This may be the first attempt to evaluate the effect of TDF / 3TC / DTG-based ARV regimen on the respiratory and peripheral muscle strength of PLWHA in treatment against HIV infection.
The sample evaluated consisted of 80.5% of men, a percentage higher than that reported by the latest HIV / AIDS epidemiological newsletter released by the Brazilian Ministry of Health (34), where it showed new cases of HIV infection of 68.6% in males. Regarding education, 65.9% of the subjects had studied until the end of high school. In addition, Brazil has been showing a reduction in the annual number of AIDS cases since 2013, however, the North and Northeast regions showed a growing trend in detection and in our study we detected the frequency of 39% of cases.
Most of our sample reported physical inactivity, and those who practiced physical activity maintained their activities during the period between T0 and T1, so this factor should not have influenced the outcomes of the outcomes found in our study. Those who were physically active had better muscle strength scores when compared to sedentary ones. A reasonable explanation for the association between HGS and inflammation is that muscle mass is a predictor of higher HGS and those who practice regular exercise tend to have higher muscle mass (35). Moreover, only 39% of the subjects were overweight. It is worth considering that, although the association between BMI and muscle strength was not measured in the present study, changes in body fat in PLWHA are associated with increased systemic inflammation and increased mortality (36).
The high prevalence of smoking among PLWHA is known when compared to the general population (5). Our sample consisted of 47.8% smokers and / or former smokers, although there was a presence of respiratory disorder in only one (4.3%) of the patients submitted to pulmonary function test. Emerging data suggest that there is a 34% prevalence of respiratory changes in PLWHA in the pre-ART era (37), although we have not identified this relationship in our data set. We believe the small size of our sample may not have represented reality. On the other hand, it is believed that the timing of ART initiation has no significant short-term effect on the rate of lung function decline in HIV-positive individuals with CD4 above 500 cells / mm³ and antiretroviral-naive HIV-infected patients (38).
Our results showed that almost 80% of patients started treatment within six months of being diagnosed with HIV infection. In this regard, antiretroviral-naive HIV-infected patients are the leading source of drug-resistant viruses in developed countries. Moreover, phylogenetic findings have suggested that proliferation of infected cells prior to initiation of ART would be primarily responsible for residual viremia (39). This sustained viral replication promotes an immune / inflammatory response that cannot be reversed after a certain point. Given the relationship between inflammation and declining functional performance in PLWHA, regardless of age (36), the beginning of ARV treatment before reaching this point may prevent the state of persistent inflammation and immune activation by decreasing CD8 and monocyte - macrophage activation, supporting the hypothesis that activation of these cells could be reversed to levels normal with early ARTs (7), avoiding, then, the loss of functionality in this population.
Besides that, the above studies confirm the findings detected in the HIV-infected African population, which suggests that virus infection alone does not have adverse effects on HGS, but rather the effects of untreated HIV and systemic inflammation leading to accelerated loss of lean mass and metabolic imbalances, leading to the reduction of HGS, thus accelerating the process of fragility (40). Not less important, the normalization of PLWHA immune status is also a favorable outcome of HIV / AIDS treatment. An increase in CD4 count to 500 cells / mm³ or higher during ART is usually considered as optimal immune recovery. It has been verified that the postponing initiation of ART after more than 12 months of estimated date of seroconversion (passage from the first phase of HIV infection to the second, the latency phase), decreases the probability of restoring immune health in HIV-1 infected individuals (41,42).
