Toyin Togun

Body Mass Index at Time of Hiv Diagnosis: A Strong and Independent Predictor of Survival

BackgroundIdentification of basic prognostic indicators of HIV infection is essential before widespread antiretroviral therapy can be implemented in low-technology settings. This study assessed how well body mass index (BMI:kg/m2) predicts survival. MethodsBMI within 3 months of HIV diagnosis was obtained from 1657 patients aged ≥15 years, recruited in a seroprevalent clinical cohort in The Gambia since 1992 and followed up at least once. Baseline CD4+ counts and clinical assessment at time of diagnosis were done. ResultsThe mortality hazard ratio (HR) of those with a baseline BMI <18 compared with those with a baseline BMI ≥18 was 3.4 (95% CI, 3.0–3.9). The median survival time of those presenting with a BMI <16 was 0.8 years, in contrast to a median survival of 8.9 years for those with a baseline BMI ≥22. Baseline BMI <18 remained a highly significant independent predictor of mortality after adjustment for age, sex, co-trimoxazole prophylaxis, tuberculosis, reported wasting at diagnosis, and baseline CD4+ cell count (adjusted HR = 2.5, 95% CI 2.0–3.0). Sensitivity and specificity of baseline BMI <18 was comparable to that of a CD4+ count <200 in predicting mortality within 6 months of diagnosis. DiscussionBMI at diagnosis is a strong, independent predictor of survival in HIV-infected patients in West Africa. In the absence of sophisticated clinical and laboratory support, BMI may also prove a useful guide for deciding when to initiate antiretroviral therapy.

Maintenance of HIV-Specific CD4+ T Cell Help Distinguishes HIV-2 from HIV-1 Infection

Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4+ T cell count and a strong HIV-specific CD4+ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a cross-sectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4+ T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57−), and more frequently produced IFN-γ or IL-2 than CD4+ T cells from HIV-1-infected donors. Polyfunctional (IFN-γ+/IL-2+) HIV-specific CD4+ T cells were found exclusively in HIV-2+ donors. The disparity in CD4+ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8+ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4+ T cell response that is associated with delayed disease progression in the majority of infected people.

Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2.

Background: In sub-Saharan Africa, tuberculosis (TB) is the most frequently diagnosed opportunistic infection and cause of death among HIV-infected patients. HIV-2 has been associated with less immune suppression, slower disease progression and longer survival. Objective: To examine whether the incidence of TB and survival after TB are associated with CD4 cell count rather than HIV type. Methods: Clinical and immunological data were retrospectively evaluated among an open clinic-based cohort of HIV-1- and HIV-2-infected patients to determine incidence of TB (first diagnosis > 28 days after HIV diagnosis) and subsequent mortality. Patients were grouped by CD4 cell count into those with < 200, 200–500 and > 500 × 106 cells/l. Results: Incident TB was diagnosed among 159 of 2012 patients, with 4973 person-years of observation time. In 105/159 (66.0%), the diagnosis was confirmed by direct microscopy or culture. Incidence of TB was highest in the group with < 200 × 106 cells/l (9.1/100 and 8.8/100 person-years in HIV-1 and HIV-2, respectively). Adjusted for CD4 cell count, there was no significant difference in incidence or mortality following TB between HIV-1- and HIV-2-infected patients. Mortality rate was higher inthose with incident TB and HIV infection, most markedly in the group with the highest CD4 cell count (hazard ratio, 10.0; 95% confidence interval, 5.1–19.7). Conclusion: Adjusted for CD4 cell count, incidence of TB was similar among HIV-1- and HIV-2-infected patients. Mortality rates after TB diagnosis were similar in both groups and high compared with those without TB.

Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic.

