Patient Input Information

The following is a summary of key information provided by one patient group that responded to the CDR call for patient input:

• Many people living with HIV experience negative mental health outcomes, either as side effects from treatment, or from facing stigma, discrimination, and related stress. Fatigue is common, both before and after treatment is initiated, making it difficult to maintain diet and exercise routines, and may impact an individual’s ability to work.
• The majority of people with HIV can live long lives by achieving an undetectable viral load (viral suppression) and manage their HIV as a chronic condition. However, adherence to HIV treatment is essential and non-adherence can lead to drug class resistance, requiring the adoption of a new regimen selected from the remaining treatment options. Treatment regimens may change often for people with HIV; hence, there needs to be a variety of HIV treatments available and accessible.

Clinical Trials

Three RCTs and one non-comparative open-label study were included in the CDR systematic review, including two in treatment-naive patients and two in treatment-experienced patients.

• Treatment-naive patients: SPRING-2 and SINGLE were phase 3, double-blind, non-inferiority RCTs conducted in antiretroviral drug naive patients. Participants in SPRING-2 were randomized to either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each in combination with either abacavir/lamivudine or tenofovir/emtricitabine once daily. Participants in SINGLE were randomized to either dolutegravir 50 mg once daily in combination with abacavir/lamivudine once daily or to efavirenz/tenofovir/emtricitabine once daily.
• Treatment-experienced patients: SAILING was a phase 3 double-blind, double dummy, active-controlled, multi-centre, parallel group, non-inferiority RCT conducted in patients resistant to ≥ 2 antiretroviral drug classes but INSTI naive. Patients were randomized to either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, both in combination with optimized background therapy (OBT) selected by the investigator. VIKING-3 was a non-comparative, open-label study in HIV patients with prior extensive exposure to antiretroviral drugs and who harboured virus with phenotypic and/or genotypic evidence of INSTI resistance. To be eligible for VIKING-3, patients had to have plasma HIV ribonucleic acid (RNA) ≥ 500 copies/mL and demonstrated resistance to raltegravir and/or elvitegravir, and to drugs in two or more other classes of antiretroviral drugs.

Outcomes

Outcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed the following:

• Virologic success — the proportion of patients with plasma HIV RNA (viral load) < 50 copies/mL through week 48 using the Food and Drug Administration (FDA)-defined snapshot analysis. In this algorithm, patients whose last available HIV RNA value in the week 48 analysis window (i.e., from week 42 through week 54) was < 50 copies/mL were considered as having had a response; patients whose HIV RNA level was ≥ 50 copies/mL in the analysis window, or who did not have available data in the analysis window, were considered as not having had a response.
• Virologic failure — the proportion of patients with plasma HIV RNA ≥ 50 copies/mL.
• EQ-5D — a generic, non-disease-specific; preference-based utility instrument that includes a descriptive system used to rate five dimensions of health; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• HIV-associated conditions/disease progression (morbidity) — recorded and assessed according to the 1993 CDC Revised Classification System for HIV Infections in Adults.
• Changes from baseline in CD4+ counts.
• INSTI resistance — the proportion of patients with detectable virus that has genotypic or phenotypic evidence of INSTI resistance by week 48.
• Serious adverse events, total adverse events, and withdrawals due to adverse events.

The primary efficacy end point was the proportion of patients with HIV RNA < 50 copies/mL at week 48 for both the SPRING-2, SINGLE, and SAILING studies, and at week 24 for the VIKING-3 study.

Efficacy

Harms (Safety and Tolerability)

• The proportion of patients with at least one adverse event was reported as follows:

  • SPRING-2: 82% with dolutegravir and 83% with raltegravir at week 48 and 85% in both groups at week 96.
  • SINGLE: 89% with dolutegravir + abacavir/lamivudine and 92% with efavirenz/tenofovir/emtricitabine at week 48 and 91% with dolutegravir and 94% with efavirenz/tenofovir/emtricitabine at week 96.
  • SAILING: 78% with dolutegravir and 79% with raltegravir at week 48.
  • VIKING-3: 91% with dolutegravir at week 48.
• The proportion of patients who reported at least one serious adverse event was reported as follows:

  • SPRING-2: 7% with dolutegravir and 8% with raltegravir at week 48 and 10% with dolutegravir and 12% with raltegravir at week 96.
  • SINGLE: 9% with dolutegravir + abacavir/lamivudine and 8% with efavirenz/tenofovir/emtricitabine at week 48 and 11% with dolutegravir and 12% with efavirenz/tenofovir/emtricitabine at week 96.
  • SAILING: 9% with dolutegravir and 12% with raltegravir at week 48.
  • VIKING-3: 21% with dolutegravir at week 48.
• The proportion of patients who withdrew as a result of adverse events was reported as follows:

  • SPRING-2: 2% with dolutegravir and 2% with raltegravir at week 48 and week 96.
  • SINGLE: 2% with dolutegravir + abacavir/lamivudine and 10% with efavirenz/tenofovir/emtricitabine at week 48 and 3% with dolutegravir and 12% with efavirenz/tenofovir/emtricitabine at week 96.
  • SAILING: 2% with dolutegravir and 4% with raltegravir at week 48.
  • VIKING-3: 4% with dolutegravir at week 48.

Cost and Cost-Effectiveness

The manufacturer submitted a cost-utility analysis in both treatment-naive and treatment-experienced (integrase inhibitor naive) patients, over a lifetime time horizon from the Canadian public-payer perspective. A micro-simulation approach was used in the economic model that allowed individual histories of accumulating events to influence the probability of disease progression, including factors such as CD4+ cell count, viral load, opportunistic infection prophylaxis status, age, gender and Framingham risk score. Simulated patients transitioned through mutually exclusive health states, defined in terms of HIV with or without opportunistic infections, combined with cardiovascular disease health state. As patients passed through the model, they experienced the natural progression of HIV infection. The clinical outcomes included: HIV RNA < 50 copies/mL at week 48, viral suppression rate, monthly CD4+ cell count, and monthly rate of viral rebound (late failure rate).

In the treatment-naive analysis, dolutegravir was compared with the following first-line regimens: raltegravir + 2 nucleoside reverse transcriptase inhibitors (NRTIs), efavirenz/tenofovir/emtricitabine (Atripla), darunavir booster with ritonavir + 2 NRTIs, atazanavir boosted with ritonavir + 2 NRTIs, cobicistat/elvitegravir/emtricitabine/tenofovir (Stribild), emtricitabine/rilpivirine/tenofovir (Complera), and lopinavir boosted with ritonavir (LPV/r) + 2 NRTIs. Comparative clinical efficacy and safety were derived from clinical trials (dolutegravir versus Atripla [SINGLE]; dolutegravir versus raltegravir [SPRING-2]; and dolutegravir versus darunavir booster with ritonavir [FLAMINGO and STARTMRK]) and a network meta-analysis for other comparators.

In the treatment-experienced (but integrase inhibitor naive) analysis, dolutegravir was compared with raltegravir, and with OBT. Efficacy data were obtained from SAILING. A regimen of darunavir booster with ritonavir + tenofovir was assumed to be OBT based on the SAILING baseline population.

The manufacturer reported, for treatment-naive patients, dolutegravir was the dominant strategy (i.e., less costly and more effective) when compared with raltegravir + 2 NRTIs, Atripla, darunavir booster with ritonavir + 2 NRTIs and other indirect comparators (Complera, Stribild, atazanavir boosted with ritonavir + 2 NRTIs, and LPV/r + 2 NRTIs). In patients who are treatment-experienced (integrase naive), the manufacturer reported dolutegravir being the dominant strategy when compared with raltegravir, each in combination with OBT.

CDR noted the following limitations with the manufacturer’s model; however, dolutegravir remained cost saving compared with most of the comparators:

• While surrogate outcomes are used in the economic model and linked to clinical outcomes, these surrogates are well-accepted markers of future clinical events, and are used by prescribers to influence treatment decisions.
• The cost of antiretroviral therapy is the key driver of costs (comprising ~87% of total costs). Antiretroviral therapy costs are lower for dolutegravir, driven by either lower drug acquisition costs of dolutegravir (in some but not all comparators), as well as a lower likelihood of treatment failure/resistance (associated with use of second through sixth-line therapies, which are more costly).
• The recommended daily dose of dolutegravir in patients who harbour the virus resistant to other integrase inhibitors is 50 mg twice daily ($37.00 per day). No economic information was provided for this patient population.

The economic attractiveness of dolutegravir is driven by the submitted price, at the recommended daily dose of 50 mg daily, dolutegravir ($18.50 per day) is less costly than raltegravir ($27.00 per day; 400 mg twice daily).