High performance of systematic combined urine LAM test and sputum Xpert MTB/RIF® for tuberculosis screening in severely immunosuppressed ambulatory adults with HIV.

BACKGROUND: In people with HIV (PWH), the WHO-recommended tuberculosis four-symptom screen (W4SS) targeting those who need molecular rapid test may be suboptimal. We assessed the performance of different tuberculosis screening approaches in severely immunosuppressed PWH enrolled in the guided-treatment group of the STATIS trial (NCT02057796). METHODS: Ambulatory PWH with no overt evidence of tuberculosis and CD4 cell count <100/µL were screened for tuberculosis prior to antiretroviral therapy (ART) initiation with W4SS, chest X-ray, urine lipoarabinomannan (LAM) test and sputum Xpert MTB/RIF® (Xpert). Correctly and wrongly identified cases by screening approaches were assessed overall and by CD4 count threshold (≤50 and 51-99 cells/µL). RESULTS: Of 525 enrolled participants (median CD4 cell count: 28/µL), 48 (9.9%) were diagnosed with tuberculosis at enrollment. Among participants with a negative W4SS, 16% had either a positive Xpert, a chest X-ray suggestive of tuberculosis or a positive urine LAM test. The combination of sputum Xpert and urine LAM test was associated with the highest proportion of participants correctly identified as tuberculosis (95.8%) and non-tuberculosis cases (95.4%), with proportions equally high among participants with CD4 counts above or below 50 cells/µL. Restricting the use of sputum Xpert, urine LAM test or chest X-ray to participants with a positive W4SS reduced the proportion of wrongly and correctly identified cases. CONCLUSIONS: There is a clear benefit to perform both sputum Xpert and urine LAM tests as tuberculosis screening in all severely immunosuppressed PWH prior to ART initiation, and not only in those with a positive W4SS. CLINICAL TRIALS REGISTRATION: NCT02057796.

Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults.

BACKGROUND: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. METHODS: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. RESULTS: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. CONCLUSIONS: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.).

Plasma sVCAM-1, antiretroviral therapy and mortality in HIV-1-infected West African adults.

OBJECTIVES: We report the association between pre-antiretroviral therapy (pre-ART) soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and long-term mortality in HIV-infected West African adults participating in a trial of early ART in West Africa (Temprano ANRS 12136 trial). METHODS: The ART-naïve HIV-infected adults were randomly assigned to start ART immediately or defer ART until the WHO criteria were met. Participants who completed the trial follow-up were invited to participate in a post-trial phase (PTP). The PTP end-point was all-cause death. We used multivariable Cox proportional models to analyse the association between baseline sVCAM-1 and all-cause death, adjusting for ART strategy, sex, CD4 count, plasma HIV-1 RNA and peripheral blood mononuclear cell HIV-1 DNA levels. RESULTS: In all, 954 adults (77% women, median CD4 count of 387 cells/µL) were randomly assigned to start ART immediately (n = 477) or to defer initiation of ART (n = 477). They were followed for a median of 5.8 years [interquartile range (IQR): 5.2-6.3]. In multivariable analysis, the risk of death was significantly associated with baseline sVCAM-1 [≥1458 vs. < 1458 ng/mL; adjusted hazard ratio = 2.86, 95% confidence interval (CI): 1.60-5.11]. The 6-year probability of death rates were 14.4% (95%CI: 9.1-22.6) and 9.4% (5.4-16.1) in patients with baseline sVCAM-1 ≥ 1458 ng/mL randomized to deferred and immediate ART, respectively, and 3.8% (2.2-6.5) and 3.5% (1.9-6.3) in patients with baseline sVCAM-1 < 1458 ng/mL randomized to deferred and immediate ART. The median difference between pre-ART and 12-month sVCAM-1 levels in patients randomized to immediate ART was -252 (IQR: -587 to -61). CONCLUSIONS: Pre-ART sVCAM-1 levels were significantly associated with mortality, independently of whether ART was started immediately or deferred, but they significantly decreased after 12 months of ART.