BackgroundAlthough AIDS is less frequent following HIV-2 than HIV-1 infection, it is unclear whether the clinical picture and clinical course of AIDS are similar in the two infections. ObjectivesTo compare the pattern of AIDS-defining events, CD4 cell count at the time of AIDS diagnosis, survival from time of AIDS, and CD4 cell count near time of death in HIV-1 and HIV-2-infected patients. MethodsAdult patients with AIDS who attended the clinics of the MRC in The Gambia were enrolled. AIDS was diagnosed according to the expanded World Health Organization case definition for AIDS surveillance (1994). ResultsThree hundred and forty-one AIDS patients with HIV-1 and 87 with HIV-2 infection were enrolled. The most common AIDS-defining events in both infections were the wasting syndrome and pulmonary tuberculosis. The median CD4 cell count at AIDS was 109 cells/μl in HIV-1 and 176 in HIV-2 (P = 0.01) and remained significantly higher in HIV-2 after adjustment for age and sex (P = 0.03). The median time to death was 6.3 months in HIV-1 and 12.6 months in HIV-2-infected patients (P = 0.03). In a multivariable analysis adjusting for age, sex and CD4 cell count, the mortality rates of HIV-1 and HIV-2-infected patients were similar (P = 0.25). The median CD4 cell count near time of death was 62 and 120 cells/μl in HIV-1 and HIV-2-infected patients, respectively (P = 0.02). ConclusionsHIV-2 patients have a higher CD4 cell count at the time of AIDS, and a longer survival after AIDS. The mortality after an AIDS diagnosis is more influenced by CD4 cell count than HIV type.

Pre-treatment mortality and loss-to-follow-up in HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients eligible for antiretroviral therapy in The Gambia, West Africa

BackgroundHigh early mortality rate among HIV infected patients following initiation of antiretroviral therapy (ART) in resource limited settings may indicate high pre-treatment mortality among ART-eligible patients. There is dearth of data on pre-treatment mortality in ART programmes in sub-Sahara Africa. This study aims to determine pre-treatment mortality rate and predictors of pre-treatment mortality among ART-eligible adult patients in a West Africa clinic-based cohort.MethodsAll HIV-infected patients aged 15 years or older eligible for ART between June 2004 and September 2009 were included in the analysis. Assessment for eligibility was based on the Gambia ART guideline. Survival following ART-eligibility was determined by Kaplan-Meier estimates and predictors of pre-treatment mortality determined by Cox proportional hazard models.ResultOverall, 790 patients were assessed as eligible for ART based on their clinical and/or immunological status among whom 510 (64.6%) started treatment, 26 (3.3%) requested transfer to another health facility, 136 (17.2%) and 118 (14.9%) were lost to follow-up and died respectively without starting ART. ART-eligible patients who died or were lost to follow-up were more likely to be male or to have a CD4 T-cell count < 100 cells/μL, while patients in WHO clinical stage 3 or 4 were more likely to die without starting treatment. The overall pre-treatment mortality rate was 21.9 deaths per 100 person-years (95% CI 18.3 - 26.2) and the rate for the composite end point of death or loss to follow-up was 47.1 per 100 person-years (95% CI 41.6 - 53.2). Independent predictors of pre-treatment mortality were CD4 T-cell count <100 cells/μL (adjusted Hazard ratio [AHR] 3.71; 95%CI 2.54 - 5.41) and WHO stage 3 or 4 disease (AHR 1.91; 95% CI 1.12 - 3.23). Forty percent of ART-eligible patients lost to follow-up seen alive at field visit cited difficulty with the requirement of disclosing their HIV status as reason for not starting ART.ConclusionApproximately one third of ART-eligible patients did not start ART and pre-treatment mortality rate was found high among HIV infected patients in our cohort. CD4 T-cell count <100 cells/μL is the strongest independent predictor of pre-treatment mortality. The requirement to disclose HIV status as part of ART preparation counselling constitutes a huge barrier for eligible patients to access treatment.

Mortality and loss to programme before antiretroviral therapy among HIV-infected children eligible for treatment in The Gambia, West Africa

