Birth defects following exposure to efavirenz-based antiretroviral therapy during pregnancy: a study at a regional South African hospital

Birth defects following exposure to efavirenz-based antiretroviral therapy during pregnancy: a study at a regional South African hospital

Bera, Ebrahim^a,b; McCausland, Katrin^a; Nonkwelo, Roxaan^a; Mgudlwa, Batembu^a; Chacko, Saji^a; Majeke, Busiwe^a

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Author Information

^aWalter Sisulu University, South Africa

^bDepartment of Obstetrics and Gynaecology, Frere Hospital, East London, Eastern Cape, South Africa.

Received 11 August, 2009

Revised 28 September, 2009

Accepted 30 September, 2009

Correspondence to Dr Ebrahim Bera, Department of Obstetrics & Gynaecology, East London Hospital Complex, Private Bag X9047, East London, Eastern Cape, South Africa. Tel: +27 76 788 6888; fax: +27 43 709 2483; e-mail: drebera@hotmail.com

Abstract

Objectives: To determine the prevalence and type of birth defects among infants following exposure to efavirenz-based antiretroviral therapy (EFV-based ART) during pregnancy.

Methods: A Pregnancy Registry was established to enable prospective follow-up of women taking EFV-based ART. In women who conceived on EFV-based ART, EFV was switched with another drug if they presented during the first trimester but was continued if they presented at or after 14 weeks' gestation. Pregnant women needing lifelong ART were commenced on EFV-based ART from 14 weeks' gestation onwards. Infants were followed up for 6 weeks after birth.

Results: Between January 2006 and December 2008, 623 ART-naive pregnant women initiated EFV-based ART in the second/third trimester and 195 women conceived on EFV-based ART. Birth defects were observed in 16 of 623 live births [2.6%; 95% confidence interval (CI) 1.5–4.2] and in six of 184 live births (3.3%; 95% CI 1.2–7.0) from women exposed to EFV in the second/third trimester and first trimester, respectively. The prevalence of birth defects was not significantly different between the first and second/third trimester EFV exposure (prevalence ratio 1.27; 95% CI 0.50–3.20; P = 0.301).

Conclusion: No significant increase in the prevalence of birth defects following exposure to EFV-based ART in the first trimester was observed in this cohort. However, the limited number of first trimester EFV-exposed infants precludes definitive conclusions on the teratogenicity or safety of EFV.

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Introduction

Efavirenz (EFV) was reclassified by the Food and Drug Administration (FDA) from a category C (‘risk cannot be ruled out’) to a category D (‘evidence of human fetal risk’) drug following case reports of birth defects in infants with first trimester EFV exposure ^[1]. These defects were similar to those observed in primate studies, in which anencephaly and anophthalmia, micropthalmia, and cleft palate occurred in three of 20 cynomolgus monkeys born after maternal exposure to EFV from day 20 to 150 at plasma concentrations comparable to those in humans. Thus far, three cases of myelomeningocele and two of Dandy–Walker malformation (DWM) have been reported in humans ^[2–5]. However, without a control group or knowledge of the denominator, the presence or magnitude of the teratogenic risk of EFV is unknown.

Although in these cases, the birth defects noted mirrored some of those found in animal studies, a recent case report of Dandy–Walker variant associated with antenatal nevirapine (NVP) exposure ^[6]highlights the poor predictive value of animal toxicology studies translated to humans. No teratogenic effects from NVP were observed during reproductive studies with rats and rabbits ^[7].

Pregnant women are generally excluded from experimental drug studies. This makes assessment of drug safety in pregnancy difficult. Clinicians make decisions on a drug's safety informed by prior extensive experience with its use in pregnancy or from prospective registries, the Acyclovir Registry being an example ^[8].

Data from the international Antiretroviral Pregnancy Registry (APR) have not demonstrated any significant increase in the prevalence of birth defects following first trimester EFV use in pregnancy. Birth defects were observed in 14 out 477 live births (2.9%), of whom one infant had a myelomeningocele and another had facial cleft and anopthalmia ^[9]. The number of women exposed to efavirenz-based antiretroviral therapy (EFV-based ART) in the European Collaborative Study, Women and infants’ Transmission Study, and from a study in Botswana were relatively small for analysis of birth defects ^[10–12]. A comprehensive study of congenital abnormalities in over 8000 infants provided some reassuring data on 205 infants with early pregnancy EFV exposure ^[13]. Birth defects occurred in five infants (2.4%), with no cases of DWM or myelomeningocele identified.

EFV use in pregnancy has declined considerably internationally, consequent to wider availability and access to different ART regimens. In resource-poor countries, however, ART options and classes of different agents are limited. In South Africa, EFV is prescribed more often than NVP for the treatment of HIV-1-infected adults, because it is safer, easier to monitor, superior on time to viral load suppression, and may be associated with improved survival rates compared with NVP^[14].

With increasing numbers of reproductive-aged women accessing ART services, it is anticipated that an increasing number of them will conceive on EFV-based ART.

Against this background, we sought to determine the prevalence and type of birth defects in women taking EFV-based ART during pregnancy.

