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Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been proposed to be effective at treating COVID-19 patients. We, and others, have previously reported on the capacity of CQ to reduce HIV-1 replication in vitro. We tested CQ administration in post-partum mothers on influencing HIV-1 viral loads in human milk as a means of lowering mother to child transmission. A Phase I/II, randomized, placebo-controlled study to evaluate chloroquine administration to reduce HIV-1 RNA levels in human milk: the CHARGE study. Thirty HIV-1 positive pregnant Rwandese women (CQ n = 20; placebo n = 10) were enrolled in a 16-week study, with the treatment group receiving a 200 mg oral dose of CQ daily. Base-line plasma viral load (pVL) measurements and CD4 counts were determined prior to delivery, and pVL, breast milk VL (bmVL) and CQ levels measured during treatment. For women receiving treatment, CQ concentration was higher in breast milk compared to plasma (over 2.5-fold), with a positive correlation between the levels in the two compartments (P < 0.003). A link between high CQ concentrations in plasma and high CD4 counts (P < 0.001) was observed. Surprisingly, we found a significant increase in pVL after CQ treatment in over half of the mothers (n=11; P < 0.001) and with no alteration to bmVL measurements. No specific amino acid alterations in the gp120 envelope sequences could be associated with CQ administration. CQ usage is associated with a significant increase to pVL in early breastfeeding mothers from Rwanda which cautions against the use of CQ in such individuals. Our results highlight a discrepancy between CQ effects on modulating HIV-1 replication in vitro versus in vivo and indicate caution when prescribing CQ to postpartum HIV-1 untreated mothers. This discrepancy should be taken into consideration when testing CQ or HCQ treatment in COVID-19 clinical trials, especially relating to the post-partum setting.

BACKGROUND: Implementation of ultrasensitive HIV drug resistance tests for routine clinical use is hampered by uncertainty about the clinical relevance of drug-resistant minority variants. We assessed different detection thresholds for pretreatment drug resistance to predict an increased risk of virological failure.METHODS: We did a case-control study nested within a prospective multicountry cohort. Our study included patients from 12 clinical sites in Kenya, Nigeria, South Africa, Uganda, and Zambia. We defined cases as patients with virological failure (ie, those who had either viral load ≥400 copies per mL at 12 months or had switched to second-line antiretroviral therapy [ART] as a result of virological failure before 12 months) and controls as those with viral suppression (viral load FINDINGS: Paired viral load results before ART and at month 12 of follow-up were available from 1896 participants. We identified 178 patients with virological failure and selected 338 matched controls. We excluded 117 patients from pretreatment drug resistance analysis; therefore, 152 cases of virological failure and 247 controls were included in the final analysis. With the IAS-USA mutation list, at a detection threshold of 20% or more in patients with pretreatment drug resistance, the adjusted odds ratio (OR) for virological failure was 9·2 (95% CI 4·2-20·1) compared with those without pretreatment drug resistance. Lowering the threshold resulted in adjusted ORs of virological failure of 6·8 (95% CI 3·3-13·9) at the 10% threshold, 7·6 (3·4-17·1) at the 5% threshold, and 4·5 (2·0-10·2) at the 1% threshold. Lowering the detection threshold from 20% improved the sensitivity (ie, ability to identify cases) from 12% (n=18) to 13% (n=19) at detection threshold 10%, to 15% (n=23) at detection threshold 5%, and to 17% (n=26) at detection threshold 1%, but caused a slight reduction in specificity (ie, ability to identify controls) from 98% (n=241) to 96% (n=238) at the 10% threshold, 96% (n=236) at the 5% threshold, and a larger reduction to 92% (n=227) at the 1% threshold. Diagnostic ORs were 5·4 (95% CI 2·1-13·9) at the 20% threshold, 3·8 (1·7-8·6) at the 10% threshold, 3·8 (1·8-8·1) at the 5% threshold, and 2·3 (1·2-4·2) at the 1% threshold. Use of the Stanford HIVDB genotypic sensitivity scores yielded similar ORs for virological failure, sensitivities, specificities, and diagnostic ORs.INTERPRETATION: Ultrasensitive resistance testing for pretreatment drug resistance improved identification of people at risk of virological failure; however, this came with a reduction in our ability to identify people with viral suppression, especially at very low thresholds. Further modelling is needed to estimate the optimal trade-off for the 5% and 20% thresholds, balancing improved case finding against unnecessary regimen switching.FUNDING: The Netherlands Ministry of Foreign Affairs, IrsiCaixa, and European Union.

Objective To assess the feasibility of providing guideline-based cardiovascular disease (CVD) prevention care within the context of a community-based health insurance program (CBHI) in rural Nigeria. Methods A prospective operational cohort study was conducted in a primary healthcare clinic in rural Nigeria, participating in a CBHI program. The insurance program provided access to care and improved the quality of the clinics participating in the program, including CVD prevention guideline implementation. Insured adults at risk of CVD were consecutively included upon clinic attendance. The primary outcome was quality of care determined by scoring of quality indicators on patient files of the cohort, 1.5 year after guideline implementation. Results Of the 368 screened patients, 349 were included and 323 (93%) completed 1 year of follow-up. The majority of patients (331, 95%) had hypertension. Process indicators showed that 114/115 (99%) new hypertension cases had a record of CVD risk assessment and 249/333 (75%) eligible cases a record of lifestyle advice. Outcome indicators showed that in 292/328 (64%) hypertension cases, blood pressure was on target. Barriers to care included limited human resources, limited affordability of diagnostic tests and multidrug regimes for the healthcare provider, frequent doctor's appointments, and inefficient drug supplies. Conclusion Implementation of CVD prevention care within the context of a CBHI program resulted in high-quality care in rural sub-Saharan Africa, comparable to high-income countries. However, guideline implementation was resource-intense and specific recommendations were not feasible. Simple models of care delivery are needed for rapid scale-up of CVD prevention services in sub-Saharan Africa.

