We asked four regional clinicians, researchers, and policy makers to share their reflections on whether integrase inhibitor drugs could be our solution to managing HIV drug resistance in the future.
(Clockwise, from top left) Drs. Thanyawee Puthanakit, Raph Hamers, Naoko Ishikawa, and Iskandar Azwa
Dr. Thanyawee Puthanakit is the Director of the Center of Excellence in Pediatric Infectious Diseases and Vaccines at Chulalongkorn University and a researcher at HIV-NAT, the Thai Red Cross AIDS Research Centre, both in Bangkok, Thailand. Dr. Puthanakit is a TREAT Asia Network pediatric investigator and has conducted several clinical research studies among children and adolescents with HIV drug resistance in Thailand.
In children and adolescents in Thailand, integrase standard transfer inhibitors (INSTIs—also called integrase inhibitors) were initially used as third-line salvage regimens in combination with the protease inhibitor darunavir for those with extensive HIV drug resistance. However, there are also other strategies to use INSTIs in first- or second-line regimens as a way to reduce the risk of developing HIV treatment failure.
Adolescents are in a vulnerable life stage where “forgiving”* regimens are needed to support them through drug adherence challenges to reduce their risk of developing drug resistance. Some patients stop HIV treatment in an effort to be more similar to their peers, or prioritize other aspects of their personal lives over their health.
In Asian settings, boosted protease inhibitors (including lopinavir and atazanavir with ritonavir) have been used as a second-line regimen, but they can be problematic in pediatric practice due to large pill size and gastrointestinal side effects. We have a cohort of adolescents unable to tolerate boosted protease inhibitors for second-line with CD4 counts under 100 cells/mm3. After a median of 16 weeks on an INSTI-based regimen using dolutegravir, more than half have viral loads of less than 200 copies/ml and 90% have viral loads under 1000 copies/ml. INSTIs have given the adolescents another chance for suppressive treatment and have empowered them to realize their ability to achieve viral suppression.
If we expect adolescents to have good adherence to their HIV treatment, it is only fair that we provide them with regimens that are feasible for them to adhere to, whether that be related to smaller pill sizes or even long-acting injectable medications.
INSTIs are the solution to HIV drug resistance in pediatrics. Besides their use after triple-class failure, they can be utilized strategically in first- and second-line regimens to enable lifelong treatment. With INSTIs, adolescents will be able to achieve high rates of viral suppression within two months of starting treatment, which will reduce both their risk of developing drug resistance and of onward HIV transmission. New data on dolutegravir at conception should be considered for sexually active female adolescents and emphasize the importance of integrating sexual and reproductive health services into HIV care.
We should do whatever we can to overcome significant access issues in the region and ensure that generic INSTIs become more available in Asia, as is being done already in Africa.
*Forgiving regimens include antiretrovirals that have higher barriers to emergent drug resistance despite occasional poor adherence.
Dr. Raph Hamers is a Senior Clinical Scientist and the Manager of the Universities of Indonesia and Oxford Clinical Research Laboratory at the Eijkman-Oxford Clinical Research Unit in Jakarta, Indonesia. He was part of the LAASER collaboration (Linking Africa and Asian Societies for an Enhanced Response to HIV/AIDS), helping to lead the PASER program in Africa (PharmAccess Studies to Evaluate Resistance), which partnered with TREAT Asia’s Studies to Evaluate Resistance (TASER) projects.
The global rise in HIV drug resistance to the core first-line antiretroviral drugs efavirenz and nevirapine (non-nucleoside reverse transcriptase inhibitors, or NNRTIs) has been forecasted to drive increases in mortality, HIV incidence, and programmatic costs, if no improvements are made to current standards of practice in many settings. In July 2017, WHO recommended the use of alternative, standard first-line ART in countries in which at least 1 in 10 patients have NNRTI resistance when they start ART, as well as in persons who report previous use of antiretroviral drugs, such as for peripartum prophylaxis (prevention of mother-to-child transmission, or PMTCT), or after defaulting ART.
Since September 2017, a new low-cost generic fixed-dose combination of tenofovir, lamivudine, and dolutegravir (TLD) has been offered to 92 low- and middle-income countries (LMIC) through the Medicines Patent Pool. Many clinicians and patients are excited about TLD because the combination provides important clinical benefits, including improved tolerability, higher effectiveness, a higher genetic barrier to resistance, and fewer drug interactions compared with other antiretroviral drugs. How to prioritize the TLD transition will depend on the country’s specific situation in terms of TLD pricing, levels of NNRTI resistance, and available laboratory capacity. No LMIC Asian countries have implemented TLD to date.
There are still some uncertainties to guide dolutegravir rollout in some important patient groups. Concomitant rifampicin use in tuberculosis co-infection may reduce dolutegravir blood levels, data on safety and effectiveness in young children and pregnant women are just beginning to accumulate, with recently released concerns regarding a potential safety issue related to neural tube defects in infants born to women who were taking DTG at the time of conception, and there are increased risks related to immune reconstitution inflammatory syndrome (IRIS) in patients who present with very low CD4 cell counts. TLD may also warrant more individualized laboratory monitoring to avoid (i) the risk of switching patients to “functional monotherapy” if they already have resistance to the dual nucleoside reverse transcriptase inhibitors (NRTI) backbone, and (ii) premature switches to second-line if resistance to dolutegravir is absent. While TLD offers unique opportunities to improve durability and effectiveness of ART across LMIC, it should not be regarded a silver bullet to curb resistance. TLD needs to be implemented in conjunction with improved quality of services and resistance monitoring frameworks.
