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FLAIR and AMBITION-cm: Perspectives for Africa
The Long and the Short of It: LA Injectables, Short CM Treatment, and Implications for Africa

Released: September 17, 2021

Expiration: September 16, 2022

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The 11th International AIDS Society (IAS) Conference on HIV Science featured important advances in HIV therapeutics and management of infectious complications of HIV. Although many interesting studies were presented, I think the FLAIR and AMBITION-CM studies have specific relevance to Africa.

FLAIR
When considering new developments in HIV therapeutics, Week 124 results of the FLAIR study of treatment-naive people with HIV showed a viral success (HIV-1 RNA <50 copies/mL) rate of 80.2%. The participants in the study were randomized to cabotegravir (CAB)/rilpivirine (RPV) after achieving viral suppression on oral dolutegravir/abacavir/lamivudine. The safety findings in the population presented were similar to the results obtained at earlier time points.

Implications in Africa
One of the highlights of this presentation by Orkin and colleagues was the description of a case of virologic failure at Week 108. This participant was infected with subtype A6 HIV-1 and had a BMI of 27.4 kg/m2. Integrase and nonnucleoside reverse transcriptase resistance associated mutations emerged at the time of virologic failure. Viral suppression was achieved again in this patient with an oral regimen of efavirenz/tenofovir disoproxil fumarate/emtricitabine.

Although long-acting (LA) CAB/RPV has opened the door to a new paradigm for HIV treatment, the virologic failure case described at IAS is a reminder of the challenges of implementing this strategy in Africa. Of note, South Africa, which has predominantly subtype C, was the only African country where FLAIR was performed. Over time, it is expected that data will accumulate from parts of Africa where other subtypes and recombinant forms of the virus are dominant.

The Bigger Picture
Overall, I believe the selection of appropriate individuals for LA CAB/RPV maintenance will be more challenging in Africa than in other settings. First, there is limited availability of HIV-1 RNA monitoring and resistance testing. Second, the requirement for cold storage of RPV will limit settings where this new paradigm may be implemented. Third, the LA regimen does not contain a drug active against hepatitis B virus, making it less attractive when considering a public health approach in Africa. Finally, successful implementation of monthly administration will require creative adaptation of clinical workflows in already stretched clinics.

Overall, LA CAB/RPV has ushered in a new era in HIV therapeutics, but its relevance for Africa is likely to be muted in comparison to other settings around the world.

AMBITION-cm
In AMBITION-cm, Lawrence and colleagues showed that all-cause mortality from cryptococcal meningitis (CM) was noninferior among participants treated with a single dose of liposomal amphotericin B (combined with 14 days of flucytosine and fluconazole) compared with those who received the standard-of-care regimen of 7 days of intravenous (IV) amphotericin B (also combined with 7 days flucytosine and fluconazole).

Implications in Africa
The results of AMBITION-cm have the potential to immediately affect the management of CM, a notorious AIDS-defining illness, since delivery of the IV component of cryptococcal therapy in 1 day vs 7 days can significantly affect access to and feasibility of therapy. Wide uptake of the strategy will depend on broader availability of flucytosine.

The intervention from the AMBITION-cm study has the potential to accelerate or simplify effective treatment. Patients who are treated with liposomal amphotericin B would have a shorter hospital stay and would not have to endure the monitoring complications that occur with IV treatment. When a patient requires the conventional IV treatment of amphotericin B every day for 7 days, additional costs are added every time the medication is administered. Due to limited healthcare resources and infrastructure, there is a major barrier in cost-effective care in Africa. Of note, the liposomal amphotericin B regimen is an innovative way to optimize resources while providing safe and effective drug therapy. In addition, excessive IV administration increases the risk of introducing new infections. Given that the liposomal amphotericin B regimen reduces IV therapy, the overall treatment profile is significantly improved.

Clinical Tips to Reduce CM Complications
CM has a subtle presentation that can be easily missed. The key is to have a high index of suspicion for CM in our patients with HIV so that we can recognize and treat it early. If a patient has CM that is not recognized before beginning antiretroviral therapy, they can experience the inflammatory response of immune reconstitution inflammatory syndrome, which leads to increased intracranial pressure that can hurt the patient long term. Accordingly, healthcare professionals must assess patients for subtle signs and symptoms of CM, especially in new patients. In addition, it is important to encourage our patients to adhere to HIV treatment, so that they do not have a CD4+ cell decline that can then lead to a CM opportunistic infection.

Monitoring the clinical care of patients with CM is really complicated because of the need to keep the intracranial pressure low. Thus, many patients require serial lumbar puncture, a procedure that is not readily available in many places where HIV/AIDS is treated in sub-Saharan Africa. In summary, an early suspicion and diagnosis of CM is important in patients with HIV before they develop the kind of immune compromise that can put them at risk.

Your Thoughts?
Do you think that LA CAB/RPV for HIV treatment and high-dose liposomal amphotericin B for HIV-associated CM will become part of the treatment landscape in your patient population? Join the discussion by posting a comment sharing your experiences.

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