Uptake of antiretroviral regimens with associated durable virologic suppression has been shown to reduce the risk of HIV transmission. Expanding antiretroviral therapy (ART) programs at a population level may serve as a vital strategy in the elimination of the AIDS epidemic. The global expansion of ART programs has greatly improved access to life-saving therapies and is likely to achieve the target of 15 million individuals on therapy set by UNAIDS. In addition to the incontrovertible gains in terms of life expectancy, growing evidence demonstrates that durable virologic suppression is associated with significant reductions in HIV transmission amongst heterosexual couples and men who have sex with men. Expansion of successful ART programs, best monitored by a program-level continuum of care cascade to assess progress in diagnosis, retention in care, and virologic suppression, is associated with reductions in HIV incidence at a population level. Expanding and sustaining successful ART delivery at a global level is a key component in a comprehensive approach to combating the HIV epidemic over the next two decades.

Background and Aim Vitamin D insufficiency plays an important role in liver fibrosis in hepatitis C virus (HCV)-infected patients. We assessed liver fibrosis by transient elastography and 25 hydroxy vitamin D [25(OH)D] status in HCV-infected patients, with (HIV/HCV) or without HIV co-infection (HCV) from Thailand. Methods Fibrosis stage was defined as mild ( 14 kPa). Hypovitaminosis D was defined as 25(OH)D 1.45 (6.30, 2.70–14.74), P 1.45, and hypovitaminosis D are strong and independent predictors for the presence of advanced fibrosis in our HCV-infected patients. These data highlight the urgent need of HCV treatment and vitamin D supplement in resource-limited settings.

Objectives To study the prevalence of target organ damage (TOD) in hypertensive adults in a general population in rural Nigeria, to assess determinants of TOD and the contribution of TOD screening to assess eligibility for antihypertensive treatment. Methods All adults diagnosed with hypertension (n=387) and a random sample (n=540) out of all nonhypertensive adults, classified during a household survey in 2009, had a blood pressure measurement and were invited for TOD (myocardial infarction, left ventricular hypertrophy, angina pectoris, kidney disease) screening in 2011. Results Participation in TOD screening was 51% (n=196) in respondents with hypertension and 33% (n=179) in those without hypertension. TOD prevalence in hypertensive and nonhypertensive adults was 32 and 15%, respectively. Hypertension severity was a strong determinant for TOD [grade 1 odds ratio (OR) 2.66, 95% confidence interval (CI)1.04-6.84; grade 2 OR 3.82, 95% CI 1.41-10.36]. Out of 196 hypertensive patients, 151 were untreated, of whom all grade 2 hypertensive patients (n=71) were eligible for treatment. Screening revealed TOD in 19 out of 80 grade 1 hypertensive respondents (24%), therefore also classifying them as eligible for treatment. TOD screening hypertensive nonrespondents had more severe hypertension than hypertensive respondents, which may have resulted in an underestimation of the true prevalence of TOD among adults with hypertension. Conclusion A high prevalence of 32% TOD in hypertensive adults in rural Nigeria was observed. Almost a quarter of respondents with grade 1 hypertension were eligible for antihypertensive treatment based on TOD screening findings. As TOD screening is mostly unavailable in sub-Saharan Africa, we propose antihypertensive treatment for all patients with hypertension.

Since the discovery of HIV as the causative agent of AIDS in 1983/1984, remarkable progress has been made in finding antiretroviral drugs (ARVs) that are effective against it. A major breakthrough occurred in 1996 when it was found that triple drug therapy (HAART) could durably suppress viral replication to minimal levels. It was then widely felt, however, that HAART was too expensive and complex for low- and middle-income countries, and so, with the exception of a few of these countries, such as Brazil, a massive scale-up did not begin until the WHO launched its ‘3 by 5′ initiative and sizeable funding mechanisms, such as the Global Fund to Fight AIDS, TB and Malaria and the US President's Emergency Plan for AIDS Relief (PEPFAR), came into existence. A pivotal enabler of the scale-up was a steady lowering of drug prices through entry of generic antiretrovirals, competition between generic manufacturers and the making of volume commitments. The WHO Prequalification of Medicines Programme and the Expedited Review Provision of the US Food and Drug Administration have been important for the assurance of quality standards. Antiretroviral drug development by research-based pharmaceutical companies continues, with several important innovative products, such as long-acting agents, in the pipeline.

IMPORTANCE Hypertension is a major public health problem in sub-Saharan Africa, but the lack of affordable treatment and the poor quality of health care compromise antihypertensive treatment coverage and outcomes. OBJECTIVE To report the effect of a community-based health insurance (CBHI) program on blood pressure in adults with hypertension in rural Nigeria. DESIGN, SETTING, AND PARTICIPANTS We compared changes in outcomes from baseline (2009) between the CBHI program area and a control area in 2011 through consecutive household surveys. Households were selected from a stratified random sample of geographic areas. Among 3023 community-dwelling adults, all nonpregnant adults (aged-18 years) with hypertension at baseline were eligible for this study. INTERVENTION Voluntary CBHI covering primary and secondary health care and quality MAIN OUTCOMES AND MEASURES The difference in change in blood pressure from baseline improvement of health care facilities. between the program and the control areas in 2011, which was estimated using difference-in-differences regression analysis. RESULTS Of 1500 eligible households, 1450 (96.7%) participated, including 564 adults with hypertension at baseline (313 in the program area and 251 in the control area). Longitudinal data were available for 413 adults (73.2%) (237 in the program area and 176 in the control area). Baseline blood pressure in respondents with hypertension who had incomplete data did not differ between areas. Insurance coverage in the hypertensive population increased from 0% to 40.1%in the program area (n = 237) and remained less than 1% in the control area (n = 176) from 2009 to 2011. Systolic blood pressure decreased by 10.41 (95%CI, ?13.28 to ?7.54)mmHg in the program area, constituting a 5.24 (?9.46 to ?1.02)-mm Hg greater reduction compared with the control area (P = .02), where systolic blood pressure decreased by 5.17 (?8.29 to ?2.05)mmHg. Diastolic blood pressure decreased by 4.27 (95%CI, ?5.74 to ?2.80)mmHg in the program area, a 2.16 (?4.27 to ?0.05)-mm Hg greater reduction compared with the control area, where diastolic blood pressure decreased by 2.11 (?3.80 to ?0.42)mmHg (P = .04). CONCLUSIONS AND RELEVANCE Increased access to and improved quality of health care through a CBHI program was associated with a significant decrease in blood pressure in a hypertensive population in rural Nigeria. Community-based health insurance programs should be included in strategies to combat cardiovascular disease in sub-Saharan Africa. Copyright © 2014 American Medical Association. All rights reserved.

