11th European AIDS Conference: Complications, Coinfections, and Comorbidities in

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Selection from: 11th European AIDS Conference: Complications, Coinfections, and Comorbidities in HIV

Approximately 4000 attendees convened in Madrid this year to participate in the 11th European AIDS Conference, sponsored by the European AIDS Clinical Society (EACS). This event has classically been driven by clinically oriented abstracts, with minor contributions from basic science studies. In addition to studies on antiretroviral therapy, the management of opportunistic diseases and coinfections had a major representation in the conference program. Among these were papers on the hepatitides -- B and C -- as well as on tuberculosis and syphilis, which will be reviewed here.

Hepatitis B

Around 5% to 8% of individuals infected with HIV in the Western world also chronically harbor hepatitis B virus (HBV) infection. As shown in the Table, 8 HBV genotypes have been identified, with differences in their geographic distribution, susceptibility to antiviral agents, and pathogenicity.

Table. Differential Features of Hepatitis B Virus (HBV) Genotypes[1-3]

Genotype

Region

Comments

A

Northern AmericaNorthern EuropeIndiaAfrica

ALT more frequentlyMore rapid 3TC (lamivudine) resistanceMore sensitive to interferon

B

Asia

More benignMore sensitive to interferon

C

Asia

More liver cancerLess response to interferon

D

Southern EuropeMiddle EastIndia

Less response to interferon

E

West and South Africa

F

Central and South America

G

United States and Europe

H

Central AmericaCalifornia

Effect of HBV Genotypes

A paper analyzing HIV/HBV coinfections looked at 1460 HIV-infected patients attending a referral center in London during 2004-2006; 5.2% had chronic hepatitis B.[4] The median age of this HBV/HIV coinfected population was 40 years; 87% were males; 45% black Africans; 49% homosexual men; 66% hepatitis B e antigen positive (HBeAg+); and 2% superinfected with hepatitis delta. Of the total group, 58 persons were found to have detectable serum HBV DNA, with a median of 436,000 copies/mL, and 51 of those were able to have successful genotyping of HBV. Of those successfully genotyped:

70% were genotype A;

10% were genotype D;

6% were genotype C;

6% were genotype G;

4% were genotype E; and

4% were genotype F.

As previously reported from other European regions,[5] homosexual men were predominantly (80%) infected by HBV genotype A. Of note, one newly diagnosed treatment-naive person showed a lamivudine-resistant HBV strain, which could have been transmitted at the time of infection. This phenomenon has been reported only sporadically[6] but may be expected to rise in the future.

Hepatitis C

Two studies on chronic hepatitis C virus (HCV) infection, conducted through the prospective observational cohort study EuroSIDA, attracted particular attention. The first described the main virologic characteristics of 2263 HIV-infected persons who also had antibodies to HCV in this large cohort of HIV individuals recruited since 1994 across Europe.[7] Overall, 1677 (74%) were positive for serum HCV RNA (95% confidence interval [CI], 71%-78%). Treatment with interferon had occurred in only 5% of this population, and less than one third of those had cleared their HCV infection. The variables most significantly associated with spontaneous clearance of HCV in the remainder of the subjects were: (1) groups at risk for infection through sexual behavior -- as compared with intravenous (IV) drug use; and (2) coinfection with hepatitis B. Although viral interference phenomena between HBV and HCV had been reported previously[8] and may explain the latter finding, it was noted that multiple episodes of exposure and reexposure to HCV among IV drug users could explain the lower rates of clearance in the drug-use population compared with individuals only occasionally exposed to HCV through sexual risk factors.