BackgroundHIV infection among children, particularly those under 24 months of age, is often rapidly progressive; as a result guidelines recommend earlier access to combination antiretroviral therapy (cART) for HIV infected children. Losses to follow-up (LTFU) and death in the interval between diagnosis and initiation of ART profoundly limit this strategy. This study explores correlates of LTFU and death prior to ART initiation among children.MethodsThe study is based on 337 HIV-infected children enrolled into care at an urban centre in The Gambia, including those alive and in care when antiretroviral therapy became available and those who enrolled later. Children were followed until they started ART, died, transferred to another facility, or were LTFU. Cox proportional hazards regression models were used to determine the hazard of death or LTFU according to the baseline characteristics of the children.ResultsOverall, 223 children were assessed as eligible for ART based on their clinical and/or immunological status among whom 73 (32.7%) started treatment, 15 (6.7%) requested transfer to another health facility, 105 (47.1%) and 30 (13.5%) were lost to follow-up and died respectively without starting ART. The median survival following eligibility for children who died without starting treatment was 2.8 months (IQR: 0.9 - 5.8) with over half (60%) of all deaths occurring at home. ART-eligible children less than 2 years of age and those in WHO stage 3 or 4 were significantly more likely to be LTFU when compared with their respective comparison groups. The overall pre-treatment mortality rate was 25.7 per 100 child-years of follow-up (95% CI 19.9 - 36.8) and the loss to programme rate was 115.7 per 100 child-years of follow-up (95% CI 98.8 - 137). In the multivariable Cox proportional hazard model, significant independent predictors of loss to programme were being less than 2 years of age and WHO stage 3 or 4. The Adjusted Hazard Ratio (AHR) for loss to programme was 2.06 (95% CI 1.12 – 3.83) for being aged less than 2 years relative to being 5 years of age or older and 1.92 (95% CI 1.05 - 3.53) for being in WHO stage 3 or 4 relative to WHO stage 1 or 2.ConclusionsEarlier enrolment into HIV care is key to achieving better outcomes for HIV infected children in developing countries. Developing strategies to ensure early diagnosis, elimination of obstacles to prompt initiation of therapy and instituting measures to reduce losses to follow-up, will improve the overall outcomes of HIV-infected children.

Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in West Africa

BackgroundThere is little data on responses to combination antiretroviral therapy (cART) among HIV-infected children in the West African region. We describe treatment outcomes among HIV-1 and HIV-2 infected children initiating cART in a research clinic in The Gambia, West Africa.MethodsAll treatment naive HIV-infected children who initiated cART according to the WHO ART guidelines for children between October 2004 and December 2009 were included in the analysis. Kaplan-Meir estimates and sign-rank test were used to investigate the responses to treatment.Results65 HIV-1 and five HIV-2 infected children aged < 15 years were initiated on cART over this time period. HIV-1 infected children were treated with a combination of Zidovudine or Stavudine + Lamivudine + Nevirapine or Efavirenz while children with HIV-2 were treated with Zidovudine + Lamivudine + ritonavir-boosted Lopinavir. HIV-1 infected children were followed-up for a median (IQR) duration of 20.1 months (6.9 – 34.3), with their median (IQR) age at treatment initiation, CD4% and plasma viral load at baseline found to be 4.9 years (2.1 – 9.1), 13.0% (7.0 – 16.0) and 5.4 log10 copies/ml (4.4 – 6.0) respectively. The median age at treatment initiation of the five HIV-2 infected children was 12 years (range: 4.6 – 14.0) while their median baseline CD4+ T cell count and HIV-2 viral load were 140 cells/mm3 (Range: 40 – 570 cells/mm3) and 4.5 log10copies/mL (Range: 3.1 - 4.9 log10copies/mL) respectively.Among HIV-1 infected children <5 years of age at ART initiation, the median (IQR) increases in CD4% from baseline to 12, 24 and 36 months were 14% (8 – 19; P = 0.0004), 21% (15 – 22; P = 0.005) and 15% (15 – 25; P = 0.0422) respectively, while the median (IQR) increase in absolute CD4 T cell count from baseline to 12, 24 and 36 months for those ≥5 years at ART initiation were 470 cells/mm3 (270 – 650; P = 0.0005), 230 cells/mm3 (30 – 610; P = 0.0196) and 615 cells/mm3 (250 – 1060; P = 0.0180) respectively. The proportions of children achieving undetectable HIV-1 viral load at 6-, 12-, 24- and 36 months of treatment were 24/38 (63.2%), 20/36 (55.6%), 8/22 (36.4%) and 7/12 (58.3%) respectively. The probability of survival among HIV-1 infected children after 12 months on ART was 89.9% (95% CI 78.8 – 95.3). CD4 T cell recovery was sub-optimal in all the HIV-2 infected children and none achieved virologic suppression. Two of the HIV-2 infected children died within 6 months of starting treatment while the remaining three were lost to follow-up.ConclusionsThe beneficial effects of cART among HIV-1 infected children in our setting are sustained in the first 24 months of treatment with a significant improvement in survival experience up to 36 months; however the outcome was poor in the few HIV-2 infected children initiated on cART.

Use of lateral flow assays to determine IP-10 and CCL4 levels in pleural effusions and whole blood for TB diagnosis.

