Roos E. Barth

Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review

Following large-scale roll-out of antiretroviral therapy in sub-Saharan Africa, the non-clinical efficacy of antiretroviral therapy has received little attention. We aimed to systematically review virological efficacy and drug-resistance outcomes of programmes of antiretroviral therapy in sub-Saharan Africa. 89 studies with heterogeneous design, definitions, and methods were identified. Overall, in on-treatment analysis, 10 351 (78%) of 13 288 patients showed virological suppression after 6 months of antiretroviral therapy, 7413 (76%) of 9794 after 12 months, and 3840 (67%) of 5690 after 24 months. Long-term virological data are scarce. Genotyping results were available for patients with virological failure (HIV-1 RNA greater than 1000 copies per mL). Most patients (839 of 849; 99%) were infected with a non-B HIV-1 subtype. However, drug-resistance patterns were largely similar to those in subtype B. Resistance profiles were associated with the antiretroviral drugs commonly used: the lamivudine-associated M184V mutation was most common, followed by K103N which is associated with non-nucleoside reverse transcriptase inhibitors. Thymidine-analogue mutations and the K65R mutation were less common. First-line antiretroviral therapy regimens used in sub-Saharan Africa are effective. Profiles of drug resistance suggest that a second-line treatment regimen based on protease inhibitors, with a backbone of nucleoside reverse transcriptase inhibitors, is a reasonable option for patients with HIV in sub-Saharan Africa who experience first-line treatment failure.

Hepatitis B/C and HIV in sub-Saharan Africa: an association between highly prevalent infectious diseases. A systematic review and meta-analysis.

OBJECTIVES Hepatitis B virus (HBV), hepatitis C virus (HCV), and the human immunodeficiency virus (HIV) are endemic in Africa. However, hepatitis co-infection rates among HIV-infected individuals remain controversial. The aim of this review was to determine the prevalence of HBV and HCV in HIV-infected patients in sub-Saharan Africa and to analyze whether HIV is associated with a higher HBV/HCV prevalence in that region. DESIGN AND METHODS We performed a systematic review and meta-analysis. Studies reporting HBV and HCV prevalence data amongst HIV-infected patients in sub-Saharan Africa were included. Weighted means and medians across studies were calculated. Studies including an HIV-negative control group were used for meta-analysis. Risk ratios (RRs) were calculated using a random effects model. RESULTS Sixty studies were included. Among HIV-infected individuals, mean HBsAg and anti-HCV prevalence rates were 15% and 7%, respectively. RRs for a positive HBsAg and a positive anti-HCV were 1.40 (95% confidence interval (CI) 1.16-1.69) and 1.60 (95% CI 1.05-2.45) for HIV-infected, as compared to HIV-uninfected, patients. CONCLUSIONS Many HIV-positive individuals in sub-Saharan Africa are HBV or HCV co-infected. HIV is associated with a higher prevalence of both HBV and HCV in this region. However, this association is less evident than that observed in Western countries and varies between studies.

Rapid accumulation of nonnucleoside reverse transcriptase inhibitor-associated resistance: evidence of transmitted resistance in rural South Africa.

In a large cohort in rural South Africa, 73% of subtype-C-infected patients initiating highly active antiretroviral therapy achieved viral suppression. In patients with subsequent virological failure, an unexpected, rapid accumulation of nonnucleoside reverse transcriptase inhibitor-associated mutations was observed, whereas no thymidine analogue-associated mutations emerged. It appeared that several patients had drug-associated mutations prior to starting antiretrovirals, suggesting that transmission of resistance may have contributed to the accumulation of nonnucleoside reverse transcriptase inhibitor-mutations. Importantly, monitoring of HIV-RNA and prompt switch of treatment may prevent development of thymidine analogue-associated mutations.

‘To bead or not to bead?’ Treatment of osteomyelitis and prosthetic joint-associated infections with gentamicin bead chains

Gentamicin-containing polymethylmethacrylate (PMMA) beads are frequently used to prevent and treat orthopaedic infections. The beads are typically inserted to fill anatomical defects secondary to surgical debridement. Local gentamicin use results in low serum levels whilst achieving high concentrations at the site of infection. However, a systematic review of the available literature showed that, despite these theoretical advantages, no prospective study has thus far proven gentamicin-containing PMMA beads to be effective in treating orthopaedic infections. Available studies are based on small patient numbers and do not show significantly better results when local and parenteral antibiotics are combined compared with systemic therapy alone. These poor results may be explained partially by reduced aminoglycoside efficacy when biofilms or gentamicin-resistant bacteria are present. Moreover, little is known regarding the potential side effects of gentamicin-containing beads. In this paper, the pros and cons regarding the use of gentamicin-containing PMMA beads are discussed. It is concluded that more well-executed, prospective studies are needed to settle the discussion on the use of gentamicin-containing beads in the treatment of orthopaedic infections.