Association of cellular HIV-1 DNA and virological success of antiretroviral treatment in HIV-infected sub-Saharan African adults.

BACKGROUND: HIV-1 DNA persists in infected cells, forming viral reservoirs. Pre-antiretroviral treatment (ART) HIV-1 DNA load was reported to predict ART success in European severely immunocompromised patients. The aim of this study was to determine whether HIV-1 DNA levels are associated with virological success in less severely immunocompromised patients who receive early ART in sub-Saharan Africa. METHODS: The association between pre-ART HIV-1 DNA and the virological response after 30 months on ART was studied in multivariate logistic regression in patients randomised to immediate ART groups in the Temprano trial, which assessed the benefits of early ART in HIV-infected adults in Côte d'Ivoire. HIV-1 DNA was quantified in peripheral blood mononuclear cell (PBMC) using real-time PCR. RESULTS: HIV-1 DNA levels were measured in 1013 patients. Their medians [IQR] of pre-ART CD4 count, HIV-1 RNA and HIV-1 DNA levels were 465 [379-578]/mm3, 4.7 [4.0-5.3] log10 copies/ml and 2.9 [2.5-3.2] log10 copies/million PBMC, respectively. Pre-ART HIV-1 DNA was significantly correlated with pre-ART HIV-1 RNA (R = 0.59, p < 0.0001). In multivariate analysis, HIV-1 DNA < 3 log10 copies/million PBMC was significantly associated with virological success at M30 after adjustment for other key variables (ART regimen, IPT, sex, age, WHO clinical stage, CD4 and HIV-1 RNA; aOR 1.57; 95% CI 1.08-2.30; p = 0.02). CONCLUSION: Low HIV-1 DNA was statistically associated with virological success in this population of sub-Saharan African adults who started treatment with a median pre-ART CD4 count at 465/mm3. HIV-1 DNA could become a useful tool for guiding some therapeutic decisions in the test-and-treat era. Trial registration TEMPRANO ANRS 12136 ClinicalTrials.gov, number NCT00495651, date of registration 03/07/2007.

Virological failure and drug resistance in West African HIV-infected adults who started ART immediately or deferred ART initiation.

BACKGROUND: Asymptomatic HIV-infected people who start ART early may feel less motivated and neglect compliance. This might promote the emergence of resistance. METHODS: In the Temprano trial, ART-naive HIV-infected adults with high CD4 counts were randomly assigned to start ART immediately (immediate group) or defer ART until the WHO criteria were met (deferred group). All participants were monitored for 30 months. Those in the deferred group who started ART were monitored for longer, until they had completed 30 months on ART. We compared the rate of virological failure and drug resistance between the immediate and deferred groups 30 months after ART initiation. RESULTS: Of the 2056 participants in Temprano, 1033 were assigned to start ART immediately and 1023 to defer ART. Of the latter, 488 started ART during trial follow-up. Patients in the deferred group who started ART had a lower median CD4 count (280 versus 465 cells/mm3) and a higher median plasma HIV-1 RNA (5.1 versus 4.7 log10 copies/mL) at baseline. During follow-up, participants in both groups had similar antiretroviral drug exposure. Thirty months after ART initiation, patients in the deferred group had a higher rate of virological failure (35.3% versus 29.9%, P = 0.04) and a lower genotypic susceptibility score (P = 0.04). CONCLUSIONS: Starting ART early decreases the risk of virological failure and drug resistance in the medium term. This benefit is of particular importance in countries where access to viral load monitoring and the number of antiretroviral drug lines is limited.

Mortality in relation to hepatitis B virus (HBV) infection status among HIV-HBV co-infected patients in sub-Saharan Africa after immediate initiation of antiretroviral therapy.

