or hepatic encephalopathy compared with published reports among people infected with HIV, people not infected with HIV in trials or public health programs. Compared with participants not receiving ART, the risk of moderate to severe hepatitis was not increased by ART. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00164281; URL: www.clinicaltrials.gov.

Neutropenia in HIV-Infected Kenyan Women Receiving Triple Antiretroviral Prophylaxis to Prevent Mother-to-Child HIV Transmission Is Not Associated with Serious Clinical Sequelae.

BACKGROUND: Absolute neutrophil counts (ANCs) are lower in East African adults. To assess the impact of lower ANCs, we reviewed data from HIV-infected Kenyan women receiving antiretroviral therapy antepartum and postpartum. METHODS: The Kisumu Breastfeeding Study (KiBS) participants received an antiretroviral regimen from 34 weeks' gestation through 6 months postpartum. Measured ANCs and subsequent illnesses were reviewed. Adverse events (AEs) potentially attributable to neutropenia were identified, and ANCs were graded using the 2004 Division of AIDS table for Grading the Severity of AEs. RESULTS: Among 478 women with ≥1 postpartum ANC measured, 298 (62.1%) women met criteria for an AE (<1.3 × 10(9) cells/L). Of those, 38 (12.5%) women experienced a nonlife-threatening illness potentially attributable to neutropenia. CONCLUSION: More than half of KiBS women met criteria for neutropenia. The mild clinical experience of most participants with low ANCs supports that these values might be typical for this population and may not result in adverse clinical sequelae.

Exclusive breastfeeding among women taking HAART for PMTCT of HIV-1 in the Kisumu Breastfeeding Study.

BACKGROUND: One of the most effective ways to promote the prevention of mother-to-child transmission (PMTCT) of HIV-1 in resource-limited settings is to encourage HIV-positive mothers to practice exclusive breastfeeding (EBF) for the first 6 months post-partum while they receive antiretroviral therapy (ARV). Although EBF reduces mortality in this context, its practice has been low. We studied the rate of adherence to EBF and assessed associated maternal and infant characteristics using data from a phase II PMTCT clinical trial conducted in Western Kenya which included a counseling intervention to encourage EBF by all participants. METHODS: We analyzed data from the Kisumu Breastfeeding Study (KiBS), conducted between July 2003 and February 2009. This study enrolled a total of 522 HIV-1 infected pregnant women. Data on breastfeeding were available for 480 mother-infant pairs. Infant feeding and general nutrition counseling began at 35 weeks gestation and continued throughout the 6 month post-partum intervention period, following World Health Organization (WHO) infant feeding guidelines. Data on infant feeding were collected during routine clinic visits and home visits using food frequency questionnaires and dietary recall methods. Participants were instructed to exclusively breastfeed until initiation of weaning at 5.5 months post-partum. We used Kaplan-Meier methods to estimate the rates of EBF at 5.25 months post-partum, stratified by maternal and infant characteristics measured at enrollment, delivery, and 2 weeks post-partum. RESULTS: The estimated EBF rate at 5.25 months post-partum was 80.4%. Only 3% of women introduced other foods (most commonly water with or without glucose, cow's milk, formula, and fruit) by 2 months; this percentage increased to 5% of women by 4 months. Women who had ≥3 previous births (p < 0.01) and who were not living with the infant's father (p = 0.04) were more likely to exclusively breastfeed. Mixed feeding was more common for male infants than for female infants (p = 0.04). CONCLUSION: Exclusive breastfeeding was common in this clinical trial, which emphasized EBF as a best practice until infants reached 5.5 months of age. Counseling initiated prior to delivery and continued during the post-partum period provided a consistent message reinforcing the benefits of EBF. The findings from this study suggest high adherence to EBF in resource limited settings can be achieved by a comprehensive counseling intervention that encourages EBF.

Enhanced personal contact with HIV patients improves retention in primary care: a randomized trial in 6 US HIV clinics.

BACKGROUND: The aim of the study was to determine whether enhanced personal contact with human immunodeficiency virus (HIV)-infected patients across time improves retention in care compared with existing standard of care (SOC) practices, and whether brief skills training improves retention beyond enhanced contact. METHODS: The study, conducted at 6 HIV clinics in the United States, included 1838 patients with a recent history of inconsistent clinic attendance, and new patients. Each clinic randomized participants to 1 of 3 arms and continued to provide SOC practices to all enrollees: enhanced contact with interventionist (EC) (brief face-to-face meeting upon returning for care visit, interim visit call, appointment reminder calls, missed visit call); EC + skills (organization, problem solving, and communication skills); or SOC only. The intervention was delivered by project staff for 12 months following randomization. The outcomes during that 12-month period were (1) percentage of participants attending at least 1 primary care visit in 3 consecutive 4-month intervals (visit constancy), and (2) proportion of kept/scheduled primary care visits (visit adherence). RESULTS: Log-binomial risk ratios comparing intervention arms against the SOC arm demonstrated better outcomes in both the EC and EC + skills arms (visit constancy: risk ratio [RR], 1.22 [95% confidence interval {CI}, 1.09-1.36] and 1.22 [95% CI, 1.09-1.36], respectively; visit adherence: RR, 1.08 [95% CI, 1.05-1.11] and 1.06 [95% CI, 1.02-1.09], respectively; all Ps < .01). Intervention effects were observed in numerous patient subgroups, although they were lower in patients reporting unmet needs or illicit drug use. CONCLUSIONS: Enhanced contact with patients improved retention in HIV primary care compared with existing SOC practices. A brief patient skill-building component did not improve retention further. Additional intervention elements may be needed for patients reporting illicit drug use or who have unmet needs. CLINICAL TRIALS REGISTRATION: CDCHRSA9272007.