Effect of HCV Replication and HCV Genotypes

This group also delineated the distribution of HCV genotypes in the EuroSIDA cohort[7] as follows: 53% HCV-1, 3% HCV-2, 30% HCV-3, and 14% HCV-4. It is worth noting that HCV-3 is overrepresented in the current, rapidly spreading epidemic of HIV and HCV among IV drug users in Eastern Europe, while HCV-4 is very rare in northern Europe. Another significant finding was the recognition of a significantly higher HCV plasma load in patients infected with HCV-1 compared with other genotypes. Three quarters of them harbored more than 400,000 HCV-RNA IU/mL, a threshold which is associated with a poorer response to pegylated interferon plus ribavirin.[9]

The other EuroSIDA analysis of interest used newly available virologic results for HCV. In a prior study from EuroSIDA, the impact of HCV on mortality and on response to antiretroviral therapy had been examined using only information on HCV serostatus.[10] HCV serostatus did not affect the risk for HIV disease progression, but the risk for liver-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to antiretroviral therapy were not affected by HCV serostatus. This same analysis was run again using the now available virologic results to assess the impact of active HCV replication and genotypes.[11] Overall, 340 patients (15%) died during follow-up, of whom 91 died from liver disease. After adjusting for other variables, patients with active HCV replication and/or those infected with distinct HCV genotypes did not have a significantly different incidence of death. Moreover, no association could be found between serum HCV RNA load and overall cause of mortality nor specifically liver-related death. This is somewhat in contrast with other reports in which active infection with HCV-1 was found to be associated with a worse outcome.[12]

Impact of Treatment on HCV Infection

Interferon-based therapy may permit eradication of HCV from HIV/HCV-coinfected persons. A French group examined the long-term outcome of 230 such coinfected patients who had received at least 1 course of interferon in comparison with 207 coinfected patients never treated for HCV.[13] The incidence of decompensated liver cirrhosis events and hepatocellular carcinoma was 16% in patients who did not achieve a sustained virologic response with interferon treatment compared with an incidence of only 2.3% in those who did. The control group of coinfected patients never treated for HCV had a more favorable liver condition at baseline; despite this, progression occurred in 4.4% of cases during the study period. Of note, regardless of anti-HCV treatment experience, patients with more elevated liver enzymes experienced more rapid progression of liver disease. Notably, no cases of late relapse of HCV infection were seen after the achievement of sustained virologic response, ie, undetectable serum HCV RNA 6 months after completion of therapy. Taken together, these results are in agreement with prior reports[14] and highlight the fact that successful treatment of chronic hepatitis C in those with HIV is associated with a significant reduction of liver-related morbidity and mortality. Therefore, these patients should be actively considered for anti-HCV therapy.

Acute Hepatitis C Among HIV-Infected Persons

Outbreaks of acute hepatitis C among HIV-infected men who have sex with men (MSM) have been reported in large European cities over the last few years. Investigators from France, the United Kingdom, and Germany compiled data from 150 of these subjects and retrospectively assessed their outcome.[15] Overall, 79% presented initially with asymptomatic liver enzyme elevations and/or HCV seroconversion. Of note, 17% had concurrent syphilis, consistent with their behavioral risk. Although 23 individuals in the study population had negative serum HCV RNA at week 12, 8 of these subjects later relapsed. Overall, spontaneous HCV clearance occurred in only 11 subjects (7%), with no clear association with HCV genotype nor with symptoms. The best time to consider prescription of hepatitis C therapy in these patients remains unclear, and it is recommended that HCV RNA testing be repeated periodically during the first year of infection given that fluctuations in viremia are relatively common.

An analysis of the incidence of HIV and HCV from 2003 to 2006 was performed in 3545 MSM who attended a Madrid sexually transmitted diseases (STD) clinic for the first time; only 0.3% acknowledged IV drug use.[16] The overall prevalence of HIV infection was 10% with a prevalence of HCV antibodies of 1.3%. A striking finding was the presence of HCV antibodies in 83% of the small group of IV drug users but in only 1.1% of non-drug users. Of note, the prevalence of HCV increased with age (0.5% in those younger than 25 years vs 3.8% in those older than 40 years) and was higher among HIV-positive than HIV-negative MSM (4.1% vs 1%, respectively). Although the prevalence of HCV slightly diminished from 1.6% in 2003 to 1.4% in 2006, HIV seroprevalence increased from 8.7% to 9.6%. Overall, only 0.5% of MSM were coinfected with HIV and HCV. In contrast with other large European cities, no outbreaks of acute hepatitis C have been seen so far in Madrid among homosexual men. A low rate of HCV infection associated with rare IV drug use, along with more predominant oral than anal sex, might explain why syphilis is rising in this population while HCV is not.

