High Time to Start Human Immunodeficiency Virus Type 1–Infected Patients on Integrase Inhibitors in Sub-Saharan Africa

Steegen and colleagues reported results from a national survey in South Africa aimed at determining the prevalence of antiretroviral drug resistance in patients who are not responding to protease inhibitor–based treatment [1]. They report at least 1 major mutation in 16.4% of 350 participants with no high-level resistance to darunavir/ritonavir (DRV/r) and low high-level resistance (5.2%) to etravirine (ETR). The number of patients who need second-line therapy are expected to rise from around 300000 in 2013 to 2–4 million by 2030 [2]. The reduction in cost for first-line treatment in Africa has increased antiretroviral therapy (ART) rollout in many countries, with a “test and treat” strategy initiated in some countries such as Uganda. This will inevitably increase the number of people on ART, as well as the frequency of human immunodeficiency virus (HIV) drug resistance. Transmitted drug resistance has been shown to increase as more people are put on ART [3], and this is associated with virological failure. These factors together result in rising drug resistance and, therefore, more first-line failures. Such patients will require second-line therapy, which may be 2.4 times more expensive than first-line therapy [2]. Lopinavir/ritonavir has been commonly used due to its high genetic barrier compared with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and its being able to be used in rifampicin-based tuberculosis treatment. However, because of toxicity and substantial cross-resistance with other protease inhibitors, it is no longer recommended [4]. Because atazanavir/ritonavir is available in a heat-stable, fixed- dose formulation and is less expensive than lopinavir/ritonavir [5], it is now commonly used as a second-line therapy.

Stegeen and colleagues highlighted the important observation of no high-level resistance to DRV/r and relatively low frequency resistance to ETR, though intermediate resistance was quite high (32.8%). This is encouraging as many patients failing on second-line therapy will eventually require third-line regimens. The recommended salvage therapy consists of raltegravir, DRV/r, and ETR. But the cost of salvage therapy is quite high. It may be 18 times and 7 times more expensive than first-line and second-line regimens, respectively [5]. Pretreatment drug resistance, which results in numerous drug switches [6], also leads to limited drug options. We have previously reported 18% drug-resistant mutations to ETR and rilpivirine in HIV subtype C–infected patients failing efavirenz- and nevirapine-based first-line therapy recruited in the Europe-Africa Research Network for Evaluation of Second line Therapy study. The striking observation in the study was high drug resistance of 40% to ETR and 51% to rilpivirine due to amino acid substitutions at Y181, H221, K101, and 138 in patients failing efavirenz [7].

Despite no NNRTI exposure at the time of HIV drug resistance testing for 347 participants in the Steegen et al study, 65% had ≥1 NNRTI mutation with K103N being the predominant one. Numerous studies have shown slow clearance of NNRTI-resistant variants in patients after exposure to efavirenz or nevirapine. Two-thirds of patients retain NNRTI mutations after many years on second-line therapy. Therefore, the success of salvage therapy will require the use of even higher genetic barrier drugs to mitigate the emergency of these resistant variants. It has been demonstrated that the majority of patients on salvage therapy can achieve viral suppression, but this comes at a cost of using more potent drugs, which are more expensive and not readily available. Indeed, there have been drug stockouts and patients going on drug holidays, resulting in viral rebound and treatment failure. Therefore, the challenge is sustainability of these patients on such medications.

The integrase strand transfer inhibitors (INSTIs), especially dolutegravir with a high genetic barrier, could be used as first-line regimens, as recommended by the World Health Organization [4]. Currently, no patient has developed resistant mutations against dolutegravir when used as first-line therapy [8]. It was superior to raltegravir when used in INSTI-naive patients [9]. Maximizing use of more potent drug options early in treatment before exposing the patient to limited and more expensive options of second and salvage therapy appears to be the most appropriate way of reducing HIV-1 drug resistance in low-income countries.

Note

Potential conflicts of interest.  Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

Author notes