It is unknown how past and active hepatitis B virus (HBV) infection affect immunorecovery and mortality in people with HIV who initiate tenofovir-based antiretroviral therapy (ART). Using data collected between 2008 and 2015, we studied people with HIV in sub-Saharan Africa initiating immediate ART in the Temprano randomized control trial. We classified participants into HBV groups at ART initiation: hepatitis B surface antigen (HBsAg)-positive with HBV DNA ≥ 2,000 IU/ml; HBsAg-positive with HBV DNA < 2,000 IU/ml; isolated HBcAb-positive; resolved infection (HBsAb-positive/HBcAb-positive); and HBV non-immune/vaccinated (HBcAb-negative). We compared square-root CD4-cell count increases using mixed-effect, non-linear regression adjusted for age, sex, baseline CD4 cell count, and HIV RNA. We compared all-cause mortality using Bayesian parametric survival regression. Among 879 participants, 24 (2.7%) had HBsAg with high HBV DNA, 76 (8.6%) HBsAg with low HBV DNA, 325 (37.0%) isolated anti-HBcAb, 226 (25.7%) resolved HBV infection and 228 (25.9%) HBV non-immune/vaccinated. We found no significant difference in CD4 cell increases between HBV-infection groups after adjustment (p = 0.16). Participants with HBsAg and high HBV DNA had the highest incidence of all-cause mortality (1.9/100 person-years, 95% Credibile Interval [CrI] = 1.0-3.4). By comparison, incidence rates of mortality were reduced by 57% (95%CrI = -79%, -13%), 60% (95%CrI = -82%, -12%) and 66% (95%CrI = -84%, -23%) in those who had isolated anti-HBcAb-positive, resolved HBV infection and HBV non-immune/vaccinated, respectively. In conclusion, individuals with HIV and past HBV infection or isolated anti-HBcAb-positive serology, much like HBV non-immune/vaccinated, experience lower mortality than those with HBsAg and high HBV DNA. Additional HBV-related management would not be necessary for these individuals.

Higher Mortality Despite Early Antiretroviral Therapy in Human Immunodeficiency Virus and Hepatitis B Virus (HBV)-Coinfected Patients With High HBV Replication.

Background: In human immunodeficiency virus (HIV)-infected patients, hepatitis B virus (HBV) coinfection increases the risk of disease progression. Tenofovir plus emtricitabine/lamivudine (TDF/XTC)-based antiretroviral therapy (ART), which suppresses HIV and HBV replication, has the potential for decreasing this risk. Here, we analyze the association between HBV replication, early ART, and mortality in West African adults. Methods: The Temprano randomized controlled trial assessed the benefits of immediately initiating vs deferring ART in HIV-infected adults with high CD4 counts. After trial completion, participants continued follow-up in a posttrial phase. We analyzed the association between HBV status, immediate ART, and mortality over the entire trial and posttrial follow-up using multivariable Cox proportional hazards regression. Results: A total of 2052 HIV-infected adults (median baseline CD4 count, 464 cells/µL) were followed for 9394 person-years. At baseline, 1862 (91%) were HIV monoinfected and 190 (9%) HIV/HBV coinfected. Of the latter, 135 (71%) had plasma HBV DNA <2000 IU/mL and 55 (29%) HBV DNA ≥2000 IU/mL. The 60-month probability of death was 11.8% (95% confidence interval [CI], 5.4%-24.5%) in coinfected patients with HBV DNA ≥2000 IU/mL; 4.4% (95% CI, 1.9%-10.4%) in coinfected patients with HBV DNA <2000 IU/mL; and 4.2% (95% CI, 3.3%-5.4%) in HIV-monoinfected patients. Adjusting for ART strategy (immediate vs deferred), the hazard ratio of death was 2.74 (95% CI, 1.26-5.97) in coinfected patients with HBV DNA ≥2000 IU/mL and 0.90 (95% CI, .36-2.24) in coinfected patients with HBV DNA <2000 IU/mL compared to HIV-monoinfected patients. There was no interaction between ART strategy and HBV status for mortality. Conclusions: African HIV/HBV-coinfected adults with high HBV replication remain at heightened risk of mortality in the early ART era. Further studies are needed to assess interventions combined with early ART to decrease mortality in this population. Clinical Trials Registration: NCT00495651.