Hepatic Safety Profile of CCR5 Antagonists

Following the discontinuation of the clinical development of aplaviroc due to reports of severe hepatotoxicity, there remains concern that hepatotoxicity might be a class safety issue for all of the CCR5 antagonists. A review of 48-week data from several studies conducted with the recently FDA-approved CCR5 antagonist maraviroc was presented by Pfizer researchers and Dutch investigators.[17] A total of 700 individuals received the drug in phase 1 and phase 2a studies. Occasional liver enzyme elevations were observed but with no clear dose-dependent relationship. One episode of grade 4 hepatotoxicity along with rash occurred in a woman exposed to maraviroc 600 mg once daily. In nearly 2000 HIV patients enrolled in phase 2b and phase 3 studies (MERIT, MOTIVATE 1, MOTIVATE 2, and A4001029), the rate of grade 3/4 liver enzyme elevations did not differ significantly in controls and patients allocated to receive maraviroc, with a range of 2.6% to 4.2%. Not surprisingly, patients with underlying chronic viral hepatitis experienced more frequent liver enzyme elevations regardless of maraviroc exposure. One patient in the once-daily arm of the MERIT trial developed severe liver failure and required liver transplantation, but this individual was receiving isoniazid and paracetamol in addition to maraviroc, and these could have played a role. Altogether, these data reinforce the hepatic safety profile of maraviroc.

Tuberculosis

Tuberculosis is one of the most frequent infectious illnesses occurring in HIV-infected persons in the developing regions of the world. The rate of the disseminated forms of tuberculosis increases as CD4 counts decline. The rapid spreading of HIV among IV drug users in Eastern Europe has been followed by an extraordinary outbreak of tuberculosis in this population. Researchers from St. sburg, Russia, alerted European clinicians that among 704 cases of tuberculosis diagnosed in the period 2000-2006 at their institution, one third were smear-negative, making the diagnosis of tuberculosis much more difficult.[18] Even more worrisome was the recognition that up to 80% of cases harbored strains resistant to at least 1 antimycobacterial agent. In more than half of these cases, the resistance was secondary, ie, the result of suboptimal adherence or of lack of completion of a course of therapy. Overall, resistance to rifampin was observed in 61% of cases, while resistance to isoniazid and streptomycin was seen in 19% and 57%, respectively.

Syphilis

Several studies presented at this conference stressed that rates of STDs, and in particular rates of syphilis, are rising among HIV-infected persons in Europe, predominantly among MSM. In a reference STD clinic located in Madrid, a total of 194 persons were diagnosed with recent syphilis (primary, secondary, and early latent) during 2005 and 2006.[19] Even though MSM represented only 40% of the total population tested for STDs (n = 11,166) during that period, they accounted for 92% of all cases of syphilis. Moreover, one third of the cases of syphilis were HIV infected. No cases of HIV with syphilis were found in female prostitutes or other risk groups. These data stress that homosexual men, including those infected with HIV, are engaged in high rates of risky sexual practices and that prevention and educational measures are urgently needed for this population.

Because HIV-infected persons with syphilis may have an increased risk for treatment failure, predictors of serologic response were assessed in 103 HIV-infected patients with early syphilis treated in 11 Spanish hospitals.[20] Of note, the diagnosis of HIV and syphilis was coincident in 37% of cases. At 48 weeks there was a 20% treatment failure rate in this population, 89% of whom had been treated with penicillin. In the multivariate analysis, the best predictor of treatment failure was a high plasma HIV RNA (odds ratio, 6.3; 95% CI, 1.4-28.0; P = .016).

Summary

Taken together, these reports of outbreaks of acute hepatitis C and tuberculosis, along with rising rates of syphilis in several European countries, should be a warning to clinicians in other parts of the world, both developed and developing. The incidence of resistant tuberculosis isolates along with a 20% failure rate of syphilis treatment with penicillin is also troubling. These reports should only reinforce the importance of early identification and aggressive treatment of HIV with antiretroviral agents as well as the impact of interferon-based therapy on HCV infection.

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