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Setting

Frere Hospital, situated in East London, is a poorly staffed regional hospital that serves as a referral centre for a large geographical area within the Eastern Cape province of South Africa. HIV prevalence among pregnant women in this province is 29% ^[15]. Approximately 7000 babies are born annually at this institution (unpublished data).

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Methods

A local Efavirenz in Pregnancy Registry was established in January 2006 to enable prospective follow-up of pregnant women within the region taking EFV-based ART.

For pregnant women with indications for lifelong ART, EFV-based ART was commenced with the following provisos – the pregnancy had progressed beyond 14 weeks gestation, a written undertaking to use contraception postpartum, a detailed ultrasound scan of fetal anatomy was performed before commencing ART, and major psychiatric illness was excluded.

Requirements for lifelong ART included CD4 cell count less than 250 cells/μl or World Health Organization (WHO) stage 4 disease.

The nucleoside reverse transcriptase inhibitors most commonly prescribed with EFV were stavudine (d4T) and lamivudine (3TC). Our local HIV directorate provided authority for the use of zidovudine (ZDV) only when toxicity to d4T occurred, and lopinavir/ritonavir (LPV/r) use was restricted to the first trimester, as a substitute for EFV in women with CD4 cell counts more than 250 cells/μl.

As per protocol, women who conceived on EFV-based ART were given the choice of termination of pregnancy (TOP) up to 20 weeks gestation. For the women who elected to continue with their pregnancies, EFV was substituted in the first trimester for NVP if their CD4 cell count was less than 250 cells/μl or for LPV/r if their CD4 cell count was more than 250 cells/μl. From January 2007, all women in the first trimester who had conceived on EFV were switched to NVP regardless of the CD4 cell count, following data that showed a lower risk of NVP toxicity in ART-experienced women ^[16].

Women who presented at or beyond 14 weeks remained on EFV-based ART, unless clinical reasons necessitated a change in treatment. Women who conceived on EFV-based ART were additionally registered with the APR since early 2008 ^[9].

Baseline demographic details (age, parity, CD4 cell count, plasma HIV-1 RNA viral load, WHO stage, and gestational age) were obtained from all women. For women who conceived on EFV-based ART, additional information was obtained: duration of EFV use prior to conception, previous miscarriage, stillbirth or neonatal death, plasma viral load at presentation and delivery, concurrent co-trimoxazole (CTX) use, and any history of birth defects. Women who had taken EFV-based ART during the entire first trimester were classified as ‘completefirst trimester EFV exposure’. Women in whom EFV was substituted for another drug were classified as ‘partial first trimester EFV exposure’. The first trimester ended at 13 weeks and 6 days.

A detailed fetal anatomy ultrasound scan was done at 18–23 weeks. An amniocentesis/cordocentesis was performed where necessary to further investigate abnormalities found on ultrasound examination.

Following delivery, the neonate was examined for birth defects by a paediatrician or a senior obstetrician. Mothers and infants were followed up until 6 weeks postpartum.

Outcomes measured were the prevalence and type of birth defects. As the follow-up in this cohort was censored at 6 weeks postpartum, case ascertainment was limited to structural defects observed within this period. The prevalence of birth defects was calculated as the ratio of the number of birth defects observed in all pregnancies beyond 24 weeks gestation and the total number of live births. A cohort of at least 200 live births exposed to EFV-based ART was deemed sufficient to detect a two-fold increase in the overall risk of birth defects compared with those observed internationally ^[17].

Miscarriage, defined as pregnancy loss prior to 24 weeks ^[18], was excluded from this analysis. However, pregnancies that were terminated at any gestation due to identification of fetal abnormality on ultrasound examination were included. Birth defects in twins were counted separately. More than one defect in a singleton was counted as one event.

Data were analysed using Epi-info software, version 3.2.2 (Centre for Disease Control and Prevention, Atlanta, Georgia, USA, 2005). Continuous variables are presented as medians with interquartile ranges (IQRs) and dichotomous data as proportions with 95% confidence intervals (CIs). Approval for this study was obtained from the hospital's research and ethics committee.

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Results

Between 1 January 2006 and 31 December 2008, 744 pregnant women initiated EFV-based ART from the second trimester onward. Eighty-nine women were still pregnant and 32 women (4.9%) were lost to follow-up. Over the same period, 220 women conceived on EFV-based ART and another 42 women conceived on NVP-based ART.

Pregnancies were ongoing in 17 women (EFV-based ART) and seven women (NVP-based ART). Eight women (3.9%) and two women (5.7%), respectively, in the two therapies were lost to follow-up.

Data on 851 women with pregnancy outcomes are presented. Table 1summarizes maternal characteristics, infant outcomes, and the prevalence of birth defects within each group.

Table 1
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Women commenced on efavirenz-based antiretroviral therapy during pregnancy (n = 623)

All women were ART-naive. Their median age was 28 years and the median gestation at ART initiation was 30 weeks. Two hundred and twenty-eight women (37%) were primigravidae. Median CD4 cell count and median plasma viral load were 171 cells/μl and 4.42 log₁₀copies/ml, respectively. Twenty-six women (4%) had WHO stage 4 disease and 41 women (7%) were concurrently on treatment for tuberculosis (TB).

