Articles tagged as "Uganda"

Role for LAM test in TB diagnosis among the sickest people living with HIV

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults.

Shah M, Hanrahan C, Wang ZY, Dendukuri N, Lawn SD, Denkinger CM, Steingart KR. Cochrane Database Syst Rev. 2016 May 10;5:CD011420. doi: 10.1002/14651858.CD011420.pub2.

Background: Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease.

Objectives: To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis). To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening).

Search methods: We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861).

Selection criteria: Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older.

Data collection and analysis: Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert(R) MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert(R) MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert(R) MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert(R) MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB). LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses. The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution.

Authors' conclusions: We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

Abstract  Full-text [free] access

Editor’s notes: Tuberculosis (TB) remains a leading cause of death among people living with HIV. Diagnostic tests for TB are suboptimal, and a test for TB with adequate performance which could be used by nurses in primary care clinics would be a great advance. Lipoarabinomannam (LAM) is a component of mycobacterial cell wall which can be found in urine. A lateral flow assay to detect LAM in urine is commercially available at low cost, and can be used in primary care settings without the need for laboratory equipment. However the test is insensitive, such that it has no useful role among HIV-negative people, but has better sensitivity among people living with HIV, leading to questions concerning its role in TB diagnostic pathways.

This systematic review puts together data concerning the performance of the LAM lateral flow assay when used either as a screening test or for diagnosis of TB among people living with HIV. Assessment is made more complicated because the recommended reference cut-off for the test has been changed, with relatively few studies performed after the recommended cut off became what is referred to here as the “higher quality” reference standard (grade two test band intensity, rather than grade one as was previously recommended). Based on the grade two cut–off, the pooled estimate of sensitivity of the test was 45%. As expected, sensitivity was better for individuals with low CD4 counts.

This review informed WHO recommendations on the use of the LAM assay, suggesting that its use should be restricted to assisting with TB diagnosis in people living with HIV with low CD4 counts who are seriously ill. This is consistent with the results of the recent trial (PMID: 26970721) comparing management of hospitalised HIV-positive people reporting one or more TB symptoms with routine testing of urine for LAM compared to standard diagnostic tests, which found that the addition of LAM testing resulted in a small reduction in eight-week mortality.

Overall, LAM is inadequate as a single test for TB, and an accurate diagnostic test that could be used in-session for TB diagnosis in primary care clinics remains a pressing priority.

Comorbidity, HIV testing
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Antiretroviral choice may affect malaria outcomes in children

Antiretroviral choice for HIV impacts antimalarial exposure and treatment outcomes in Ugandan children.

Parikh S, Kajubi R, Huang L, Ssebuliba J, Kiconco S, Gao Q, Li F, Were M, Kakuru A, Achan J, Mwebaza N, Aweeka FT. Clin Infect Dis. 2016 May 3. pii: ciw291. [Epub ahead of print]

Background: The optimal treatment of malaria in HIV-infected children requires consideration of critical drug-drug interactions in co-infected children, as these may significantly impact drug exposure and clinical outcomes.

Methods: We conducted an intensive and sparse pharmacokinetic and pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on three different first-line antiretroviral therapies (ART) were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin (DHA) and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated.

Results: 145 and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared to no ART, efavirenz reduced exposure to all antimalarial components by 2.1 to 3.4-fold; lopinavir/ritonavir increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on efavirenz versus lopinavir/ritonavir-based ART, changes that were associated with an approximately 4-fold higher odds of recurrent malaria by day 28 in those on efavirenz versus lopinavir/ritonavir-based ART.

Conclusions: The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. Efavirenz-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on efavirenz, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure is warranted.

Abstract access

Editor’s notes: This study looks at the pharmacokinetic (PK) and clinical outcomes for artemether/lumefantrine therapy of falciparum malaria in Ugandan children aged 1-8 years living without HIV and with HIV on antiretroviral therapy (ART) regimes containing efavirenz, nevirapine or lopinavir. The stand-out result is that malaria outcomes were better in children who were taking lopinavir-based ART, without any significant drug adverse effects. 