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa.

BACKGROUND: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.).

What Level of Risk Compensation Would Offset the Preventive Effect of Early Antiretroviral Therapy? Simulations From the TEMPRANO Trial.

Whether risk compensation could offset the preventive effect of early initiation of antiretroviral therapy (ART) on human immunodeficiency virus (HIV) transmission remains unknown. Using virological and behavioral data collected 12 months after inclusion in the TEMPRANO randomized trial of early ART (Abidjan, Côte d'Ivoire, 2009-2012), we estimated the risk of HIV transmission and compared it between the intervention (early ART; n = 490) and control (deferred ART; n = 467) groups. We then simulated increases in various sexual risk behaviors in the intervention group and estimated the resulting preventive effect. On the basis of reported values of sexual behaviors, we estimated that early ART had an 89% (95% confidence interval: 81, 95) preventive effect on the cumulative risk of HIV transmission over a 1-month period. This preventive effect remained significant for a wide range of parameter combinations and was offset (i.e., nonsignificant) only for dramatic increases in different sexual behaviors simulated simultaneously. For example, when considering a 2-fold increase in serodiscordance and the frequency of sexual intercourse together with a 33% decrease in condom use, the resulting preventive effect was 47% (95% confidence interval: -3, 74). An important reduction of HIV transmission may thus be expected from the scale-up of early ART, even in the context of behavioral change.

Antiretroviral treatment regardless of CD4 count: the universal answer to a contextual question.

After a period where it was recommended to start antiretroviral therapy (ART) early, the CD4 threshold for treating asymptomatic adults dropped to 200/mm(3) at the beginning of the 2000s. This was mostly due to a great prudence with regards to drug toxicity. The ART-start CD4 threshold in most international guidelines was then raised to 350/mm(3) in 2006-2009 and to 500/mm(3) in 2009-2013. Between 2012 and 2015, international guidelines went the last step further and recommended treating all HIV-infected adults regardless of their CD4 count. This ultimate step was justified by the results of three randomized controlled trials, HPTN 052, Temprano ANRS 12136 and START. These three trials assessed the benefits and risks of starting ART immediately upon inclusion ("early ART") versus deferring ART until the current starting criteria were met ("deferred ART"). Taken together, they recruited 8427 HIV-infected adults in 37 countries. The primary outcome was severe morbidity, a composite outcome that included all-cause deaths, AIDS diseases, and non-AIDS cancers in the three trials. The trial results were mutually consistent and reinforcing. The overall risk of severe morbidity was significantly 44-57 % lower in patients randomized to early ART as compared to deferred ART. Early ART also decreased the risk of AIDS, tuberculosis, invasive bacterial diseases and Kaposi's sarcoma considered separately. The incidence of severe morbidity was 3.2 and 3.5 times as high in HPTN052 and Temprano as in START, respectively. This difference is mostly due to the geographical context of morbidity. The evidence is now strong that initiating ART at high CD4 counts entails individual benefits worldwide, and that this is all the more true in low resource contexts where tuberculosis and other bacterial diseases are highly prevalent. These benefits in addition to population benefits consisting of preventing HIV transmission demonstrated in HPTN052, justify the recommendation that HIV-infected persons should initiate ART regardless of CD4 count. This recommendation faces many challenges, including the fact that switching from "treat at 500 CD4/mm(3)" to "treat everyone" not only requires more tests and more drugs, but also more people to support patients and help them remain in care.

High prevalence of being Overweight and Obese HIV-infected persons, before and after 24 months on early ART in the ANRS 12136 Temprano Trial.