Median gestation at delivery was 39 weeks. Plasma viral load results were available for 459 women (74%) at delivery, 320 of whom (70%) had viral load less than 50 copies/ml.

Twenty-eight women (5%) had tubal ligation performed at delivery upon request. Sixteen women (2.6%) had twin pregnancies and one had a set of triplets. There were six miscarriages (including a set of triplets) and 10 stillbirths. Of the 623 live births, 319 (51.2%) were male.

Birth defects occurred in 16 of 623 live births, a corresponding prevalence of 2.6% (95% CI 1.5–4.2). The birth defects noted were arachnoid cyst, pulmonary stenosis (unconfirmed), postaxial polydactyly (seven cases), facial asymmetry and overlapping fingers, bilateral clubfeet, congenital naevus, and umbilical hernia (four cases).

The infant with arachnoid cyst benefited from ultrasound diagnosis at the time of ART initiation. A posterior fossa cyst was identified in the fetus at 26 weeks gestation. Following delivery, a computed tomography (CT) scan confirmed the presence of an arachnoid cyst. The newborn with pulmonary stenosis had severe intrapartum asphyxia at birth, was ventilated, and developed congestive cardiac failure. Pulmonary stenosis was strongly suspected, but the baby demised prior to confirmation of the defect. Due to a lack of perinatal postmortem services at our institution, we were unable to confirm or refute the diagnosis of pulmonary stenosis in this newborn. All the infants with postaxial polydactyly had fleshy digits involving their hands, tied off in four infants by means of a suture at the base of the digit.

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Women who conceived on efavirenz-based antiretroviral therapy (n = 195)

All pregnancies were unintended. One hundred and eighty-one women (93%) had been on EFV-based ART for longer than 1 month before conception.

Their median age was 30 years and 48 women (25%) were primigravidae. Median CD4 cell count at presentation was 275 cells/μl. Fifty women (26%) were on treatment for TB at the time of initial ART commencement and 37 (19%) had ART initiated as a result of WHO stage 4 disease prior to conception. Sixty-five women (33%) were taking CTX prophylaxis at confirmation of pregnancy. Two women had a family history of birth defects.

Median gestational age at presentation was 19 weeks. Only nine women (5%) presented prior to 6 weeks, whereas 46 women (24%) presented between 6 and 13 weeks and 140 (72%) at/after 14 weeks' gestation.

EFV was substituted with NVP in 55 women (28%) and with LPV/r in eight women. Of 140 women who presented after 14 weeks, 134 had complete first trimester EFV exposure. Six women had already been switched from EFV to NVP at their local ART centres prior to referral.

All but three women with pregnancies less than 20 weeks declined TOP. Two women had ectopic pregnancies, necessitating salpingectomy.

Five women (2.6%) had twin pregnancies. There were six miscarriages (including a set of twins) and four stillbirths (including an in-utero fetal death in a twin pregnancy). Of the 184 live births, 90 (48.9%) were male.

Data on viral load at delivery were available for 131 (72%) of 181 women with live-born infants (including three sets of twins), 103 of those women (79%) had viral load less than 50 copies/ml. Significantly more women who continued EFV throughout pregnancy (75/90, 83%; 95% CI 74–90) had undetectable viral load at delivery compared with women who were switched to NVP or LPV/r (28/41, 68%; 95% CI 52–82) (P = 0.031).

One of the four stillbirths was an intrapartum fetal death at 32 weeks' gestation following induction of labour in a 43-year-old woman. Trisomy 18 was diagnosed in this fetus by ultrasound examination, confirmed on amniotic fluid analysis.

A rare but serious birth defect, arthrogryposis multiplex congenita (AMC), was the attributable cause of an early neonatal death in this group. This neonate was born with severe joint contractures, webbed limbs, pulmonary hypoplasia, absent sacrum, and a unilateral cleft lip and palate. Fetal akinesia and polyhydramnios were the pre-eminent findings on ultrasound examination. Chromosomal studies done on amniotic fluid obtained antenatally were normal.

Birth defects were observed in five of 184 live births and in one of four stillbirths, a prevalence of 3.3% (95% CI 1.2–7.0). The birth defects noted were Trisomy 18, AMC, oesophageal atresia with tracheo-oesophageal fistula (OA-TOF), postaxial polydactyly of fingers and preaxial polydactyly with syndactyly of toes, postaxial polydactyly, and lower central incisor tooth. Details of birth defects and outcomes are shown in Table 2.

Table 2
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No significant difference in the prevalence of birth defects was observed between first and second/third trimester EFV use (prevalence ratio 1.27; 95% CI 0.50–3.20, P = 0.301). The prevalence was similar with maternal CTX use (2/63; 3.2%) compared with no CTX exposure (4/121; 3.3%) (prevalence ratio 0.96; 95% CI 0.18–5.10, P = 0.664). The prevalence of birth defects also did not differ between complete (4/131; 3.1%) and partial (2/53; 3.8%) first trimester EFV exposure (prevalence ratio 0.81; 95% CI 0.15–4.29, P = 0.556).

