The clinical trials for Dovato (a combination of dolutegravir and 3TC) for the initial treatment of HIV or for a change to a simpler regimen have found this dual-drug therapy as effective as standard triple-drug therapy.

Dovato has been approved by regulatory authorities in North America and the European Union for use as HIV therapy. Since 1996, treatment guidelines in North America have only recommended regimens containing three (or, in some cases, four) drugs for HIV treatment. In thecontext of initial HIV treatment, the use of Dovato is unusual and perhaps revolutionary. Note that Dovato’s use comes with caveats that we will mention later.

Guidelines

When treating people with HIV, physicians and nurses rely on the largest and most comprehensive HIV treatment guidelines produced under the aegis of the U.S. Department of Health and Human Services (DHHS). People in the field of HIV treatment commonly call this document the DHHS guidelines. These guidelines will be updated sometime in the autumn of 2019 and will list the place of Dovato in HIV treatment—indicating whether or not it is a preferred regimen for the initial treatment of HIV infection.

Starting treatment, past experiments

Other dual regimens that have been studied in the past—used either for the initiation of HIV treatment (ART) or for reducing the number of drugs (simplification)—have not produced high and relatively fast rates of virological suppression as dolutegravir + 3TC did. Or, if they did, such suppression did not last and such studies were relatively small compared to Gemini. Some early studies that attempted to use a reduced number of drugs for initial ART or after achievement of viral suppression with a more complex regimen included some of the following drugs:

• indinavir (Crixivan)
• ritonavir + lopinavir (in Kaletra)
• ritonavir + atazanavir; atazanavir + 3TC
• ritonavir + darunavir

What is different with this regimen is that Dovato contains dolutegravir, an integrase inhibitor with powerful anti-HIV activity. Yet, despite the very good results seen in clinical trials of dolutegravir + 3TC, doctors and their patients have to sometimes deal with more than two decades of received wisdom from clinical trials in which dual regimens were not successful. It may not be easy to break through this psychological barrier, at least initially.

The importance of the CD4+ cell count

Gemini contained a relatively small proportion of  people with a CD4+ count of 200 or less cells. Such people usually have issues affecting absorption (intestinal inflammation, diarrhea) because of underlying HIV-related injury to the intestines and/or other infections and usually require three anti-HIV drugs. Although Dovato performed well in this sub-group of participants, some doctors may wish to see more data from clinical trials in people with less than 200 CD4+ cells/mm³ before prescribing it in this population.

Viral load at baseline

In Gemini, the proportions of participants who entered the study with a viral load greater than 100,000 copies/mL and who subsequently achieved and maintained a suppressed viral load at week 48 were distributed as follows:

• dolutegravir dual therapy – 92% (129 of 140 people)
• dolutegravir triple therapy – 90% (135 of 153 people)

By week 96, the proportions of people who entered the study with a high viral load and who still maintained a suppressed viral load were distributed as follows:

• dolutegravir dual therapy – 84% maintained an undetectable viral load
• dolutegravir triple therapy – 86% maintained an undetectable viral load

Analyses of clinical trials of dolutegravir + 3TC (Dovato)—such as Gemini, done by Dovato manufacturer ViiV Healthcare, and a smaller study by the American AIDS Clinical Trials Group (ACTG)—have shown that people who initiate treatment with dolutegravir + 3TC seem to do well as long as their initial viral load is not greater than 500,000 copies/mL. Whether this gives doctors the confidence to initiate dolutegravir dual treatment in patients with viral loads that are high (less than but close to 500,000 copies/mL) remains to be seen.

Good adherence is critical for long-term success

For some people, taking ART as one pill a day for many years is not a problem; it is easily integrated into their lives. For other people, perhaps those who have chaotic lives and have difficulty taking medication because of struggles with other issues, it is not clear if dolutegravir dual therapy is the best option. People who have difficulty with adherence are not usually enrolled in large pivotal studies of ART.

