HIV This Week

Association of schistosomiasis with false positive HIV test results in an African adolescent population.

Everett DB, Baisely KJ, McNerney R, Hambleton I, Chirwa T, Ross DA, Changalucha J, Watson-Jones D, Helmby H, Dunne DW, Mabey D, Hayes RJ. J Clin Microbiol. 2010; 48:1570-7

The aim of the study was to investigate factors associated with the high rate of false positive test results observed on the 4(th) generation Murex HIV Ag/Ab Combination EIA when used in Tanzania. Clinical and socio-demographic factors associated with false positive HIV results were analysed in 6940 Tanzanian adolescents and young adults in the Northwestern region. Immunological factors, including IgG antibodies to malaria and schistosomiasis, heterophile antibody and rheumatoid factor titre, were analysed in a sub-sample of 284 Murex negative and 240 false positive sera. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals (CI). HIV false positive test results were associated with evidence of other infections. False positivity was strongly associated with increasing levels of Schistosoma haematobium worm IgG1, with adolescents with ODs in the top quartile at highest risk (adjusted OR=40.7,  CI=8.5-194.2 compared with those in the bottom quartile). False positivity was also significantly associated with increasing S. mansoni egg IgG1, and RF titre >/= 80 (adjusted OR=8.2, CI=2.8-24.3). There was a significant negative association between Murex false positivity and levels of S. mansoni worm IgG1 and IgG2, and Plasmodium falciparum IgG1 and IgG4. In Africa, endemic infections may affect the specificity of immunoassays for HIV infection. Caution should be used when interpreting 4(th) generation HIV test results in African adolescent populations.

For abstract access click here: 

http://jcm.asm.org/cgi/content/abstract/48/5/1570

Editor’s note: Cross-reactivity between HIV-1 peptides and antibodies to Schistosoma appear to have contributed to the very high false positive HIV test results found among adolescents in this Tanzanian study. Pressure to develop highly sensitive HIV assays so that early infections are not missed has led to development of 4^th generation assays that detect both HIV antigen and HIV antibody. Such tests clearly don’t perform well in adolescents that are disproportionately affected by schistosomiasis. In this study, schistosomiasis IgG antibody was associated with Rheumatoid factor (RF) titres and these in turn were associated with false positive HIV test results. RF is found in autoimmune diseases such as rheumatoid arthritis but it is also associated with viral, bacterial, and other parasitic infections. Further research on the cross-reactivity of HIV diagnostic tests is warranted, with the findings used in the design and evaluation of tests specific for African populations.

First-year lymphocyte T CD4+ response to antiretroviral therapy according to the HIV type in the IeDEA West Africa collaboration.

Drylewicz J, Eholie S, Maiga M, Zannou DM, Sow PS, Ekouevi DK, Peterson K,Bissagnene E, Dabis F, Thiébaut R; International epidemiologic Databases to Evaluate AIDS (IeDEA) West Africa Collaboration. AIDS. 2010 24:1043-50

The objective of the study was to compare the lymphocyte T CD4+ (CD4) response to combinations of antiretroviral therapy in HIV-1, HIV-2 and dually positive patients in West Africa. The study was a collaboration of 12 prospective cohorts of HIV-infected adults followed in Senegal (2), Gambia (1), Mali (2), Benin (1) and Côte d'Ivoire (6). Nine thousand, four hundred and eighty-two patients infected by HIV-1 only, 270 by HIV-2 only and 321 dually positive, who initiated an antiretroviral therapy. CD4 change over a 12-month period. Observed CD4 cell counts at treatment initiation were similar in the three groups [overall median 155, interquartile range (IQR) 68; 249 cells/microl). In HIV-1 patients, the most common antiretroviral therapy regimen was two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor (N = 7714)  as well as for dually positive patients (N = 135). HIV-2 patients were most often treated with a protease inhibitor-based regimen (N = 193) but 45 of them were treated with an non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy. In those treated with a non-nucleoside reverse transcriptase inhibitor-containing regimen, the estimated mean CD4 change between 3 and 12 months was significantly  lower in HIV-2 (-41 cells/microl per year) and dually positive patients (+12 cells/microl per year) compared to HIV-1 patients (+69 cells/microl per year, overall P value 0.01). The response in HIV-2 and dually positive patients treated by another regimen (triple nucleoside reverse transcriptase or protease inhibitor-containing antiretroviral therapy) was not significantly different than the response obtained in HIV-1-only patients (all P values >0.30). An optimal CD4 response to antiretroviral therapy in West Africa requires determining HIV type prior to initiation of antiretroviral drugs. Non-nucleoside reverse transcriptase inhibitors are the mainstay of first-line antiretroviral therapy in West Africa but are not adapted to the treatment of HIV-2 and dually positive patients.

For abstract access click here: 

http://journals.lww.com/aidsonline/pages/articleviewer.aspx?year=2010&issue=04240&article=00014&type=abstract

Editor’s note: Non-nucleoside reverse transcriptase inhibitors (NNRTI) are part of first-line regimens in West Africa, the epicenter of the HIV-2 epidemic, but are inappropriate for treatment of HIV-2 infection. Although HIV-2 infection has a longer symptom-free period, lower viral load, and slower disease progression, it can lead to AIDS. This observational study of more than 9000 patients in West Africa found poor CD4+ responses to treatment in patients with HIV-2 infection placed on NNRTI but comparable responses to treatment in people with HIV-2 infection, dual infections, and HIV-1 infection placed on protease inhibitor-containing regimens. This points to the need for medical training, appropriate medications, and diagnostic protocols at clinic level but also underscores the rationale for randomized controlled trials to determine the best drug regimens for patients with HIV-2 infection.

Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.

Siegfried N, Uthman OA, Rutherford GW. Cochrane Database Syst Rev. 2010;3:CD008272

According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of antiretroviral therapy is clearly complex and must, therefore, be balanced between individual and broader public health needs. The objective of the study was to assess the evidence for the optimal time to initiate antiretroviral therapy in treatment-naive, asymptomatic, HIV-infected adults. The authors formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published,unpublished, in press, and in progress). In August 2009, they searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. They also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. They contacted researchers and relevant organizations and checked reference lists of all included studies. Randomized controlled trials that compared the effect of antiretroviral therapy consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial were selected. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating antiretroviral therapy at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial. Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, they meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs).  They found that one completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. They combined the mortality data for both trials comparing initiating antiretroviral therapy at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of antiretroviral therapy to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting antiretroviral therapy at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting antiretroviral therapy early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI:0.26, 1.12; P = 0.01). Starting antiretroviral therapy at enrolment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One randomised controlled clinical trial found no statistically significant difference in the number of independent Grade  3 or 4 adverse events occurring in the early and standard antiretroviral therapy groups when the authors conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = .06). However, when analyzing only participants who actually commenced antiretroviral therapy in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02). The authors conclude that there is evidence of moderate quality that initiating antiretroviral therapy at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, antiretroviral therapy-naive, HIV-infected people. Practitioners and policy-makers may consider initiating antiretroviral therapy at levels </= 350 cells/microL for patients who present to health services and are diagnosed with HIV early in the infection.

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Editors’ note: Why do people say that there is equipoise (meaning that we really don’t know which way the answer will go) for the trials that are currently underway to determine whether it is beneficial to start antiretroviral treatment at even higher CD4 counts than the 350 cells/µl currently recommended by WHO? It is because the two small trials described here only looked at CD4 counts under 350 cells/µl. Pooled data from the Haiti study (816 people) and the antiretroviral treatment naive sub-sample from the SMART study (248 people) found that starting antiretroviral treatment between 200-250 and 350 CD4+ cells/µl compared with under 200 cells/µl reduces mortality in treatment-naïve people living with HIV who have no symptoms. A small proof of concept trial http://clinicaltrials.gov/ct2/show/NCT00491556 is recruiting 100 people aged 18-24 to start treatment above 350 cells or wait until their CD4 counts fall below 350 cells while a large trial, Strategic Timing of Antiretroviral Treatment (START) http://clinicaltrials.gov/ct2/show/NCT00867048, is  enrolling 4000 antiretroviral-naive people with CD4 counts greater than 500 cells/µl at 87 sites in 23 countries. Participants will be randomized to start antiretroviral treatment immediately or wait until their first CD4 count of less than 350 cells/µl or clinical signs of AIDS. At issue is whether adherence challenges, long-term side-effects, chances of developing other illnesses, resistance to HIV medicines, frequency of doctor visits, and cost of medical care associated with early antiretroviral treatment are outweighed by reduced risk of HIV disease progression conferred by these medicines. The bottom line for most people is which strategy improves general health, quality of life, and satisfaction.

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

Walker A, Ford D, Gilks C, Munderi P, Ssali F, Reid A, Katabira E, Grosskurth H, Mugyenyi P, Hakim J, Darbyshire J, Gibb D, Babiker A. Lancet. 2010 375:1278-86

Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy is unclear. The authors estimated the effect of prophylaxis after antiretroviral therapy initiation in adults. Participants in their observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug antiretroviral therapy with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. They estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, body-mass index, and previous WHO stage 3 or 4 events on antiretroviral therapy. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on antiretroviral therapy was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but the authors observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or body-mass index (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. These results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination antiretroviral therapy in Africa.

For full text access click here:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60057-8/full text

Editors’ note: DART delivers again, this time with data supporting the use of cotrimoxasole (trimethoprim-sulfamethoxasole) at the start of antiretroviral therapy in resource-limited settings, if it hasn’t been started before. Co-trimoxasole is off-patent, low-cost, simple to take (once daily), safe, and tolerable. First-year mortality on antiretroviral treatment in sub-Saharan Africa ranges from 8 to 26%, most in the first 3 to 6 months. Mortality in this large study was halved in the first 72 weeks on antiretroviral treatment with daily cotrimoxasole prophylaxis. The mortality reduction was greatest in the first 12 weeks and then was sustained out to 72 weeks for both patients with CD4 counts under 200 and over 200. The effects on malaria in the Uganda patients was sustained out past 72 weeks. Clearly, starting on antiretroviral treatment is not reason to stop or not to start cotrimoxasole prophylaxis. Whether cotrimoxasole works by helping reduce immune activation before antiretroviral treatment starts to kick in or acts through another mechanism is unknown but these data support the World Health Organisation recommendation to start or continue cotrimoxasole prophylaxis when antiretroviral treatment is started. There is now justification for continuing it for at least 72 weeks.