Long-term outcome of children receiving antiretroviral treatment in rural South Africa: substantial virologic failure on first-line treatment.

Background: Long-term (>12 months follow-up) virologic data of children receiving antiretroviral therapy (ART) in Sub-Saharan Africa are limited. Data from rural areas are especially scarce. The aim of this study was to evaluate the long-term virologic outcome of a pediatric cohort in rural South Africa. Methods: We performed a retrospective, observational cohort study, including children who initiated ART at least 1 year before data-analysis. Regular monitoring, including HIV-RNA testing, was performed. Genotypic resistance testing was done for children with virologic failure (HIV-RNA >1000 copies/mL). Logistic regression analysis was used to determine predictors of virologic failure. Results: A total of 101 children were included. Median duration since beginning ART was 31 months. Overall patient retention-rate was 76% (77/101), with early mortality being the main cause of attrition (13/24, 54%). Initial immunologic and virologic responses were excellent. However, 38% (31/81) of children subsequently experienced virologic failure. Correlation between virologic failure and immunologic decline was nearly absent. At the time of failure, multiple non-nucleoside reverse transcription inhibitor-associated mutations were observed in 52% (12/23) of children. No definite predictors of virologic failure could be determined. Conclusions: ART provides significant benefits for children in this rural African setting, but the finding that a large proportion of children had virologic failure and developed major drug-resistance mutations on first-line ART is worrying. Causes of failure need to be analyzed and effective prevention strategies are needed. Because of the lack of a correlation between immunologic and virologic failure, treatment failure generally stays unnoticed in settings where HIV-RNA testing is not available.

Pro-Inflammatory Markers in Relation to Cardiovascular Disease in HIV Infection. A Systematic Review

Background In the past years many inflammatory markers have been studied in association with clinically manifest cardiovascular disease (CVD) and carotid intima-media thickness (CIMT) in HIV-infected patients, to obtain insights in the increased cardiovascular risk observed in HIV infection. This systematic review provides an oversight of the current knowledge. Methods A search was performed in PubMed, Embase and Cochrane in July 2014, identifying all articles from 1996 onwards addressing the relation between inflammatory markers and CVD or CIMT in HIV-positive adults. Two authors, using predefined criteria, independently conducted the selection of articles, critical appraisal and extraction of the data. Analysis was focused on the immune markers that were most frequently assessed. The review protocol was registered in the PROSPERO database at 11 July 2014 (registration number CRD42014010516). This review was performed according to the PRISMA guideline. Findings Forty articles were selected; eight addressing cardiovascular disease (CVD) and thirty-two addressing CIMT. C-reactive protein (CRP), interleukin-6 (IL-6) and d-dimer were assessed most frequently in relation to the occurrence of CVD; in four out of eight studies. All three markers were positively related to CVD in three out of four studies. Studies addressing CIMT were too heterogeneous with respect to patient populations, inflammatory markers, CIMT measurement protocols and statistical methods to allow for a formal meta-analysis to obtain summary statistics. CRP, IL-6 and soluble vascular cell adhesion molecule (sVCAM-1) were the most studied markers in relation to CIMT. None of the inflammatory markers showed an association with CIMT. Interpretation This review showed a relation between some inflammatory markers and CVD, however, no consistent relation is observed for CIMT. Statistical approaches that yields effect estimates and standardized CIMT protocols should be chosen. Further research should focus on prospective studies and a selected set of inflammatory markers.

Presence of occult HBV but near absence of active HBV and HCV infections in people infected with HIV in rural South Africa.

Human immunodeficiency (HIV), hepatitis B (HBV), and hepatitis C (HCV) viruses are endemic in Sub‐Saharan Africa, but data regarding the prevalence of hepatitis co‐infections in HIV‐positive individuals residing there are limited. The aim of the study was to determine the prevalence of HBV, HCV, and occult HBV (presence of HBV‐DNA in the absence of HBsAg) in a rural, South African cohort. The results were compared to various ethnic groups in a Dutch cohort of people infected with HIV. Antiretroviral‐naïve individuals with HIV from both a rural South African clinic (n = 258), and a Dutch University hospital (n = 782), were included. Both serological (HBV and HCV) and molecular (occult HBV) assays were performed. Logistic regression analysis was used to define independent predictors of a hepatitis co‐infection. HBV and HCV prevalence rates in the South African cohort were exceptionally low (0.4%, 1/242 and 0.8%, 2/242, respectively), compared to those observed in Caucasians (HBV 4.4% and HCV 10.9%) and African immigrants (HBV 8.9% and HCV 4.8%). Conversely, occult HBV was observed in a considerable proportion (10%, 6/60) of South African patients who were anti‐HBc‐positive but HBsAg‐negative. Occult infections were less frequent in Caucasians and Africans in the Dutch cohort (3.2% and 1.4%, respectively). Independent predictors for occult HBV were not identified, but a trend towards more occult HBV at lower CD4 counts was observed. Local HBV/HCV prevalence data are needed to optimize vaccination and antiretroviral treatment strategies. Occult HBV in patients with HIV may be missed regularly when molecular analyses are not available. J. Med. Virol. 83:929–934, 2011.