If resistance to dolutegravir + 3TC develops because of poor adherence, the consequences could be serious, particularly for people who are heavily treatment experienced. HIV that is resistant to dolutegravir and 3TC will probably also be resistant to other integrase inhibitors such as bictegravir (in Biktarvy), elvitegravir (in Genvoya), raltegravir and the experimental integrase inhibitor cabotegravir. HIV that is resistant to one drug in a class can become resistant to other members of that class—this is called cross-resistance.

If a person is resistant to 3TC, they are also likely resistant to FTC, which is in many regimens. Thus, people who have resistance to dolutegravir + 3TC will have limited treatment options and their doctors will have to cobble together regimens using older, less tolerable drugs, likely with twice-daily schedules.

For people with chaotic lives or who have difficulty taking a pill on a daily basis, long-acting ART, which is likely to be approved in high-income countries by mid-2020, might be a useful option. However, people with resistance to integrase inhibitors and nucleoside analogues (3TC, FTC and so on) will likely not be able to use the first generation of long-acting treatment due to cross-resistance.

Pre-existing resistance

ViiV Healthcare recommends that dolutegravir + 3TC not be used by people who have HIV that is resistant to these medicines.

Co-infection with hepatitis B virus (HBV)

HBV co-infection occurs among some people with HIV. Having 3TC as the only drug in a regimen with anti-HBV activity is likely not an optimal approach to treatment for co-infected people. A regimen containing a combination of drugs that are active against both HIV and HBV—such as TDF + FTC or TAF (tenofovir alafenamide, the safer form of tenofovir) + FTC—is likely better at suppressing HBV and keeping it suppressed.

Does U=U apply to dolutegravir dual regimens?

Standard triple treatment usually consists of two nucleoside analogues anchored by a powerful drug, such as the following:

• an integrase inhibitor
• a boosted protease inhibitor (for example darunavir + a small dose of ritonavir)
• a non-nuke (such as efavirenz or rilpivirine)

These standard regimens have been used in well-designed clinical trials to assess the potential for the sexual transmission of HIV. In these clinical trials, once participants achieved a suppressed viral load and maintained the suppressed viral load by continuing to take ART exactly as directed, scientists found that HIV was not spread to their sexual partners. This finding led to the expression “undetectable equals untransmittable”—meaning that people who have undetectable HIV in the blood do not spread HIV to their sexual partners. This idea has been popularized as “U=U.” However, what about dolutegravir dual regimens? Can they support U=U and also suppress HIV in the blood and genital fluids?

Scientists in the U.S. sought to explore this issue by assessing data from a sub-group of people in clinical trials of dolutegravir + 3TC vs. standard triple therapy. The scientists focused on two groups of people as follows:

• Group 1: 38 people—18 who switched to dolutegravir + 3TC from a standard triple-drug regimen and 20 who remained on triple-drug therapy
• Group 2: 13 people whose initial ART was dolutegravir + 3TC

Among the 51 people were 45 men and six women. Researchers analysed a total of 76 semen samples collected at different points in time over 48 weeks. They also collected 12 swabs of vaginal fluid over the same period.

Results

The scientists found that three men and no women had detectable (more than 40 copies/mL) viral loads. The cases of these three men were as follows:

• The first case was one of 20 men taking triple-drug therapy (rilpivirine + TDF + FTC), with a viral load in his blood of 179 copies and a semen HIV viral load of 42 copies/mL, both at week 48. This person had missed doses of his medicine in the past two weeks.
• In the second case, a man had been taking dolutegravir + 3TC with very low viral loads in his blood—less than 20 copies/mL at week 36 and 31 copies/mL at week 48. The viral load in his semen at week 36 was 488 copies/mL and 79 copies/mL at week 48. He did not miss any doses of ART (it is not clear how adherence was assessed in this sub-study).
• In the third case, another man was taking dolutegravir + 3TC and routinely had a suppressed viral load (less than 40 copies/mL). At week 24 he had a viral load in his semen of 48 copies/mL. His adherence was good.

The scientists did not detect any chlamydia or gonorrhoea. Sexually transmitted infections (STIs) in the genital tract could cause localized inflammation and increase HIV replication there. However, larger studies have found that even HIV-positive people with STIs who have a suppressed viral load in their blood from ART do not spread HIV to sexual partners.