Table 3 outlines a summary of birth defects by organ system of all pregnancies exposed to EFV-based ART, utilizing the APR system of classification of birth defects ^[9].

Table 3
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Women who conceived on nevirapine-based antiretroviral therapy (n = 33)

From this group, one woman had a set of twins and one a miscarriage. A birth defect (umbilical hernia) was observed in one of 33 infants, yielding a prevalence of 3.0% (95% CI 0.1–15.8). There was no significant difference in prevalence of birth defects following conception on EFV compared with conception on NVP (prevalence ratio 1.08; 95% CI 0.13–8.65, P = 0.690).

Table 1 shows a comparison of pregnancy outcomes among women who initiated EFV-based ART, who conceived on EFV-based ART, and who conceived on NVP-based ART.

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Discussion

This is the largest study to-date on EFV-based ART exposure from the second trimester of pregnancy onward. All women were prospectively enrolled and patient retention was high. Previously published cohorts on second/third trimester EFV use were not sufficiently large to detect a two-fold increase in the overall risk of birth defects ^[9,11,13]. We found that the prevalence in this cohort was 2.6%, which is consistent with between 1.4 and 3.5% from the published data on other classes of commonly used antiretroviral drugs internationally ^[9–11,13]. The observed birth defects in our study were of questionable relation to EFV, and in the case of the infant with arachnoid cyst, was unrelated to EFV exposure. The commonest defect observed was postaxial polydactyly, which is relatively common in South Africa, with a reported prevalence of 15.49 per 1000 live births ^[19]. Prevalence estimates of birth defects from the South African health department range from 2.5 to 8% ^[20].

Several ART guidelines recommend the use of NVP ahead of EFV after the first trimester, even for women with TB or with CD4 cell counts more than 250 cells/μl ^[7,21,22].

This recommendation is based on the paucity of infant safety data following second/third trimester EFV exposure, and the potential for birth defects in a future pregnancy with continued EFV use after delivery. At our centre, EFV was preferred, owing to concern over significant drug interactions between NVP and rifampicin in women on TB treatment ^[23]. At very low CD4 cell counts, NVP appears less effective than EFV ^[24]. In addition, hepatotoxicity is more frequent, especially in women with CD4 cell counts higher than 250 cells/μl ^[25]. The results from this cohort are reassuring, and our findings suggest a need to review current recommendations favouring NVP from the second trimester onward.

The prevalence of birth defects following first trimester EFV-based ART exposure was not significantly different from the prevalence after second/third trimester EFV exposure. There were no cases of anophthalmia, neural tube defects, or DWM following first trimester EFV use in this cohort. Although no specific pattern of birth defects was found, the number of exposed infants does not permit any definitive conclusions to be made on the teratogenicity or safety of EFV. Furthermore, the finding of cleft palate and sacral agenesis in the neonate with AMC remains a concern, as these defects may occur following teratogen exposure, which is consistent with those found in EFV-exposed cynomolgus monkeys.

Despite the size limitation of this study, the value of switching from EFV to another drug in the first trimester needs to be revisited. This practice did not meaningfully influence the prevalence of birth defects in this cohort, although our study was not adequately powered to detect this difference. EFV has a long half-life and can be detected in plasma up to 8 weeks later following its discontinuation ^[26].

The majority of women (95%) presented at/after 6 weeks' gestation (4 weeks after conception), suggesting EFV use for at least 11 days into the embryonic phase (day 17–56 postconception), which is a critical period of organogenesis.

Switching therapy during or after the embryonic phase may not alter the teratogenic risk and may compromise the woman's ability to achieve undetectable plasma viral load at delivery, as was observed in this cohort.

The prevalence of neural tube defects (NTD) in the United Kingdom is 1.4 per 1000 live births ^[27], but in some regions of South Africa, it is estimated at 3.55 per 1000 live births ^[19,28]. In our setting, follow-up of more than 3000 first trimester EFV-based ART exposures would be required to detect a doubling in the rate of NTD.

It is unlikely that any single centre will amass sufficient number of first trimester EFV exposures to enable the magnitude of its risk to be defined. Healthcare workers caring for women who conceive on ART are, therefore, encouraged to register themselves with the APR antenatally ^[9].

In resource-poor countries where ART options are limited, coupled with the high burden of TB ^[29], it is likely that EFV will remain an important component of ART. It is equally anticipated that more women will present to antenatal clinics, having conceived on treatment. The declining international use of EFV-based ART in pregnancy has made the establishment of a national South African registry necessary. Such calls have been made previously ^[30].

Our study has some limitations. First, a relatively small number of infants were exposed to EFV and the duration of follow-up was limited to 6 weeks. In our routine clinical setting, newborns are generally examined only at birth for defects. Only about a quarter of birth defects diagnosable at 5 years of age are detected at birth ^[19].

Hence, long-term outcomes of children exposed to in-utero ART still require evaluation. Second, we lacked a control group for the women initiated on EFV and the comparator group of women who conceived on NVP-based ART was very small.

Third, the risk of birth defects following the use of drugs in combination with EFV was not considered. However, international data on the prevalence of birth defects following ZDV, d4T, 3TC, and LPV/r use in pregnancy are reassuring ^[9].