Effective contraception has been widely promoted for HIV-positive women. However, there are limited data on the interactions between combined hormonal contraceptives and nonnucleoside reverse transcriptase inhibitors . This study assessed the steady-state contraceptive effectiveness and safety of combined oral contraceptive (COC) containing 0.150 mg desogestrel /0.030 mg ethinyl estradiol with either nevirapine (NVP) or efavirenz (EFV) in 34 HIV-positive women. The targeted level for contraceptive effectiveness was endogenous progesterone level < 3.0 ng/mL. We measured NVP/EFV plasma concentrations 12 hours after administration (C12) with and without COC. The desired therapeutic levels were >3.1 mg/L for NVP and 1.0-4.0 mg/L for EFV, respectively. All 18 subjects in the NVP group had serum progesterone 1.0 ng/mL, including 3 subjects with >3.0 ng/mL (might indicate ovulation). The difference in progesterone levels between the 2 groups was statistically significant (P = 0.04). The median C12 of NVP increased insignificantly by 17% with COC; the median C12 of EFV decreased significantly (P = 0.02) by 22%. In 3 of 16 subjects (19%) in the EFV group, C12 of EFV dropped below 1.0 mg/L. In contrast to NVP, coadministrating desogestrel/ethinyl estradiol containing COC with EFV was associated with unfavorable progesterone and antiretroviral levels. Our results suggest that NVP may be superior to EFV when used with COC in HIV-positive women

Objective The aim of this study was to determine the prevalence of hepatitis B virus (HBV) infection in a cohort of HIV-infected Rwandan children and adolescents on combination antiretroviral therapy (cART), and the success rate of HBV vaccination in those children found to be HBV negative. Methods HIV-infected children and adolescents (age 8-17 years) receiving cART with CD4 T-cells count ≥200 cells/mm and/or ≥15% and without prior HBV vaccination (by history, vaccination cards and clinic records) underwent serologic testing for past (negative HBV surface antigen [HBsAg] with positive antibody to HBV core antigen [cAb] and to HBsAg [anti-HBs]) or active HBV infection (positive HBsAg). Children with any positive HBV serologic tests were excluded from further vaccination; all others completed 3 HBV immunizations with 10 µg of ENGERIX-B. Anti-HBs titer was measured 4-6 weeks after the last immunization. Results Of 88 children, 6 (7%) children had active HBV infection and 8 (9%) had past HBV infection. The median (interquartile range) age, CD4 T-cell count and cART duration were 12.3 (10.1-13.9) years, 626 (503 to 942) cells/mm and 1.9 (1.5-2.7) years, respectively. Seventeen children had detectable plasma HIV-1 RNA. Seventy-3 children completed 3 immunizations with median (interquartile range) postimmunization anti-HBs concentration of 151 mIU/mL (1.03-650). Overall, 52 children (71%, 95% confidence interval: 61-82) developed a protective anti-HBs response. HIV-1 RNA and CD4 T-cell count were independent predictors of a protective anti-HBs response. Protective anti-HBs response was achieved in 82% of children with undetectable HIV-1 RNA and 77% with CD4 T cells ≥350/mm. Conclusions The substantial HBV prevalence in this cohort suggests that HIV-infected Rwandan children should be screened for HBV before cART initiation. HIV viral suppression and CD4 T cells ≥350/mm favored the likelihood of a protective response after HBV vaccination.

Background There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz (EFV) compared to nevirapine (NVP) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large, urban HIV clinic in Uganda. Methods Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multi-variable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. Results ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (sd 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43–182). Overall, 60% ( n=3,484) were initiated on NVP and 40% ( n=2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count 3 (HR 2.05 [95% CI 1.29, 3.27]; P=0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P=0.428). These estimates were robust to all sensitivity analyses. Conclusions There was a higher incidence of TB in patients with baseline CD4+ T-cell counts 3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.

Item does not contain fulltext Abstract Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged >/=18 years with HIV RNA 42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC0-24 71.2 vs. 53.1 mg.h/liter, Cmax 8.5 vs. 5.5 mg/liter, and Ctrough 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV Ctrough levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg.h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.

Objectives To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. Methods In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Results Included were 511 patients with a median baseline CD4 count of 57 cells/mm3 (interquartile range: 22–130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: −22.3 cells/mm3 (95% confidence interval −43.2 to −1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Conclusions Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution. Objectifs: Determiner si un diagnostic de la tuberculose meconnue au debut de l’ART influence le taux de recuperation ulterieure des lymphocytes T CD4+ (CD4) dans une clinique urbaine du VIH en Ouganda. Methodes: Dans une etude de cohorte retrospective, un modele polynome multivariea effets mixtes a ete utilise pour estimer la recuperation des CD4 au cours des 96 premieres semaines de l’ART dans deux groupes de patients: TB prevalente (qui ont commence l’ART durant le traitement de la TB), TB meconnue (qui ont developpe la TB 6 mois apres le debut de l’ART). Resultats: 511 patients ont ete inclus avec un taux median de CD4 de base de 57 cellules/mm3 (intervalle interquartile 22, 130), dont 368 (72.0%) avaient une TB prevalente et 143 (28.0%) avaient une TB meconnue. Par rapport a la TB prevalente, la TB meconnue etait associee a une recuperation inferieure des CD4 a 96 semaines: -22,3 cellules/mm3 (intervalle de confiance 95% de -43.2 a -1.5; P = 0.036). Ces estimations ont ete ajustees pour le sexe, l’âge, le taux de CD4 de base et l’utilisation d’un traitement a base d’AZT. Conclusions: La TB meconnue au moment de l’initiation de l’ART mene a une recuperation alteree des CD4 par rapport a la TB traitee avant le debut de l’ART. Un depistage plus vigilant avec un diagnostic plus sensible et rapide de la TB avant le debut de l’ART est necessaire pour diminuer le risque de TB associee a l’ART et une reconstitution immunitaire sous-optimale. Objetivos: Investigar si un diagnostico no reconocido de TB al comienzo del TAR tiene posteriormente influencia sobre la recuperacion del conteo de linfocitos T CD4+ en una clinica urbana para VIH en Uganda. Metodos: En un estudio de cohortes retrospectivo, se utilizo un modelo polinomial multivariable de efectos mixtos para calcular la recuperacion de CD4 durante las primeras 96 semanas de TAR en dos grupos de pacientes: TB prevalente (comenzo TAR mientras recibia tratamiento para TB), TB no reconocida (desarrollo TB dentro de los 6 meses siguientes al comienzo del TAR). Resultados: Se incluyeron 511 pacientes con una mediana en el conteo de base de CD4 de 57 celulas/mm3 (rango intercuartil 22, 130), de los cuales 368 (72.0%) tenian una TB prevalente y 143 (28.0%) tenian una TB no reconocida. Comparada con la TB prevalente, la TB no reconocida estaba asociada con una menor recuperacion en el conteo de CD4 a las 96 semanas: -22.3 celulas/mm3 (IC 95% -43.2 a -1.5, P = 0.036). Estas estimaciones se ajustaron para genero, edad, conteo de base de CD4 y el uso de un regimen basado en AZT. Conclusiones: La TB no reconocida en el momento de iniciar el TAR resulto en un deterioro en la recuperacion de CD4 comparada con la TB tratada antes de la iniciacion del TAR. Se requiere una mayor vigilancia antes de la iniciacion del TAR, con pruebas diagnosticas para TB mas sensibles y rapidas, para disminuir el riesgo de la TB asociada al TAR y una reconstitucion inmune suboptima.