(Left to right) Drs. Praphan Phanuphak and Iskandar Azwa at the 2014 TREAT Asia Network Annual Meeting in Siem Reap, Cambodia.
Dr. Iskandar Azwa is an infectious diseases physician at the University Malaya Medical Centre in Kuala Lumpur. He is a site principal investigator for the TREAT Asia HIV Observational Database, and participates in regional research on HIV drug resistance.
Routine HIV resistance testing is not currently recommended for patients starting HIV therapy in resource-limited settings in Asia. In 2011, the TASER-M Study1 from 8 TREAT Asia network sites reported a 6.5% prevalence of NNRTI resistance. With the scale-up of NNRTI-based first-line treatment regimens in the Asia-Pacific, it was inevitable that the prevalence of both pre-treatment and acquired drug resistance to NNRTIs would increase with time. Up to 90% of patients experiencing virologic failure on these regimens have evidence of NNRTI resistance. A systematic review of pre-treatment HIV drug resistance in low- and middle-income countries2 reported an annual increase in the odds of pre-treatment NNRTI resistance of 11% in Asia.
Part of the WHO initiative to address rising rates of NNRTI resistance is to recommend that countries with pre-treatment NNRTI resistance prevalence greater than 10% transition to a dolutegravir-based regimen. Dolutegravir is an integrase inhibitor, which is taken once daily, is highly tolerable, and has a high genetic barrier to resistance almost comparable to that of protease inhibitors. The ability to transition our treatment recommendations will largely depend on the affordability of dolutegravir and access to generic dolutegravir. Where this is not feasible, measures may be needed to support pre-treatment drug resistance testing to guide first-line ART regimen selection.
More recently, the DAWNING study3 showed superiority of a regimen with dolutegravir to ritonavir-boosted lopinavir as second-line treatment. While this indicates dolutegravir’s potential role in second-line regimens in resource-limited settings in Asia, dolutegravir rollout as first-line is unlikely to be the only solution to rising rates of resistance in the region. Other measures include strengthening individual country surveillance of HIV drug resistance, scaling up viral load testing to detect earlier virologic failure, monitoring treatment retention rates at both the clinic and population levels, and developing strategies to target and support those who are at highest risk of drug resistance—specifically, those who have disengaged from care.
1Sungkanuparph S, Phanuphak P et al ; TREAT Asia Studies to Evaluate Resistance-Monitoring Study (TASER-M). HIV-1 drug resistance mutations among antiretroviral-naive HIV-1-infected patients in Asia: results from the TREAT Asia Studies to Evaluate Resistance-Monitoring Study. Clin Infect Dis. 2011 Apr 15.
2Gupta RK. Bertagnolio S et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2018 March.
3Aboud M, Kaplan R, Lombaard J, et al. Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment: interim data from the DAWNING study. IAS 2017; Paris. Abstract TUAB0105LB.
Dr. Naoko Ishikawa is the Coordinator of the HIV, Hepatitis and Sexually Transmitted Infections Unit of the Division of Communicable Diseases of the WHO’s Regional Office for the Western Pacific (WPRO). Her team oversees implementation of the WHO’s global strategic plan to prevent HIV drug resistance in their region.
Treatment of HIV infection has evolved significantly. Safer and more efficacious antiretroviral drugs are available, and integrase inhibitors are becoming increasingly affordable for low- and middle-income countries. The 2016 WHO consolidated guidelines on the use of antiretrovirals for treating and preventing HIV infection included the integrase inhibitor dolutegravir as a new alternative option in first-line antiretroviral therapy (ART) regimens.1 A systematic review and meta-analysis showed that dolutegravir is comparatively more effective, better tolerated, and more protective against treatment discontinuation from adverse drug reactions.
A WHO HIV drug resistance report published in 2017 showed that rates of pre-treatment HIV drug resistance are increasing globally, especially for NNRTIs.2 In 2017, the WHO published new guidelines for a public health response to pre-treatment resistance, recommending that when the prevalence of resistance to NNRTIs, such as efavirenz or nevirapine, in populations initiating first-line therapy exceeds 10%, national programs should consider transitioning to an alternative regimen based on a new class of medicines such as integrase inhibitors.3
With its higher genetic barriers to drug resistance, better safety profile compared with efavirenz, and availability as fixed-dose combination at competitive cost, dolutegravir is one of the most promising options for future HIV treatment towards universal access and ending the AIDS epidemic by 2030. The WHO is supporting countries to adopt and transition to new antiretrovirals, in particular the introduction of dolutegravir. In the Western Pacific Region, Cambodia and Lao PDR are in the process of introducing dolutegravir as a preferred first-line regimen, and several other countries are to follow.
The WHO plans to update the recommendations for HIV treatment in July 2018 based on evidence from studies addressing safety and efficacy in specific groups, including pregnant women and patients co-infected with tuberculosis. For example, concerns have emerged around dolutegravir use at conception, which have led to a recent statement on potential safety issues, released on May 18th. The WHO will continue monitoring ongoing and future clinical studies on new drugs and will develop necessary normative and operational tools for countries to safely introduce and roll out new treatment regimens.
1Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection - Recommendations for a public health approach - Second edition 2016. Geneva: World Health Organization.
2HIV drug resistance report 2017. Geneva: World Health Organization.
3Guidelines on the public health response to pretreatment HIV drug resistance - July 2017. Geneva: World Health Organization.
WHO’s Global Action Plan on HIV Drug Resistance 2017-2021 – July 2017