One of the key problems in combating TB is the lack of fast and accurate diagnostic tests that are affordable and easy to use in resource-limited settings. We have used a field-friendly up-converting phosphor (UCP) reporter technology in a lateral flow (LF) based test for the diagnosis of respiratory infections. In this study we analysed samples obtained from patients presenting with symptoms suggestive of TB but prior to confirmation by microbiology in The Gambia. Following clinical and microbiological evaluation they were classified as either having TB or other respiratory disorder (ORD). Analysis of blood was performed for those with pulmonary TB and pleural fluid for those with pleural TB. UCP-LF test for detection and quantitation of IP-10 and CCL4 were used being the two chemokine markers that have been shown to increase in active TB disease. UCP-LF test accurately determined concentrations of both markers as compared to ELISA and multiplex cytokine array. However, only IP-10 could discriminate between TB and ORD, and this was significantly enhanced by analysing the site of infection (pleural fluid), which showed 92% correct classification. Future work will assess the use of multiple markers to increase diagnostic accuracy.

Rapid diagnosis of tuberculosis using ex vivo host biomarkers in sputum

To the Editor: Tuberculosis continues to be a major public health problem in developing countries [1]. One of the roadblocks in reducing tuberculosis transmission is the lack of accurate laboratory-free diagnostic tests for use at the point of care. If tuberculosis is to be eliminated, we need a robust, low-cost and safe point-of-care diagnostic test, which in turn requires identification of appropriate biomarkers [2]. Rapid tests based on microfluidics (lateral flow tests) hold great promise for tuberculosis diagnostics. They are easy to use, cheap, provide an answer within minutes, do not require specialised equipment and are stable at room temperature, making them ideal for use in high tuberculosis burden, resource-poor settings. To date, however, no such test has been developed for tuberculosis due to lack of sensitivity related to the markers and/or sample type. Development of tests based on host biomarkers requires evaluation of different sample types [3]–[5] and markers other than interferon (IFN)-γ [5] to provide differential diagnosis of active tuberculosis, latent infection and other respiratory disorders. We have previously shown that a combination of three host factors in pleural fluid resulted in 96% correct classification of tuberculosis among other respiratory diseases (ORD) (including bacterial pneumonia) regardless of HIV status [6]. However, this sample type is not easy to obtain and we therefore wanted to determine if we could use ex vivo sputum, which is noninvasive and easy to obtain in adult pulmonary tuberculosis patients. Subjects were consecutively recruited from the outpatient clinic and ward at the Medical Research Council Unit, Fajara, the Gambia. All subjects were adults (≥18 years of age) with symptoms suggestive of tuberculosis. Subjects were subsequently classified into two groups: those with culture-confirmed tuberculosis and those with ORD. 75% of the tuberculosis and …

Depression and Posttraumatic Stress Disorder Among HIV-Infected Gambians on Antiretroviral Therapy

Mood disorders are more frequent among people with HIV infection than among non-HIV-infected individuals of the same age, socioeconomic status, and HIV risks. They have been associated with worse adherence and clinical outcomes, yet remain underdiagnosed and undertreated in sub-Saharan Africa. We explored the relationship between mood disorders using the 10-item depression scale of the Centers for Epidemiological Studies (CES-D10) and the 22-item Impact of Events Scale-Revised (IES-R) for posttraumatic stress disorder, and a range of demographic and HIV-related variables among 252 consecutive subjects on antiretroviral therapy (ART). The study was conducted in the Genito-Urinary Medicine Clinic of the Medical Research Councils Gambia Unit. These screening tests were positive in 7% and 30%, respectively, of the patients, with higher scores (more depression or more post-traumatic stress) associated with female gender, more advanced WHO clinical stage, and lower Karnofsky Perfomance Scale rating. Higher CES-D10 scores were also seen among those on their second ART regimen. No relationship was seen with age, time on ART, viral load, or CD4 cell count. Compared to an earlier study at the same site in subjects prior to starting ART, the prevalence of depression in those stabilized on ART was dramatically reduced (by 34%, from 41%) while that of PTSD dropped less (by 13%, from 43%). Integrating the CES-D10 or a similar instrument into patient preparation for ART is recommended in order to identify those who may benefit from further mental health investigations, specific therapy, or closer follow-up during early ART.