Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Clinical screening for HIV in a health centre setting in urban Kenya: an entry point for voluntary counselling, HIV testing and early diagnosis of HIV infection?

A study was conducted among patients attending a public health centre in Nairobi, Kenya in order to (a) verify the prevalence of HIV, (b) identify clinical risk factors associated with HIV and (c) determine clinical markers for clinical screening of HIV infection at the health centre level. Of 304 individuals involved in the study,107(35%) were HIV positive. A clinical screening algorithm based on four clinical markers, namely oral thrush, past or present TB, past or present herpes zoster and prurigo would pick out 61 (57%) of the 107 HIV-positive individuals. In a resource-poor setting, introducing a clinical screening algorithm for HIV at the health centre level could provide an opportunity for targeting voluntary counselling and HIV testing, and early access to a range of prevention and care interventions.

[Obesity, high blood pressure, hypercholesterolaemia, and untreated diabetes in HIV-infected and HIV-uninfected Adults in Mbuji-Mayi (Democratic republic of congo)]. / Obésité, hypertension artérielle, hypercholestérolémie et diabète non traités chez les adultes infectés ou pas par le VIH à Mbuji-Mayi (République démocratique du Congo).

Little is known about the major cardiovascular risk factors in HIV-infected as compared to the HIV-uninfected patients in the Democratic Republic of Congo (DR Congo). We determined the prevalence of hypertension, obesity (BMI ≥ 30 kg/m2), total cholesterol > 200 mg/dl, HDLcholesterol &≤ 40 mg/dl, and glycemia > 126 mg/dl. We also calculated the average and/or median of total cholesterol, HDL-cholesterol, and glycemia among HIV-infected and HIV-uninfected patients.We conducted a cross-sectional study that enrolled 592 HIV-uninfected and 445 HIV-infected patients of whom 425 (95.5%) were on first-line antiretroviral therapy based on stavudine-lamivudine-nevirapine. Clinical and laboratory data of the patients were collected. The results were analyzed by chi-square, t-student, and Wilcoxon rank sum tests. 11.5% of HIV-infected patients had an average blood pressure suggesting hypertension versus 10.6% of HIV-uninfected (P = 0.751). But in absolute value, HIVinfected patients had a median of diastolic blood pressure of 90 mmHg versus 85 mmHg of HIV-uninfected (P < 0.001). 4.04% of HIV-infected patients had a BMI suggesting obesity versus 6.08% of HIV-uninfected patients (P = 0.187). For fasting glucose: 2.50% of HIV-infected patients versus 4.20% of HIV-uninfected patients had a serum fasting glucose suggesting diabetes (P<0.176). 11.9% of HIV-infected patients had a total cholesterol greater than 200 mg/dl versus 7.4% of HIVuninfected patients (P=0.019). For HDL-cholesterol: 36.40% of HIV-infected patients had a serum fasting ≤ 40 mg/dl versus 15.70% of HIV-uninfected patients (P < 0.001). HIV-infected patients had a median fasting total cholesterol higher (140 mg/ dl) thanHIV-uninfected patients (133mg/dl) [P=0.015].HIVuninfected patients had a median fasting HDL-cholesterol higher (58.5 mg/dl) than HIV-infected patients (49 mg/dl) [P < 0.001]. HIV-infected women were more likely to have a higher mean of total cholesterol: 147.70 #x00B1; 52.09 mg/dl versus 135.72 ± 48.23 mg/dl for the HIV-infected men (P = 0.014) and of HDL-cholesterol: 55.80 ± 30.77 mg/dl versus 48.24 ± 28.57mg/dl for the HIV-infected men (P = 0.008). In this study population, prevalence of hypertension was elevated in HIVinfected versus HIV-uninfected patients. Being HIV positive on first-line antiretroviral therapy based on stavudine-lamivudine-nevirapine was associated with high prevalence of total cholesterol > 200 mg/dl and HDL-cholesterol ≤ 40 mg/dl. Proactive screening and prompt management of dyslipidemia and hypertension in this population should be a priority.

Haptoglobin polymorphism, iron metabolism and mortality in HIV infection.

BACKGROUND: Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1-1, Hp 2-1 and Hp 2-2. OBJECTIVES: To investigate the outcome of HIV infection according to haptoglobin type. DESIGN AND METHODS: Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls. RESULTS: The haptoglobin type distribution amongst the patients (17.6% Hp 1-1, 49.9% Hp 2-1, 32.5% Hp 2-2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2-2 group (P = 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25-2.54). Median survival time was 11.0 years (Hp 1-1 and Hp 2-1) versus 7.33 years (Hp 2-2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2-2 patients (P = 0.03 and 0.003, respectively). The Hp 2-2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P < 0.0001). CONCLUSION: HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries.