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Conclusion

Our data provide some reassurance on second/third trimester EFV use, facilitating the possibility of expanding treatment options for pregnant women, especially those in whom the currently recommended drugs may not be suitable. No conclusions can be drawn from this study on the safety or teratogenicity of EFV following first trimester use, given the limited number of exposed infants. We underscore the importance of establishing national surveillance programs in resource-poor countries for pregnant women taking EFV-based ART.

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Cuales son las implicaciones de una pobre respuesta inmunologica al Tratamiento Antiretroviral / What Are the Implications of Poor Immunologic Response to ART?

HIV/AIDS Clinical Care

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HIV/AIDS Clinical Care for December 12, 2011 SUMMARY AND COMMENT What Are the Implications of Poor Immunologic Response to ART? December 12, 2011 | Keith Henry, MD Among patients with virologic suppression, those with initially poor immunologic response continued to have persistently low CD4-cell counts and had an increased risk for morbidity and mortality. Reviewing: Van Lelyveld SFL et al. AIDS 2011 Nov 22; ANTIRETROVIRAL ROUNDS If At First You Don't Succeed . . . Free! December 12, 2011 An HIV-infected patient who has discontinued antiretroviral therapy (ART) needs to restart treatment, but the choice of regimen is complicated by a history of hyperlipidemia on ART, severe adverse drug reactions, and antiviral resistance. What would you do? SUMMARY AND COMMENT Monitoring Decisions Depend on Risk for Virologic Failure — and on Cost Free! December 12, 2011 | Mauro Schechter, MD, PhD When risk for failure is high, and resources are available, virologic monitoring is preferred over CD4-cell monitoring. When risk is low or funding is unavailable, both may be skipped altogether. Reviewing: Rawizza HE et al. Clin Infect Dis 2011 Dec 15; 53:1283 Mermin J et al. BMJ 2011 Nov 9; 343:d6792 Kahn JG et al. BMJ 2011 Nov 9; 343:d6884 SUMMARY AND COMMENT Raltegravir for Bone Health? Or Just Lose the PI? December 12, 2011 | Abigail Zuger, MD One year after switching from boosted protease inhibitors to raltegravir, patients had significant improvement in some bone-mineral density measurements. Reviewing: Curran A et al. AIDS 2011 Nov 22; SUMMARY AND COMMENT Optimizing the Approach to HIV Testing December 12, 2011 | Charles B. Hicks, MD What adds value in the STI clinic? Reviewing: Truong HM et al. PLoS ONE 2011 Oct 6; 6:e25281 FEATURE Big TB Prevention Study Important, Highly Relevant — Even Here Free! December 12, 2011 Dr. Paul Sax offers both a personal and professional take on the study, in his blog HIV and ID Observations. Free Full-Text Article Summary and Comment What Are the Implications of Poor Immunologic Response to ART? Among patients with virologic suppression, those with initially poor immunologic response continued to have persistently low CD4-cell counts and had an increased risk for morbidity and mortality. Most HIV-infected patients who achieve virologic success on potent antiretroviral therapy (ART) also experience adequate CD4-cell recovery. However, a small proportion do not, and the clinical implications of this discordant response to treatment have been unclear. In this retrospective observational study, participants in the Dutch ATHENA cohort who achieved viral loads <500 copies/mL during the first 2 years on ART were divided into four groups based on their CD4 counts at 1 to 2 years (<200, 200–350, 351–500, and >500 cells/mm3). Those with CD4 counts <200 cells/mm3 were considered to have poor immunologic recovery. Outcomes of interest included a composite endpoint (cardiovascular events, AIDS, cancer, cirrhosis, or death), non–AIDS-defining diseases overall, cardiovascular events, and non–AIDS-defining malignancies specifically. The 3068 patients included in the analysis (83% male) had a median age of 41, a median nadir CD4 count of 170 cells/mm3, and a median baseline CD4 count of 360 cells/mm3; 6.5% had poor CD4-cell recovery. Independent predictors of poor CD4-cell recovery included older age, lower nadir CD4-cell count, and lower viral load at ART initiation. During more than 10,000 person-years of follow-up, patients with poor CD4-cell recovery had the highest frequency of the composite endpoint, non–AIDS-defining diseases overall, and cardiovascular events. A key observation was that the patients with poor immunologic recovery had a median CD4 count of only 320 cells/mm3 after 7 years of potent ART. Comment: The low median nadir CD4 count for the entire cohort (170 cells/mm3), together with the failure of many patients to achieve CD4 counts >500 cells/mm3 after years of suppressive ART, underscores the need for expansion of HIV testing and outreach efforts. The aim of those efforts would be to identify recently infected individuals, engage them in care, and initiate potent ART at higher CD4-cell counts, thus optimizing immune recovery and clinical benefit, with decreased transmission of HIV as a likely public health bonus. Although the potential benefits of early treatment seem clear, actual experience and the current economic outlook indicate that expanding provision of care to include most individuals with new HIV diagnoses will be difficult. — Keith Henry, MD Published in Journal Watch HIV/AIDS Clinical Care December 12, 2011 Citation(s): Van Lelyveld SFL et al. Long term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2011 Nov 22; [e-pub ahead of print]. (http://dx.doi.org/10.1097/QAD.0b013e32834f32f8)