The most commonly-used ART combinations have extensive interactions with other classes of drugs.  The effects of these interactions on clinical outcomes cannot always be accurately predicted from PK studies in healthy adults. This is especially so for sick children whose drug handling may be different. Large PK studies of unwell children are difficult to do, so this study is a rare gem. In fact the PK results are largely as expected. Exposure to artemether and its active metabolite are reduced by efavirenz and nevirapine; and exposure to lumefantrine is reduced by efavirenz and increased by lopinavir with ritonavir. Lumefantrine is the component of the combination malaria therapy with a longer effect and is intended to provide protection from recurrence.

The big question is, what is the impact of these PK differences on clinical outcomes? This is where it gets complicated. In total some 370 malaria episodes were studied. The authors illustrate that the efavirenz group had substantially higher malaria recurrence than the lopinavir group. The lopinavir group had the highest levels of lumefantrine. The efavirenz group had similar outcomes to the HIV-negative group, despite having lower levels of lumefantrine.

The recurrence rate in this study, in an area of intense malaria transmission, is dominated by early reinfection rather than recrudesence. The great majority of children taking ART were also taking co-trimoxazole, which provides protection against malaria infection, giving all children taking ART additional protection versus malaria compared to HIV-negative children. The difference between the efavirenz and lopinavir groups is likely to be due to lumefantrine levels. Higher levels of lumefantrine persist in combination with lopinavir / ritonavir – an effect that might also apply to other protease inhibitors. WHO guidelines recommend lopinavir/ritonavir as part of first-line ART for children under three years old. Whether this effect is large enough to influence ART choices in older children will depend on local circumstances, particularly the malaria transmission rate 

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Trial shows improvements to uptake of VMMC and linkage into HIV care but little effect on ART initiation

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda.

Barnabas RV, van Rooyen H, Tumwesigye E, Brantley J, Baeten JM, van Heerden A, Turyamureeba B, Joseph P, Krows M, Thomas KK, Schaafsma TT, Hughes JP, Celum C. Lancet HIV. 2016 May;3(5):e212-20. doi: 10.1016/S2352-3018(16)00020-5. Epub 2016 Mar 10.

Background: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision.

Methods: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with, number NCT02038582.

Findings: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0.668 for clinic facilitation and p=0.273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1.72, 95% CI 1.36-2.17; p<0.0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1.67, 1.29-2.14; p=0.0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma.

Interpretation: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression.

Abstract access

Editor’s notes: This study described a robust evaluation of approaches to enhance uptake of antiretroviral therapy (ART) and voluntary medical male circumcision (VMMC) following community-based approaches of HIV testing (home-based and mobile HIV testing). For HIV negative men, the close to 50% uptake of VMMC from the text message reminder approach is especially encouraging as it seems a low cost method for wider scale-up. The limitation however is that reliable and private access to a phone would be necessary. Nonetheless, with the increasing availability of mobile phones in Africa, this is a promising approach.

The findings for people living with HIV are more complex. There was remarkably high (93%) linkage into care in the study settings at nine months – even in the referral only arm. Unfortunately, this did not translate into high proportions initiating ART overall, 37%. The benefits from the approaches to enhance uptake of ART were also mixed. ART initiation was increased with lay-counsellor follow-up but not with clinic facilitation, even though the latter did illustrate benefits for linkage to care. Further, viral suppression at nine months was similar across the study arms. Point-of-care CD4-counts did not affect rates of linkage, ART initiation or viral suppression.

The findings from this comprehensive evaluation of approaches to enhance uptake of services remind us of the opportunity not only to actively promote VMMC for HIV-negative men as part of HIV-testing services, but also that both text messages and lay counsellor follow-up can increase uptake. The study also highlights that increasing linkage to care for people living with HIV does not necessarily translate into increasing uptake of treatment. The authors describe possible reasons for this and it seems that addressing health systems challenges within facilities and innovations around treatment delivery should be priorities.

Health care delivery
South Africa, Uganda
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Silent transfers result in underestimation of retention on ART

Retention in care and patient-reported reasons for undocumented transfer or stopping care among HIV-infected patients on antiretroviral therapy in eastern Africa: application of a sampling-based approach.

Geng EH, Odeny TA, Lyamuya R, Nakiwogga-Muwanga A, Diero L, Bwana M, Braitstein P, Somi G, Kambugu A, Bukusi E, Wenger M, Neilands TB, Glidden DV, Wools-Kaloustian K, Yiannoutsos C, Martin J, East Africa International Epidemiologic Databases to Evaluate AIDS (EA-IeDEA) Consortium. Clin Infect Dis. 2016 Apr 1;62(7):935-44. doi: 10.1093/cid/civ1004. Epub 2015 Dec 17.

