Effectiveness and safety of dolutegravir two-drug regimens in virologically suppressed people living with HIV: a systematic literature review and meta-analysis of real-world evidence.

OBJECTIVES: Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV). METHODS: This was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations. RESULTS: Pooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4-1.3] and 0.6% (95% CI: 0.0-1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3-87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0-97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1-16.2) and 7.2% (95% CI: 2.1-14.4) of patients, respectively, at W48. Similar results were observed at W96. CONCLUSIONS: Treatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.

Microstructured beta-tricalcium phosphate for alveolar cleft repair: a two-centre study.

The current standard of care in alveolar cleft repair is timing the procedure in the mixed dentition stage and making use of autologous bone to restore the maxillary defect. Using a synthetic bone substitute bypasses the risk of donor site morbidity and reduces the operation time. In this study, the outcome of alveolar cleft repair using microporous beta-tricalcium phosphate (ß-TCP) was investigated in patients with unilateral cleft lip and palate. Twenty patients were enrolled prospectively in this study, divided between two centres. Continuity of the alveolar process, recurrence of oronasal fistulas, and eruption of teeth into the repaired cleft were evaluated at 1year postoperative. Also, cone beam computed tomography scans were analyzed using a volume-based semi-automatic segmentation protocol. No adverse events were reported. The mean residual bone volume in the repaired cleft at 1year postoperative was 65%. There was no recurrence of oronasal fistula. Furthermore, 90% of the teeth adjacent to the cleft erupted spontaneously and all patients showed a continuous alveolar process. Secondary alveolar grafting using microporous ß-TCP can safely be used in the clinical situation. Residual calcified tissue, canine eruption, and complication rates at the recipient site are comparable to those with autologous grafts.

Pregnancies in older women living with HIV in the UK and Ireland.

OBJECTIVES: The aim of the study was to compare maternal characteristics and pregnancy outcomes in women aged < 40 years and ≥ 40 years in a large unselected population of HIV-positive women delivering in the UK and Ireland between 2000 and 2014. METHODS: Comprehensive population-based surveillance data on all HIV-positive pregnant women and their children seen for care in the UK and Ireland are collected through the National Study of HIV in Pregnancy and Childhood. All singleton and multiple pregnancies reported by the end of June 2015 resulting in live birth or stillbirth to women diagnosed with HIV infection before delivery and delivering in 2000-2014 were included. Logistic regression models were fitted in analyses examining the association between older maternal age and specific outcomes (preterm delivery and stillbirth). RESULTS: Among 15 501 pregnancies in HIV-positive women, the proportion in older women (≥ 40 years) increased from 2.1% (73 of 3419) in 2000-2004 to 8.9% (510 of 5748) in 2010-2014 (P < 0.001). Compared with pregnancies in younger women, those in older women were more likely to result in multiple birth (3.0 vs. 1.9% in younger women; P = 0.03), stillbirth (adjusted odds ratio 2.39; P = 0.004) or an infant with a chromosomal abnormality (1.6 vs. 0.2%, respectively; P < 0.001). However, there was no increased risk of preterm delivery, low birth weight or mother-to-child HIV transmission among older mothers. CONCLUSIONS: There has been a significant increase over time in the proportion of deliveries to women living with HIV aged ≥ 40 years, which has implications for pregnancy management, given their increased risk of multiple births, stillbirth and chromosomal anomalies, as also apparent in the general population.

Duration of ruptured membranes and mother-to-child HIV transmission: a prospective population-based surveillance study.