Situación del VIH en el Ecuador 2008

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Hepatitis for December 5, 2011 SUMMARY AND COMMENT Histologic Features Can Differentiate Drug-Induced Liver Injury from Autoimmune Hepatitis December 2, 2011 | Atif Zaman, MD, MPH | Gastroenterology Investigators report progress in using histologic data to more accurately distinguish between the two conditions. Reviewing: Suzuki A et al. Hepatology 2011 Sep 54:931 SUMMARY AND COMMENT Long-Term Morbidity and Mortality with NAFLD and Advanced Fibrosis December 2, 2011 | Atif Zaman, MD, MPH | Gastroenterology At 7 years of follow-up, about 20% of patients with NAFLD developed liver complications and 13% died or received a transplant. Adjusted outcomes were favorable compared with similar patients with HCV infection. Reviewing: Bhala N et al. Hepatology 2011 Oct 54:1208 SUMMARY AND COMMENT Perioperative Death Rate from Bariatric Surgery Is Higher with Cirrhosis Free! November 18, 2011 | Atif Zaman, MD, MPH | Gastroenterology Clinicians should assess whether patients receiving bariatric surgery for obesity have cirrhosis and, if so, possibly refer them to a high-volume center for the procedure. Reviewing: Mosko JD and Nguyen GC. Clin Gastroenterol Hepatol 2011 Oct 9:897 FEATURE HCV Treatment Studies at AASLD: Wow . . . and I Mean WOW! Free! November 14, 2011 | HIV/AIDS Clinical Care Dr. Paul Sax reviews the "breathtaking" results just presented at The Liver Meeting, in his blog HIV and ID Observations. SUMMARY AND COMMENT Emerging Treatment Options for Severe Acute Alcoholic Hepatitis November 10, 2011 | Atif Zaman, MD, MPH | Gastroenterology Adding N-acetylcysteine to glucocorticoid therapy did not improve 6-month survival. Early liver transplant did, but in a selectively chosen subgroup. Reviewing: Nguyen-Khac E et al. N Engl J Med 2011 Nov 10; 365:1781 Mathurin P et al. N Engl J Med 2011 Nov 10; 365:1790 Brown RS Jr. N Engl J Med 2011 Nov 10; 365:1836 Free Full-Text Article Summary and Comment Histologic Features Can Differentiate Drug-Induced Liver Injury from Autoimmune Hepatitis Investigators report progress in using histologic data to more accurately distinguish between the two conditions. The clinical scenario of a patient who presents with acute hepatitis on potentially hepatotoxic medications, with negative viral serologies but low-level autoimmune markers, can be challenging. The difficulty lies in determining whether the patient has drug-induced liver injury (DILI), for which there is no specific treatment, or autoimmune hepatitis (AIH), for which immunosuppressants are indicated. To date, histologic findings have generally not been helpful. To explore possible differences in histologic profiles that could improve diagnostic accuracy, four experienced hepatopathologists conducted detailed, blinded reviews of 63 liver biopsies of clinically well-characterized cases of AIH and DILI. All were reviewed from clinical and histologic standpoints to verify diagnoses. Concordance of clinical diagnosis with histologic diagnosis was 65%. However, among the four hepatopathologists, complete agreement on histologic diagnosis was only 46%. Based on statistical modeling, several histologic characteristics predicted DILI versus AIH: portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis (area under the curve, 0.9). Specifically, the presence of intra-acinar lymphocytes and canalicular cholestasis favored DILI, whereas the presence of rosette formation, portal plasma cells, and severe portal inflammation favored AIH. Of note, the presence of intra-acinar eosinophils, which has been regarded as one of the histologic findings suggesting DILI, was more frequently seen in AIH in this cohort. Comment: Results should be interpreted with caution because of the small sample size, and because even experts frequently disagreed on histologic diagnosis. Nonetheless, a larger study to assess interobserver variation and cross-validate these findings should be performed. Histologic criteria such as these that reliably differentiate DILI from AIH would be extremely useful in clinical practice. — Atif Zaman, MD, MPH Published in Journal Watch Gastroenterology December 2, 2011 Citation(s): Suzuki A et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 2011 Sep; 54:931. Medline abstract (Free)