Background: Improving the implementation of the global response to human immunodeficiency virus requires understanding retention after starting antiretroviral therapy (ART), but loss to follow-up undermines assessment of the magnitude of and reasons for stopping care.

Methods: We evaluated adults starting ART over 2.5 years in 14 clinics in Uganda, Tanzania, and Kenya. We traced a random sample of patients lost to follow-up and incorporated updated information in weighted competing risks estimates of retention. Reasons for nonreturn were surveyed.

Results: Among 18 081 patients, 3150 (18%) were lost to follow-up and 579 (18%) were traced. Of 497 (86%) with ascertained vital status, 340 (69%) were alive and, in 278 (82%) cases, updated care status was obtained. Among all patients initiating ART, weighted estimates incorporating tracing outcomes found that 2 years after ART, 69% were in care at their original clinic, 14% transferred (4% official and 10% unofficial), 6% were alive but out of care, 6% died in care (<60 days after last visit), and 6% died out of care (≥60 days after last visit). Among lost patients found in care elsewhere, structural barriers (eg, transportation) were most prevalent (65%), followed by clinic-based (eg, waiting times) (33%) and psychosocial (eg, stigma) (27%). Among patients not in care elsewhere, psychosocial barriers were most prevalent (76%), followed by structural (51%) and clinic based (15%).

Conclusions: Accounting for outcomes among those lost to follow-up yields a more informative assessment of retention. Structural barriers contribute most to silent transfers, whereas psychological and social barriers tend to result in longer-term care discontinuation.

Abstract access 

Editor’s notes: The authors explore outcomes by tracing a sample of people who were lost to follow-up from antiretroviral therapy (ART) clinics. They collected data on reasons provided by patients for undocumented transfer out, or stopping ART. The findings are important, both to be able to critically evaluate the success of ART programmes (and individual clinics) in retaining people in care, and to identify barriers to retention which may be amenable to change. Consistent with findings elsewhere, the most common outcome among “lost” ART clinic attendees was “silent” (unofficial) transfer to another clinic, which, in this three-country study, accounted for a 10% underestimation of retention in care over two years. This highlights the pressing need for improved electronic medical record systems with centralised identification, in order to be able to track individuals between facilities so that accurate retention data can be collated.

As ART programmes move towards universal immediate initiation, the rate of stopping care (or transferring) will likely increase. In this study, 22% of people who had stopped care gave “I felt well” as a reason. The need for programmes to respond to the structural, psychological and social barriers identified will become even more important. 

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Profound effect of ART on mortality through reduction of opportunistic infections

Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low and middle income countries: a systematic review and meta-analysis. 

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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A new drug for cryptococcal meningitis?

Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR, Team A-CS. Lancet Infect Dis. 2016 Mar 9. pii: S1473-3099(16)00074-8. doi: 10.1016/S1473-3099(16)00074-8. [Epub ahead of print]

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.

Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with, number NCT01802385. 

Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0.37 colony forming units per mL per day (95% CI -0.41 to -0.33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1.27, 95% CI 0.69-2.32; p=0.45).

Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy.

Editor’s notes: Mortality from cryptococcal meningitis remains unacceptably high, especially in low-income settings. This is partly due to high cost and limited availability of effective antifungal agents.  Even when antifungal drugs are available, toxic side effects and suboptimal clearance of cryptococcus from the cerebrospinal fluid (CSF) result in continued morbidity and mortality.  There is an urgent need for new effective antifungal drugs in the treatment of cryptococcal meningitis which improve the rate of CSF sterilisation, have low toxicity, and are readily available.

Sertraline, a commonly used selective serotonin reuptake inhibitor antidepressant with excellent brain parenchymal penetration, has been shown to have potent in vitro and in vivo fungicidal activity against cryptococcus in mice. This is the first clinical study in humans to assess the efficacy of adjunctive sertraline for cryptococcal meningitis, when added to standard amphotericin B and high-dose fluconazole antifungal treatment. Faster cryptococcal CSF clearance and lower incidence of immune reconstitution inflammatory syndrome and relapse were seen in people receiving oral sertraline compared to a historical cohort. Repurposing of sertraline, a drug which is widely available, non-toxic and affordable, as an effective novel adjunctive fungicidal agent shows early promise. It is yet to be seen if improved cryptococcal CSF clearance will translate into better survival.  We will have to wait until 2018 to see the outcome of the Adjunctive Sertraline for the Treatment of Cryptococcal Meningitis (ASTRO-CM) randomised clinical trial.