OBJECTIVE: To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically. DESIGN AND METHODS: Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients. RESULTS: The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations. CONCLUSIONS: MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.

Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations.

Direct sequencing of the pol gene was assessed retrospectively with protease inhibitor susceptibility in a longitudinal study. A total of 134 samples from 26 patients were analysed at regular intervals up to 2 years. Patients were included in virological failure despite indinavir, ritonavir or saquinavir based triple-drug therapy. Both the type and number of certain secondary protease mutations modulated the effect of primary mutations on phenotypic resistance. This was notably applicable to L101/V, and to lesser extents to A711V/T. However, combinations of primary mutations, including 154V could predict resistance to the drug used and nelfinavir in more than 80%. In contrast, in vitro cross-resistance to amprenavir was rarely encountered. In addition, there was a relationship between a higher number of key mutations and poorer virological and clinical outcomes, respectively, from 6 and 3 months on. The key mutations were the protease mutations independently conferring phenotypic resistance and/or the reverse transcriptase mutations predicting treatment outcome. This relationship was independent from drug history, viral load and CD4 cell count measurements. In summary, even on a small sample size, sequence-based genotyping seems to be a good prognostic marker when performed longitudinally. In the context of primary resistance mutations, including additional secondary mutations, it may be useful in the prediction of phenotypic and clinical resistance. This should be assessed to optimize treatment monitoring before emergence of broadly cross-resistant virus.

Computer assisted diagnosis of malformation syndromes: an evaluation of three databases (LDDB, POSSUM, and SYNDROC).

Computer programs which can be used as an aid to diagnose multiple congenital anomaly syndromes have been used for many years, but up to now they have been evaluated very rarely. The diagnostic abilities of three of these systems [LDDB (London Dysmorphology Database), POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations), and SYNDROC] were analyzed. All three programs are based on an algorithm which defines a diagnosis by a set of phenotypic components all having the same weight (descriptive algorithm). A second algorithm is applied by SYNDROC to rank competing diagnoses in order of probability. This pseudo-Bayesian algorithm provides a coefficient of certitude (CC). For a test the clinical findings of 102 patients who had received a firm diagnosis were used. Two search strategies were tried: "novice's strategy" with all findings taken for a search and "expert's strategy" with a selected set of anomalies. Only those diagnoses that were suggested with the 1st rank, defined as the highest degree of agreement, or the highest CC were studied. The greatest resemblance between suggestions of the databases and the clinical diagnosis was obtained with the expert strategy. The highest number of matches were produced by SYNDROC (80 with expert strategy) and the lowest by POSSUM (54 with novice strategy). The overall agreement between the databases is about 40% for the 1st rank. This number reflects that different authors use different pivotal signs for the description of a syndrome. With the pseudo-Bayesian algorithm 59 cases obtained the highest CC value. Great difficulties exist with the subjective estimates for the calculation of these values; the absolute CC values seem to be meaningless. A small number of unusual cases with special combinations of anomalies provide serious problems for correct diagnosis.

Three-year effectiveness of highly active antiretroviral treatment in the Luxembourg HIV cohort.

UNLABELLED: Clinical trials have shown that highly active antiretroviral treatment (HAART) is able to reduce HIV plasma viral loads to undetectable in 70% to 90% of patients and to increase CD4 cell counts. HAART in community settings (i.e., nonclinical trial situations) is reported to be much less effective. STUDY DESIGN: Observational study. PURPOSE: The aim of our study was to evaluate the effectiveness of protease inhibitor (PI)-based HAART in the Luxembourg HIV cohort after 36 months of treatment in previously treated and untreated patients. The secondary aim was to identify surrogate markers associated with long-term virologic and immunologic outcomes. PATIENTS AND METHOD: Seventy-three PI-naive patients, who started on HAART, combining one PI and two nucleoside reverse transcriptase inhibitors (NRTIs),with a follow-up of 3 years, were evaluated with plasma viral load and CD4 cell counts every 3 months and were analyzed retrospectively. Patients who had been treated previously with NRTI (n = 48) were at a more advanced stage of disease. RESULTS: Overall, there was a mean decrease in viral load compared to baseline of -1.89 log RNA copies/mL (SD = 1.40) that persisted at month 36. Sixty-two percent (62%) of patients reached an undetectable viral load (i.e., below 500 copies/mL): 82% and 53% of NRTI-naive and NRTI-experienced patients, respectively (p =.013). CD4 cell counts increased progressively in both groups with a sustained effect (mean increase of 146 cells/mL +/- 241) at month 36. NRTI-naive patients had a mean increase of 257 cells/mL (SD = 305), in contrast to experienced patients who had an increase of 108 cells/mL (SD = 206) at 3 years. Proportions of patients with a CD4 count under 200 cells/mL fell after 3 years for NRTI-naive (from 66% to 43%) and for experienced patients (from 32% to 13%). Predictors of short duration of viral load response were in decreasing order of importance: clinical AIDS, the use of saquinavir hard gel formulation as initial PI, and the number of NRTIs previously used. Viral load response was the only significant predictor of CD4 changes. CONCLUSION: In a community setting, effectiveness of PI-based HAART at 3 years is still achieved for most patients. NRTI-experienced patients have a good long-term response rate even if it is lower than NRTI-naive patients. A poor treatment response is associated with a more advanced stage of disease before HAART is introduced.