Cuidado Clinico de VIH/sida

HIV/AIDS Clinical Care

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HIV/AIDS Clinical Care for December 5, 2011 NEWS IN CONTEXT Microbicide Use Discontinued in HIV Prevention Trial Free! December 5, 2011 | Raphael J. Landovitz, MD, MSc But the devil's in the details. SUMMARY AND COMMENT Suboptimal Control of HIV Is Associated with Poor Control of Comorbidities December 5, 2011 | Keith Henry, MD Poor adherence to treatments is likely the key factor behind the association. Reviewing: Monroe AK et al. J Acquir Immune Defic Syndr 2011 Dec 15; 58:458 FEATURE World AIDS Day Wanderings Free! December 5, 2011 Musings from Dr. Paul Sax, in his blog HIV and ID Observations CLINICAL PRACTICE GUIDELINE WATCH Updated AAP Policy Statement Promotes Routine HIV Testing in Adolescents Free! November 30, 2011 | Alain Joffe, MD, MPH, FAAP Routine testing should be offered to all adolescents in areas with high HIV prevalence at least once by age 16 to 18. Reviewing: Committee on Pediatric AIDS. Pediatrics 2011 Nov 128:1023 Editor's Picks from across Journal Watch SUMMARY AND COMMENT Low Vitamin D Levels Linked to Active Tuberculosis Free! November 30, 2011 | Richard T. Ellison III, MD | Infectious Diseases Seasonal declines in mean vitamin D levels were followed by seasonal increases in TB notifications. Reviewing: Martineau AR et al. Proc Natl Acad Sci U S A 2011 Nov 22; 108:19013 Realegeno S and Modlin RL. Proc Natl Acad Sci U S A 2011 Nov 22; 108:18861 Free Full-Text Article News in Context Microbicide Use Discontinued in HIV Prevention Trial But the devil's in the details. Just 2 months after the use of oral tenofovir was discontinued in the VOICE trial (JW AIDS Clin Care Oct 3 2011), study investigators have announced that the use of vaginal tenofovir gel is also being discontinued. The decision is based on an interim review at 2 years, showing similar rates of HIV acquisition in women assigned to a daily tenofovir-based vaginal microbicide and those assigned to placebo gel (6.0% and 6.1%, respectively). Notably, the review did not identify any safety concerns. The VOICE trial originally included five study arms — oral tenofovir (Viread), oral tenofovir/FTC (Truvada), oral placebo, vaginal tenofovir gel, and vaginal placebo gel — with each intervention prescribed for daily use. About 1000 HIV-uninfected women were assigned to each arm. At this point, only those receiving oral tenofovir/FTC or oral placebo will continue as planned. The trial is expected to be completed by mid-2012, with final results available by early 2013. Comment: In the past 18 months, HIV prevention research has yielded both tremendously exciting results and extremely disappointing ones, and this news from the VOICE trial is clearly in the latter category. Not only was the trial intended to clarify the comparative effectiveness of oral versus vaginal-gel strategies for HIV prevention in women, but it was also intended to be the second study required by regulatory bodies for approval of tenofovir gel — assuming the results of the CAPRISA 004 study could be replicated or improved upon. The negative results of the VOICE trial confirm the complexity of using medication-based HIV prevention strategies. Of note, the CAPRISA 004 study used a coitus-dependent dosing regimen (12 hours prior and 12 hours after intercourse), whereas VOICE used daily dosing. If an analogy can be made to the iPrEx trial (and it remains to be seen if such analogy is appropriate), it's that participants in HIV prevention studies seem to adhere poorly to daily dosing and thus potentially leave some episodes of intercourse "uncovered" by protective antiretrovirals. Details on adherence levels, drug levels in vaginal tissues, and risk behaviors are critical for understanding the vastly different results of VOICE and CAPRISA 004 — and also the conflicting results of various tenofovir/FTC trials in women (Partners PrEP, TDF2, and FEM-PrEP). Until the detailed results of all these trials are fully presented, it is virtually impossible to proceed with much-needed implementation research and demonstration projects in female populations. — Raphael J. Landovitz, MD, MSc Dr. Landovitz is Assistant Professor, Division of Infectious Diseases, Center for Clinical AIDS Research and Education, University of California, Los Angeles. He reports no conflicts of interest. Published in Journal Watch HIV/AIDS Clinical Care December 5, 2011 Citation(s): MTN statement on decision to discontinue use of tenofovir gel in VOICE, a major HIV prevention study in women [press release]. Pittsburgh, PA: Microbicide Trials Network; Nov 25 , 2011. (http://www.mtnstopshiv.org/node/3909)

VIH en jovenes

http://www.cdc.gov/hiv/youth/index.htm?source=govdelivery

HIV among Youth

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Fast Facts Young people aged 13–29 accounted for 39% of all new HIV infections in 2009. With regard to youth, HIV disproportionately affects young gay and bisexual men and young African Americans. All young people should know how to protect themselves from HIV infection.

Too many young people in the United States (US) are at risk for HIV infection. This risk is especially notable for young gay, bisexual, and other men who have sex with men (MSM) ¹ , especially young African American or Latino MSM, and all youth of minority races and ethnicities. Continual HIV prevention outreach and education efforts, including programs on abstinence, delaying the initiation of sex, and negotiating safer sex, are required as new generations replace the generations that benefited from earlier prevention strategies.

The Numbers

New HIV Infections (Ages 13–29 Years)

• In 2009, young persons accounted for 39% of all new HIV infections in the US. For comparison's sake, persons aged 15–29 comprised 21% of the US population in 2010.
• Young MSM, especially those of minority races and ethnicities, are at increased risk for HIV infection. In 2009, young MSM accounted for 27% of new HIV infections in the US and 69% of new HIV infections among persons aged 13–29. Among young black MSM, new HIV infections increased 48% from 2006 through 2009.