The assessment of HGS has a good correlation with measurements of muscle function, such as knee extension and peak forced expiratory volume (43) besides being able to predict both death and disease from vascular causes (44). In this context, it is worth to alarming the results of our study, where 97.6% of PLWHA had dynapenia before the beginning of ART, in contrast to the 15.4% found in the first study conducted in Brazilian Northeast evaluating the functional profile of PLWHA before treatment (37). Despite having recorded values of VL of the evaluated individuals, there was no description of this variable in the results, only of CD4 (403 ± 284 cel / mm³), a value lower than that recorded in our study (462.9 ± 230.8 cells / mm3). Thus, we believe that the high frequency of HGS below the predicted value found in our study is related to the high viremia of our population (172062.9 ± 219876.9 copies / mL), configuring systemic inflammatory status. This finding is in line with that obtained in the above-mentioned study, suggesting that HIV infection plays a role in promoting dynapenia in untreated patients. Likewise, it should be considered that men and women may react differently to HIV infection and ART use, so women may have less muscle strength than men (45), as found in a previous study (37). Our analyzes were not stratified by gender, as only 19.5% of our sample consisted of women.
Some authors believe that in PLWHA systemic biochemical abnormalities may occur, resulting in inspiratory muscle dysfunction, with weakness of this musculature (12).The initial evaluation of our study found that 31.7% of patients had IMW and / or EMW, with lower than expected MIP and MEP values, respectively. MEP is intrinsically linked to respiratory muscle capacity, and reduced values of this pressure imply various physical and pulmonary conditions, including neuromuscular disorders (13).
In the light of the results of previous studies, which indicated that HGS measurements would not be an adequate substitute for well-controlled clinical performance testing in PLWHA. (46), we performed the 6MWT assessment in order to obtain more robust data regarding the functional capacity of this population. In the evaluation performed before starting treatment for infection, 95.12% of the subjects did not reach the predicted 6MWD, corroborating a study in antiretroviral-naive HIV-infected patients, which also found lower than expected 6MWD values in both genders (37). Our results also support those obtained in a study conducted with PLWHA, which observed an influence of CD4 lower than 200 cells / mm³ on inspiratory muscle strength and 6MWD (12). Like these authors, we agree that this is happens due to HIV infection, because the patients in our study had high viremia at the time of the first assessment, and HIV alone could have a negative influence on functional capacity in these individuals. It is also noteworthy that the high frequency of dynapenia may explain non-compliance with the 6MWD, as reduced muscle strength may contribute to the feeling of fatigue and functional limitation (47).
Of the PLWHA evaluated at T0, 61% had no immunosuppression, in other words, had CD4 count above 350 copies / mm³, and this showed a positive correlation with HGS. So all patients without compromised immune system presented higher values of HGS. These findings contradicted those found in the Multicenter AIDS Cohort Study (MACS) substudy (36), an American cohort that evaluated for 30 years (1994-2014) a large population of HIV-infected gay and bisexual men, where no association was found between HGS and current CD4 or nadir CD4. Additionally, another study conducted in Africa also found no independent effects between CD4 count and HGS in a cross-sectional analyzes (40). On the other hand, considering that a previous study found concentrations of Interferon Gamma-Induced Protein 10 (IP-10), an immune activation biomarker, associated with low CD4 levels (48), we suggest that the best HGS values found in the higher CD4 patients would be due to the lower inflammatory status in these patients. However, due to the absence of inflammation markers collection at the time of the evaluations, we cannot conclude the existence of this association.
HGS values obtained in the evaluation before the initiation of ART showed a negative correlation with VL. In this way, lower HGS values correlated with high levels of VL. Given these observations, we hypothesized that this reduction in HGS would be associated with the inflammatory status caused by high viremia. This hypothesis is supported by a previous study, which found a relationship between IP-10 concentrations with high VL, even suggesting that this biomarker may be associated with HIV pathogenesis and immune depletion (48). In addition, our findings also corroborate those found in the substudy, suggesting that VL cumulative increased exposure seems to be an important factor in the decline in HGS, and further highlights the importance of early initiation of ART (14).
Considering reduction in muscle strength may contribute to the feeling of fatigue and functional limitation (47), HGS provides data not available from routine clinical and laboratory evaluations. Thus, the measurement of this variable during follow-up with the infectologist may provide additional information for risk stratification during the evaluation of outpatient PLWHA.