OBJECTIVE: To investigate the association between duration of rupture of membranes (ROM) and mother-to-child HIV transmission (MTCT) rates in the era of combination antiretroviral therapy (cART). DESIGN: The National Study of HIV in Pregnancy and Childhood (NSHPC) undertakes comprehensive population-based surveillance of HIV in pregnant women and children. SETTING: UK and Ireland. POPULATION: A cohort of 2398 singleton pregnancies delivered vaginally, or by emergency caesarean section, in women on cART in pregnancy during the period 2007-2012 with information on duration of ROM; HIV infection status was available for 1898 infants. METHODS: Descriptive analysis of NSHPC data. MAIN OUTCOME MEASURES: Rates of MTCT. RESULTS: In 2116 pregnancies delivered at term, the median duration of ROM was 3 hours 30 minutes (interquartile range, IQR 1-8 hours). The overall MTCT rate for women delivering at term with duration of ROM ≥4 hours was 0.64% compared with 0.34% for ROM <4 hours, with no significant difference between the groups (OR 1.90, 95% CI 0.45-7.97). In women delivering at term with a viral load of <50 copies/ml, there was no evidence of a difference in MTCT rates with duration of ROM ≥4 hours, compared with <4 hours (0.14% for ≥4 hours versus 0.12% for <4 hour; OR 1.14, 95% CI 0.07-18.27). Among infants born preterm with infection status available, there were no transmissions in 163 deliveries where the maternal viral load was <50 copies/ml. CONCLUSIONS: No association was found between duration of ROM and MTCT in women taking cART. TWEETABLE ABSTRACT: Rupture of membranes of more than 4 hours is not associated with MTCT of HIV in women on effective ART delivering at term.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

British HIV Association and Children's HIV Association position statement on infant feeding in the UK 2011.

To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.

Pregnancy in HIV-infected teenagers in London.

OBJECTIVE: The aim of the study was to describe pregnancies in HIV-infected teenagers. METHODS: A review of the case notes of HIV-infected pregnant teenagers aged 13-19 years from 12 London hospitals was carried out for the period 2000-2007. RESULTS: There were 67 pregnancies in 58 young women, of whom one was known to have acquired HIV vertically. The overall mother-to-child transmission (MTCT) rate of HIV was 1.5% (one of 66). There were 66 live births. Median ages at HIV diagnosis and conception were 17 and 18 years, respectively. Sixty-three per cent of women were diagnosed with HIV infection through routine antenatal screening. Eighty-two per cent of pregnancies (41 of 50) were unplanned, with 65% of women (26 of 40) using no contraception. Forty-three per cent of the women (20 of 46) had a past history of a sexually transmitted infection (STI). In 63 pregnancies, antiretroviral therapy was started post-conception, with prevention of HIV MTCT the only indication in 81% of cases. Fifty-eight per cent of those on highly active antiretroviral therapy (HAART) had an undetectable HIV viral load by delivery. Eighty-seven per cent were uncomplicated pregnancies. Seventy-one per cent delivered by Caesarean section and 21% (14 of 64) had a preterm delivery (<37 weeks). In the 12 months after delivery, 45% of women received contraceptive advice and 25% of women became pregnant again. CONCLUSION: Obstetric and virological outcomes were favourable in this group of HIV-infected young women. However, the majority of pregnancies were unplanned with poor documentation of contraception use and advice and low rates of STI screening. A quarter of women conceived again within 12 months of delivery. Effective measures to reduce STIs, unplanned pregnancies and onward HIV transmission in HIV-infected teenagers are needed.

Effect on the contour of bone and soft tissue one year after harvesting chin bone for alveolar cleft repair.

In this study the authors evaluate and quantify the residual bony defect in the mandibular symphysis and its effect on the soft tissue contour a minimum of 1 year after harvesting chin bone. 59 ASA I cleft lip and palate patients, aged 8-19 years were included. In all patients an autologous bone graft from the mandibular symphysis was harvested for transplantation to the alveolar cleft. Lateral cephalograms were used to measure the donor site defects, and the effects on the soft tissue contour. An evident residual defect was measured at the donor site 1 year after harvesting chin bone. A significant relation was seen between age at time of surgery and size of the defect 1 year postoperatively. In older patients a larger defect remained. Using the current surgical technique of harvesting chin bone, complete bony repair of the defect was not achieved. This study shows postoperatively persisting defects that comprise on average 14% of the original peroperative defects. A significant increase in soft tissue thickness was seen at the mandibular symphysis at a minimum of 1 year postoperatively. These changes in the soft tissue chin contour 1 year after harvesting bone are similar to normal growth changes.

Application of NHG guidelines in patients referred for stable chest pain syndromes.