Comorbidity, HIV Treatment
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Combining community-based HIV testing methods to achieve high testing coverage

A hybrid mobile approach for population-wide HIV testing in rural east Africa: an observational study. 

Chamie G, Clark TD, Kabami J, Kadede K, Ssemmondo E, Steinfeld R, Lavoy G, Kwarisiima D, Sang N, Jain V, Thirumurthy H, Liegler T, Balzer LB, Petersen ML, Cohen CR, Bukusi EA, Kamya MR, Havlir DV, Charlebois ED. Lancet HIV. 2016 Mar;3(3):e111-9. doi: 10.1016/S2352-3018(15)00251-9. Epub 2016 Jan 26.

Background: Despite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population-wide testing coverage.

Methods: We enumerated adult (≥15 years) residents of 32 communities in Uganda (n=20) and Kenya (n=12) using a door-to-door census. Stable residence was defined as living in the community for at least 6 months in the past year. In each community, we did 2 week multiple-disease community health campaigns (CHCs) that included HIV testing, counselling, and referral to care if HIV infected; people who did not participate in the CHCs were approached for home-based testing (HBT) for 1-2 months within the 1-6 months after the CHC. We measured population HIV testing coverage and predictors of testing via HBT rather than CHC and non-testing.

Findings: From April 2, 2013, to June 8, 2014, 168 772 adult residents were enumerated in the door-to-door census. HIV testing was achieved in 131 307 (89%) of 146 906 adults with stable residence. 13 043 of 136 033 (9.6%, 95% CI 9.4-9.8) adults with and without stable residence had HIV; median CD4 count was 514 cells per µL (IQR 355-703). Among 131 307 adults with stable residence tested, 56 106 (43%) reported no previous testing. Among 13 043 HIV-infected adults, 4932 (38%) were unaware of their status. Among 105 170 CHC attendees with stable residence 104 635 (99%) accepted HIV testing. Of 131 307 adults with stable residence tested, 104 635 (80%; range 60-93% across communities) tested via CHCs. In multivariable analyses of adults with stable residence, predictors of non-testing included being male (risk ratio [RR] 1.52, 95% CI 1.48-1.56), single marital status (1.70, 1.66-1.75), age 30-39 years (1.58, 1.52-1.65 vs 15-19 years), residence in Kenya (1.46, 1.41-1.50), and migration out of the community for at least 1 month in the past year (1.60, 1.53-1.68). Compared with unemployed people, testing for HIV was more common among farmers (RR 0.73, 95% CI 0.67-0.79) and students (0.73, 0.69-0.77); and compared with people with no education, testing was more common in those with primary education (0.84, 0.80-0.89).

Interpretation: A hybrid, mobile approach of multiple-disease CHCs followed by HBT allowed for flexibility at the community and individual level to help reach testing coverage goals. Men and mobile populations remain challenges for universal testing.

Abstract access

Editor’s notes: Achieving high levels of HIV testing coverage remains a challenge in many parts of sub-Saharan Africa. Conventional facility-based HIV testing models are insufficient to achieve the UNAIDS 90-90-90 targets and maximise the prevention benefits of treatment. This study was able to achieve extremely high levels of HIV testing coverage in a short period of time by strategically combining two community-based testing approaches. By offering testing through multiple-disease community health campaigns (CHC), followed by focused home-based testing (HBT) for individuals who did not attend the CHCs, nearly 90% of adult stable residents accepted HIV testing. This near-universal coverage was achieved in all 32 communities (range 84%‒95%) across two countries, in a variety of settings with different rates of HIV prevalence and of previous testing. Testing uptake in the CHCs varied considerably across the communities (52%‒82%), demonstrating the value of this hybrid approach to expand coverage. Non-stable residents, who were 13% of the population, had low rates of testing uptake (22%). High rates of mobility remain a particular challenge for universal HIV testing coverage, and additional strategies are necessary to engage this group. A potential limitation of a focused approach to HBT is the need for community enumeration.  Still the results illustrate that achieving high HIV testing coverage is feasible with a combination of community-based approaches.

