Monitoring adherence helps protect HIV main drug’s gains

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For years, dolutegravir was hailed as Africa’s game-changer, the powerful HIV drug that helped millions suppress the virus with a single daily pill. Clinics across Uganda shifted to it. Patients stabilised. Deaths declined. It was, many believed, the backbone of a durable future in HIV care. Now, troubling signs are emerging.

Across parts of Africa, a small but worrying number of patients on dolutegravir are returning to clinics with rising viral loads, a red flag that treatment is failing. In some cases, the cause is missed doses. In others, the virus may be adapting, developing resistance to one of the continent’s most important medicines.

For countries like Uganda, where dolutegravir anchors first-line treatment for the majority of people living with HIV, the implications are stark: when this drug fails, options narrow quickly. A new African-led study is now confronting that threat head-on.

Launched across Kenya, Tanzania, Lesotho and Mozambique, the Ndovu Study is generating critical evidence on what happens when patients on dolutegravir-based treatment begin to fail therapy, either because they struggle to take it consistently or because the virus has developed resistance.

For Uganda, where DTG forms the backbone of first-line HIV treatment under national guidelines, the stakes are enormous. Health officials have long celebrated the drug’s potency and relatively low side-effect profile. But clinicians are increasingly worried about patients returning with rising viral loads, a signal that the virus is rebounding.

HIV treatment works by suppressing the virus in the blood. When taken consistently, antiretroviral drugs reduce viral load to very low levels, protecting the immune system and preventing transmission. But when adherence falters, the virus resurfaces. In some cases, it mutates and becomes resistant — rendering standard medicines ineffective.

Failure on dolutegravir is especially concerning. Treatment alternatives are limited and often more complex or expensive. Patients with uncontrolled virus risk severe immune damage, dangerously low CD4 counts and life-threatening infections such as tuberculosis and cryptococcal meningitis — conditions still all too familiar in Ugandan hospitals.

The Ndovu project is enrolling patients with high viral loads who are already on dolutegravir, signalling possible adherence problems or drug resistance. Researchers are following them closely, strengthening adherence support, conducting drug-resistance testing and identifying cases of advanced HIV disease earlier. The goal is to redefine how treatment failure is detected, managed and prevented — not just in participating countries, but globally.

“It is deeply concerning that some people are experiencing treatment failure due to lack of adherence to therapy and potentially developing resistance to dolutegravir, placing their lives at risk,” said Dr Loice Ombajo, Chief Investigator of the Ndovu Study and Co-Director at the Centre for Epidemiological Modelling and Analysis (CEMA) at the University of Nairobi.

“We urgently need evidence to guide how patients should be managed when they fail treatment and when drug resistance develops. Data from this study will help inform global guidelines on how to care for people living with HIV who do not respond to currently available treatment options.”

Globally, the numbers are sobering. The World Health Organisation estimates that in 2024, 40.8 million people were living with HIV, 1.3 million newly acquired the virus, and 630,000 died from HIV-related illnesses. Africa carries the heaviest burden.

Although Uganda is not formally a Ndovu study site, its HIV programme stands to benefit from the findings. The country has made remarkable gains in expanding access to DTG-based regimens. But like its neighbours, it faces persistent challenges around retention in care, adherence — especially among adolescents and mobile populations — and emerging resistance.

In late January, principal investigators from across the four participating countries met in Naivasha, Kenya, alongside ministries of health and implementing partners, to review progress and align priorities for the next phase. The study is sponsored by CEMA in collaboration with national institutions and funded by the Bill & Melinda Gates Foundation.

For clinicians in Kampala, Gulu or Mbarara, the implications are practical. Better evidence could mean clearer guidelines on when to switch regimens, stronger laboratory systems for resistance testing, and earlier interventions before patients deteriorate. For patients, it could mean something simpler: another chance.

Dr Joanita Kigozi, the deputy head of department, Health Systems Strengthening at Infectious Diseases Institute, weighs in.

“DTG [dolutegravir] is currently the backbone of first-line treatment for HIV. It is a very good drug with a high genetic barrier to resistance. The combination TDF/3TC/DTG, which most people start with, is a single pill, taken once a day and is convenient. If taken well, it is likely to lead a full life with good life expectancy.”

She opines that it is important that the drug is protected because “failure means you switch to more complex and more expensive regimens”.

“So, from a public health perspective, it is important that programs strengthen adherence systems for patients, ensure the drug is available so that people don't miss; monitoring like viral load testing and resistance testing for those with high viral load is done to pick resistance early, and manage treatment failure early.”

After decades of progress, Africa’s HIV response stands at a crossroads. The promise of dolutegravir remains powerful. But without sustained adherence, vigilant monitoring and smarter policy, that promise can falter.

Ndovu — named after the Swahili word for elephant — is designed to remember what the epidemic has already taught Africa: that science must move as quickly as the virus does, and that no patient should be left behind when treatment fails.