UNLABELLED: Purpose. Guidelines of the Dutch Association of General Practitioners (NHG) dictate the evaluation, treatment, and referral process of patients with stable chest pain syndromes (CPS). Adherence to this guideline was assessed in a consecutive group of patients referred to our hospital. Methods. We retrospectively studied the records of 296 subjects referred to our outpatient department in 2007 for evaluation of stable CPS. Referral letters were checked for completeness (past and present history, mentioning of risk factors for cardiovascular disease, physical examination, listing of medication) and used to judge adherence to the guideline. In a subset of patients, additional information regarding the referral process was gathered by telephone interview.Results. The referral letter was complete in only 67 patients (23%); items most often not reported were physical examination (63%) and cardiovascular risk factors (62%). Judging from the referral letter, 23 patients (8%) were evaluated in accordance with the NHG guideline prior to their referral. In patients in whom the final diagnosis of angina pectoris was made by the cardiologist, this was 20%. Seventy-nine patients were contacted by telephone after their work-up by the cardiologist; 36 of them (44%) reported being referred at their first visit to their primary physician, while 14 (18%) were referred at their own request. CONCLUSION: Prior to referral, only a minority of patients with stable CPS were evaluated and treated in accordance with NHG guidelines. Furthermore, their referral letter was often incomplete. (Neth Heart J 2010;18:178-82.).

Immunosuppression among HIV-1-positive patients attending for care: experience from two large HIV centres in the United Kingdom.

OBJECTIVES: The aim of the study was to describe the prevalence of and examine the factors associated with immunosuppression (CD4 < 200 cells/microL) among HIV-infected patients attending two large inner London treatment centres. METHODS: Patients attending for care who had a CD4 count < 200 cells/microL during a 6-month period (1 January to 30 June 2007) were identified from the UK national CD4 surveillance database. Corresponding case notes were reviewed and factors associated with the most recent immunosuppressive episode examined. Patients either previously had a CD4 count > 200 cells/microL at any time under follow-up which had decreased (group A) or never had a CD4 count > 200 cells/microL (group B; late presenters). RESULTS: Of 4589 patients, 10.2% (467) had at least one CD4 count < 200 cells/microL. In group A (60.1% of patients), 70.4% were not receiving antiretroviral therapy (ART) at the time at which the CD4 count fell to < 200 cells/microL. Reasons included: treatment interruption (TI; 32.6%), patient declined ART (20.2%), infrequent attendance (19.1%), physician delay in offer (23.1%) and transient CD4 cell count decrease (3.9%). Among those receiving ART, one in three had poor adherence. In group B, 92.3% had started ART after presentation: most had recently started and were responding virologically. AIDS-defining diagnoses occurred in the year preceding the decrease in CD4 cell count in 12.6% of patients in group A and 33.3% of those in group B. CONCLUSION: The majority of patients became immunosuppressed while under care. Our findings suggest that, in addition to strategies aimed at earlier diagnosis, there are further opportunities to reduce severe immunosuppression in patients already attending for HIV care.

New mutations associated with resistance not detected following zidovudine monotherapy in pregnancy when used in accordance with British HIV Association guidelines.

OBJECTIVES: To determine whether mutations conferring drug resistance are detectable after zidovudine monotherapy (ZDVm) in pregnancy, using both standard genotyping and more sensitive cloning assays. METHODS: Post-delivery samples from women meeting the British HIV Association guidelines criteria for the use of ZDVm in the prevention of mother-to-child transmission (MTCT) and who received ZDVm were analysed using the Trugene HIV-1 genotyping assay. In order to detect drug-resistant minority species, samples from a sub-group of 14 women were evaluated for minority drug-resistant variants. Nested polymerase chain reaction (PCR) products from the reverse transcriptase (RT) gene (codons 1-258) were cloned into the pCR4 Blunt TOPO cloning vector. Sequences were submitted to the Stanford University HIV Drug Resistance Database for analysis. RESULTS: Eighty women met the inclusion criteria. Successful genotypes were obtained from 53. There were no new mutations conferring resistance to ZDV detected post-delivery using either standard genotyping or cloning for minority species. CONCLUSIONS: A short course of ZDVm in carefully selected women does not lead to the emergence of drug resistance based on either standard genotyping or cloning for the detection of minority species. Therefore, this strategy can still be considered in women wishing to prevent MTCT while minimizing antiretroviral exposure, without fear of compromising their future HIV care.

Safety of nevirapine in pregnancy.

BACKGROUND: Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years. OBJECTIVES: The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy. DESIGN: This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997-2003. METHODS: All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed. RESULTS: Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%). CONCLUSIONS: Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD(4) count may be less predictive of toxicity in pregnancy.

National review of maternity care for women with HIV infection.