We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intra-muscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-γ ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4+ and CD8+ T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field.

Background Therapy for chronic hepatitis B with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) is currently recommended for HIV–HBV coinfection. However, there is limited randomized data on the efficacy of combined therapy with TDF and FTC, especially in antiretroviral (ARV)-naive patients. Methods This was a prospective randomized clinical trial comparing the efficacy of HBV monotherapy with FTC versus TDF/FTC combination therapy in ARV-naive HIV– HBV coinfection. HIV–HBV-coinfected patients initiating ARV were randomized to either FTC/zidovudine/efavirenz (EFV; n=6) or TDF/FTC/EFV ( n=10). The primary end point was the time-weighted area under the curve (TWAUC) of HBV DNA at 48 weeks. Results The median baseline CD4+ T-cell count was 64 cells/μl (interquartile range [IQR] 36–172), plasma HIV type-1 RNA was 4.90 log10 copies/ml (IQR 4.58–5.44) and plasma HBV DNA was 8.76 log10 copies/ml (IQR 8.45–8.82). A total of 11/16 (69%) patients were hepatitis B e antigen (HBeAg)-positive. The median TWAUC decrease in HBV DNA was -5.32 log10 copies/ml in the TDF/FTC group compared with -3.25 log10 copies/ml in the FTC group ( P=0.03). At week 48, 90% of the TDF/FTC group and 33% of the FTC group had plasma HBV DNAConclusions TDF/FTC combination therapy resulted in a significantly greater decrease in HBV DNA than FTC monotherapy, with a greater proportion of patients with undetectable HBV DNA at week 48. Our study supports the current recommendation of ARV containing TDF/FTC as the treatment of choice for patients with HIV–HBV coinfection.

Background Transient episodes of HIV type-1 viraemia are frequently observed in patients on suppressive combination antiretroviral therapy (cART). We studied the effect of such episodes and of treatment interruptions on clinical outcome and immunological response. Methods A total of 3,321 patients from the ATHENA cohort had virological suppression (HIV type-1 RNA400 copies/ml) viraemia and the outcomes death, AIDS or immunological response (CD4+ T-cell count increase ≥50% from 24 weeks) was studied with Poisson regression models, including either time-updated cumulative follow-up, time spent per type of episode or modelling episodes as binary status indicators. Results During 11,165 person-years of follow-up, 88 patients died, 111 developed AIDS and 2,019 had an immunological response. Longer follow-up time in treatment interruptions increased the risk of AIDS (relative risk [RR] 8.07, 95% confidence interval [CI] 3.98–16.4 per year longer) and impaired immunological response (RR 0.22, 95% CI 0.12–0.41). High-level viraemia was only associated with immunological response (RR 0.55, 95% CI 0.40–0.74), whereas low-level viraemia was not associated with any of the three outcomes. Status indicator models gave similar results. When also including time-updated CD4+ T-cell counts, the observed associations diminished. Conclusions Treatment interruptions and high-level, but not low-level, viraemia are strongly associated with clinical outcome, mainly via their effect on CD4+ T-cell counts.

HIV testing policies and practices vary widely across Europe. It is clear that there are individuals who might present late for HIV diagnosis and care within all risk groups, and potentially in any healthcare setting. This article explores the need to ensure earlier identification and treatment of late-presenting patients by reviewing strategies that might be considered. Such strategies could include routine provider-initiated HIV testing of at-risk groups in settings such as sexually transmitted infection clinics, drug dependency programmes or antenatal care. Healthcare providers might also consider routine HIV testing in all healthcare facilities, in settings including emergency and primary care, where local HIV prevalence is above a threshold that should be further evaluated. They should also take advantage of rapid testing technologies and be aware of barriers to HIV testing among specific groups to provide opportunities for testing that are relevant to local communities.

Background Nevirapine (NVP) is often prescribed once daily in clinical practice in combination with a once daily nucleoside backbone. We investigated the relationship of NVP dosing with safety and efficacy. Methods Patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study, Canadian HAART Observational Medical Evaluation and Research (HOMER) cohort and Swiss HIV Cohort Study (SHCS) using NVP-based combination therapy either once daily or twice daily were included. Risk factors for discontinuing NVP because of hypersensitivity reactions (HSRs) were investigated using multivariate logistic regression. Risk factors for virological failure 96 weeks after NVP initiation were identified using logistic regression and Cox models. Results Of 5,636 patients (774 once daily and 4,862 twice daily), 268 (4.8%) discontinued NVP because of HSR between 2 and 18 weeks. Logistic regression showed that, compared with patients with detectable HIV type-1 (HIV-1) RNA starting twice-daily NVP, there was a significantly higher risk of discontinuation of once-daily NVP because of HSR in patients with detectable HIV-1 RNA at the start of NVP (odds ratio [OR] 1.52; P=0.04), whereas the risk was actually significantly lower in patients starting once-daily NVP with undetectable HIV-1 RNA (OR 0.44; P=0.04). Cox models showed that risk of virological failure was not different for twice- versus once-daily NVP in treatment-naive patients (twice-daily versus once-daily hazard ratio [HR] 1.01; P=0.95), treatment- experienced patients experiencing treatment failure (twice-daily versus once-daily HR 1.22; P=0.30) or patients with undetectable HIV-1 RNA simplifying treatment with NVP (twice-daily versus once-daily HR 1.29; P=0.30). Conclusions Initiation of a once-daily NVP-based regimen in patients with suppressed viraemia carries a low risk of treatment-limiting HSR. Once- or twice-daily NVP-based regimens appear to have similar antiretroviral efficacy.

