Adding rituximab to chemotherapy regimens improves outcomes for AIDS-related lymphomas

The addition of rituximab to chemotherapy regimens for the treatment of AIDS-related lymphomas improves both overall survival and progression-free survival, German investigators report in the online edition of AIDS.

Therapy with rituximab appeared to be safe, and no deaths were associated with its use.

“Rituximab was beneficial for AIDS-related lymphoma even in the setting of severe immune deficiency and was not associated with an increased risk of fatal infections,” comment the authors.

Cases of AIDS-related lymphoma have fallen significantly since the introduction of effective antiretroviral therapy. There has also been a marked improvement in the outcomes of individuals diagnosed with the malignancy.

Nevertheless, these cancers are an important cause of the excess mortality that still occurs in HIV-positive patients. Their treatment is controversial and there is some uncertainty about the benefits of adding rituximab – a monoclonal CD20 antibody – to traditional CHOP-based (cyclophosphamide, doxorubicin, vincristine and prednisone ) chemotherapy regimens.

Investigators from Germany therefore analysed the outcomes of patients diagnosed with AIDS-related lymphomas between 2005 and 2008 according to their treatment regimen and the use of the rituximab.

A total of 156 individuals who received care at 25 clinics across Germany were included in the study. These patients had a median age of 45 years, and almost all (92%) were men.

Many of the patients had severe immunosuppression at the time of cancer diagnosis.

Median CD4 cell count was 205 cells/mm3, and a quarter of patients had a CD4 cell below 100 cells/mm3. In two-thirds of patients, the lymphoma was the first AIDS diagnosis. Over half the patients had never taken antiretroviral therapy.

“Thus, a relevant proportion of our patients were late presenters”, emphasise the authors.

Forty-seven per cent of patients were treated with rituximab in addition to their CHOP-based regimen. A median of four rituximab doses were administered.

By the end of 2008, a total of 61 patients (37%) had died after a median of 15 months of follow-up.

After taking into account potentially confounding factors, the investigators found a strong relationship between treatment with rituximab and the chances of survival.

Compared to individuals treated with a traditional CHOP-based regimen, the chances of overall survival were significantly better for patients who also received rituximab (OR = 0.43; 95% CI, 0.21-0.89). The addition of the drug also improved progression-free survival (OR = 0.44; 95% CI, 0.23-0.84).

Expression of CD20 was also a significant predictor of survival (OR = 0.24; 95% CI, 0.12-0.47). A subgroup analysis was therefore performed involving patients with this immune characteristic. This once again showed that rituximab improved both overall survival (OR = 0.42; 95% CI, 0.20-0.87) and progression-free survival (OR = 0.44; 95% CI, 0.23-0.84).

A CD4 cell count above 100 cells/mm3 also predicted the chances of survival in both sets of analysis.

The investigators then turned their attention to the safety of rituximab therapy. As has been noted, 61 patients died. In two-thirds of cases, the cause of death was lymphoma. Infections caused a fifth of deaths, and 11% were due to other causes such as heart attack, liver failure and suicide.

All deaths due to fatal infections were considered to be treatment-related. Three of these twelve deaths involved patients treated with rituximab. Immune suppression appeared to be the main cause of these deaths. Regardless of treatment regimen, the median CD4 cell count at the time of death was in the region of 100 cells/mm3.

“We did observe an increased risk of fatal infections due to use of rituximab,” write the authors. “However, the patients who died from treatment-associated infections had lower CD4 T-cells than the entire group. These findings emphasise the need for prospective trials evaluating the benefits of intensified supportive care.”

They conclude, “the use of rituximab improved overall and progression free- survival.  This effect was seen even in the setting of severe immune deficiency and without an increased risk of fatal infections.”

Noting the substantial mortality rate, the investigators call “for further clinica research in AIDS related lymphomas.”

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Hepatitis B genotype B associated with poorer liver-related outcomes in Taiwanese patients co-infected with HIV and hepatitis B

Liver-related outcomes are poorer in HIV-positive patients who are co-infected with hepatitis B virus genotype B compared to co-infected patients with hepatitis B genotype C, Taiwanese investigators report in the online edition of Clinical Infectious Diseases.

The prospective, observational study involved individuals who commenced antiretroviral therapy containing 3TC (lamivudine, Epivir, also in the combination pill Combivir), a drug which has activity against both viruses. The patients were recruited between 1997 and 2008, and followed until 2010.

“Patients with [hepatitis B virus] genotype B co-infection were at higher risk of developing hepatitis flares, liver disease-related deaths, HBeAg seroconversion, and lamivudine resistance mutations than those with genotype C coinfection,” write the authors. Genotype did not affect HIV-related outcomes.

HIV and hepatitis B share transmission modes. Therefore, large numbers of patients are co-infected with these viruses. There are eight hepatitis B genotypes (A – H). The distribution of genotypes varies according to geographical region, and genotypes B and C predominate in Asia.

Little is known about the differential impact of these two genotypes on liver-related outcomes in patients co-infected with HIV and hepatitis B.

Therefore, investigators in Taiwan recruited 145 co-infected patients starting antiretroviral therapy to a study analysing the clinical, immunological and virological outcomes of patients according to hepatitis B genotype.

The hepatitis B-related outcomes included the risk of hepatitis flares, liver disease-related death, hepatitis B e antigen (HBeAg) seroconversion, and the development of strains of hepatitis B with resistance to 3TC. Changes in CD4 cell count and HIV viral load were also compared according to genotype.

A total of 96 patients were co-infected with genotype B and 49 with genotype C were recruited. There were no significant baseline differences between the patients.

However, they had severe immune suppression at the time they started HIV treatment, and their median CD4 cell count was just 117 cells/mm3. Median baseline HIV viral load was approximately 125,000 copies/ml. Median hepatitis B viral load at the start of the study was 63,000 copies/ml.