As viral loads were generally low in both blood and semen, it was difficult to analyse HIV for the presence of virus that had developed the ability to resist ART. In the case of one man whose semen viral load was 488 copies (case two), technicians did not find any drug-resistant HIV.

Note that from time to time, even on standard triple therapy, it is possible that a very small proportion of people can occasionally have low but detectable levels of HIV in their genital fluids even when the amount of virus in their blood is suppressed. These low levels of HIV in the genital fluid are not sufficient to cause infection in a partner as long as the person with HIV continues to take ART exactly as prescribed and directed and their viral load in the blood is suppressed.

Putting it all together

The U.S. scientists reviewed their results and made the following statement:

“In our pilot study of 51 adults living with HIV, the frequency of genital HIV shedding while virologically suppressed in the blood was similar between those who were on standard 3-drug ART and those were who on dolutegravir + 3TC as initial or maintenance therapy. The frequency of genital [HIV] shedding fell within the lower end of the range reported for 3-drug regimens in other studies (2% to 20%)…. Taken together, these results suggest that dolutegravir + 3TC is effective in controlling genital HIV shedding, which accounts for most HIV transmission.”

Furthermore, the U.S. scientists also stated:

“In conclusion, in this small pilot study, we did not detect concerning signals about the efficacy of the 2-drug regimen of dolutegravir + 3TC in controlling genital HIV RNA shedding, hence prevention of viral transmission when HIV RNA is undetectable in blood plasma. These preliminary results suggest that dolutegravir + 3TC likely confers similar transmission prevention benefits as triple therapy.”

HIV and the brain

HIV-infected cells can enter the brain and spinal cord—the central nervous system (CNS). Once in those locations, infected cells can release viral proteins that affect brain cells and their ability to function. Dolutegravir and 3TC penetrate the CNS, which bodes well for maintaining brain health among people with HIV. However, when doctors are dealing with suspected or confirmed cases of HIV-related brain injury, more complex regimens are likely required and they are extremely unlikely to prescribe only a combination of dolutegravir and 3TC.

The long-term effects of HIV and ART

ART helps to restore the immune system to the point where the risk of AIDS-related complications (serious infections and certain cancers) is virtually zero among the vast majority of ART users whose viral load is suppressed and who have a robust increase in CD4+ cell counts.

Yet, despite excellent adherence and suppressed viral loads over the long term, scientists have found that subtle immunological defects persist. Small amounts of HIV are found in samples from deep within the body, in some lymph nodes and organs of the immune system such as the spleen, brain, and so on. Persistent HIV infection, even in ART users, is associated with higher-than-normal levels of inflammation and immune activation. It is possible that over the long term this inflammation and immune activation could degrade the immune system. What’s more, as people grow older, their immune system’s effectiveness gradually wanes. Taken together, these issues—the combination of an aging immune system and subtly impaired immunity—do not mean that AIDS will (re)appear. Rather, the accumulation of subtle immunological defects could increase the risk for cancer in some HIV-positive people.

Some scientists theorize that taking ART for decades could in some way contribute to a small degree of harm to susceptible tissues or parts of cells. However, this is a theory. Given the massive survival advantage conferred by ART (with many people having near-normal life expectancy), this benefit easily outweighs any theoretical disadvantage, particularly when modern drugs are used.

Some doctors may decide, for whatever reason(s), to decrease the amount of anti-HIV medication taken from three to two drugs in patients with the following profile:

• the absence of HIV with any resistance to treatment
• a history of very good adherence
• no hepatitis B virus co-infection

In such patients, Dovato (dolutegravir + 3TC) and Juluca (dolutegravir + rilpivirine) could be options to consider.

In high-income countries

Today in Canada and many high-income countries, regimens for first- and second-line use are highly effective and generally well tolerated. This situation is likely to continue for the foreseeable future. There will always be a small proportion of people who have issues with one or more drugs for the following reasons:

• genetics – this can make a person more susceptible to a hypersensitivity reaction to a new or old anti-HIV drug
• complex underlying conditions – some people have liver or kidney injury and so their doctor must devise a carefully tailored regimen to reduce the risk of toxicity to injured organs
• initiating ART when the immune system is severely weakened – people who do this are more susceptible to inflammatory syndromes and drug side effects until their immune system becomes stronger

However, for now, there is no evidence that recommended first-line regimens in 2019 cause a harmful and clinically significant degree of impact on the health and well-being of the vast majority of people with HIV who take them.