Long-Term Outcome of an HIV-Treatment Programme in Rural Africa: Viral Suppression despite Early Mortality

Objective. To define the long-term (2–4 years) clinical and virological outcome of an antiretroviral treatment (ART) programme in rural South Africa. Methods. We performed a retrospective observational cohort study, including 735 patients who initiated ART. Biannual monitoring, including HIV-RNA testing, was performed. Primary endpoint was patient retention; virological suppression (HIV-RNA < 50 copies/mL) and failure (HIV-RNA > 1000 copies/mL) were secondary endpoints. Moreover, possible predictors of treatment failure were analyzed. Results. 63% of patients (466/735) have a fully suppressed HIV-RNA, a median of three years after treatment initiation. Early mortality was high: 14% died within 3 months after treatment start. 16% of patients experienced virological failure, but only 4% was switched to second-line ART. Male gender and a low performance score were associated with treatment failure; immunological failure was a poor predictor of virological failure. Conclusions. An “all or nothing” phenomenon was observed in this rural South African ART programme: high early attrition, but good virological control in those remaining in care. Continued efforts are needed to enrol patients earlier. Furthermore, the observed viro-immunological dissociation emphasises the need to make HIV-RNA testing more widely available.

Interferon-gamma release assays (IGRAs) in high-endemic settings: could they play a role in optimizing global TB diagnostics? Evaluating the possibilities of using IGRAs to diagnose active TB in a rural African setting

The number of patients suffering from tuberculosis (TB) globally is increasing. Due to the HIV epidemic, most patients suffering from TB reside in sub-Saharan Africa. In order to improve TB diagnostics, new tests - interferon-gamma release assays (IGRAs) - have been developed over the last decade. In this paper we evaluate the possible use of these tests in diagnosing or excluding active TB in high HIV-burden, resource-limited settings. The inability to differentiate between active and latent TB, limited data on IGRA performance in HIV-infected patients, observed false-negative results, high costs, and logistic problems limit the potential benefit of IGRAs. We also present two theoretical study designs in order to further assess IGRAs. Setting up a study on this subject is complicated by the frequent unavailability of mycobacterial cultures, the difficulty in acquiring prospective data, and the impossibility of denying treatment to a patient suspected of having active TB. We feel that current evidence does not support the implementing of IGRAs in clinical practice in settings with high endemic latent TB infection (LTBI) and high HIV prevalence. As these settings are the ones that suffer the most from the TB epidemic, we believe that the role of IGRAs in global TB control is questionable.

Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa

Objective This study aims to describe the virological, immunological and clinical efficacy of protease inhibitor (PI)-based second-line antiretroviral therapy (ART) in rural South Africa. Methods An observational cohort study was performed on 210 patients (including 39 children) who initiated PI-based second-line therapy at least 12 months prior to data collection. Biannual clinical, immunological and virological monitoring was performed. Primary endpoints were adequate virological response (plasma HIV-1 RNA<400 copies/ml), full virological suppression (plasma HIV-1 RNA<50 copies/ml) and treatment failure (virological failure (plasma HIV-1 RNA>1000 after initial virological response) or on-going viremia (plasma HIV-1 RNA never<400 copies/ml for more than six months)). Data were analyzed by an on-treatment (OT) and intention-to-treat (ITT) approach. Analyses were primarily performed on the group of patients who switched following first-line virological failure. Results Median duration of follow-up after switch to second-line treatment was 20 months [IQR 11–35]. 191 patients had switched to second-line ART due to first-line virological failure. 139/191 of them (72.8%, ITT) were in care and on treatment at the end of follow-up and 11/191 (5.8%, ITT) had died. After twelve months, an adequate virological response was seen in 92/128 patients (71.9%, OT), of which 78/128 (60.9%, OT) experienced full virological suppression. Virological response remained stable after 24 months. Virological efficacy was similar amongst adult and pediatric patients. As in first-line ART, we observed a lack of correlation between virological failure and WHO-defined immunological failure. Conclusions Good virological outcomes following first-line failure can be achieved with PI-based, second-line antiretroviral therapy in both adult and pediatric patients in rural South Africa. Retention rates were high and virological outcomes were sustainable during the two-year follow-up period, although persisting low-level viremia occurred in a subset of patients. The observed viro-immunological dissociation emphasizes the need for virological monitoring.