BACKGROUND: HIV is usually associated with weight loss. World health Organization (WHO) recommends early antiretroviral (ART) initiation, but data on the progression of body mass index (BMI) in participants initiating early ART in Africa are scarce. METHODS: The Temprano randomized trial was conducted in Abidjan to assess the effectiveness of early ART and Isoniazid (INH) prophylaxis for tuberculosis in HIV-infected persons with high CD4 counts below 800 cells/mm(3) without any indication for starting ART. Patients initiating early ART before December 2010 were included in this sub-study. BMI was categorized as: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (≥30 kg/m(2)). At baseline and after 24 months of ART, prevalence of being overweight or obese and factors associated with being overweight or obese were estimated using univariate and multivariate logistic regression. RESULTS: At baseline, 755 participants (78 % women; median CD4 count 442/mm(3), median baseline BMI 22 kg/m(2)) initiated ART. Among them, 19.7 % were overweight, and 7.2 % were obese at baseline. Factors associated with being overweight or obese were: female sex aOR 2.3 (95 % CI 1.4-3.7), age, aOR for 5 years 1.01 (95 % CI 1.0-1.2), high living conditions aOR 2.6 (95 % CI 1.5-4.4), High blood pressure aOR 4.3 (95 % CI 2.0-9.2), WHO stage 2vs1 aOR 0.7 (95 % CI 0.4-1.0) and Hemoglobin ≥95 g/dl aOR 3.0 (95 % CI 1.6-5.8). Among the 597 patients who attended the M24 visit, being overweight or obese increased from 20.4 to 24.8 % (p = 0.01) and 7.2 to 9.2 % (p = 0.03) respectively and factor associated with being overweight or obese was immunological response measured as an increase of CD4 cell count between M0-M24 (for +50 cells/mm(3): aOR 1.01; 95 % CI 1.05-1.13, p = 0.01). CONCLUSION: The weight categories overweight and obese are highly prevalent in HIV-infected persons with high CD4 cell counts at baseline, and increased over 24 months on ART in this Sub-Saharan African population.

Community Health Workers. Reinforcement of an Outreach Strategy in Rural Areas Aimed at Improving the Integration of HIV, Tuberculosis and Malaria Prevention, Screening and Care Into the Health Systems. "Proxy-Santé" Study.

Background: In Côte d'Ivoire, the health system remains poorly accessible and inefficient, particularly in rural areas. Malaria, tuberculosis and HIV remain a major concern. Tasks shifting to Community Health Workers (CHWs) in rural areas has been proposed in terms of responses and has shown encouraging results with some limitations. Objective is therefore to develop and implement, in a health district, at the level of a neighborhood, a sub-prefecture, two villages and two camps, innovative strategies aimed at improving the integration of HIV, malaria and tuberculosis prevention and care into the health system at the community level through CHWs. Methods: Introduce innovations to be integrated into the national system: (i) Selection and strengthening of the capacities of CHWs to provide care for the three diseases through home visits [Information Education and Counseling/Communication for Behavior Change (IEC/CBC)], simple malaria screening and management, referral of suspected tuberculosis cases and Directly Observed Treatment, short-course (DOTS), screening, prophylaxis and distribution of antiretrovirals (ARVs) to HIV-infected patients; (ii) monthly animation of village health committees by target groups (women of childbearing age, children under 5 years old, young adolescents); (iii) use of an application and tablets for data collection. Discussion: This innovative project integrates new activities such as ARV distribution by CHWs, management of pre-exposure prophylaxis in rural areas and electronic data capture by communities. Several lessons can be learned on the relevance of the role and activities to be carried out by these CHWs in the fight against these three diseases.

Elite and viremic HIV-1 controllers in West Africa.

BACKGROUND: Data on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa. METHODS: For the Temprano trial, antiretroviral therapy (ART)-naive HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30 months. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral <2000 copies/ml and still off ART at month 30 were defined as HIV-1 controllers. Controllers with all viral loads <50 copies/ml were defined as elite controllers, the rest as viremic controllers. RESULTS: Of the 1023 HIV-1-infected adults randomized in the Temprano deferred-ART group, 18 (1.8%) met the criteria for classification as HIV controllers, of whom seven (0.7%) were elite controllers and 11 (1.1%) viremic controllers. The HIV-1 controllers had low peripheral blood mononuclear cell HIV-1 DNA and low inflammatory marker levels. They maintained high CD4+ cell count and percentages and had a low morbidity rate. DISCUSSION: HIV controllers exist in Africa at a proportion close to that reported elsewhere. They represent a small fraction of all HIV-1-infected patients but raise important questions. Further studies should assess whether starting ART might represent more risk than benefit for some controllers, and where it does, how to identify these patients before they start ART.

