Focus on HIV-2 Infection: A Clinician Roundtable

As part of the UNAIDS/WHO 90-90-90 campaign to end AIDS, goals to be reached by 2020 include awareness of HIV status in 90% of affected individuals, sustained antiretroviral therapy (ART) in 90% of people diagnosed with HIV and viral suppression in 90% of people receiving ART.¹ While these targets are focused on HIV-1, they “also implicitly include HIV-2, which is endemic in West Africa and has achieved limited spread to other countries outside the region,” wrote the investigators in a review published in in the Lancet HIV.² “To help meet the goal of ending the AIDS pandemic by 2030, new attention must be given to HIV-2, which poses distinct challenges for prevention, diagnosis, and treatment.”

One key challenge is the dearth of evidence to guide ART for HIV-2 infection. However, recently completed and ongoing trials of first-line integrase inhibitor-based ART for HIV-2 may begin to fill this knowledge gap. An open-label 48-week trial examined the effects of raltegravir plus emtricitabine and tenofovir disoproxil fumarate in 30 adults with HIV-2 infection who were antiretroviral naïve.³ The results demonstrated that 40% of patients reached a composite end point of success (survival at 48 weeks with none of the following: CD4 gain from baseline <100 cells/μL, confirmed plasma viral load ≥40 copies/mL from week 24, raltegravir permanent discontinuation, and incident B or C event).

In another 48-week trial with the same sample size and type, there were no deaths and no new AIDS-associated clinical events associated with a single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate.⁴ By the end of the study period, CD4 counts had increased by a median of 161 cells/µL (27 to 547) from the median baseline count of 408 cells/µL (range 34 to 747). Baseline HIV-2 viral loads of <50 copies per mL of plasma were found in 25 patients. A modified intent-to-treat analysis showed viral suppression in 28 of 30 participants (93.3%; 95% CI, 77.9-99.2) at 48 weeks.

There are 2 trials currently investigating the effects of a protease-inhibitor-based regimen compared with an integrase-inhibitor-based regimen and the effects of dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), in this population.^5,6 Results of these trials should help inform the development of guidelines regarding first-line therapy for HIV-2.

Infectious Disease Advisor interviewed the following experts to discuss the challenges and clinical implications pertaining to HIV-2: review co-investigator Geoffrey S. Gottlieb, MD, PhD, professor of medicine in the division of allergy and infectious diseases, adjunct professor of global health and medical director of infectious diseases for the employee health clinic at the University of Washington in Seattle, and Helen C. Koenig, MD, MPH, associate professor of medicine in the division of infectious diseases at the University of Pennsylvania in Philadelphia, and medical director of the MacGregor Infectious Diseases Clinic at the Perelman Center for Advanced Medicine.

Infectious Disease Advisor: Why is HIV-2 infection often neglected in the efforts to end the AIDS epidemic?

Dr Gottlieb: This is likely due to a combination of factors including that HIV-2 is mostly isolated to West Africa, infects fewer people than HIV-1, is less pathogenic than HIV-1, and the fact that overall awareness about HIV-2 is lacking.

Dr Koenig: HIV-2 is much less common than HIV-1 and thus often flies under the radar. In clinical practice in the United States, we tend to think of it only when patients are from West Africa and/or in patients whose CD4 counts continue to decline despite an undetectable HIV-1 viral load on a regimen that may not be effective against HIV-2. Only then do we sometimes think to go back and ask whether that patient has had partners from West Africa or has traveled to West Africa themselves.

On a public health and policy level, HIV-2 is “lumped in” with HIV-1 as they are very similar in many ways and share many common treatment regimens. This practice is furthered by the fact that HIV-2 is not seen as a more urgent or acute problem than HIV-1 and requiring separate consideration, as the clinical course is typically much slower in patients with HIV-2 or patients co-infected with HIV-1/HIV-2 compared with patients who are HIV-1 mono-infected.

Infectious Disease Advisor: What are some of unique challenges regarding the diagnosis and treatment of HIV-2 compared to HIV-1?