Objective: HIV treatment failure is commonly associated with drug resistance and the selection of a new regimen is often guided by genotypic resistance testing. The interpretation of complex genotypic data poses a major challenge. We have developed artificial neural network (ANN) models that predict virological response to therapy from HIV genotype and other clinical information. Here we compare the accuracy of ANN with alternative modelling methodologies, random forests (RF) and support vector machines (SVM). Methods: Data from 1204 treatment change episodes (TCEs) were identified from the HIV Resistance Response Database Initiative (RDI) database and partitioned at random into a training set of 1154 and a test set of 50. The training set was then partitioned using an L-cross (L=10 in this study) validation scheme for training individual computational models. Seventy six input variables were used for training the models: 55 baseline genotype mutations; the 14 potential drugs in the new treatment regimen; four treatment history variables; baseline viral load; CD4 count and time to follow-up viral load. The output variable was follow-up viral load. Performance was evaluated in terms of the correlations and absolute differences between the individual models' predictions and the actual @DVL values. Results: The correlations (r^2) between predicted and actual @DVL varied from 0.318 to 0.546 for ANN, 0.590 to 0.751 for RF and 0.300 to 0.720 for SVM. The mean absolute differences varied from 0.677 to 0.903 for ANN, 0.494 to 0.644 for RF and 0.500 to 0.790 for SVM. ANN models were significantly inferior to RF and SVM models. The predictions of the ANN, RF and SVM committees all correlated highly significantly with the actual @DVL of the independent test TCEs, producing r^2 values of 0.689, 0.707 and 0.620, respectively. The mean absolute differences were 0.543, 0.600 and 0.607log"1"0copies/ml for ANN, RF and SVM, respectively. There were no statistically significant differences between the three committees. Combining the committees' outputs improved correlations between predicted and actual virological responses. The combination of all three committees gave a correlation of r^2=0.728. The mean absolute differences followed a similar pattern. Conclusions: RF and SVM models can produce predictions of virological response to HIV treatment that are comparable in accuracy to a committee of ANN models. Combining the predictions of different models improves their accuracy somewhat. This approach has potential as a future clinical tool and a combination of ANN and RF models is being taken forward for clinical evaluation.

Contains fulltext : 81713.pdf (Publisher’s version ) (Closed access) Currently, the optimal boosting dose for saquinavir is unknown. Therefore, we evaluated the pharmacokinetics profiles in a cross over setting comparing saquinavir/ritonavir 1500/50 mg (plus NRTI backbone) to saquinavir/ritonavir 1500/100 mg in the same HIV-infected, Thai individuals. The 50% reduction of ritonavir boosting did not result in a change in the pharmacokinetics of saquinavir, whereas the ritonavir exposure was significantly lower when a dose of 50 mg was administered.

In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-gamma Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-T-cell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.

Objective: An important pending question is whether temporary highly active antiretroviral therapy during primary HIV infection can influence viral rebound dynamics and the subsequently established viral setpoint, through preservation and enhancement of HIV-1-specific immune responses, or through other mechanisms. Methods: We included all patients from two prospective studies who underwent a single treatment interruption while being well suppressed on highly active antiretroviral therapy. One group started highly active antiretroviral therapy during primary HIV infection, and the other group started it during chronic HIV infection with CD4 cell counts above 350 cells/ml. Data were collected up to 48 weeks from treatment interruption.Themediantimetoviralreboundwasanalysedforthreelevelsofviraemia: 50, 500 and 5000 copies HIV-RNA/ml plasma. Results: The median time to viral rebound was significantly longer in primary HIV infection patients (n ¼24) than in chronic HIV infection patients (n ¼46): 8 versus 4 weeks (P

BackgroundThe pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.MethodsRelationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.ResultsRitonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).ConclusionsReduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that in most treatment guidelines is recommended to be taken combined with two nucleoside analogue reverse transcriptase inhibitors, as a preferred first-line regimen for the treatment of HIV-1 infection. The antiretroviral efficacy of efavirenz-based combination regimens is good, as has been demonstrated in many clinical trials. Efavirenz has a long plasma half-life, which allows for once-daily dosing, but, as a consequence of this and the low genetic barrier, it is also prone to select for viral resistance when adherence to therapy is suboptimal. The most frequently encountered side effects are neuropsychiatric symptoms. These side effects are usually transient, but have been shown to persist for up to 2 years after initiation of therapy in some patients. This review outlines important and recent pharmacological and clinical data, which explain why efavirenz became a component of preferred treatment regimens today.

Objective: To evaluate the safety and efficacy of discontinuing highly active antiretroviral therapy (HAART) in HFV-1-positive patientswho initiated HAART at a CD4(+) T-cellcount > 350cells mm(3). Methods: Eligible patients were identified from the Dutch AIDS Therapy Evaluation, The Netherlands (ATHENA) national observational cohort. Interruption or continuation of HA ART was offered to all. Results: Of 71 patients enrolled, 46 (64%) interrupted HAART (STOP group) and 25 (36%) continued HAART (control group). The median CD4(+) T-cell nadirs at the start of HAART were 469 (interquartile range [IQR]: 430-720) cells/n,1113 and 5 10 (IQR: 440637) cells/mm(3), respectively. At week 48, the median plasma HIV RNA level in the STOP group had stabilized at approximately pre-HAART values (4.55 log(10), IQR: 4.2-4.9 copies/mL), but the CD4(+) T-cell count still exceeded the pre-HAART count (563 cells/mm(3), IQR: 450-710 cells/mm(3)). Only 5 patients (11%) had reinitiated HAART after 48 weeks, all for personal reasons. No Centers for Disease Control and Prevention category events or death occurred after interruption. In 6 (13%) of 46 patients, mild symptoms of acute retroviral rebound syndrome (ARVS) were identified. No improvement was observed in mental or physical health scores. In 37% of patients, nonnucleoside reverse transcriptase inhibitor drug concentrations were still detectable 1 week after stopping. Conclusions: Although HAART can safely be interrupted in patients with a high CD4 T-cell nadir, no improvement in quality of life was established. Patients call experience ARVS, the risk for development of resistance after treatment interruption is realistic, and there is a potential hazard of HIV transmission to sexual partners. We would not actively advise stopping treatment in patients who started treatment too early according to current guidelines