Higher risk of mortality in HIV-HBV co-infected patients from sub-Saharan Africa is observed at lower CD4+ cell counts.

BACKGROUND: Hepatitis B virus (HBV) co-infection in human immunodeficiency virus (HIV)-positive individuals increases the risk of overall mortality, especially when HBV DNA levels are high. The role of CD4+ cell counts in this association is poorly defined. We aimed to determine whether HIV-HBV co-infection influences changes in CD4+ cell count before and during antiretroviral therapy and whether it affects mortality risk at levels of CD4+. METHODS: 2052 HIV-positive participants from Côte d'Ivoire in a randomized-control trial assessing early or deferred ART were included. HBV-status was determined by hepatitis B surface antigen (HBsAg). Changes in CD4+ cell levels were estimated using a mixed-effect linear model. The incidence rates of all-cause mortality were estimated at CD4+ counts ≤350, 351-500, >500/mm3 and were compared between HBV-status groups as incidence rate ratios (IRR). RESULTS: At baseline, 190 (9%) were HBsAg-positive [135 (71%) with HBV DNA <2000 IU/mL, 55 (29%) ≥2000 IU/mL]. Follow-up was a median 58 months (IQR = 40-69). Between co-infection groups, there were no differences in CD4+ decline before ART initiation and no differences in CD4+ increase after ART initiation. After adjusting for sex, age, baseline HIV RNA level, and early/deferred ART arm, mortality rates were not significantly different between HBsAg-positive versus HBsAg-negative participants across strata of CD4+ levels. However, HBsAg-positive individuals with HBV-DNA ≥2000 IU/mL versus HBsAg-negative individuals had increased mortality rates at ≤350/mm3 (adjusted-IRR = 3.82, 95% CI = 1.11-9.70) and 351-500/mm3 (adjusted-IRR = 4.37, 95% CI = 0.98-13.02), but not >500/mm3 (adjusted-IRR = 1.07, 95% CI = 0.01-4.91). CONCLUSION: Despite no effect of HBV-infection on CD4+ levels, HIV-HBV co-infected individuals with high HBV replication are at higher risk of mortality when CD4+ is <500/mm3.

Association of Plasma Soluble Vascular Cell Adhesion Molecule-1 and sCD14 With Mortality in HIV-1-Infected West African Adults With High CD4 Counts.

BACKGROUND: Several biomarkers of inflammation and coagulation were reported to be associated with HIV disease progression in different settings. In this article, we report the association between 11 biomarkers and medium-term mortality in HIV-infected West African adults. METHODS: In Temprano ANRS 12136, antiretroviral therapy (ART)-naive HIV-infected adults with high CD4 counts were randomly assigned either to start ART immediately or defer ART until the World Health Organization criteria were met. Participants who completed the 30-month trial follow-up were invited to participate in a posttrial phase. The posttrial phase end point was all-cause death. We used multivariate Cox proportional models to analyze the association between baseline plasma biomarkers [IL-1ra, IL-6, soluble vascular cell adhesion molecule 1 (sVCAM-1), sCD14, D-dimer, fibrinogen, IP-10, sCD163, albumin, high-sensitivity C-reactive protein, and 16S rDNA] and all-cause death in the Temprano participants randomized to defer ART. RESULTS: Four hundred seventy-seven patients (median age 35 years, 78% women, and median CD4 count: 379 cells/mm) were randomly assigned to defer starting ART until the World Health Organization criteria were met. The participants were followed for 2646 person-years (median 5.8 years). In the follow-up, 89% of participants started ART and 30 died. In the multivariate analysis adjusted for the study center, sex, baseline CD4 count, isoniazid preventive therapy, plasma HIV-1 RNA, peripheral blood mononuclear cell HIV-1 DNA, and ART, the risk of death was significantly associated with baseline sVCAM-1 (≥1458 vs. <1458: adjusted hazard ratio 2.57, 95% confidence interval: 1.13 to 5.82) and sCD14 (≥2187 vs. <2187: adjusted hazard ratio 2.79, interquartile range 1.29-6.02) levels. CONCLUSIONS: In these sub-Saharan African adults with high CD4 counts, pre-ART plasma sVCAM-1 and sCD14 levels were independently associated with mortality.