Dr Gottlieb: To diagnose HIV-2, the clinician first has to think about whether the patient is at risk for HIV-2. Second, appropriate HIV-2-specific testing must be performed. Fortunately, in the United States the Centers for Disease Control and Prevention (CDC) HIV testing guidelines specify differential testing for HIV-1 and HIV-2.

Regarding ART for HIV-2, many of US Food and Drug Adminstration (FDA)-approved antiretroviral drugs used for HIV-1 are not effective against HIV-2. Monitoring ART in a patient infected with HIV-2 can be challenging as there is limited access to HIV-2 viral load testing in many locales, and drug resistance testing in not widely available for individuals with virologic failure.

Dr Koenig: The diagnosis of HIV-2 always confuses me, which is perhaps part of the problem. First of all, in the current fourth generation test used throughout the United States, HIV-1 and HIV-2 are both detectable and can be distinguished from each other. However, not all previous antibody screening tests routinely screened for HIV-2. Second, a separate test must be ordered for HIV-2 viral load testing, and this testing is not offered in many places outside of specialized, often academic, centers.

Third, resistance testing is not commercially available for HIV-2, even in academic centers. Finally, treatment of HIV-2 differs slightly from HIV-1, although as we migrate to integrase strand transfer inhibitor (INSTI)-based regimens and away from non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens in the developed world, these differences are becoming minimal. However, in patients in the developing world, many of whom are still being treated with NNRTI-based regimens, we may be under-treating a fair number of individuals.

Infectious Disease Advisor: What are additional takeaways for clinicians?

Dr Gottlieb: Clinicians should be aware of the possible presence of HIV-2 infection in their patients coming from endemic areas, especially West Africa. Consultation with an HIV-2 expert is warranted, especially in patients who do not respond to ART.

Dr Koenig: The biggest takeaway is when to think of HIV-2 in someone already on HIV-1 treatment, as in theory all newly diagnosed patients are being screened for HIV-1 and HIV-2. This should be considered in patients whose CD4 counts continue to fall despite being on adequate ART for HIV-1 with an undetectable viral load, and patients who are from West Africa or have had sex with (or exchanged needles with) partners from West Africa.

Infectious Disease Advisor: What should be the focus of additional studies regarding HIV-2?

Dr Gottlieb: Areas of research that require attention include well-controlled clinical trials to determine the best first- and second-line ART regimens, research on how to manage patients with a multidrug resistant-virus, and the development of inexpensive point of care (POC) HIV-2 viral load assays. Ultimately, we need an HIV-2 vaccine.

Dr Koenig: Future studies should focus on resistance testing for HIV-2, how HIV-1 and HIV-2 affect each other in co-infected patients, and guidelines for first-line and second-line therapy in patients infected with HIV-2.

References

1. United Nations AIDS (UNAIDS). 90-90-90: an ambitious treatment target to help end the AIDS epidemic. 2014. www.unaids.org/en/resources/909090 Accessed August 27, 2018.
2. Gottlieb GS, Raugi DN, Smith RA. 90-90-90 for HIV-2? Ending the HIV-2 epidemic by enhancing care and clinical management of patients infected with HIV-2. Lancet HIV. 2018; 5:e390-e399.
3. Matheron S, Descamps D, Gallien S, et al. First line raltegravir/ emtricitabine/tenofovir combination in HIV-2 infection: phase 2 non-comparative trial (ANRS 159 HIV-2) [published online March 24, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy245
4. Ba S, Raugi DN, Smith RA, et al. A trial of a single tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for the initial treatment of HIV-2 infection in a resource-limited setting: 48 week results from Senegal, west Africa [published online April 17, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy324
5. National Institute of Health (NIH). ClinicalTrials.gov. Dolutegravir plus 2 NRTIs, in treatment-naïve HIV-2 infected subjects [NCT03224338]. https://clinicaltrials.gov/ct2/show/NCT03224338 Accessed August 27, 2018.
6. National Institute of Health (NIH). ClinicalTrials.gov. First-line treatment for HIV-2 (FIT-2) [NCT02150993]. https://clinicaltrials.gov/ct2/show/NCT02150993 Accessed August 27, 2018.