Worse HIV control at diagnosis doesn't mean worse lymphoma outcomes

The outcomes of lymphoma – one of the most common types of cancer in people with HIV – seem to be largely uninfluenced by viral suppression at the time of diagnosis. Although people with detectable viral load had lower CD4 counts and more advanced lymphoma when diagnosed, their chances of remission and survival were similar to those of people whose HIV was suppressed.

The higher rates of lymphoma, a cancer of the immune system, in people with HIV may be triggered by several mechanisms, including increased immune cell turnover, inflammation, immune suppression and direct virus interactions with the cells. Therefore, ongoing viral replication might be expected to contribute to lymphoma development and possibly worsened outcomes. However, the findings of Dr Teresa Aldámiz-Echevarria and colleagues, published in the journal HIV Medicine, suggest that once lymphoma has developed, its outcomes are mainly driven by immune status (including CD4 count), age and lymphoma type.

While there are several types of cancer that affect the immune system, lymphoma affects a branch of it called the adaptive immune system composed mainly of T and B lymphocytes; for instance, CD4 cells are a subtype of T lymphocytes. This adaptive branch is responsible for creating immune memory, responding to vaccines and fighting infections in a more targeted way. During untreated HIV infection, the adaptive immune system is not simply weakened; it is also repeatedly stimulated, like an alarm that cannot switch off. Over time this can lead to exhaustion, loss of CD4 cells and abnormal patterns on cell division.

The type of the lymphoma is determined by the types of lymphocytes that become cancerous. Hodgkin lymphoma usually arises from B lymphocytes, while non-Hodgkin lymphoma can involve any lymphocyte or natural killer cells; the distinction also involves other characteristics seen when the lymphocytes are examined under a microscope. Non-Hodgkin lymphoma is usually the more common type and often more difficult to treat. 

Before HIV treatment was available, non-Hodgkin lymphoma was often seen in people with advanced HIV. While the mechanism is not fully understood, constant high-level immune activation and impaired function, quick lymphocyte death and division and associated damage from the rapid viral replication in the body are the main factors thought to be responsible. With HIV now effectively treated with antiretrovirals, the frequency of non-Hodgkin lymphoma has significantly dropped.

The study

The researchers used data from the large Spanish CoRIS cohort – a long-term study that has been gathering data on people with HIV receiving treatment at many centres in Spain since 2004. The analysis included people in CoRIS diagnosed with lymphoma between 2004 and 2022 whose viral load was available at the time of their lymphoma diagnosis.

Among 18,573 people in the cohort, 291 were diagnosed with lymphoma in the given period and 245 of them had viral load data available at the time of diagnosis who were then included in the analysis. Of these, 49 people were virally suppressed at diagnosis.

The majority of the participants were men (86%) with a mean age of 45 years at the time of diagnosis. Most characteristics were similar across both groups – those with detectable and those with suppressed viral load, however time since HIV diagnosis was significantly shorter for those with unsuppressed virus. While all of the virally suppressed participants were on HIV therapy, about half of the unsuppressed participants hadn’t started ART at the time of lymphoma diagnosis.

The researchers used a non-standard cut-off for undetectable viral load – 100 virus copies, instead of the commonly used 50-copy cut-off – because lower limits of detection were not available in all of the centres in the earlier years. However, the cut-off is well within the definition used for ‘Undetectable equals Untransmittable’ (U=U) – 200 copies.

The researchers compared clinical outcomes in participants with a detectable or suppressed viral load at the time of diagnosis. The survival rate was assessed at one year for lymphoma-related death and five years for any death after diagnosis; the same way it’s assessed for most cancers. 

More lymphomas in virally suppressed people

Over the study period, viral suppression became more frequent in people with lymphoma. Between 2004 and 2009, only 10% of people with lymphoma were virally suppressed, while between 2010 and 2014 it rose to 14%. In the period from 2015 to 2019, 33% people with lymphoma were suppressed, remaining almost unchanged between 2020 and 2022 at 31%.

Find out more: Non-Hodgkin lymphoma and HIV

This does not mean that viral suppression increased lymphoma risk, but reflects the changing characteristics of people with HIV. More people with HIV now receive effective treatment, which means that more people with HIV and lymphoma are now virally suppressed.