Patients were treated with 3TC-containing antiretroviral therapy for a median of 2.8 years. During this time, none of the patients received any other antiretroviral drugs with activity against hepatitis B.

Compared to patients with genotype C, those with genotype B co-infection were significantly more likely to experience hepatitis flares (44% vs. 27%, p = 0.04), die of liver-related causes (9% vs. 0%, p = 0.03), have HBeAg seroconversion (62% vs. 25%, p = 0.03), and developed strains of hepatitis B with resistant to 3TC (31% vs. 12%, p < 0.001).

Analysis that controlled for potentially confounding factors confirmed the relationship between genotype B co-infection and a number of liver-related outcomes.

Compared to individuals with genotype C, those with genotype B had a higher risk of hepatitis flares (AHR = 4.13; 95% CI, 2.87-5.39; p = 0.01) and were also more likely to develop 3TC-resistant hepatitis B (AHR = 8.67; 95% CI, 6.37-10.98, p = 0.001).

However, there was no significant difference in mortality risk between the genotypes. Nor did HIV-related outcomes differ between the two groups of patients, who had similar falls in viral load and increases in CD4 cell count.

“Hepatitis B genotype B is the most predominant genotype in hepatitis B virus and HIV-co-infected Taiwanese patients,” conclude the investigators. “Patients with genotype B co-infection are more likely to experience acute exacerbations of hepatitis, HBeAg seroconversion, lamivudine resistance, and liver disease-related death than those with genotype C coinfection when they receive [HIV therapy] containing lamivudine as the only active agent against hepatitis B virus.”

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Co-infection with hepatitis B worsens HIV-related outcomes

Co-infection with hepatitis B virus increases the risk of AIDS or death for patients newly diagnosed with HIV, investigators from the US military report in the online edition of the Journal of Infectious Diseases.

Individuals with chronic hepatitis B infection were twice as likely to progress to AIDS/death compared to patients who were only infected with HIV.

“With compelling data confirming the risk for persons with co-infection, it is imperative that we commit to implement…additional steps to combat hepatitis B now,” write the authors of an accompanying editorial.

HIV and hepatitis B share modes of transmission. These include sexual exposure, injecting drug use and mother-to-child transmission. Therefore a significant proportion of HIV-positive patients are co-infected with HIV.

Infection with HIV can accelerate the course of hepatitis B disease.

“HIV co-infection is known to influence the natural history and course of hepatitis B by impairing the quantity and quality of the innate and adaptive immune response,” explain the authors.

There is no cure for hepatitis B, but a number of antiretroviral drugs are active against both HIV and hepatitis B and can thus help prevent liver damage and disease progression.

Studies exploring the impact of hepatitis B on HIV-related outcomes have yielded conflicting results. However, these studies were limited by their inability to control for a number of factors, including duration of infection with HIV.

In order to overcome this limitation, investigators from the US military designed a retrospective study, involving patients with an approximate date of HIV-seroconversion who were categorised according to their hepatitis B infection status. A series of analysis were then conducted to assess the impact of co-infection on the risk of progression to AIDS and death.

Patients diagnosed with HIV since 1986 were included in the study. All had been repeatedly screened for the infection and it was possible to estimate the date of their seroconversion within three years.

Their routine care involved testing for hepatitis B. This screening showed that 74% had never been infected with the virus; 20% had resolved hepatitis B infection; 4% had isolated hepatitis B core antigen (HBcAb); and 3% had chronic hepatitis B infection.  

Importantly, 48% of patients were diagnosed with HIV before the advent of effective HIV therapy in 1996.

The investigators had 16, 946 person years of follow-up available for analysis. During this time, 305 patients developed AIDS and 164 died.

Initial analysis showed that hepatitis B infection status was significantly associated with these outcomes.

Compared to individuals with no hepatitis B infection, patients with chronic hepatitis B were over twice as likely to develop AIDS or die (RR = 2.23; 95% CI, 1.51-3.28). The risk of these outcomes was also significantly increased for patients with isolated HBcAb (RR = 1.54; 95% CI, 1.02-2.34), and for those with resolved hepatitis B infection (RR = 1.35; 95% CI, 1.09-1.66).

Subsequent analysis that controlled for potential confounding factors, such as year or diagnosis and use of potent HIV therapy showed that showed that chronic hepatitis B infection remained associated with a significant risk of AIDS or death (HR = 1.80; 95% CI, 1.20-2.69). There was also a non-significant trend suggesting that resolved hepatitis B infection (HR = 1.17; 95% CI, 0.94-1.46) and isolated HBcAb (HR = 1.14; 95% CI, 0.75-1.75) were also associated with AIDS or death.

“We found that hepatitis B virus infection has a significant impact on HIV outcomes,” comment the investigators. “We also found an increased risk of AIDS or death in the HAART [highly active antiretroviral therapy] era, despite the fact that the majority of participants received an hepatitis B-active drug as part of their regimen.”

Only a fifth of patients had been vaccinated against hepatitis B, leading the investigators to suggest: “Our findings underscore the need to prevent hepatitis B in those with HIV and also in cohorts of HIV-negative individuals with risk factors for HIV acquisition.”

However, the study had a number of limitations. Most notably, it did not differentiate the causes of death, and many of the deaths in co-infected patients could have been due to factors other than hepatitis B.

Nevertheless, the authors of an accompanying editorial believe the research “adds to the weight of evidence that co-infection is deleterious by demonstrating that in a well-characterised cohort, it doubles the risk of AIDS-defining illness and death.”

They believe this underscores the importance of vaccinating individuals with or at risk of HIV against HIV and the inclusion of drugs that work against both infections in the antiretroviral therapy of co-infected patients.

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