Enfuvirtide: from basic investigations to current clinical use.

IMPORTANCE OF THE FIELD: Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use. AREAS COVERED IN THIS REVIEW: Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 - June 2010) using the search terms 'enfuvirtide', 'T-20' and 'fusion inhibitor'. WHAT THE READER WILL GAIN: Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy. TAKE HOME MESSAGE: The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes.

High mortality associated with an outbreak of hepatitis E among displaced persons in Darfur, Sudan.

BACKGROUND: Hepatitis E virus (HEV) causes acute onset of jaundice and a high case-fatality ratio in pregnant women. We provide a clinical description of hospitalized case patients and assess the specific impact on pregnant women during a large epidemic of HEV infection in a displaced population in Mornay camp (78,800 inhabitants), western Darfur, Sudan. METHODS: We reviewed hospital records. A sample of 20 clinical cases underwent laboratory confirmation. These patients were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody to HEV (serum) and for amplification of the HEV genome (serum and stool). We performed a cross-sectional survey in the community to determine the attack rate and case-fatality ratio in pregnant women. RESULTS: Over 6 months, 253 HEV cases were recorded at the hospital, of which 61 (24.1%) were in pregnant women. A total of 72 cases (39.1% of those for whom clinical records were available) had a diagnosis of hepatic encephalopathy. Of the 45 who died (case-fatality ratio, 17.8%), 19 were pregnant women (specific case-fatality ratio, 31.1%). Acute hepatitis E was confirmed in 95% (19/20) of cases sampled; 18 case-patients were positive for IgG (optical density ratio > or =3), for IgM (optical density ratio >2 ), or for both, whereas 1 was negative for IgG and IgM but positive for HEV RNA in serum. The survey identified 220 jaundiced women among the 1133 pregnant women recorded over 3 months (attack rate, 19.4%). A total of 18 deaths were recorded among these jaundiced pregnant women (specific case-fatality ratio, 8.2%). CONCLUSIONS: This large epidemic of HEV infection illustrates the dramatic impact of this disease on pregnant women. Timely interventions and a vaccine are urgently needed to prevent mortality in this special group.

A large outbreak of hepatitis E among a displaced population in Darfur, Sudan, 2004: the role of water treatment methods.

BACKGROUND: The conflict in Darfur, Sudan, was responsible for the displacement of 1.8 million civilians. We investigated a large outbreak of hepatitis E virus (HEV) infection in Mornay camp (78,800 inhabitants) in western Darfur. METHODS: To describe the outbreak, we used clinical and demographic information from cases recorded at the camp between 26 July and 31 December 2004. We conducted a case-cohort study and a retrospective cohort study to identify risk factors for clinical and asymptomatic hepatitis E, respectively. We collected stool and serum samples from animals and performed a bacteriological analysis of water samples. Human samples were tested for immunoglobulin G and immunoglobulin M antibody to HEV (for serum samples) and for amplification of the HEV genome (for serum and stool samples). RESULTS: In 6 months, 2621 hepatitis E cases were recorded (attack rate, 3.3%), with a case-fatality rate of 1.7% (45 deaths, 19 of which involved were pregnant women). Risk factors for clinical HEV infection included age of 15-45 years (odds ratio, 2.13; 95% confidence interval, 1.02-4.46) and drinking chlorinated surface water (odds ratio, 2.49; 95% confidence interval, 1.22-5.08). Both factors were also suggestive of increased risk for asymptomatic HEV infection, although this was not found to be statistically significant. HEV RNA was positively identified in serum samples obtained from 2 donkeys. No bacteria were identified from any sample of chlorinated water tested. CONCLUSIONS: Current recommendations to ensure a safe water supply may have been insufficient to inactivate HEV and control this epidemic. This research highlights the need to evaluate current water treatment methods and to identify alternative solutions adapted to complex emergencies.

Violence and mortality in West Darfur, Sudan (2003-04): epidemiological evidence from four surveys.

BACKGROUND: Violence in Darfur, Sudan, has rendered more than one million people internally displaced. An epidemiological study of the effect of armed incursions on mortality in Darfur was needed to provide a basis for appropriate assistance to internally displaced people. METHODS: Between April and June, 2004, we did retrospective cluster surveys among 215?400 internally displaced people in four sites of West Darfur (Zalingei, Murnei, Niertiti, El Geneina). Mortality recall periods covered both the pre-displacement and post-displacement periods in Zalingei, Murnei, and Niertiti, but not in El Geneina. Heads of households provided dates, causes, and places of deaths, and described the family structure. FINDINGS: Before arrival at displacement sites, mortality rates (expressed as deaths per 10?000 per day), were 5.9 (95% CI 2.2-14.9) in Zalingei, 9.5 (6.4-14.0) in Murnei, and 7.3 (3.2-15.7) in Niertiti. Violence caused 68-93% of these deaths. People who were killed were mostly adult men (relative risk 29.1-117.9 compared with children younger than 15 years), but included women and children. Most households fled because of direct village attacks. In camps, mortality rates fell but remained above the emergency benchmark, with a peak of 5.6 in El Geneina. Violence persisted even after displacement. Age and sex pyramids of surviving populations were skewed, with a deficit in men. INTERPRETATION: This study, which was done in a difficult setting, provides epidemiological evidence of this conflict's effect on civilians, confirming the serious nature of the crisis, and reinforcing findings from other war contexts.