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per µL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Association between cellular HIV-1 DNA level and mortality in HIV-1 infected African adults starting ART with high CD4 counts.

BACKGROUND: High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. METHODS: In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality. FINDINGS: 2019 patients were followed for 9253 patient-years (median 4.9 years). At baseline, the median CD4 count was 462/mm3 [IQR 368-571], the median plasma HIV-1 RNA 4.7 log10 copies/ml [IQR 4.0-5.2], and the median HIV-1 DNA 2.9 log10 copies/million PBMC [IQR 2.5-3.3]. During follow-up, 86 participants died. In univariate analysis, the hazard ratio [HR] of death was 2.67 (95% CI, 1.68-4.22) for patients with HIV-1 DNA ≥3 log10 copies/million PBMC vs. others, and 2.10 (95% CI, 1.38-3.21) for patients with HIV-1 RNA ≥5 log10 copies/ml vs. others. In multivariate Cox regression analysis, HIV-1 DNA levels ≥3 log10 copies/million PBMC were strongly associated mortality (adjusted HR = 2.09, 95% CI 1.24-3.52, p= 0.005) while the association between baseline plasma HIV-1 RNA and mortality was not significant. INTERPRETATION: In these African adults who started ART with high CD4 counts, HIV-1 DNA was a strong independent predictor of death. The HIV reservoir still plays a prognostic role in the early ART era. FUNDING: This trial was supported by the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France; Grants ANRS 12136, 12224 and 12253).

[Aortic aneurism dissection in an adult patient with tuberculosis infected with HIV-1 during immune reconstitution inflammatory syndrome]. / Dissection aortique anévrismale chez un adulte infecté par le VIH-1 dans le cadre d'un syndrome de reconstitution immune avec tuberculose.

We here report the case of a 35-year old man with HIV-1 but with no previous medical-surgical history hospitalized in Abidjan, Côte d'Ivoire, due to fever, cough, dyspnea, chest pain and unfolding of the aortic arch observed on chest x-ray a week after having started antiretroviral therapy (ART). CT angiography of the thoracic aorta showed overall, extended aortic ectasia with mural thrombus. Transesophageal echocardiography objectified type A ascending aortic dissection (Stanford classification). The diagnosis of tuberculosis was confirmed based on Mycobacterium tuberculosis culture isolation. Eight years after, the patient was still alive without surgical treatment and complained of intermittent chest pain. Blood pressure was stable with moderate renal failure. We here report a rare case of aortic aneurism dissection in an adult patient with tuberculosis infected with HIV-1 during immune reconstitution inflammatory syndrome.

High correlation between Framingham equations with BMI and with lipids to estimate cardiovascular risks score at baseline in HIV-infected adults in the Temprano trial, ANRS 12136 in Côte d'Ivoire.