Compliance with cotrimoxazole prophylaxis for the prevention of opportunistic infections in HIV-positive tuberculosis patients in Thyolo district, Malawi.

OBJECTIVE: To verify compliance with cotrimoxazole prophylaxis in human immunodeficiency virus (HIV) infected tuberculosis (TB) patients during the continuation phase of anti-tuberculosis treatment, and to assess the sensitivity, specificity and positive predictive values of verbal verification and pill counts as methods of checking compliance. DESIGN: Cross-sectional study. METHODS: Cotrimoxazole compliance was assessed in a cohort of TB patients who were attending four TB follow-up centres during the continuation phase of anti-TB treatment between months 4 and 6. Verbal verification of drug intake, physical verification of pill count balance, and urine trimethoprim detection by gas chromatography and mass spectrometry were used for assessing compliance. RESULTS: Using urine trimethoprim detection as the gold standard for compliance, trimethoprim was detected in 82 (94%) of 87 patients in the cohort. Verbal verification of cotrimoxazole intake and objective pill count balances showed high sensitivity and positive predictive values compared with the gold standard of urine trimethoprim detection. CONCLUSIONS: In a rural district in Malawi, compliance with cotrimoxazole as an adjunct to anti-tuberculosis treatment in HIV-infected TB patients was good, and can be assessed simply and practically by verbal verification and pill counts.

Characteristics of a cholera outbreak, patterns of Vibrio cholerae and antibiotic susceptibility testing in rural Malawi.

The cumulative cholera attack rate in an epidemic in Malawi in 1999/2000 was 59/100,000 population, case-fatality rate 4%, and 98% of all cases presenting to health facilities required intravenous therapy. Microbiological studies showed high resistance of Vibrio cholerae to commonly recommended antibiotics, predominant Ogawa serotypes and no O139 isolates.

Changes in Escherichia coli resistance to co-trimoxazole in tuberculosis patients and in relation to co-trimoxazole prophylaxis in Thyolo, Malawi.

In Thyolo district, Malawi, an operational research study is being conducted on the efficacy and feasibility of co-trimoxazole prophylaxis in preventing deaths in HIV-positive patients with tuberculosis (TB). A series of cross-sectional studies were carried out in 1999 and 2001 to determine (i) whether faecal Escherichia coli resistance to co-trimoxazole in TB patients changed with time, and (ii) whether the resistance pattern was different in HIV-positive TB patients who were taking co-trimoxazole prophylaxis. Co-trimoxazole resistance among E. coli isolates in TB patients at the time of registration was 60% in 1999 and 77% in 2001 (P < 0.01). Resistance was 89% among HIV-infected TB patients (receiving cotrimoxazole), while in HIV-negative patients (receiving anti-TB therapy alone) it was 62% (P < 0.001). The study shows a significant increase of E. coli resistance to co-trimoxazole in TB patients which is particularly prominent in HIV-infected patients on co-trimoxazole prophylaxis. Since a high degree of plasmid-mediated transfer of resistance exists between E. coli and the Salmonella species, these findings could herald limitations on the short- and long-term benefits to be expected from the use of co-trimoxazole prophylaxis in preventing non-typhoid Salmonella bacteraemia and enteritis in HIV-infected TB patients in Malawi.

Behavioural characteristics, prevalence of Chlamydia trachomatis and antibiotic susceptibility of Neisseria gonorrhoeae in men with urethral discharge in Thyolo, Malawi.

A study was carried out in 2000/2001 in a rural district of Malawi among men presenting with urethral discharge, in order to (a) describe their health-seeking and sexual behaviour, (b) determine the prevalence of Neisseria gonorrhoeae and Chlamydia trachomatis, and (c) verify the antibiotic susceptibility of N. gonorrhoeae. A total of 114 patients were entered into the study; 61% reported having taken some form of medication before coming to the sexually transmitted infections clinic. The most frequent alternative source of care was traditional healers. Sixty-eight (60%) patients reported sexual encounters during the symptomatic period, the majority (84%) not using condoms. Using ligase chain reaction on urine, N. gonorrhoeae was detected in 91 (80%) and C. trachomatis in 2 (2%) urine specimens. Forty five of 47 N. gonorrhoeae isolates produced penicillinase, 89% showing multi-antimicrobial resistance. This study emphasizes the need to integrate alternative care providers and particularly traditional healers in control activities, and to encourage their role in promoting safer sexual behaviour. In patients presenting with urethral discharge in our rural setting, C. trachomatis was not found to be a major pathogen. Antimicrobial susceptibility surveillance of N. gonorrhoeae is essential in order to prevent treatment failures and control the spread of resistant strains.