The type of lymphoma may be shifting when virally suppressed

Viral suppression affects the distribution of Hodgkin and non-Hodgkin lymphoma. Among those with viral suppression, half of the lymphomas were Hodgkin, while 43% were non-Hodgkin, with three cases missing data on the type of lymphoma. Among people with a detectable viral load non-Hodgkin lymphoma made up the majority of cases at 69%, with only 19% receiving Hodgkin diagnoses, again the rest had an unknown type. This highlights a possibly different lymphoma profile in people with suppressed HIV, while the higher predominance of non-Hodgkin lymphoma in those with detectable virus is more consistent with the historical link between a weakened immune system and more aggressive lymphomas. 

People with detectable virus had more advanced lymphoma and immune suppression at diagnosis

People with a detectable viral load had a median CD4 count of 180 cells, significantly lower than those who were virally suppressed – 371 cells. (Median refers to the midpoint value where half of the people had CD4 counts below that number, while the other half had a value above it.) They were also more likely to have an advanced stage of lymphoma; 82% of those with a detectable viral load were diagnosed with either stage three of four compared to 64% of those who were virally suppressed.

Cancer staging goes from stage one to four, where stage one represents a local tumour while stage four is the last stage when the cancer has formed multiple tumours across different organs.

Outcomes remained similar despite lower CD4 count and more advanced lymphoma at diagnosis

In terms of treatment, most people received chemotherapy. Treatment intensity reflected lymphoma type and stage: people with unsuppressed viral load more often had more advanced lymphoma and were more likely to undergo autologous stem cell transplantation, while those with viral suppression more often received radiotherapy, which is usually used in less advanced disease.

Complete remission was achieved by 67% of people with detectable viral load, compared to 76% of those with viral suppression. Relapse rates were also similar: 12% of people with detectable viral load and 14% of those with viral suppression experienced relapse.

At one year, lymphoma-related death occurred in 28% of people with detectable viral load and 24% of those with viral suppression. Longer-term survival followed the same pattern. In the analysis, viral suppression at lymphoma diagnosis was not directly associated with either one-year lymphoma-related survival or five-year overall survival.

Instead, survival was more strongly linked to age, CD4 count, duration of known HIV infection and lymphoma type. Each ten-year increase in age at lymphoma diagnosis was linked to a 28% higher risk of death within five years and a 36% higher risk of lymphoma-related death within one year.

People with a CD4 count of 200 or above had a 44% lower risk of death during five-year follow-up than those with CD4 counts below 200. A CD4 count above 200 was also linked to a 37% lower risk of lymphoma-related death within one year.

Concluding thoughts

As more people are now ageing with HIV and maintaining a stable undetectable viral load, lymphomas are increasingly being diagnosed in people whose HIV is already well controlled. In this study, Hodgkin lymphoma was more frequent among people with viral suppression, while non-Hodgkin lymphoma remained the major type overall.

Despite worse presentation (lower CD4 counts and more advanced lymphoma) at diagnosis, detectable viral load did not appear to worsen treatment response, relapse rates or survival. Therefore, the study contributes to the argument that modifying the lymphoma treatment protocols used in people who don’t have HIV based on viral suppression for people with HIV may not be necessary. Another reason why following standard treatment protocols may be appropriate is that modern HIV drugs are less likely to interact with the cancer treatment.

These findings are consistent with recent guidance from the European Haematology Association (EHA) and the European Society for Medical Oncology (ESMO) on HIV-associated lymphomas, which supports using standard lymphoma treatment approaches in people with HIV wherever possible, while still managing antiretroviral therapy, drug interactions, immune suppression and infection risk.

Since lymphoma is a disease influenced by many factors from lifestyle to genetic predisposition; from exposure to environmental toxins to having common viruses, two important limitations arise that may undermine the strength of the conclusions from this study. First, the participants were not tested for the presence of lymphoma-associated viruses such as Epstein-Barr virus so we have to assume that both the virally suppressed and unsuppressed groups had somewhat equal frequency of these viruses. Second, there was no comparison group of participants without HIV, which limits many possible important interpretations.