Outcomes in a cohort of women who discontinued maternal triple-antiretroviral regimens initially used to prevent mother-to-child transmission during pregnancy and breastfeeding--Kenya, 2003-2009.

BACKGROUND: In 2012, the World Health Organization (WHO) amended their 2010 guidelines for women receiving limited duration, triple-antiretroviral drug regimens during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV (tARV-PMTCT) (Option B) to include the option to continue lifelong combination antiretroviral therapy (cART) (Option B+). We evaluated clinical and CD4 outcomes in women who had received antiretrovirals for prevention of mother-to-child transmission and then discontinued antiretrovirals 6-months postpartum. METHODS AND FINDINGS: The Kisumu Breastfeeding Study, 2003-2009, was a prospective, non-randomized, open-label clinical trial of tARV-PMTCT in ARV-naïve, Kenyan women. Women received tARV-PMTCT from 34 weeks' gestation until 6-months postpartum when women were instructed to discontinue breastfeeding. Women with CD4 count (CD4) <250cells/mm3 or WHO stage III/IV prior to 6-months postpartum continued cART indefinitely. We estimated the change in CD4 after discontinuing tARV-PMTCT and the adjusted relative risk [aRR] for factors associated with declines in maternal CD4. We compared maternal and infant outcomes following weaning-when tARV-PMTCT discontinued-by maternal ARV status through 24-months postpartum. Compared with women who continued cART, discontinuing antiretrovirals was associated with infant HIV transmission and death (10.1% vs. 2.4%; P = 0.03). Among women who discontinued antiretrovirals, CD4<500 cells/mm3 at either initiation (21.8% vs. 1.5%; P = 0.002; aRR: 9.8; 95%-confidence interval [CI]: 2.4-40.6) or discontinuation (36.9% vs. 8.3%; P<0.0001; aRR: 4.4; 95%-CI: 1.9-5.0) were each associated with increased risk of women requiring cART for their own health within 6 months after discontinuing. CONCLUSIONS: Considering the serious health risks to the woman's infant and the brief reprieve from cART gained by stopping, every country should evaluate the need for and feasibility to implement WHO Option B+ for PMTCT. Evaluating CD4 at antiretroviral initiation or 6-months postpartum can identify pregnant women who would most benefit from continuing cART in settings unable to implement WHO Option B+.

Attitudes toward family planning among HIV-positive pregnant women enrolled in a prevention of mother-to-child transmission study in Kisumu, Kenya.

BACKGROUND: Preventing unintended pregnancies among HIV-positive women through family planning (FP) reduces pregnancy-related morbidity and mortality, decreases the number of pediatric HIV infections, and has also proven to be a cost-effective way to prevent mother-to-child HIV transmission. A key element of a comprehensive HIV prevention agenda, aimed at avoiding unintended pregnancies, is recognizing the attitudes towards FP among HIV-positive women and their spouse or partner. In this study, we analyze FP attitudes among HIV-infected pregnant women enrolled in a PMTCT clinical trial in Western Kenya. METHODS AND FINDINGS: Baseline data were collected on 522 HIV-positive pregnant women using structured questionnaires. Associations between demographic variables and the future intention to use FP were examined using Fisher's exact tests and permutation tests. Most participants (87%) indicated that they intended to use FP. However, only 8% indicated condoms as a preferred FP method, and 59% of current pregnancies were unintended. Factors associated with positive intentions to use FP were: marital status (p = 0.04), having talked to their spouse or partner about FP (p<0.001), perceived spouse or partner approval of FP (p<0.001), previous use of a FP method (p = 0.006), attitude toward the current pregnancy (p = 0.02), disclosure of a sexually transmitted infection (STI) diagnosis (p = 0.03) and ethnic group (p = 0.03). CONCLUSION: A significant gap exists between future FP intentions and current FP practices. Support and approval by the spouse or partner are key elements of FP intentions. Counseling services should be offered to both members of a couple to increase FP use, especially given the high number of unplanned pregnancies among HIV-positive women. Condoms should be promoted as part of a dual use method for HIV and STI prevention and for contraception. Integration of individual and couple FP services into routine HIV care, treatment and support services is needed in order to avoid unintended pregnancies and to prevent mother-to-child HIV transmission.

Nelfinavir and its active metabolite, hydroxy-t-butylamidenelfinavir (M8), are transferred in small quantities to breast milk and do not reach biologically significant concentrations in breast-feeding infants whose mothers are taking nelfinavir.

Antiretroviral drugs cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations. We measured concentrations of nelfinavir and its active metabolite (M8) in maternal plasma and breast milk from women and in dried blood spots collected from their infants at delivery and postnatal weeks 2, 6, 14, and 24 in the Kisumu Breastfeeding Study, Kisumu, Kenya. Nelfinavir-based antiretroviral regimens given to mothers as prevention of mother-to-child HIV transmission (PMTCT) do not expose the breast-feeding infant to biologically significant concentrations of nelfinavir or M8.