OBJECTIVE. To improve adherence and virologic suppression, we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1–infected children.METHODS. HIV-1–infected children naive to efavirenz were treated with a combination of efavirenz, abacavir, didanosine, and lamivudine in an observational, prospective, single-center study. Virologic failure-free survival was assessed with Kaplan-Meier analysis. The CD4+ T-cell increase was estimated by using a generalized linear model incorporating repeated measurements.RESULTS. Thirty-six children received the study medication for a median of 69 weeks. Virologic failure-free survival rates were 76% and 67% after 48 weeks and 96 weeks, respectively. No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy. All children receiving highly active antiretroviral therapy showed a sustained CD4+ T-cell increase, irrespective of virologic suppression. Growth rates improved with highly active antiretroviral therapy. Study medication administration was stopped for 14 children, mostly because of nonadherence (4 cases) or virologic rebound (5 cases) and because of adverse events (unrelated death and grade 2 liver toxicity) in 2 cases. Lipid abnormalities and abacavir-related hypersensitivity were not observed.CONCLUSIONS. For the first time, once-daily highly active antiretroviral therapy is demonstrated to be a safe, convenient, and potent antiretroviral regimen for HIV-1–infected children.

PURPOSE: To objectively assess changes in body fat distribution in a subgroup of antiretroviral therapy-naïve participants in a randomized comparative trial of regimens including a nucleoside analogue backbone of didanosine with either lamivudine or stavudine. METHOD: Whole body dual-energy X-ray absorptiometry (DEXA) scans were performed at baseline and weeks 48 and 96 of therapy in all 19 patients from one of the sites participating in the Antiretroviral Regimen Evaluation Study (ARES). Patients had been randomized to receive nelfinavir/didanosine/stavudine (n = 8), nevirapine/didanosine/lamivudine (n = 7), or ritonavir-boosted saquinavir/didanosine/lamivudine (n = 4). RESULTS: In an intent-to-treat analysis, patients allocated to didanosine plus stavudine-containing treatment after 96 weeks had lost a median of 1,825 g (-26%) of total limb fat, as compared to a median gain of 1,639 (48%) and 403 (6%) g in those randomized to the didanosine/lamivudine plus nevirapine or saquinavir-containing regimens, respectively. These changes in limb fat were statistically significantly different when comparing patients allocated to stavudine-containing treatment with both of the other two treatment arms combined (p = .01). CONCLUSION: This study suggests that didanosine/lamivudine, when combined with either nevirapine or ritonavir-boosted saquinavir over 96 weeks of therapy, is possibly not associated with limb fat atrophy, in contrast to when treatment contained didanosine, stavudine, and nelfinavir combined

Introduction The world is becoming increasingly urban. Of the projected increase of 1·1 billion in the world population between 2010 and 2025, virtually all will be urban dwellers. Urbanisation is mostly happening in lowincome regions, with Africa having the highest rate of all continents. The population growth rate in urban areas is almost double the rural rate but, more importantly, the slum growth rate is higher than the overall urban rate. In the next few decades, the proportion of the urban population living in slums in sub-Saharan Africa might therefore get even higher than the estimated 60% in 2010. Overall, the number of slum dwellers in low-income and middle-income countries is projected to double from one to two billion during the next 30 years. The UN Human Settlements Programme has identifi ed fi ve characteristics that defi ne a slum, namely inadequate access to safe water, inadequate access to sanitation and infrastructure, poor structural quality of housing, overcrowding, and insecure residential status. Govern ments, development partners, civil society, and other stakeholders recognise the need to develop social programmes that respond eff ectively to the needs of slum dwellers. However, little evidence exists for how to best design and implement such programmes in these deprived, often unpredictable, and dynamic settings, and for what challenges one might encounter in the process. The African Population and Health Research Center, in collaboration with international partners, has been working for the past decade in slum settings in Nairobi, Kenya, doing research and intervention projects. The aim of this Viewpoint is to share our experiences working in the centre and provide some insights into the complexities surrounding design and implementation of programmes aimed at improvement of health and wellbeing in such a dynamic setting. Key challenges for people working in slums To implement a health programme in the slums, the complex and multifactorial eff ects of urban settings on health programming and outcomes need to be acknowledged. We describe the specifi c challenges facing people working in the slums, which can be placed within the conceptual framework for urban health and relate to their eff ect on delivery and intended outcome of health programmes. In the national and international political arena, a substantial gap exists between rising awareness of the growth and importance of slums and an absence of actual health-generating policies, structures, and inter ventions on the ground. This absence is not just in the area of health care, but also in areas and sectors that have a direct and indirect bearing on the health of slum dwellers. These areas include urban planning and infrastructure, education and employment, law enforcement, and the environment. This list implies that health programmes have to contend with other factors that have an eff ect on health but might also disrupt the programme, hence curtailing its eff ect. From time to time, high-level politics at the level of national or municipal government might have a substantial eff ect on research and project work in the slums. For example, an attempt by the central government in collaboration with a UN agency to upgrade the road networks in a slum in Nairobi in the late 2000s led to demolition of housing structures and displacement of residents, some of whom had been recruited into various pro grammes and were thus lost to follow-up. With the near absence of public or state actors, the private sector dominates the market in health care and other social sectors in slums. These actors range from local traditional healers and quacks to well established and structured local non-governmental, faith-based organisations or other actors within the civil society. Faith-based organisations are more likely to collaborate in research and health programmes. Public–private partnership initiatives for health service delivery have been introduced in the slums to increase access to and demand for quality health-care services. Health research and programmes therefore have to engage with non-state actors for greater eff ect and reach. Within the physical environment of the slums, the main challenge for health programmes is the high amount of crime. Insecurity is also seen by the population as the major concern in daily life, and violence-related injuries contribute substantially to morbidity and mortality in the urban poor. Early research in the slums of Nairobi showed that injuries ranked second to HIV/AIDS as a cause of death in individuals aged 5 years and older. Depending on the location within the slum and the hour of the day, project workers are often exposed to a high risk of crime (panel 1). This risk is Lancet 2015; 386: 2114–16

