New Publications in HIV

01 February 2012

A watershed moment in the treatment of hepatitis C. (editorial)

Chung RT. N Engl J Med 2012;366:273–5. • This open-label, phase IIa study included 21 patients with chronic HCV genotype 1 infection who had not responded to previous therapy with peginterferon and ribavirin. • Patients were randomly assigned to daclatasvir 60 mg qd plus asunaprevir 600 mg bid (group A, n=11) alone or in combination with peginterferon alfa-2a and ribavirin (group B, n=10) for 24 weeks. • The primary endpoint was the percentage of patients with a sustained virologic response 12 weeks after the end of treatment. • Four patients in group A (36%) had a sustained virologic response at 12 and 24 weeks after treatment. • Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases. • All 10 patients in group B had a sustained virologic response at 12 weeks after treatment and nine had a sustained virologic response at 24 weeks after treatment. • Conclusions: Patients with HCV genotype 1 infection who had not responded to prior therapy showed a sustained virologic response with two direct-acting antiviral agents. In addition, a high rate of sustained virologic response was achieved with these two agents in combination with peginterferon alfa-2a and ribavirin. Link 01 February 2012

Preliminary study of two antiviral agents for hepatitis C genotype 1.

Lok AS et al. N Engl J Med 2012;366:216–24. • This open-label, phase IIa study included 21 patients with chronic HCV genotype 1 infection who had not responded to previous therapy with peginterferon and ribavirin. • Patients were randomly assigned to daclatasvir 60 mg qd plus asunaprevir 600 mg bid (group A, n=11) alone or in combination with peginterferon alfa-2a and ribavirin (group B, n=10) for 24 weeks. • The primary endpoint was the percentage of patients with a sustained virologic response 12 weeks after the end of treatment. • Four patients in group A (36%) had a sustained virologic response at 12 and 24 weeks after treatment. • Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases. • All 10 patients in group B had a sustained virologic response at 12 weeks after treatment and nine had a sustained virologic response at 24 weeks after treatment. • Conclusions: Patients with HCV genotype 1 infection who had not responded to prior therapy showed a sustained virologic response with two direct-acting antiviral agents. In addition, a high rate of sustained virologic response was achieved with these two agents in combination with peginterferon alfa-2a and ribavirin. Link 27 January 2012

Preventing deaths in persons with HIV/hepatitis B virus coinfection: a call to accelerate prevention and treatment efforts. (Editorial)

Peters PJ, Marston BJ. J Infect Dis 2012;205:166–8. • This study investigated HBV co-infection and HIV-related disease progression in a cohort of HIV seroconverters. • Patients with an HIV diagnosis seroconversion window of ≤3 years and serologically confirmed HBV infection were classified at baseline into four HB groups. The risk of clinical AIDS/death was calculated according to HB status. • Of 2,352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. • Unadjusted rates (95% CI) of clinical AIDS/death for the HB–, resolved HB, isolated HBcAb and chronic HB patients were 2.43 (2.15–2.71), 3.27 (2.71–3.84), 3.75 (2.25–5.25) and 5.41 (3.41–7.42), respectively. • The risk of clinical AIDS/death was significantly higher for chronic HB vs HB– patients (HR: 1.80; 95% CI: 1.20–2.69). • Conclusions: HBV coinfection had a significant impact on HIV outcomes, almost doubling the hazard for an AIDS event or death. Link 27 January 2012

Hepatitis B virus coinfection negatively impacts HIV outcomes in HIV seroconverters.

Chun HM et al. J Infect Dis 2012;205:185–193. Jan • This study investigated HBV co-infection and HIV-related disease progression in a cohort of HIV seroconverters. • Patients with an HIV diagnosis seroconversion window of ≤3 years and serologically confirmed HBV infection were classified at baseline into four HB groups. The risk of clinical AIDS/death was calculated according to HB status. • Of 2,352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. • Unadjusted rates (95% CI) of clinical AIDS/death for the HB–, resolved HB, isolated HBcAb and chronic HB patients were 2.43 (2.15–2.71), 3.27 (2.71–3.84), 3.75 (2.25–5.25) and 5.41 (3.41–7.42), respectively. • The risk of clinical AIDS/death was significantly higher for chronic HB vs HB– patients (HR: 1.80; 95% CI: 1.20–2.69). • Conclusions: HBV coinfection had a significant impact on HIV outcomes, almost doubling the hazard for an AIDS event or death. Link 23 December 2011

Long term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort.

Van Lelyveld SF et al. AIDS 2011 Nov 22 [Epub ahead of print]. • This retrospective, observational study investigated the risk of AIDS and serious non-AIDS defining diseases according to the degree of immunological recovery after 2 years of virological successful HAART resulting in viral suppression (<500 copies/mL) in 3,068 patients. • Patients were grouped according to their CD4 cell count after 2 years of HAART: <200 (A), 200–350 (B), 351–500 (C) and >500 cells/mm3 (D). • Analyses assessed predictors for poor immunological recovery and the occurrence of a composite endpoint (death, AIDS, malignancies, liver cirrhosis and cardiovascular events), non-AIDS defining diseases (non-ADD), cardiovascular events (CVE) and non-AIDS defining malignancies (non-ADM). • The composite endpoint, non-ADD and CVE were observed most frequently in group A (overall log rank, p < 0.0001, p = 0.002 and p = 0.01). • In adjusted analyses, age was a strong independent predictor for all endpoints. • Conclusions: Poor immunological recovery despite virological successful HAART was associated with a higher risk for morbidity, mortality and cardiovascular events, demonstrating the importance of starting HAART at higher CD4 cell counts, especially for older patients. Link 21 November 2011

Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

Blanc FX et al. N Engl J Med 2011;365:1471–81. Oct • This study tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to ARV drugs who had newly diagnosed TB and CD4+ cell counts ≤200/mm3. • After starting standard 6-month TB treatment, patients were randomly assigned to either early (2 weeks after starting TB treatment) or late (8 weeks after) treatment with d4T, 3TC and EFV. The primary endpoint was survival. • The risk of death was significantly reduced with early (59 deaths among 332 patients, 18%), versus late (90 deaths among 329 patients, 27%) ART (HR: 0.62; 95% CI: 0.44–0.86; p=0.006). • The risk of TB-associated immune reconstitution inflammatory syndrome was significantly increased with early ART (HR: 2.51; 95% CI: 1.78–3.59; p<0.001). • Conclusions: Initiating ART 2 weeks after the start of TB treatment significantly improved survival among HIV+ adults with CD4+ cell counts ≤200/mm3. Link 21 November 2011

Timing of antiretroviral therapy for HIV-1 infection and tuberculosis.

Havlir DV et al. N Engl J Med 2011;365:1482–91. Oct • This open-label, randomised study compared early (within 2 weeks after the initiation of TB treatment) with late (8–12 weeks after initiation) ART in HIV+ patients with CD4+ cell counts <250/mm3 and suspected TB. • The primary endpoint was the proportion of patients who survived without a new (previously undiagnosed) AIDS-defining illness at 48 weeks. • With early ART, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks versus 16.1% with late ART (95% CI: –1.8–8.1; p=0.45). • In patients with screening CD4+ cell counts <50/mm3, 15.5% of those who received early versus 26.6% of those who received late ART had a new AIDS-defining illness or died (95% CI: 1.5–20.5; p=0.02). • TB-associated immune reconstitution inflammatory syndrome was more common with early versus late ART (11% versus 5%; p=0.002). • Conclusions: Overall, early versus late ART did not reduce the rate of new AIDS-defining illness and death. In patients with a CD4+ cell count <50/mm3, early ART was associated with a lower rate of new AIDS-defining illnesses and death. Link 21 November 2011

When to start antiretroviral therapy in HIV-associated tuberculosis.

Török ME, Farrar JJ. N Engl J Med. 2011;365:1538–40. Oct • This three-group, open-label, randomised, controlled study conducted in South Africa in ambulatory HIV+ patients with TB and a CD4+ cell count <500/mm3 investigated early (within 4 weeks after the start of TB treatment) versus late (during the first 4 weeks of the continuation phase of TB treatment) initiation of ART. • The incidence rate of AIDS or death was 6.9 cases per 100 person-years with early (18 cases) versus 7.8 per 100 person-years with late ART initiation (19 cases) (incidence-rate ratio: 0.89; 95% CI: 0.44–1.79; p=0.73). • In patients with CD4+ cell counts <50/mm3, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio: 0.32; 95% CI: 0.07–1.13; p=0.06). • The incidence rates of the immune reconstitution inflammatory syndrome were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio: 2.62; 95% CI: 1.48–4.82; p<0.001). • Conclusions: Early initiation of ART in patients with CD4+ cell counts <50/mm3 increased AIDS-free survival. Late initiation in patients with higher CD4+ cell counts reduced the risk of immune reconstitution inflammatory syndrome and other adverse events related to ART without increasing the risk of AIDS or death. Link Editorial 21 November 2011

Integration of antiretroviral therapy with tuberculosis treatment.

Abdool Karim SS et al. N Engl J Med 2011;365:1492–501. Oct • This three-group, open-label, randomised, controlled study conducted in South Africa in ambulatory HIV+ patients with TB and a CD4+ cell count <500/mm3 investigated early (within 4 weeks after the start of TB treatment) versus late (during the first 4 weeks of the continuation phase of TB treatment) initiation of ART. • The incidence rate of AIDS or death was 6.9 cases per 100 person-years with early (18 cases) versus 7.8 per 100 person-years with late ART initiation (19 cases) (incidence-rate ratio: 0.89; 95% CI: 0.44–1.79; p=0.73). • In patients with CD4+ cell counts <50/mm3, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio: 0.32; 95% CI: 0.07–1.13; p=0.06). • The incidence rates of the immune reconstitution inflammatory syndrome were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio: 2.62; 95% CI: 1.48–4.82; p<0.001). • Conclusions: Early initiation of ART in patients with CD4+ cell counts <50/mm3 increased AIDS-free survival. Late initiation in patients with higher CD4+ cell counts reduced the risk of immune reconstitution inflammatory syndrome and other adverse events related to ART without increasing the risk of AIDS or death. Link 21 November 2011

Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 cells/mm³: assessment of need following changes in treatment guidelines.

Lodi S et al. Clin Infect Dis 2011;53:817–25. Oct • This study used Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) data from patients with well-estimated dates of HIV seroconversion to fit mixed models on the square root of CD4+ cell counts, measured before initiation of combination ART. • Restricting analyses to adults aged >16 years, the time between seroconversion and a CD4+ cell count <200, <350 and <500 cells/mm3 as well as the CD4+ cell-count distribution and the proportion of patients reaching these thresholds at 1, 2 and 5 years after seroconversion were predicted. • Estimated median times from seroconversion to a CD4+ cell count <500, <350 and <200 cells/mm3 were 1.19 (95% CI: 1.12–1.26), 4.19 (95% CI: 4.09–4.28) and 7.93 (95% CI: 7.76–8.09) years, respectively. • Almost half of HIV+ patients would require treatment within 1 year of seroconversion for guidelines recommending ART initiation at 500 cells/mm3 versus 26% and 9% for guidelines recommending initiation at 350 and 200 cells/mm3, respectively. • Conclusions: The results indicate that there will be a substantial increase in the number of patients requiring treatment and a need for early HIV testing. Link