CONTEXT: Data on cardiovascular risk (CVR) score among HIV-infected patients in sub-Saharan Africa are scarce. Our first objective was to compare the CVR score of Framingham utilizing BMI and lipids at baseline, and secondary to assess evolution of CVR score over time at Month 30 in the Temprano trial. METHODS: HIV-infected adults with CD4 <800/mm3 without criteria for initiating ART were included and followed for 30 months in the Temprano trial, which assessed the benefits and risks of early antiretroviral treatment (ART) vs deferred ART. CVR score was estimated at baseline and Month-30 using Framingham equations with either BMI or lipids and classified as high (>20%), moderate (10-20%), and low risk (<10%). At baseline, we compare these two estimations utilizing the Pearson correlation test and analyze the increasing CV risk score over time by Proportional odds cumulative logit models for people attending the Month-30 (M30) visit. RESULTS: Among the 2056 patients, 78% were women, median age was 35 years, and median CD4 count was 464/mm3, 6.8% were obese, 6.3% had hypertension, 7.8% were smokers (1.8% women, 26.8% men), 19% had Total Cholesterol (TC) >5mmol/L, and 1% diabetes at baseline. At baseline the concordance between the two Framingham equations was excellent (r = 0.95; p<0.0001). Among the 1700 patients who attended M30 visit and with available data, 1.3% had a high CV risk score at baseline and 3.1% at M30 visit using Framingham equation with BMI. Adjusted odds ratio (aOR) of being at a higher CV risk score at M30 visit compared to a higher CV risk score at M0 visit was 1.35 (CI 95% 1.17-1.57). Stratified by sex, the increasing CV risk score was OR 1.73 (CI 95%: 1.30-2.29) for women and OR 1.24 (CI 95%: 1.02-1.50) for men. Early ART was not associated with an increasing CV risk score (p = 0.88). Results for the 1422 patients with Framingham equation using lipids were similar. CONCLUSION: In a large trial evaluating early ART for HIV infection in Côte d'Ivoire, Framingham equation with BMI and lipids were highly correlated and CV risk score increases over time. Early ART was not significantly associated with this increasing CV risk score.

Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term follow-up of the Temprano ANRS 12136 trial.

BACKGROUND: Temprano ANRS 12136 was a factorial 2 × 2 trial that assessed the benefits of early antiretroviral therapy (ART; ie, in patients who had not reached the CD4 cell count threshold used to recommend starting ART, as per the WHO guidelines that were the standard during the study period) and 6-month isoniazid preventive therapy (IPT) in HIV-infected adults in Côte d'Ivoire. Early ART and IPT were shown to independently reduce the risk of severe morbidity at 30 months. Here, we present the efficacy of IPT in reducing mortality from the long-term follow-up of Temprano. METHODS: For Temprano, participants were randomly assigned to four groups (deferred ART, deferred ART plus IPT, early ART, or early ART plus IPT). Participants who completed the trial follow-up were invited to participate in a post-trial phase. The primary post-trial phase endpoint was death, as analysed by the intention-to-treat principle. We used Cox proportional models to compare all-cause mortality between the IPT and no IPT strategies from inclusion in Temprano to the end of the follow-up period. FINDINGS: Between March 18, 2008, and Jan 5, 2015, 2056 patients (mean baseline CD4 count 477 cells per µL) were followed up for 9404 patient-years (Temprano 4757; post-trial phase 4647). The median follow-up time was 4·9 years (IQR 3·3-5·8). 86 deaths were recorded (Temprano 47 deaths; post-trial phase 39 deaths), of which 34 were in patients randomly assigned IPT (6-year probability 4·1%, 95% CI 2·9-5·7) and 52 were in those randomly assigned no IPT (6·9%, 5·1-9·2). The hazard ratio of death in patients who had IPT compared with those who did not have IPT was 0·63 (95% CI, 0·41 to 0·97) after adjusting for the ART strategy (early vs deferred), and 0·61 (0·39-0·94) after adjustment for the ART strategy, baseline CD4 cell count, and other key characteristics. There was no evidence for statistical interaction between IPT and ART (pinteraction=0·77) or between IPT and time (pinteraction=0·94) on mortality. INTERPRETATION: In Côte d'Ivoire, where the incidence of tuberculosis was last reported as 159 per 100 000 people, 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected people, even in people with high CD4 cell counts and who have started ART. FUNDING: National Research Agency on AIDS and Viral Hepatitis (ANRS).