Adult women (n=113) and men (n=100) initiating combination antiretroviral therapy (cART) and women not yet eligible for cART (n=199) in Kigali, Rwanda, were followed for 6–24 months between 2007 and 2010. In the cART groups, 21% of patients required a drug change due to side effects and 11% of patients had virological failure (defined as >1,000 HIV RNA copies/mL) after 12 months of cART. About a third of the pregnancies since HIV diagnosis were unintended. The proportion of women in the pre-cART group using modern contraception other than condoms (50%) was similar to women in the general population, but this proportion was only 25% in women initiating cART. Of the women who carried at least one pregnancy to term since having been diagnosed HIV-positive, a third reported to have participated in a prevention-of-mother-to-child-transmission (PMTCT, option A) intervention. Many patients were coinfected with herpes simplex virus type 2 (79–92%), human papillomavirus (38–53%), and bacterial sexually transmitted infections (STIs) with no differences between groups. We applaud the Rwandan government for having strengthened family planning and PMTCT services and for having introduced HPV vaccination in recent years, but additional work is needed to strengthen STI and HPV-related cancer screening and management in the HIV-positive population.

This article is about the complete Evidence-based Use of Antiretroviral Therapies.

Epstein-Barr virus (EBV) is a widespread, persistent herpesvirus that can transform B cells and that is associated with malignant lymphomas. EBV dynamics and specific immunity in human immunodeficiency virus (HIV)-1-infected children are unknown. We found that, in 74% of EBV-seropositive, HIV-1-infected children, EBV DNA loads at the start of highly active antiretroviral therapy (HAART) were comparable with those in acutely EBV-infected, HIV-negative children. EBV DNA load remained elevated in most HIV-1-infected children for months to years of follow-up. Frequencies of interferon-gamma-producing EBV-specific CD8+ T cells were comparable with those in healthy control children, and antibodies to EBV nuclear antigen were detected in 73% of EBV-seropositive children. Detectable EBV DNA load was not correlated with HIV-1 RNA level or with CD4+ T cell count increase after the start of HAART. Because of its resemblance to chronic active EBV, we studied the cellular tropism of EBV in these patients. EBV DNA was found not only in the CD19+ B cell fraction but also--at stable levels--in the CD4+ and CD8+ T cell fractions. Although the reason for the aberrant T cell tropism of EBV remains unclear, these data may provide an explanation for the differential EBV dynamics in the presence of normal serological findings.

In this study we investigated the long-term effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4+T-cell responses in comparison with virus-specific CD4+T-cell responses against the persistent herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). To this end, HIV- and herpes virus-specific cellular immune responses were measured longitudinally in 10 seroconverters with long-term follow-up including 55 months of successful suppression of viral load by HAART. HIV- and CMV-specific CD4+T cells producing interferon-γ (IFNγ) or interleukin-2 (IL-2) were analysed as well as proliferative capacity. EBV-specific CD4+T cells were determined using a 12-day ex vivo assay. Initiation of HAART resulted in a transient increase of HIV-specific IL-2+IFNγ+CD4+T cells and, to a lesser extent, IL-2+CD4+T cells. Long-term HAART resulted in an increase in HIV-, CMV- and EBV-specific CD4+T-cell proliferative capacity. The increase in HIV- and herpes-virus-specific CD4+T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART.

OBJECTIVE. We sought to provide long-term data on the clinical, immunologic, and virologic response to highly active antiretroviral therapy in infants and children who are naive to protease inhibitors. METHODS. HIV-1–infected children who were naive to protease inhibitors were treated with a combination of nelfinavir and 2 nucleoside reverse transcriptase inhibitors (stavudine and lamivudine) in an observational, prospective, single-center study. Virologic failure-free survival was assessed by Kaplan-Meier analyses. The increase in CD4+ T cells during follow-up was estimated with a generalized linear model incorporating repeated measurements. RESULTS. Thirty-nine HIV-1–infected children were included and followed for a median period of 227 weeks (interquartile range: 108–275 weeks). The virologic failure-free survival rate was 74%, 66%, 58%, and 54% after 48, 96, 144, and 240 weeks, respectively. Children who experienced virologic failure in 48 weeks (or 96 weeks) were younger at baseline compared with the responders (0.8 vs 5.3 years). Eighteen children remained on the regimen for >5 years. All children, including the nonresponders, showed a sustained immunologic response. Grades 3 to 4 toxicity was observed in 2 patients only. Eleven developed clinically evident lipodystrophy. CONCLUSION. Combination therapy can be used safely in infants and children over a long period. Young age is strongly associated with virologic failure. Although the virologic response declined, immunologic parameters and clinical improvement were sustained up to 7 years, at the expense of lipodystrophy.

Background Universal health care coverage has been identified as a promising strategy for improving hypertension treatment and control rates in sub Saharan Africa (SSA). Yet, even when quality care is accessible, poor adherence can compromise treatment outcomes. To provide information for adherence support interventions, this study explored what low income patients who received hypertension care in the context of a community based health insurance program in Nigeria perceive as inhibitors and facilitators for adhering to pharmacotherapy and healthy behaviors. Methods We conducted a qualitative interview study with 40 insured hypertensive patients who had received hypertension care for > 1 year in a rural primary care hospital in Kwara state, Nigeria. Supported by MAXQDA software, interview transcripts were inductively coded. Codes were then grouped into concepts and thematic categories, leading to matrices for inhibitors and facilitators of treatment adherence. Results Important patient-identified facilitators of medication adherence included: affordability of care (through health insurance); trust in orthodox “western” medicines; trust in Doctor; dreaded dangers of hypertension; and use of prayer to support efficacy of pills. Inhibitors of medication adherence included: inconvenient clinic operating hours; long waiting times; under-dispensing of prescriptions; side-effects of pills; faith motivated changes of medication regimen; herbal supplementation/substitution of pills; and ignorance that regular use is needed. Local practices and norms were identified as important inhibitors to the uptake of healthier behaviors (e.g. use of salt for food preservation; negative cultural images associated with decreased body size and physical activity). Important factors facilitating such behaviors were the awareness that salt substitutes and products for composing healthier meals were cheaply available at local markets and that exercise could be integrated in people’s daily activities (e.g. farming, yam pounding, and household chores). Conclusions With a better understanding of patient perceived inhibitors and facilitators of adherence to hypertension treatment, this study provides information for patient education and health system level interventions that can be designed to improve compliance. Trial registration ISRCTN47894401. Electronic supplementary material The online version of this article (doi:10.1186/s12913-014-0624-z) contains supplementary material, which is available to authorized users.

