Both malaria and HIV are highly prevalent in tropical and subtropical regions of the world, which may result in an increased prevalence of such co-infection41. Several studies have reported on HIV and P. falciparum co-infection, mainly in Africa41–43, but only a few studies have described cases of HIV/PvCo patients. Indeed, from our initial search, only 2% of studies dealt with HIV/PvCo. This could be due to several factors, such as low co-infection rates, low prevalence of severe cases and therefore, lack of reporting, and most importantly, lack of systematic HIV screening in vivax malaria positive patients.
HIV and malaria affect millions of people in overlapping geographical areas. Traditional risk factors for HIV and P. vivax malaria may apparently be dissociated, which could possibly explain the HIV/PvCo low prevalence reported here compared to similar studies from other vivax endemic regions 44–54. Local characteristics may account for the predisposition of HIV/PvCo. About 90% of all malaria episodes in Brazil is caused by P. vivax and these are concentrated in the Amazon region55. The clinical spectrum varies from asymptomatic cases to mild clinical symptomology, and complications may occur. Male subjects present a higher incidence of malaria with the younger individuals predisposed to a higher risk of clinical complications56. Malaria transmission in the Amazon region occurs mainly in peri-urban and rural areas, with an increase in the number of cases occurring in the dry season and after public holidays and regional festivities 57. On the other hand, HIV infection, which is prevalent in 0.4% of the general population in Brazil, occurs mainly in key groups, as like in men who have sex with men, sex workers and transgender individuals58. For instance, in 2019, the AIDS detection rate was 29.1 cases/100,000 habitants in the state of Amazonas, while in the capital, Manaus, 46.9 cases/100,000 habitants, which is significantly higher when compared to the rest of the state, and in comparison with the Brazilian national rate (17.8 cases/100,000 habitants)58. HIV transmission occurs mainly in urban environments59. In the state of Amazonas, Manaus, Parintins, and Tabatinga cities are some of the major HIV hotspots60. In most municipalities in the interior of the state of Amazonas, there is not a clear delimitation between urban, peri-urban and rural regions. Constant population displacement between such regions and between municipalities is very common. This may partially explain the exposure of people living with HIV to malaria. In addition, it is uncertain to what extent cultural and social characteristics significantly overlap between both diseases to produce a low prevalence as seen in this study. However, since the systematic screening of HIV infection is not done in acute malaria cases in Brazil, the real HIV/PvCo burden is unknown. Furthermore, it is important to mention that HIV-positive cases have been increasing in recent years in the northern region of Brazil 61.
Separately, HIV, malaria, and TB are considered to be the most common and severe infectious diseases in the world62. Interestingly, a triple infection with these three diseases was more prevalent in this study when compared with other studies from Africa, although this may be attributed to screening, as previously mentioned43,63.
Two patients presented with G6PDd. The lower the G6PD activity, the lower the individual’s ability to tolerate oxidative stress and, when faced with oxidative stressors, such as certain foods, e.g., fava beans, and drugs, such as primaquine or sulfonamides, G6PDd individuals may develop acute life-threatening hemolysis64. The prevalence of G6PDd applies to both HIV and malaria. HIV infection and antiretroviral therapy (ART) are both associated, separately and together, with increased oxidative stress. The impact of G6PDd on the oxidative stress of people living with HIV (PLHIV) on ART is controversial65–67. PLHIV have significantly lower levels of antioxidants, hematological parameters, and CD4+ T cells compared to healthy subjects. Nonetheless, PLHIV on ART have presented a higher level of antioxidants compared to ART naïve subjects68. Also, antioxidant status has been shown to be significantly higher in those with CD4+ T cells > 200 /mm3, 68.
The prevalence of G6PDd varies across Latin American and Caribbean countries, with the African variant present in a wide range in this region69. Primaquine is a strong oxidative drug and may cause severe acute hemolysis in G6PDd individuals who take primaquine for malaria treatment70. G6PDd testing is currently recommended by the WHO prior to starting primaquine in the radical cure of P. vivax and P. ovale malaria30,71. Systematic screening for G6PDd is however not a requirement when starting HIV treatment29. Therefore, we could not determine whether G6PD deficiency in HIV/PvCo influenced clinical outcomes.
Separately, malaria and HIV cause significant laboratory abnormalities; a co-infection scenario may intensify such alterations27,41. Anemia, thrombocytopenia, and leukopenia, for both malaria and HIV, and in malaria/HIV co-infected patients, have been reported to be strong and independent predictors of morbidity and mortality54. The prevalence of anemia in our case series was high, with most patients presenting mild to moderate anemia, similar to other studies of HIV/PfCo26,72,73. Nonetheless, this is higher when compared to P. vivax mono-infected adults from the Amazonas74.
A high prevalence of thrombocytopenia (85.7%) was also observed in this study. Two studies conducted in patients with P. vivax showed a similar prevalence (62.9% and 72%, respectively)75. In a systematic review76, severe and fatal thrombocytopenia was observed in 10.1% of patients with vivax-mono-infection malaria, while severe thrombocytopenia was more prevalent in this study. Anemia and thrombocytopenia in HIV-malaria co-infections have a multifactorial origin and are a frequent complication that may become clinically important in HIV infection41,54,77.
The impact of HIV on the clinical severity of falciparum malaria seems to be primarily motivated by the inability of the immune system to control the parasitic burden42,78,79. Severe malaria was observed in approximately 30% of adults with falciparum malaria and HIV in the urban area of Burkina Faso80. Studies in areas of low malaria transmission in South Africa and India showed an association between severe malaria and HIV78,81–83. For severe vivax malaria, the current study showed a higher prevalence compared to another study with severe vivax malaria in children and adult patients (23.8% versus 12.6%)84. Despite the low number of cases, HIV co-infection seems to exacerbate clinical worsening of vivax malaria, as it has a higher prevalence than that found in vivax malaria mono-infection patients treated at FMT-HVD (approximately 14%)56. Some studies have shown that the risk of malaria severity increases in HIV patients with a CD4+ T cell count <200 x 106 cells/L or <350 cells/μl82,14. In this study, 42.1% of patients with malaria infection had CD4+ T cell counts of less than 200 cells/μl, and one of them had severe malaria.
This study had several limitations. Regarding the systematic review, prevalence studies and those exploring severe clinical outcomes may underestimate the HIV/malaria co-infection, since it is rarely screened in vivax malaria-endemic regions. The comparison of clinical disease dynamics and important outcomes was not possible due to the absence of control groups, e.g., P. vivax mono-infection and HIV mono-infection to address associations of laboratory and clinical outcomes with HIV/PvCo, which was mainly due to the lack of systematic screening. Moreover, there is a low prevalence of severe cases of P. vivax, especially when opportunely diagnosed and treated, or in the absence of comorbidities. Despite the analysis of the present results, we cannot assume that malaria increases anemia and thrombocytopenia in PLHIV, or vice-versa. Finally, an accurate prevalence of HIV/PvCo, and roughly all other co-infections, is significantly hampered by the absence of a systematic screening, which in low- and middle-income countries is performed at the discretion of a clinician upon clinical suspicion.