HIV and AIDS Diagnoses² (Ages 13–24 Years)

• An estimated 8,294 young persons were diagnosed with HIV infection in 2009 in the 40 states with long-term HIV reporting, representing about 20% of the persons diagnosed during that year.
  • Seventy-five percent (6,237) of these diagnoses occurred in young people aged 20–24 years. Indeed, those aged 20–24 had the highest number and rate of HIV diagnoses of any age group (36.9 new HIV diagnoses/100,000 people).
• In 2009, young blacks accounted for 65% (5,404) of diagnoses of HIV infection reported among persons aged 13–24 years.
• In 2008, an estimated 22% of persons aged 13–24 living with diagnosed HIV infection were infected through hemophilia, blood transfusion, birth, or unknown transmission mode, with the majority being infected perinatally.

Diagnoses of HIV Infection in the United States, 2009, by Age

Prevention Challenges

Sexual Risk Factors

Early age at sexual initiation; unprotected sex; older sex partners. According to CDC's 2009 National Youth Risk Behavior Survey (YRBS), many adolescents begin having sexual intercourse at early ages: 46.0% of high school students have had sexual intercourse, and 5.9% reported first sexual intercourse before the age of 13. Of the 34.2% of students reporting sexual intercourse during the 3 months before the survey, 38.9% did not use a condom. Young people with older sex partners may be at increased risk for HIV. HIV education needs to take place before young people engage in sexual behaviors that put them at risk. Parent communication and monitoring may play an important role in reaching youth early with prevention messages.
Male-to-male sex. CDC data have shown that young gay, bisexual, and other MSM, especially young African American and young Latino MSM, have high rates of new HIV infections. Another CDC study showed that young MSM and minority MSM were more likely to be unaware of their HIV infection, a situation that puts their health and the health of their partners at risk. Young MSM may be at risk because they have not always been reached by effective HIV interventions or prevention education—especially because some sex education programs exclude information about sexual orientation. A CDC study of MSM in 15 cities found that 80% had not been reached in the past year by HIV interventions known to be most effective. Young MSM may also have increased risk factors for HIV (such as risky sexual behaviors) due to isolation and lack of support.
Sexual abuse. Young adults, both male and female, who have experienced sexual abuse are more likely to engage in sexual or drug-related risk behaviors that could put them at risk for HIV infection.
Sexually transmitted infections (STIs). The presence of an STI greatly increases a person's likelihood of acquiring or transmitting HIV. Some of the highest STI rates in the country are among young people, especially young people of minority races and ethnicities.
Substance Use
Young people in the US use alcohol, tobacco, and other drugs at high rates. CDC's 2009 National YRBS found that 24.2% of high school students had had five or more drinks of alcohol in a row on at least 1 day during the 30 days before the survey, and 20.8% had used marijuana at least one time during the 30 days before the survey. Both casual and chronic substance users are more likely to engage in high-risk behaviors, such as unprotected sex, when they are under the influence of drugs or alcohol. Runaways, homeless young people, and young persons who have become dependent on drugs are at high risk for HIV infection if they exchange sex for drugs, money, or shelter.
Lack of Awareness
Research has shown that a large proportion of young people are not concerned about becoming infected with HIV. This lack of awareness can translate into not taking measures that could protect their health. Abstaining from sex and drug use is the most effective way to avoid HIV infection, but adolescents need accurate, age-appropriate information about HIV and AIDS, how to reduce or eliminate risk factors, how to talk with a potential partner about risk factors and how to negotiate safer sex, where to get tested for HIV, and how to use a condom correctly. Parents also need to reinforce health messages, including how to protect oneself from HIV infection.

What CDC Is Doing

CDC employs a multifaceted approach to addressing the high number of HIV infections occurring in young people in the US.

Programs: CDC provides effective interventions that can be carried out locally for the highest impact. Examples include Project AIM to reduce HIV risk behaviors among at-risk youth; Mpowerment for young gay and bisexual men of diverse backgrounds to reduce sexual risk-taking, encourage regular HIV testing, and build positive social connections; Choosing Life: Empowerment! Action! Results! for those older than 16 living with HIV infection or AIDS or at high risk for HIV; and Focus on Youth for African American young people aged 12–15.

Research: CDC is engaged in research to better understand certain populations and to create or adapt interventions to reduce their risk for HIV infection. For example,

• The Division of Adolescent and School Health collects and reports data on youth health risk behaviors and school-based health policies and practices, and develops guidelines for schools to promote health among young people, among other activities.
• The Youth Risk Behavioral Surveillance System is a CDC surveillance system that monitors six types of health-risk behaviors that contribute to the leading causes of death and disability among youth and adults, including alcohol and other drug use, and sexual risk behaviors.
• The Division of HIV/AIDS Prevention evaluates HIV prevention interventions, such as those for adolescent African American girls in juvenile detention facilities, young African American MSM, and Hispanic parents; adapts current interventions for transgender young adults; and explores new forms of media, such as motion comics, that can deliver stories and content with HIV prevention messages over mobile phones, gaming systems, websites, and social media.

Overall, a multifaceted approach to HIV prevention, which includes individual, peer, familial, school, church, and community programs, is necessary to reduce the incidence of HIV infection and AIDS in young people.