Objectives In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. Methods Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. Results We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 ±2.66mg/l, whereas in the control group the mean nevirapine concentration was 8.72 ±3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (Conclusion Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations >3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.

Objectives: Differential exposure to saquinavir/ritonavir may lead to therapy failure. The objective was to identify factors that influence variability of saquinavir/ritonavir plasma concentrations. Methods: Saquinavir/ritonavir data, dosed as 1600/100 mg once daily, from three separate pharmacokinetic studies, in 45 patients from Thailand and the UK, were pooled. Pharmacokinetic parameters were based on non-compartmental analysis. Univariate analysis was performed with saquinavir as the dependent variable, and ritonavir area under the curve (AUC), gender, body weight, body mass index (BMI) and study site as independent variables. Variables with a P value

The incidence of (EBV-related) malignancies in HIV-infected subjects has declined since the introduction of highly active antiretroviral therapy (HAART). To investigate the effect of HAART on EBV infection, we performed a longitudinal analysis of the T cell response to both a latent and a lytic Ag and EBV viral load in 10 subjects from early in HIV infection up to 5 years after HAART. All individuals responded to HAART by a decline in HIV viral load, a restoration of total CD4+ T cell numbers, and a decline in T cell immune activation. Despite this, EBV load remained unaltered, even after 5 years of therapy, although a decline in both CD4+ and CD8+ T cells specific for the lytic EBV protein BZLF1 suggested a decreased EBV reactivation rate. In contrast, latent EBV Ag EBNA1-specific CD4+ and CD8+ T cell responses were restored after 5 years of treatment to levels comparable to healthy individuals. In two individuals who were treated by HAART late during HIV progression, a lymphoma developed shortly after initiation of HAART, despite restoration of EBV-specific CD4+ and CD8+ T cells. In conclusion, long-term HAART does not alter the EBV DNA load, but does lead to a restoration of EBNA1-specific T cell responses, which might allow better control of EBV-infected cells when applied early enough during HIV infection.

Background. Mitochondrial DNA ( mtDNA) in peripheral blood mononuclear cells (PBMCs) has been suggested as a potential marker of mitochondrial toxicity associated with nucleoside analogue reverse-transcriptase inhibitor - containing therapy. Methods. We quantified mtDNA and mitochondrial RNA (mtRNA) in PBMCs over the course of 48 weeks in 78 patients infected with human immunodeficiency virus type 1 (HIV-1) who were randomly assigned to receive ritonavir-boosted indinavir and efavirenz with or without stavudine. Furthermore, we analyzed the association of mtDNA and mtRNA with clinical signs and symptoms and/or abnormalities in laboratory markers attributed to mitochondrial toxicity. Results. No statistically significant difference was found in mtDNA and mtRNA content over time between the 2 treatment arms. When arms were combined, both median mtDNA and mtRNA content showed statistically significant increases over the course of 48 weeks, from 206 to 278 copies/cell (P

Objective: To examine HIV disease progression in a cohort of adult patients treated with antiretroviral therapy (ART) via a clinical research network in Thailand. Design, setting, participants and intervention: A cohort of 417 patients enrolled in a series of randomized ART trials, between 1996 and December 2002. Main outcome measures: Progression to combined endpoint of AIDS defining illness or death according to baseline characteristics, ART used, immunological and virological responses to initial 6 months of ART. Results: During 1677 person years of follow-up, 29 of 417 patients progressed; tuberculosis was the most common event defining progression (14 of 29 events). The rates of progression to combined endpoint or death alone were 1.7 [95% confidence interval (Cl), 1.1-2.4] and 0.7 (95% Cl, 0.3-1.3) per 10 person years respectively. Compared to patients with baseline CD4 cell counts >= 350 x 10(6)/l, the adjusted hazard ratio (HR) for progression was 3.67 (95% Cl, 1.31-10.27) for patients with 4 log(10). Compared to patients with a 6-month CD4 cell count >= 350 x 10(6)/l, HR for progression was 5.22 (95% Cl, 1.90-14.37) for patients with

Objective: To determine the incidence and risk factors for rash in Thai patients taking four different non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Methods: HIV-positive antiretroviral-naive patients enrolled in the 2NN study in Thailand and followed for at least 1 week were included. Patients were randomized to efavirenz (EFV) 600 mg once daily (OD) versus nevirapine (NVP) 200 mg twice daily (BD) versus NVP 400 mg (OD versus NVP 400 mg OD + EFV 800 mg OD with stavudine/lamivudine. Results: Of 202 patients 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI respectively. For NNRTI-related rash the incidence were EFV (20%) NVP BD (21%) NVPOD (38%) and NVP + EFV (67%). The proportions of patients with grade I II and III within the four treatment arms are as follows: EFV 4.3 13 and 2.9%; NVP BD 2.3 5.9 and 2.3%; NVP OD 12.8 19.1 and 6.4%; and NVP + EFV 11.9 47.6 and 7.1%. Multivariate analyses showed females with CD4 cell count =250 x 10(6) cells/l high body mass index (>21.3 kg/m(2) and a rise in CD4 (=53 x 10(6) cells/l) and alanine aminotransferase (ALT) (=34 U/l) at week 4 to be risk factors for rash. Conclusions: Thai patients had a high incidence of NNRTI- related rash when treated with NVP + EFV or NVP OD. NVP if used BD had the same rash incidence as EFV for rash of all grades. Females and persons with earlier HIV disease or with a large rise in CD4+ cell count after starting therapy are at greater risk for NNRTI-related rash. (authors)