Sexually transmitted infections and sexual behaviour among commercial sex workers in a rural district of Malawi.

In Thyolo District, Malawi, a study was conducted among commercial sex workers (CSWs) attending mobile clinics in order to; determine the prevalence and pattern of sexually transmitted infections (STIs), describe sexual behaviour among those who have an STI and identify risk factors associated with 'no condom use'. There were 1817 CSWs, of whom 448 (25%) had an STI. Of these, the commonest infections included 237 (53%) cases of abnormal vaginal discharge, 109 (24%) cases of pelvic inflammatory disease and 95 (21%) cases of genital ulcer disease (GUD). Eighty-seven per cent had sex while symptomatic, 17% without condoms. Having unprotected sex was associated with being married, being involved with commercial sex outside a known rest-house or bar, having a GUD, having fewer than two clients/day, alcohol intake and having had no prior medication for STI. The high levels of STIs, particularly GUDs, and unprotected sex underlines the importance of developing targeted interventions for CSWs and their clients.

HIV prevalence and demographic risk factors in blood donors.

OBJECTIVES: To estimate HIV prevalence in various blood donor populations, to identity sociodemographic risk factors associated with prevalent HIV and to assess the feasibility of offering routine voluntary counselling services to blood donors. DESIGN: Cross-sectional study. SETTING: Thyolo district, Malawi. METHODS: Data analysis involving blood donors who underwent voluntary counselling and HIV testing between January 1998 and July 2000. RESULTS: Crude HIV prevalence was 22%, while the age standardised prevalence (>15 years) was 17%. Prevalence was lowest among rural donors, students and in males of the age group 15-19 years. There was a highly significant positive association of HIV prevalence with increasing urbanisation. Significant risk factors associated with prevalence for both male and female donors included having a business-related occupation, living in a semi-urban or urban area and being in the age group 25-29 years for females and 30-34 years for males. All blood donors were pre-test counselled and 90% were post test counselled in 2000. CONCLUSIONS: HIV prevalence in blood donors was alarmingly high, raising important concerns on the potential dangers of HIV transmission through blood transfusions. Limiting blood transfusions, use of a highly sensitive screening test, and pre-donation selection of donors is important. The experience also shows that it is feasible to offer pre and post test counselling services for blood donors as an entry point for early diagnosis of asymptomatic HIV infection and, broader preventive strategies including the potential of early access to drugs, for the prevention of opportunistic infections.

[Fatigue fracture of the femoral neck in an HIV-positive female patient on antiretroviral therapy]. / Fracture pathologique de hanche chez une patiente VIH-positive sous trithérapie anti-rétrovirale.

The authors report the case of an HIV-infected patient on highly active antiretroviral therapy (HAART) who presented with spontaneous fracture of the right femoral neck with avascular necrosis, probably related with her HIV status and HAART, and who was treated by non-cemented arthroplasty.

[Short-term ciprofloxacin treatment of bacillary dysentery due to Shigella dysenteriae type 1 in Rwandan refugees]. / Traitement court par la ciprofloxacine de la dysenterie bacillaire à Shigella dysenteriae type 1 chez des réfugiés Ruandais.

In 1994, an outbreak of dysentery caused by Shigella dysenteriae type I resistant to all public health antibiotics in vitro occurred among rwandan refugees in Zaïre. The only active antimicrobial agent available was ciprofloxacin. It was administered to hospitalized patients in a conventional 5-day schedule. To ration the supply for the benefit of the greatest number, a randomized blinded study was performed to compare the effectiveness of short-term treatment (1 g of ciprofloxacin in a single daily doses for 2 days) with that of the standard treatment (1 g of ciprofloxacin in two daily doses for 5 days). The study included 57 refugees over the age of 15 years with dysentery. Shigella dysenteriae type I was identified in 26 patients. Except for sex distribution, there was no significant difference in clinical and bacteriologic features of the two populations. Treatment failed in 12 cases, i.e., 7 of 29 patients who received the short-term treatment and 5 of 28 patients who received the standard treatment. Efficacy of ciprofloxacin was not dependent on the mode of treatment, taking into account clinical or bacteriologic criteria. These results indicated that the duration of ciprofloxacin treatment for dysentery caused by Shigella dysenteriae type 1 could be shortened to two days. Short-term treatment has several advantages. One is cost-effectiveness since fluoroquinolones are costly and scarce. Another is to allow treatment of a greater number of patients by improving compliance.