In our study, the frequency of RMW in antiretroviral-naive HIV-infected patients was greater than 30%, however, this weakness did not correlate with CD4 and CD8 count, CD4/CD8 ratio, and VL. This results may have been influenced by the small sample size. MIP measurement is earlier than changes in lung volume to diagnose inspiratory weakness. MEP has a low accuracy to predict coughing capacity, as it generates a high false positive index for EMW, and may overestimate the number of patients with EMW, since low values are caused by submaximal efforts or leakage around the mouthpiece, which is frequent in patients with facial muscle weakness. Both depend on the coordination between the evaluated and the examiner, so a low value may not mean weakness, but lack of collaboration of the evaluated subject (49). We believe that this did not interfere with the results of our study, since 65.9% of the sample had a medium level of education, having completed at least high school, obtaining a good understanding of the commands given to perform the tasks evaluations, besides that the vast experience of the examniner’s in such evaluations.
Newer medications tend to cause less mitotoxicity. Thus, the incidence of this toxicity may be decreasing even as more patients are submitted to treatment with Reverse Transcriptase Nucleoside Inhibitors (NTRs) such as Tenofovir and Lamivudine (50). Furthermore, studies indicate that DTG is a useful drug in terms of rapid virologic suppression in patients with good treatment adherence (21), showing superiority over the previous regiment containing EFZ Our results showed a significant increase in MIP and HGS after more than 50 days of ART, presumably through control of viral replication and subsequent reduction of inflammation and immune activation, as more than 80% of patients progressed to undetectable VL in this period. This effect is hypothesized to be mediated by ART's ability to reduce inflammation, immune activation, and endothelial dysfunction by suppressing HIV replication (7). Conclusive findings in previous research support our theory. The English Longitudinal Study of Ageing (ELSA), conducted in England with an eight-year follow-up showed that higher HGS would be associated with lower levels of inflammation (35). In another interesting study of hospitalized patients with and without TB, proved that higher levels of Tumor Necrosis Factor Alpha (TNF-α) but not Interleukin-6 (IL-6) were associated with a reduction in MIP, MEP and HGS (47). In addition, previous study data pointed out that HGS appears to steadily increase over time for ART in men, although it has stabilized after the first 12 weeks of treatment in women (40), corroborating with our findings.
Notably, the loss of 36.6% of patients during follow-up associated with the short interval between evaluations denotes a major limitation of our study. The loss to follow‑up of HIV infected patients is a problem that is frequently reported on in the literature (51) and even registered in the HIV-Brazil Cohort, with the highest proportion of loss (50.4%) in the first year of follow-up, identifying the Northeast as the second largest region of loss of follow-up of patients (52). The fact that we conducted our study at a single state referral center for HIV treatment may have caused some bias. Similarly, the decrease in sample size over time limits our statistical power, although it is highly relevant, since most patients had dynapenia, even without major functional impairment. We found important, although weak, correlations between HGS and CD4 count and VL, but the lack of collection of immune activation markers such as IL-6, TNF-α and C-reactive protein (CRP) at T0 and T1 prevented the analysis of the inflammatory status of the patients at the time of the evaluation and it was not possible to establish a causal relationship between these variables. The instrument used to evaluate MIP and MEP, the analog manovacuometer, was limited to maximal pressures of 120 cmH2O and could have underestimated our results. However, the cost, availability, and ease of use may determine whether the techniques are best suited to clinical practice or useful for research (26). In this context, we chose to use a lower cost instrument in order to try to reproduce as much as possible the reality of the public hospital service.
Considering these observations, it is worth highlighting that this is the first study to evaluate the association between HGS and CD4 count and VL, as well as the effect of ART combined with TDF / 3TC / DTG on PLWHA musculature. Longitudinal studies with longer follow-up time allow a more accurate assessment, establishing a causal relationship.