Aging

HIV-positive people will take multiple medicines over the course of their lives because they are living longer. Such additional medicines could include those to manage the following conditions:

• abnormal cholesterol levels
• anxiety or depression
• arthritis
• excessive formation of blood clots
• higher-than-normal blood pressure
• problems with sleep
• problems breathing
• substance dependency

In this context, if doctors have an opportunity to safely reduce the burden of medicines, then perhaps a simplified regimen such as Dovato (or Juluca) could be considered in carefully selected patients.

—Sean R. Hosein

REFERENCES:

1. Gianella S, Marconi VC, Berzins B, et al. Genital HIV-1 shedding with dolutegravir (DTG) plus lamivudine (3TC) dual therapy. Journal of Acquired Immune Deficiency Syndromes. 2018 Dec 15;79(5):e112-e114.
2. Nelson JAE, de Paris K, Ramirez C, et al. Female genital tract shedding of HIV-1 is rare in women with suppressed HIV-1 in plasma. AIDS. 2019; in press.
3. Pasquier C, Walschaerts M, Raymond S, et al. Patterns of residual HIV-1 RNA shedding in the seminal plasma of patients on effective antiretroviral therapy. Basic and Clinical Andrology. 2017 Sep 8;27:17.
4. Hocqueloux L, Gubavu C, Prazuck T, et al. Genital human immunodeficiency virus-1 RNA and DNA shedding in virologically suppressed individuals switching from triple- to dual- or monotherapy: Pooled results from 2 randomized, controlled trials. Clinical Infectious Diseases. 2019; in press.
5. Prazuck T, Chaillon A, Avettand-Fènoël V, et al. HIV-DNA in the genital tract of women on long-term effective therapy is associated to residual viremia and previous AIDS-defining illnesses. PLoS One. 2013 Aug 21;8(8):e69686.
6. Krentz HB, John Gill M. Long-term HIV/AIDS survivors: Patients living with HIV infection retained in care for over 20 years. What have we learned? International Journal of STD and AIDS. 2018 Nov;29(11):1098-1105.
7. Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019 Jun 15;393(10189):2428-2438.
8. Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA 2016; 316: 171–81.
9. Heath JJ, Fudge NJ, Gallant ME, et al. Proximity of cytomegalovirus-specific CD8+ T cells to replicative senescence in human immunodeficiency virus-infected individuals. Frontiers in Immunology. 2018 Feb 15;9:201.
10. Ballegaard V, Brændstrup P, Pedersen KK, et al. Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV. Scientific Reports. 2018 Feb 28;8(1):3778.
11. Shive CL, Clagett B, McCausland MR, et al. Inflammation perturbs the IL-7 axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. Journal of Acquired Immune Deficiency Syndrome. 2016 Apr 15;71(5):483-92.
12. Appay V, Sauce D. Assessing immune aging in HIV-infected patients. Virulence. 2017 Jul 4;8(5):529-538.
13. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annual Review of Immunology. 2019 Apr 26;37:457-495.
14. Buggert M, Nguyen S, McLane LM, et al. Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease. PLoS Pathogens. 2018 Apr 13;14(4):e1006973.
15. Samarani S, Abulkhir A, Amre D, et al. The anti-inflammatory IL-37/SIGIRR axis is functionally compromised in HIV infection. AIDS. 2019 Sep 1;33(11):1693-1703.
16. Korencak M, Byrne M, Richter E, et al. Effect of HIV infection and antiretroviral therapy on immune cellular functions. Journal of Clinical Investigation Insight. 2019 Jun 20;4(12). pii:126675.
17. Sereti I, Sheikh V, Shaffer D, et al. Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people with HIV and severe lymphopenia. Clinical Infectious Diseases. 2019; in press.