Zambian patients on dolutegravir and recycled tenofovir regimens have high risk of TB even after switch

Dr Nyuma Mbewe at AIDS 2022. Photo©Steve Forrest/Workers’ Photos/IAS

A study conducted among people on regimens of dolutegravir and recycled tenofovir in Zambia shows tuberculosis remains a deadly threat in the months after switching treatment and is a risk factor for poor viral suppression. The study presented at the recent 24th International AIDS Conference (AIDS 2022) reaffirms the need for regular screening.

Recently, the NADIA, ARTIST and VISEND studies showed that the nucleoside reverse transcriptase inhibitors tenofovir and lamivudine can be safely reused (or ‘recycled’) in first and second-line regimens for patients with treatment failure. The shift goes against decades of conventional thinking that it was impossible to switch out a single antiretroviral drug within a regimen or reuse medicines in first and second-line treatment without risking the emergence of drug resistance. Many clinicians in southern Africa are now advocating that countries change national guidelines to allow for this practice.

Still, extremely rare cases of patients developing resistance to dolutegravir have been reported in those that switched to these regimens but had poor adherence.


immune reconstitution inflammatory syndrome (IRIS)

A collection of inflammatory disorders associated with paradoxical worsening (due to the ‘waking’ and improvement of the immune system) of pre-existing infectious processes following the initiation of antiretroviral therapy.


second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

active TB

Active disease caused by Mycobacterium tuberculosis, as evidenced by a confirmatory culture, or, in the absence of culture, suggestive clinical symptoms.

treatment failure

Inability of a medical therapy to achieve the desired results. 

Additionally, there are concerns that because dolutegravir works quickly to suppress HIV viral loads, newly initiated patients may be at an increased risk of developing TB-associated immune reconstitution inflammatory syndrome or TB-IRIS. In people who have TB-IRIS, the immune system goes into overdrive, attacking the bacteria that cause tuberculosis — whether that bacteria is dead or alive.

Studies in high TB burden countries have found that between 8 to 51% of patients coinfected with HIV and active TB developed TB-IRIS after starting antiretroviral treatment. The condition is in some cases deadly but can be treated. Still, it remains poorly understood. Additionally, there is a lack of research on TB-IRIS among dolutegravir users in countries with high rates of HIV and tuberculosis co-infection, Dr Nyuma Mbewe of Zambia’s University Teaching Hospital told the conference.

Study sought to characterise TB risk after changing HIV regimen

A sub-analysis of the VISEND study led by Mbewe sought to characterise the risk of TB and TB-IRIS among patients with a previous viral load over 1000 in the first year after switching to regimens containing dolutegravir with recycled tenofovir.

The study included 783 patients who had experienced treatment failure on a regimen of tenofovir disoproxil fumarate (TDF) / lamivudine or emtricitabine / efavirenz. The research then randomly assigned participants to one of four new regimens.

About 200 patients each were given regimens with recycled tenofovir and dolutegravir, namely TDF / lamivudine / dolutegravir or tenofovir alafenamide (TAF) / emtricitabine / dolutegravir.

The other half of participants were given standard second-line treatment: zidovudine and lamivudine with either ritonavir-boosted lopinavir or boosted atazanavir.

The study also offered daily isoniazid preventive tuberculosis therapy (IPT) to all participants. IPT has been shown to reduce the risk of developing active TB in people living with HIV by as much as 64% when taken for at least six months, according to 2020 World Health Organization (WHO) guidelines. Although IPT can be taken for six or nine months, WHO guidelines recommend 36 months of treatment for people with HIV in settings with a high burden of TB.

Additionally, patients who were not virally suppressed after six months or who developed TB also received monthly enhanced adherence support.

Developing TB is a risk factor for poor viral suppression

Ultimately, the research found that 4% of patients developed TB, largely within the first three months after switching treatment – before participants would have been fully protected by IPT. The TB incidence rate seen in the study is about ten times higher than Zambia’s national TB incidence of 455 cases per 100,000 population, Mbewe told

Among those who developed tuberculosis, about 13% died of it — a significant death rate, she explained. Tuberculosis cases were confirmed by urine-based testing and x-rays.

Ultimately, 14 (3.3%) of 419 patients receiving dolutegravir-based therapy developed tuberculosis while 18 (4.9%) of 364 patients receiving older second-line therapy were diagnosed with tuberculosis.

Developing active tuberculosis was a risk factor for poor viral suppression, the study showed. Seventy nine per cent (11) of patients with tuberculosis who were on dolutegravir-based treatment were virally suppressed by the end of the year-long study as compared to 89% (16) of those on older treatment regimens who developed tuberculosis.

Overall, 94% of the 419 patients in the study who were on dolutegravir-based regimens were virally suppressed after one year.

“If TB is recognised early enough and the correct interventions are put in place, this is actually an opportunity to ensure our desired virological outcomes in patients,” Mbewe explained.

Drug-resistance data from the study has been submitted to a peer-reviewed journal and is forthcoming, she said.

Anecdotally, two instances of TB-IRIS were reported after patients became severely ill and had to be hosptialised. However, Mbewe explained that the study was unable to confirm other suspected cases in part because CD4 count testing was done every six months according to national guidelines. To detect TB-IRIS, she said, the study would have had to perform monthly CD4 count monitoring.

Findings reaffirm the need for regular TB screening in patients switching regimens

Mbewe says the study’s incidence and mortality rates from tuberculosis are a reminder that clinicians should continue to screen patients newly initiated on dolutegravir and recycled tenofovir regimens for the airborne disease — particularly in the first few months of treatment.

"It's so important to look for the occurrence of tuberculosis in patients on dolutegravir-based therapy especially when transitioning them to second line therapy with recycled [antiretrovirals],” she explained. “If not, this is a possibility for emergent dolutegravir resistance and —  while patients do have tuberculosis — there's a possibility of TB IRIS."


Mbewe N et al. Incident tuberculosis as a risk factor for viral non-suppression 48 weeks among patients switched to dolutegravir-based therapy with recycled nucleoside reverse transcriptase inhibitors in Lusaka, Zambia. 24th International AIDS Conference, Montreal, abstract OALBB0105, 2022

View the abstract on the conference website.