Kenya, Uganda
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The conundrum of future funding for HIV – who pays and how?

Long-term financing needs for HIV control in sub-Saharan Africa in 2015-2050: a modelling study. 

Atun R, Chang AY, Ogbuoji O, Silva S, Resch S, Hontelez J, Barnighausen T. BMJ Open. 2016 Mar 6;6(3):e009656. doi: 10.1136/bmjopen-2015-009656.

Objectives: To estimate the present value of current and future funding needed for HIV treatment and prevention in 9 sub-Saharan African (SSA) countries that account for 70% of HIV burden in Africa under different scenarios of intervention scale-up. To analyse the gaps between current expenditures and funding obligation, and discuss the policy implications of future financing needs.

Design: We used the Goals module from Spectrum, and applied the most up-to-date cost and coverage data to provide a range of estimates for future financing obligations. The four different scale-up scenarios vary by treatment initiation threshold and service coverage level. We compared the model projections to current domestic and international financial sources available in selected SSA countries.

Results: In the 9 SSA countries, the estimated resources required for HIV prevention and treatment in 2015-2050 range from US$98 billion to maintain current coverage levels for treatment and prevention with eligibility for treatment initiation at CD4 count of <500/mm3 to US$261 billion if treatment were to be extended to all HIV-positive individuals and prevention scaled up. With the addition of new funding obligations for HIV–which arise implicitly through commitment to achieve higher than current treatment coverage levels–overall financial obligations (sum of debt levels and the present value of the stock of future HIV funding obligations) would rise substantially.

Conclusions: Investing upfront in scale-up of HIV services to achieve high coverage levels will reduce HIV incidence, prevention and future treatment expenditures by realising long-term preventive effects of ART to reduce HIV transmission. Future obligations are too substantial for most SSA countries to be met from domestic sources alone. New sources of funding, in addition to domestic sources, include innovative financing. Debt sustainability for sustained HIV response is an urgent imperative for affected countries and donors

Abstract  Full-text [free] access 

Editor’s notes: The authors of this interesting paper use the most up-to-date cost and coverage data to provide a range of estimates for future treatment financing obligations. Epidemiological parameters are included to fit the Goals model and key prevention services such as ‘prevention of mother-to-child HIV transmission’ and ‘voluntary medical male circumcision’ are also included.

Financing needs for the nine countries are estimated by varying treatment initiation threshold (everyone initiated on treatment versus initiation at CD4 of <500cells/mm3) and/or coverage level for prevention and treatment (‘current’ levels and a ‘scale up’ scenario). The authors also attempt to assess both the ethics and the cost of different approaches.

For all scenarios, there is a steady decline in proportion of treatment costs and an increase in the proportion of prevention costs. This apparent contradiction is largely because there will be fewer individuals on treatment over time but prevention costs rise because they are mostly invested in non-infected populations, which increases with population growth.

In the nine countries, estimated resources required for HIV prevention and treatment from 2015-2050 will be large. This is increased further when human resources and supplies increase at the rate of GDP per capita.

However, there is undoubtedly an ethical responsibility to not only continue financing people receiving ART, but, that the responsibility extends to people in equal need who are not on treatment. The ethics is underpinned by the evidence. This illustrates how ‘front-loading’ investments in HIV scale-up now to ensure high levels of coverage, will significantly reduce future HIV incidence and prevalence. 

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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. 

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, Adult ACTGAST. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert® MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Abstract access

Editor’s notes: Tuberculosis (TB) remains the leading cause of death among HIV-positive people worldwide. Existing diagnostic tests for TB lack sensitivity, particularly among HIV-positive people, and autopsy studies consistently illustrate that TB is common at death, but often not identified prior to death. This has led to questions about whether empirical TB treatment, meaning treatment for TB in the absence of bacteriological confirmation, should be more widely used among HIV-positive people.

This trial compared empirical TB treatment to isoniazid preventive therapy among adult outpatients with very low CD4 counts starting antiretroviral therapy (ART). People could be enrolled in the study if they did not have confirmed or suspected TB based on symptoms, locally-accessible diagnostic tests (including chest radiography and sputum smear) and, when available, testing with Xpert® MTB/RIF. There was no difference in mortality at six months between participants given empirical TB treatment compared to isoniazid preventive therapy. Mortality was remarkably low overall, particularly considering that participants had very low CD4 counts. It seems likely that the enrolment criteria excluded people at highest risk of death from participating in the study.