OBJECTIVE: To assess adherence to the British HIV Association (BHIVA) 2001 guidelines for the management of HIV-infected pregnant women. METHODS: A survey and a case note review were carried out using structured questionnaires sent to providers of adult HIV care in the UK and Ireland. Participants were women with HIV infection who delivered a live or stillborn infant between October 2002 and September 2003. The main outcome measures were the appropriate use of antiretroviral therapy, the use and timing of elective Caesarean section, and support for the avoidance of breast-feeding. RESULTS: Of 186 centres, 100 (54%) responded with data on 501 eligible pregnancies. CONCLUSIONS: In general, practice was in accordance with the BHIVA 2001 guidelines. However, in a number of cases Caesarean sections were planned later than the recommended 38 weeks.

Multicentric Castleman's disease in HIV infection.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder. The precise incidence is unknown, although it is more common in HIV-positive than HIV-negative individuals. The pathological features of MCD strongly suggest a chronic antigen stimulation response, and human herpes virus 8 (HHV8) has been found to be universal in cases of HIV-related MCD. The presentation is non-specific with a wide differential diagnosis, which often results in a significant delay in its diagnosis. Diagnosis is made on the clinical presentation of a lymphoproliferative disorder, with evidence of multisystem involvement with classical histopathology on lymph node biopsy. Although no standard of care has been established for its treatment, symptomatic recurrences are often treated with corticosteroids and chemotherapy. The contribution of highly active antiretroviral treatment to the treatment of MCD remains debated. Novel treatments targeted at HHV8 show promising results, although evidence is currently limited to case reports. Randomized control trials assessing whether 'prophylactic' treatment with ganciclovir may prevent flares as currently used against cytomegalovirus disease in transplant patients are proposed. The prognosis of MCD in HIV-positive patients remains generally poor with a median survival of 48 months from diagnosis, and a 15-fold increased risk of non-Hodgkin's lymphoma.

Multicentric Castleman's disease in a patient with HIV.

Multicentric Castleman's disease (MCD) was originally described in non-HIV patients. It is a rare lymphoproliferative disorder, which is more commonly seen in HIV-positive patients and is associated with human herpes virus-8 (HHV-8). We describe a patient with advanced HIV who responded well to conventional highly active antiretroviral treatment. She was diagnosed with MCD soon after her diagnosis of HIV. She presented with multiple flares of her MCD. The case illustrates the difficulty of differentiating between episodes of septicaemia and a flare of MCD. The patient was treated with various chemotherapy regimens, which included several cycles of liposomal doxyrubicin and etoposide. There is currently no consensus on the treatment of MCD and various therapies are described in the literature, which include chemotherapy. Chemotherapy must be chosen with the immunosuppressive effects of the treatment being considered with caution. Both doxyrubicin and etoposide are well tolerated and successfully controlled the symptoms of MCD in our patient.

Genotyping of B and non-B subtypes of human immunodeficiency virus type 1.

Current HIV-1 genotyping assays were developed using subtype B viruses prevalent in Western countries. It is not clear whether these assays are appropriate for use among African patients, who are likely to be infected with non-B subtypes. We evaluated the Bayer TRUGENE HIV-1 genotyping (TG) assay using prospectively collected samples from HIV-1-infected individuals who acquired infection in either sub-Saharan Africa or the West (Europe, North America, and Australia). Plasma samples from 208 individuals with an HIV-1 viral load of >1,000 copies/ml were tested using version 1 primers supplied with the TG assay. If these failed, an alternative primer set version 1.5 was used. Of the 208 individuals, the likely origin of infection was Africa (n = 104), Western (n = 87) and "Others" (i.e., all other geographic locations or origin not certain; n = 17). Among the three groups, the version 1 primers were successful in 85 (82%), 77 (89%), and 13 (76%) individuals, respectively (P = 0.1). Of the remaining 32 samples, 30 were successfully amplified by using the version 1.5 primers. HIV-1 subtypes deduced from the reverse transcriptase sequences correlated with the likely origin of infection: Africa (28A, 3B, 33C, 13D, 6G, 4J, 2K, 5CRF01_AE, and 10CRF02_AG), Western (86B and 1K), and Others (1A and 16B). The success of the version 1 primers correlated with viral load (P < 0.014) and not with HIV-1 subtypes. A protocol based on version 1 primers, followed by 1.5 primers, was successful in sequencing 99% of the samples in this cohort.