Screening for TB at the time of starting ART could reduce mortality if the tests are sufficiently sensitive, and if people identified to have TB receive effective treatment. However, this study was not designed to address how best to do this in resource-limited settings, where chest radiography and Xpert® MTB/RIF are often not accessible. This study does suggest that isoniazid preventive therapy can be given at the time of ART initiation among people who have been effectively screened for TB. The results of other studies of empirical TB treatment, with different designs in different populations, are awaited. Data from all these studies together may provide evidence to guide the optimal package of care for people presenting with advanced HIV disease. 

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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ART reduces fertility differences by HIV status among women living in sub-Saharan Africa

Measuring the impact of antiretroviral therapy roll-out on population level fertility in three African countries. 

Marston M, Nakiyingi-Miiro J, Hosegood V, Lutalo T, Mtenga B, Zaba B, and on behalf of the ALPHA network. PLoS One. 2016 Mar 25;11(3):e0151877. doi: 10.1371/journal.pone.0151877. eCollection 2016.

Background: UNAIDS official estimates of national HIV prevalence are based on trends observed in antenatal clinic surveillance, after adjustment for the reduced fertility of HIV positive women. Uptake of ART may impact on the fertility of HIV positive women, implying a need to re-estimate the adjustment factors used in these calculations. We analyse the effect of antiretroviral therapy (ART) provision on population-level fertility in Southern and East Africa, comparing trends in HIV infected women against the secular trends observed in uninfected women.

Methods: We used fertility data from four community-based demographic and HIV surveillance sites: Kisesa (Tanzania), Masaka and Rakai (Uganda) and uMkhanyakude (South Africa). All births to women aged 15-44 years old were included in the analysis, classified by mother's age and HIV status at time of birth, and ART availability in the community. Calendar time period of data availability relative to ART introduction varied across the sites, from 5 years prior to ART roll-out, to 9 years after. Calendar time was classified according to ART availability, grouped into pre ART, ART introduction (available in at least one health facility serving study site) and ART available (available in all designated health facilities serving study site). We used Poisson regression to calculate age adjusted fertility rate ratios over time by HIV status, and investigated the interaction between ART period and HIV status to ascertain whether trends over time were different for HIV positive and negative women.

Results: Age-adjusted fertility rates declined significantly over time for HIV negative women in all four studies. However HIV positives either had no change in fertility (Masaka, Rakai) or experienced a significant increase over the same period (Kisesa, uMkhanyakude). HIV positive fertility was significantly lower than negative in both the pre ART period (age adjusted fertility rate ratio (FRR) range 0.51 95%CI 0.42-0.61 to 0.73 95%CI 0.64-0.83) and when ART was widely available (FRR range 0.57 95%CI 0.52-0.62 to 0.83 95%CI 0.78-0.87), but the difference has narrowed. The interaction terms describing the difference in trends between HIV positives and negatives are generally significant.

Conclusions: Differences in fertility between HIV positive and HIV negative women are narrowing over time as ART becomes more widely available in these communities. Routine adjustment of ANC data for estimating national HIV prevalence will need to allow for the impact of treatment.

Abstract  Full-text [free] access 

Editor’s notes: Antenatal care (ANC) clinics records on demographic characteristics and HIV status of attenders are a major component of primary data used to estimate HIV prevalence in sub-Saharan Africa. Prior to scale-up of antiretroviral therapy (ART), the fertility of women living with HIV was lower than that for people without HIV. This means that prevalence estimates from ANC data were adjusted to avoid underestimating the true population fertility rates.

This paper analyses the changing fertility patterns in four longitudinal community-based cohorts in eastern and southern Africa. The study finds that differences in fertility rates between women living with HIV and women without HIV are narrowing as ART is scaled-up, although substantial differences still exist. There was considerable variation in the patterns between the sites reflecting the differing local epidemic profiles. The authors explain this variation as being due to various factors including biological (increased fertility associated with viral suppression), or behavioural (increased fertility among women experiencing widowhood and then forming new partnerships). The impact of treatment on fertility needs to be incorporated into models of HIV prevalence estimated from ANC data, to inform national policy makers measuring their progress towards HIV elimination targets.

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